UNIVERSIDAD COMPLUTENSE DE MADRID FACULTAD DE FARMACIA TESIS DOCTORAL Estudio para la calculadora de edad vascular como herramienta para reducir el riesgo cardiovascular de la farmacia comunitaria Study of the vascular age calculator as a tool to reduce cardiovascular risk in community pharmacies MEMORIA PARA OPTAR AL GRADO DE DOCTOR PRESENTADA POR Marjan Manouchehri Directoras María Soledad Fernández Alfonso Marta Gil Ortega Madrid © Marjan Manouchehri, 2021 UNIVERSIDAD COMPLUTENSE DE MADRID FACULTAD DE FARMACIA TESIS DOCTORAL ESTUDIO DE LA CALCULADORA DE EDAD VASCULAR COMO HERRAMIENTA PARA REDUCIR EL RIESGO CARDIOVASCULAR DE LA FARMACIA COMUNITARIA STUDY OF THE VASCULAR AGE CALCULATOR AS A TOOL TO REDUCE CARDIOVASCULAR RISK IN COMMUNITY PHARMACIES MEMORIA PARA OPTAR AL GRADO DE DOCTOR PRESENTADA POR Marjan Manouchehri DIRECTOR/AS María Soledad Fernández Alfonso y Marta Gil Ortega Madrid, 2021 To my lovely family who believed in me. Acknowledgements I would like to express my special thanks of gratitude to my tutor Prof. María S. Fernández- Alfonso, who gave me the lifetime opportunity to be part of her splendid research group, who unveiled some of the most important lessons of my life and taught me how to be a better scientist. I would like to express my appreciation for my director Dr Marta Gil Ortega, whose guidance, support and encouragement have been invaluable throughout this thesis, especially in correcting protocols and helping me in Spanish. I like to take this opportunity to give my immense gratitude to my kind father and mother for believing in me, financially supporting me and I am forever in depth for their kindness. I can never repay my brother, Víctor and Tara for their ongoing support and passionate encouragement, without whom I would not have been able to complete this PhD and would not have made it through the pandemic. I would like to give special thanks to my partner Víctor for his dedicated support extended with love, continuous encouragement, and willingness to assist in any way. I also like to give my thanks to my wonderful and kind mother and father-in-law for their support and kindness. I like to extend my special gratitude to Dr Leonor Huete González for her continuous kind support and professional guidance, for providing insight and documents related to pharmacy practice in Spain. My biggest thanks to my friend and fellow PhD student Francisco Javier Manzano Lista for assisting me in launching the vascular age calculator on the website and for his supportive guidance during my doctorate. I submit my heartiest gratitude to Dr Lucia Cea Soriano for her sincere guidance on data analysis and pharmacoepidemiology. I like to thank my colleagues in laboratory Elena, Marta, Anna, Jose Luis and Dani for being my friend and supporting me throughout the PhD program and for their technical assistance and guidance. I thank my friend and fellow PhD students Mahdiye for her help in data collection. I further like to extend my gratitude to all the pharmacists who took the time to assess the vascular age website and fill out the survey without whom I would have no content for my thesis. I am deeply indebted to my best friend Yvonne and Ehsan, Maryam, Mahya, Sanam, Motahare, Mohsen, Susan, Wayne, Anisa, Atosa, Shahriyar and many more for their words of encouragement and support with extended love. A sincere thank you to Gladys Livingstone for her diligent proofreading of this thesis. My appreciations to the University of Complutense administrators (Víctor and Macarena) for their help and kindness. My biggest thanks for Go Fit gym staff for running most wonderful classes (Yoga, Spinning and Plate). “In the fell clutch of circumstance I have not winced nor cried aloud. Under the bludgeonings of chance My head is bloody, but unbowed. It matters not how strait the gate, How charged with punishments the scroll, I am the master of my fate, I am the captain of my soul.” William Ernest Henley “In order to reach the moon, you have to start with little steps.” Prof. María S. Fernández-Alfonso Table of Contents LIST OF FIGURES ................................................................................................................ 1 LIST OF TABLES .................................................................................................................. 3 LIST OF ABBREVIATIONS .................................................................................................... 4 Abstract ............................................................................................................................ 5 Resumen ........................................................................................................................... 6 INTRODUCTION ................................................................................................................. 7 1. Cardiovascular diseases (CVDs) ...................................................................................... 8 1.1 Non-modifiable risks factors ........................................................................................ 9 1.1.1 Age ........................................................................................................................... 9 1.1.2 Sex/gender ............................................................................................................. 10 1.1.3 Family history and genomics ................................................................................... 12 1.1.4 Ethnicity ................................................................................................................. 13 1.2 Modifiable risk factors ............................................................................................... 14 1.2.1 Hypertension .......................................................................................................... 14 1.2.2 Obesity ................................................................................................................... 16 1.2.3 Dyslipidaemia ......................................................................................................... 17 1.2.4 Diabetes mellitus .................................................................................................... 18 1.2.5 Other comorbidities ................................................................................................ 19 1.2.6 Mental health ......................................................................................................... 20 1.2.7 COVID-19 ................................................................................................................ 21 1.2.8 Smoking .................................................................................................................. 23 1.2.9 Diet ......................................................................................................................... 26 1.2.10 High alcohol consumption ..................................................................................... 28 1.2.11 Caffeine ................................................................................................................ 29 1.2.12 Poor medication compliance ................................................................................. 30 1.2.13 Pharmacological treatments ................................................................................. 33 1.2.14 Physical activity .................................................................................................... 34 1.2.15 Health Inequalities ................................................................................................ 34 1.2.16 Climate change ..................................................................................................... 36 1.3 Cardiovascular health in Spain ................................................................................... 36 1.4 Cardiovascular Risk estimation .................................................................................. 37 1.4.1 Relative risk calculation .......................................................................................... 39 1.4.2 Absolute risk calculation ......................................................................................... 39 1.4.3 High-risk or population intervention approach ....................................................... 42 1.5 Personalisation of intervention according to patient's risk estimation ....................... 42 1.5.1 Patient's perception of their CVR ............................................................................ 42 1.6 Empanelment ............................................................................................................ 43 2. Spanish community pharmacy system ......................................................................... 44 2.1 Provision of community pharmacist intervention ...................................................... 45 2.2 Consistency in healthcare provision and coherence in medical records ...................... 46 2.3 Role of community pharmacists in health empanelment in Spain .............................. 46 2.3.1 Hypertension control .............................................................................................. 50 2.3.2 Weight management by community pharmacist via diet and lifestyle advice .......... 51 2.3.3 Dyslipidaemia management .................................................................................... 53 2.3.4 Diabetes control ..................................................................................................... 54 2.3.5 Smoking cessation .................................................................................................. 54 2.3.6 Alcohol advice ........................................................................................................ 55 2.3.7 Medicine reconciliation .......................................................................................... 56 2.3.8 Telepharmacy ......................................................................................................... 57 3. Vascular age calculator (VAC) ...................................................................................... 58 HYPOTHESIS AND OBJECTIVES ......................................................................................... 59 MATERIALS AND METHODS ............................................................................................. 61 1.1. Literature search ...................................................................................................... 62 1.2. Vascular age questionnaire ....................................................................................... 63 1.3 Algorithm for vascular age calculator ......................................................................... 63 1.4 Ethical approval ......................................................................................................... 65 1.5 Patient confidentiality ............................................................................................... 65 1.6 Informed consent ...................................................................................................... 66 1.7 General Data Protection Regulation (GDPR) compliance ............................................ 67 1.8 Data storage and handling ......................................................................................... 67 1.9 Study pilot among community pharmacists ............................................................... 67 1.10 Pilot survey analysis ................................................................................................. 68 1.11 Adoption of QR barcode for the website and the questionnaire ............................... 69 RESULTS .......................................................................................................................... 70 1. Creating a data collection tool ..................................................................................... 71 1.1 Questionnaire ............................................................................................................ 71 1.2 Vascular age calculator and interpretation of the results for patients ........................ 77 1.3 Study protocol ........................................................................................................... 82 1.4 Study design .............................................................................................................. 83 1.5 Inclusion criteria ........................................................................................................ 83 1.6 Exclusion criteria ....................................................................................................... 84 1.7 Patient recruitment ................................................................................................... 84 1.8 Sample size ................................................................................................................ 88 1.9 Standard Operating Procedure (SOP) for patient’s consultation ................................. 89 1.10 Premises requirements for pharmacies and pharmacist ........................................... 93 1.11 Telepharmacy .......................................................................................................... 95 1.12 Record management ................................................................................................ 96 1.13 Data collection process ............................................................................................ 96 1.14 Referral to the Doctor .............................................................................................. 98 1.14.1 Red flag symptoms in referral to a doctor ....................................................... 101 1.15 Detailed pharmacist intervention protocol ............................................................ 102 1.15.1 Management of patients with obesity ................................................................ 102 1.15.2 Management of patients with Dyslipidaemia ...................................................... 108 1.15.2.1 Referral to doctor ........................................................................................ 113 1.15.3 Management of patients with diabetes .............................................................. 114 1.15.3.1 Referral to doctor ........................................................................................ 118 1.15.4 Smoking cessation services ................................................................................. 119 1.15.4.1 Pre-quit smoking ......................................................................................... 121 1.15.4.2 Carbon monoxide breath test ...................................................................... 125 1.15.4.3 Remote consultation for smoking cessation ................................................. 131 1.15.5 Medication reconciliation ................................................................................... 131 1.15.6 Hypertension control .......................................................................................... 133 1.15.7 Advice on reduction of alcohol consumption ...................................................... 138 1.15.8 Other CVD intervention ...................................................................................... 142 1.16 Website validation by the community pharmacist ................................................. 146 1.17 Reflexive thematic analysis results: ........................................................................ 151 DISCUSSION .................................................................................................................. 153 1.1 Provoking factors for vascular aging in the Spanish population ................................ 158 1.2 Interpretation of findings of the vascular age questionnaire .................................... 159 1.3 Implication of the eHealth vascular age tool on pharmacy practice in Spain ............. 164 1.4 Limitation ................................................................................................................ 165 CONCLUSION ................................................................................................................. 166 REFERENCE .................................................................................................................... 168 APPENDICE .................................................................................................................... 186 Appendix I: The questionnaire used in the vascular age website pilot ............................ 186 Appendix II: Community pharmacist responses in Spanish for question 26 of the pilot. . 190 Appendix III: The themes that merged from the pharmacist’s responses coding ............ 191 Appendix IV: NVivo analysis of the vascular age website pilot word repetition .............. 193 Appendix V: Application for the provision of waste management services, SRCL Consenur company form. .............................................................................................................. 194 1 LIST OF FIGURES Figure 1: Impact of smoking on major organs in the body ..................................................... 24 Figure 2: Visual display of empanelment in population health management ......................... 43 Figure 3: Illustration of appropriateness of healthcare panel size ........................................... 44 Figure 4: Risk of bias assessment in RCT studies ................................................................... 49 Figure 5: Risk of bias assessment in NRSIs studies ................................................................ 49 Figure 6: Vascular age calculated based on the SCORE system ............................................. 64 Figure 7: Ethical approval documents location on the website ............................................... 65 Figure 8: Patient’s confidentiality by anonymizing the participants ....................................... 66 Figure 9: QR barcode for the vascular age website ................................................................. 69 Figure 10: Questions 1- 6 of the vascular age tool .................................................................. 71 Figure 11: The anthropometric and biochemical values section of the vascular age tool ....... 72 Figure 12: The smoking status question .................................................................................. 73 Figure 13: Women specific risk factor or protective elements data collection ....................... 73 Figure 14: The question on family history of premature CHD ............................................... 74 Figure 15: Medical and medication history of the patient ....................................................... 75 Figure 16: The physical activity question in vascular age tool ............................................... 75 Figure 17: Alcohol habits assessment ..................................................................................... 76 Figure 18: Stress assessment test ............................................................................................. 76 Figure 19: Spanish midday nap habit test ................................................................................ 77 Figure 20: Dietary habits of Spanish population ..................................................................... 77 Figure 21: Social interaction assessment ................................................................................. 77 Figure 22: Illustrate how vascular age tool can improve patient’s comprehension ................ 79 Figure 23: Vascular age tool improves smoking cessation ..................................................... 79 Figure 24: Blood pressure reduction by vascular age tool ...................................................... 80 Figure 25: Blood cholesterol reduction by vascular age tool .................................................. 81 Figure 26: Improvement of patient’s comprehension by vascular age tool ............................ 81 Figure 27: Methodology of the study ...................................................................................... 82 Figure 28: Principal investigator contact details in webpage home section ............................ 85 Figure 29: Webpage snapshot on study documents ................................................................ 88 Figure 30: Patient’s consent form ............................................................................................ 89 Figure 31: Study follow-up schedule ...................................................................................... 91 Figure 32: ADHFARM questionnaire for patient follow-up ................................................... 92 Figure 33: Criteria for pharmacies that participate in the cardiovascular health campaign .... 93 Figure 34: Pharmacists' contract for participation location ..................................................... 95 Figure 35: Pharmacists access to the Vascular age calculator ................................................. 97 Figure 36: initial registration of the pharmacy in the database ............................................... 97 Figure 37: Doctor referral form ............................................................................................... 99 Figure 38: Webpage snapshot of pharmacist’s intervention guide for obesity control ......... 103 Figure 39: Webpage snapshot of PIL on obesity prevention ................................................ 106 Figure 40: Patient information leaflet on obesity .................................................................. 107 Figure 41: Webpage snapshot of pharmacist’s intervention guide for lipid measurement and control .................................................................................................................................... 108 Figure 42: Webpage snapshot of patient information leaflet for lipid measurement ............ 108 Figure 43: Patient’s information leaflet in relation to hypercholesteremia ........................... 109 Figure 44:TC, LDL-C, HDL-C and triglyceride level and related risk of CV ...................... 111 Figure 45: Pharmacist course of action depends on patient’s LDL-C, total cholesterol, ...... 112 Figure 46: Webpage snapshot of pharmacist’s intervention guide for diabetes management and control ............................................................................................................................. 114 Figure 47: Webpage snapshot of patient information leaflet for diabetes intervention ........ 114 2 Figure 48: Patient’s information leaflet in relation to diabetes management and control ..... 115 Figure 49 : Diabetes control protocol .................................................................................... 117 Figure 50: Webpage snapshot of pharmacist’s intervention on smoking cessation .............. 119 Figure 51: Webpage snapshot of patient information leaflet on smoking cessation ............. 119 Figure 52: Patient information leaflet in relation to diabetes management and control ........ 120 Figure 53: protocol for smoking cessation services .............................................................. 122 Figure 54: Richmond test ...................................................................................................... 124 Figure 55: Fagerström Test for Nicotine Dependence (FTND) ............................................ 125 Figure 56: Direct relation between carbon monoxide (CO) carboxyhemoglobin (CO-Hb) exhaled in 15 second and smoking ........................................................................................ 126 Figure 57: Demonstrate the smoking cession protocol for initial visit ................................. 127 Figure 58: Patient treatment options according to their level of dependency ....................... 128 Figure 59: Exhibit the advantages of stopping smoking ....................................................... 129 Figure 60: Smoking cessation protocol for the community pharmacist ................................ 130 Figure 61: Protocol for follow up on STOPPING smoking services at 6 months and one year ............................................................................................................................................... 130 Figure 62: Webpage snapshot of pharmacist’s intervention on medication adherence ........ 131 Figure 63: Morisky-Green test .............................................................................................. 132 Figure 64: Adopted Morisky Green test for assessing patients’ medication compliance ..... 133 Figure 65: Webpage snapshot of pharmacist’s intervention on hypertension ....................... 134 Figure 66: Webpage snapshot of patient information leaflet about hypertension ................. 136 Figure 67: Patient information leaflet in relation to hypertension management ................... 137 Figure 68: Webpage glimpse of pharmacist’s intervention on reduction in alcohol use ...... 138 Figure 69: Guide to unit of alcohol definition ....................................................................... 139 Figure 70: Alcohol misuse health implications ..................................................................... 140 Figure 71: Webpage snapshot on patient information leaflet about alcohol consumption ... 140 Figure 72: Alcohol consumption Patient information leaflet ................................................ 142 Figure 73: Stress and mental state patient information guide ............................................... 143 Figure 74: Women & cardiovascular health patient information guide ................................ 144 Figure 75: Aging and cardiovascular health patient information guide ................................ 145 Figure 76: Gender distribution for vascular age pilot participants. ....................................... 146 Figure 77: Age distribution for vascular age pilot in community pharmacies. ..................... 146 Figure 78: Ratio of community pharmacists accredited for the provision of pharmaceutical care. ....................................................................................................................................... 147 Figure 79: Community pharmacist’s various form of accreditation for providing pharmaceutical care. .............................................................................................................. 148 Figure 80: Accreditation bodies for pharmaceutical care across Spain. ................................ 148 Figure 81: Patient’s visiting time from community pharmacy with vascular age services, Data are expressed in percentage of the total number of participants. ........................................... 150 Figure 82: Relation between community pharmacists’ increase in workload and vascular age intervention. Data are expressed in percentage of the total number of participants. ............ 150 Figure 83: Reflective thematic analysis for qualitative research ........................................... 151 Figure 84: Vascular age pilot from community pharmacist’s viewpoint world cloud .......... 152 3 LIST OF TABLES Table 1. Diagnostic criteria for diabetes mellitus .................................................................... 19 Table 2: Initiating consultation by using I2C6 technique ....................................................... 90 Table 3: WHO classification for BMI (kg/m2) measures in white Caucasian adult ............. 103 Table 4: Classification of patient’s risk based on waist circumference in cm ...................... 104 Table 5: Classification of patient’s risk by BMI, waist circumference & comorbidities ...... 104 Table 6: The choice of intervention adequate for patient’s risk ............................................ 104 Table 7: Suggested regimen for therapeutical treatment protocol ......................................... 129 Table 8: Exercise protocol in the elderly ............................................................................... 135 Table 9: Scoring system to quantify the patients’ risk based on their weekly alcohol consumption .......................................................................................................................... 141 Table 10: Age and gender distribution for vascular age pilot participants ............................ 146 Table 11: Stratification of pharmacists according to the age group, level of training and provision of pharmaceutical care ........................................................................................... 147 4 LIST OF ABBREVIATIONS ABPM Ambulatory blood pressure monitoring ACC/AHA American College of Cardiology/American Heart Association ADRs Adverse drug reactions ALT Alanine Aminotransferase ASCVD Atherosclerotic cardiovascular diseases AST Aspartate transaminase BMI Body mass index BP Blood pressure CHD Coronary heart disease CKD Chronic kidney disease CMPs Cardiomyopathies CP Community pharmacist CVDs Cardiovascular diseases CVR Cardiovascular risks DALYs Disability-adjusted life years DBP Diastolic Blood Pressure DASH Dietary Approaches to Stop Hypertension FBG Fasting blood glucose FHS Framingham Heart Study HbA1c Glycated haemoglobin HDL-C High-density lipoprotein cholesterol HOMA-IR Homeostatic Model of Assessment-Insulin Resistance Index HVA Healthy vascular aging IGT Impaired glucose tolerance IHD Ischemic heart disease LDL-C Low-density lipoprotein cholesterol MedDiet Mediterranean diet MI Myocardial Ischemia MONICA Multinational Monitoring of Trends and Determinates in Cardiovascular Disease NICE National Institute for Health and Care Excellence NCDs Non-communicable diseases NSAIDs Non-steroidal anti-inflammatory drugs OGTT Oral glucose tolerance test OTC Over the counter PCS Pharmaceutical care services QALY Quality-adjusted life year RR Relative risk or risk ratio RCT Randomized controlled trial SBP Systolic Blood Pressure SCORE Systematic Coronary Risk Evaluation SNS Spanish national health system SPD Sistemas Personalizados de Dosificación T2DM Type 2 diabetes mellitus TG Triglycerides VA Vascular age VAC Vascular age calculator WHO World Health Organization 5 Abstract Background: Cardiovascular disease (CVD) is one of the leading causes of morbidity and mortality in Spain. According to the World Health Organization (WHO), 80% of these premature deaths are avoidable by reducing the modifiable risk factors of CVD. Research indicates that patients better understand their true risk when information is presented to them in vascular age (VA). Community pharmacists (CP) are well situated to assess patients VA, provide professional educational advice, and implement interventions for reducing cardiovascular risk (CVR). Aim: The explicit objective of this thesis was to create a patient-centred, accurate and accessible tool that allows the CPs in Spain to estimate the VA and design a personalized intervention aimed at reducing the patient’s VA. Method: A website was created and included an original questionnaire, the vascular age calculator (VAC), detailed protocols for the pharmacist’s intervention and the patient’s information leaflets on CVR factors. The webpage user’s perceptions were analysed via a 26- item self-completion online survey distributed among CPs using a Google forum. Informed consent was taken from the CPs to participate in the study. The responses to the survey were collected anonymously. Open and closed questions were used to gain a wide range of replies and an in-depth understanding. The questionnaire from the pilot study was available online from the 1st August 2020to the 31st of February 2021. The results were analysed using the STATA package version 12.0 (StataCorp LP, College Station, TX, USA). The NVivo software was used for assessing the descriptive findings. Results: The website included a questionnaire of 35 items to assess individual’s different CVR profiles, the VAC, pharmacists’ interventional protocols for hypertension, obesity, dyslipidaemia, diabetes, smoking cessation, alcohol reduction and medicine reconciliation, as well as patient information leaflets. A total of 24 pharmacists from Madrid were included in the pilot study, of whom 54% were female. Most participants were in the 20-29 (50%) age group. 66% of the participants had prior training or been accredited for providing pharmaceutical care services (PCS), but only six (25%) claimed to be actively involved in providing those services. The majority of CPs claimed that the website is straightforward to use, the design and protocols to be easy to follow. Most CPs said that the patient information designed is appropriate in terms of language and content. 62% of pharmacists, all in the group already providing PCS, strongly agreed that the time to fill out the VA questionnaire is reasonable. Most pharmacists (87%) claimed that they would recommend the VA tool to their colleagues. About the barriers pharmacists face in providing CV services, the majority claimed that this tool could improve their sense of job satisfaction, professional image with patients and the pharmacist’s relation with doctors. Very interestingly, 79% claimed that the VA tool would improve pharmaceutical care delivery. Conclusion: The VA tool can constitute a key component in cardiovascular health promotion services by CPs throughout Spain. Further studies are required to explore its use in CPs across Spain in the post-COVID era. 6 Resumen Antecedentes: La enfermedad cardiovascular (ECV) es una de las principales causas de morbilidad y mortalidad en España. Según la Organización Mundial de la Salud, el 80% de estas muertes prematuras se podrían evitar reduciendo los factores de riesgo cardiovascular modificables. Diversos estudios indican que los pacientes entienden mejor su riesgo real cuando se les presenta la información en forma de edad vascular. Los farmacéuticos comunitarios (FC) están bien posicionados para evaluar la edad vascular de los pacientes, proporcionar asesoramiento educativo profesional y aplicar intervenciones para reducir el riesgo cardiovascular (RCV). Objetivo: El objetivo explícito de esta tesis fue crear una herramienta centrada en el paciente, precisa y accesible que permita a los FC de España estimar la edad vascular y diseñar un plan de intervención personalizado encaminado a reducirla. Método: Se creó una página web que incluía un cuestionario original, la calculadora de la edad vascular, protocolos detallados para la intervención del farmacéutico y folletos informativos para el paciente sobre factores de RCV. Se analizó la percepción de los usuarios sobre la página web a través de una encuesta online de veintiséis preguntas distribuida entre los FC mediante un formulario de Google. Se obtuvo el consentimiento informado de los FC para participar en el estudio. Las respuestas a la encuesta se recogieron de forma anónima. Se utilizaron preguntas abiertas y cerradas para obtener una amplia gama de respuestas y de mayor profundidad. El cuestionario del estudio piloto estuvo disponible en línea desde el 1 de agosto de 2020 hasta el 31 de febrero de 2021. Los resultados se analizaron con el paquete STATA versión 12.0 (StataCorp LP, College Station, TX, USA). Para evaluar los resultados descriptivos se utilizó el programa informático NVivo. Resultados: La página web incluye un cuestionario de 35 preguntas para evaluar los diferentes perfiles de RCV, la calculadora de la edad vascular, los protocolos de intervención de los farmacéuticos para el manejo de la hipertensión, la obesidad, la dislipidemia, la diabetes, la deshabituación tabáquica, la reducción del consumo de alcohol y la conciliación de medicamentos, así como, folletos informativos para los pacientes. Un total de 24 farmacéuticos de Madrid fueron incluidos en el estudio piloto, de los cuales el 54% eran mujeres. La mayoría de los participantes estaban en el grupo de edad de 20 a 29 años (50%). El 66% de los participantes tenían formación previa o estaban acreditados para la prestación de servicios de atención farmacéutica, pero sólo 6 (25%) afirmaron estar involucrados activamente en la prestación de dichos servicios. La mayoría de los FC afirmaron que el sitio web es sencillo de utilizar y que el diseño y los protocolos son fáciles de seguir. La mayoría de los FC afirmaron que la información diseñada para el paciente es apropiada tanto en términos de lenguaje como de contenido. El 62% de los farmacéuticos del grupo que ya prestaba servicios de atención farmacéutica consideraban que el tiempo empleado para rellenar el cuestionario de la edad vascular es razonable. La mayoría de los farmacéuticos (87%) afirmó que recomendaría la herramienta de edad vascular a sus colegas. Con respecto a las barreras a las que se enfrentan los FC en la prestación de servicios a nivel cardiovascular, la mayoría afirmó que esta herramienta tiene potencial para mejorar su grado de satisfacción en el trabajo, la imagen profesional con los pacientes y la relación del farmacéutico con los médicos. Es interesante señalar que el 79% afirmó que la herramienta de la edad vascular mejorará la prestación de los servicios de atención farmacéutica. Conclusión: La herramienta de la edad vascular puede constituir un componente clave en los servicios de promoción de la salud cardiovascular por parte de los FC en toda España. Se necesitan más estudios para explorar su uso con los FC de toda España en la era post COVID. 7 INTRODUCTION 8 Introduction 1. Cardiovascular diseases (CVDs) Cardiovascular disease (CVD) is one of the leading causes of morbidity and mortality globally. CVDs are defined as a collection of disorders affecting the heart and its blood vessels, caused by the process of endothelial dysfunction and/or atherosclerosis (1). CVDs can be further classified into coronary heart disease (CHD), cerebrovascular disease, peripheral arterial disease, rheumatic heart disease, congenital heart disease, as well as, deep vein thrombosis and pulmonary embolism. However, ischemic heart disease (IHD) and stroke are among the most common significant public health issues which took 15.2 million lives worldwide in 2016 (2). Development of CVD as a heterogeneous non-communicable disease (NCDs) is due to a mixture of genetic predisposition and environmental exposure of the patients. The first study to use the population-based approach on a large scale to investigate the possible risk factors of CVD was the Framingham study, which began in 1948. The original cohort of this study was 5,209 men and women aged between 30 and 62 years, from a town in Framingham, Massachusetts. The study subjects were initially assessed and observed for development of CVD such as a heart attack or stroke over 20 years (3). Another scientific milestone for the identification of CVD's risk factors was the WHO MONICA (Multinational Monitoring of Trends and Determinates in Cardiovascular Disease) project. The unique characteristic of the MONICA study was the large multinational study cohort and the long period of follow up, which have made it ideal for risk estimate analysis (4). They placed a heavy emphasis on the accumulated risk that leads to the development of CVDs. The risk factors for CVD can further 9 be classified into modifiable and non-modifiable causes. The healthcare system currently focuses on implementing measures to control the modifiable causes in order to reduce the prevalence of CVDs. 1.1 Non-modifiable risks factors 1.1.1 Age Research has shown that an advanced age is an independent and most potent risk factor in the development of CVD (5). On the other hand, the extent of a patient’s comorbidity and, in turn, the number of medicines they consume increases with age. The age-associated changes were predictable. For instance, in the study done by Strait et al. 2012, the age-associated changes in the cardiovascular system were described as being manifold. According to Strait, aging causes structural changes such as vascular rigidity, thickening of the left ventricle muscles, slight increase of the heart in size and fibrosis, leading to diastolic dysfunction. On the other hand, functional changes, reduction in the cardio-protection and repair processes of the heart is conducive to CVD development. According to the WHO report from 2020, Spain which is the third largest country in western Europe, had one of the highest average life expectancies in the world with 80.6 years for men and 85.6 years for women (6). The NCDs report of the WHO showed that CVD with a 28% proportional mortality is the leading cause of death throughout Spain (7). The WHO has defined the term geriatric to be the chronological age of 65 and above (8). More advanced age is associated with deterioration of multiple organs known as multimorbidity. According to the United Nations advanced age above 70 years is associated with at least 2 or more chronic diseases (9). Another ground-breaking study of 1,741,841 individuals in 10 Scotland showed that multimorbidity increased with age and was present in most people aged 65 years and over (10). They have reported that the world’s elderly population will increase to one in five people by 2050 (8). Research has shown advanced age is the most potent risk factor for CVD. Older age is associated with comorbidities such as hypertension, diabetes mellitus, chronic heart disease, lipid disturbances and renal diseases, etc. (11). These individuals take various medications which give rise to the phenomena of polypharmacy or polymedicated (12). Polymedicated, as defined by the WHO, is concomitant use of five or more medicines by the same individual (13). It is a real public health challenge, especially in geriatric patients. The negative impact of polypharmacy covers poor medication adherence, potential chance of developing drug-drug or drug-disease interaction or greater risk of adverse drug reactions (ADRs). Research has shown these, in turn, lead to increased patient hospital admission, healthcare cost and mortality. This is due to pharmacokinetic and pharmacodynamic differences within the general population. Aging causes metabolic fluctuations and reduced drug clearance by kidneys which may lead to the development of various unwanted side effects (14). 1.1.2 Sex/gender Aetiology and clinical presentation of CVD differs between female and male subjects. Sex is the biological characteristic that marks male, female, and/or intersexuality in individuals. Sex can be defined by various factors such as chromosomes, reproductive system, or hormones or environmental disposition (15). Females are XX and males are XY chromosome holders. On the other hand, gender is distinct from sex, and it is multidimensional. It can be defined by sociocultural norms, individual behaviours, identities, and relations. Indeed, testosterone in men and 17beta-estradiol and progesterone in women cause CVD sex-based differences (16). 11 Although estrogens have a cardioprotective effect, they will wear off naturally in post- menopausal women. Thereafter, these individuals require extra cardiac protection and precaution which is often dismissed in interventional risk prevention (17, 18) . Heart disease has been principally defined to be male dominant. Therefore, risk estimation metrics and treatments have been previously tailored more for the male gender. However, advancements in science have proven that women and gender-diverse individuals can get underdiagnosed by using such gender-blind diagnostic and treatment tools. Sex and gender segregation in research studies is crucial. The biological differences between male and female will produce considerable differences in the outcome of the research. However, a gender-blind positioning is a common practice among researchers and has caused poor scientific outcome and misleading results. Heidari et al. 2016 have provided an outline for researchers to take into account these differences from research method design to reporting of final results (19). Most academic research use sex and gender as interchangeable terms. The researchers ask participants to indicate if they are male or female. However, this gender binary framework does not consider the sexually dimorphic hormonal system defined by both sex and gender explicitly. To overcome this shortcoming, Strafford university, as well as scholars such as Heidari, suggested a two-step method in which the researcher first asks the sex assigned at birth and then the gender identity of the study subjects. This method of conducting a survey, allows the researcher to reach a conclusion based on direct investigation and reasoning rather than from the explicit sexual orientation or even the appearance of subjects (20). Although research in gender-related differences in terms of CVD has shown a lower rate of CVDs in women up to the age of the menopause, research has shown women have higher mortality and a worse prognosis after acute cardiovascular events (21). Furthermore, the risk of CVDs is underestimated in women, leading to a delay in diagnosis 12 and a poor prognosis. This highlights the need for healthcare to use more robust and gender- specific risk estimate tools for prevention and management of CVD' risk in women. Several studies have outlined woman-specific risk factors in developing atherosclerotic cardiovascular diseases (ASCVD). Examples are preterm delivery, hypertensive pregnancy disorders, gestational diabetes, breast cancer treatments, autoimmune diseases and depression (22). Vascular aging starts with arterial stiffening which differs in the sexes, with stiffer vessels detected in men from adolescence to age 58 (years) and in women after the age of the menopause. Interestingly, elderly women showed stiffer vessels than men after the age of 58 (23). Some have argued that conventional risk factors such as diabetes mellitus, hypertension, dyslipidaemia, obesity, physical inactivity and smoking have an excessively fatal risk and a far more significantly negative impact on the CV system of women compared to men (22). Yet studies indicate that women receive less aggressive treatment, such as lipid- lowering therapy or aspirin, and less educational advice, than men with a similar CV risk profile (24-26). The 2018 AHA/American College of Obstetricians and Gynecologists advisory board emphasized the importance of the use of a gender specific guideline known as “Life's Simple 7” cardiovascular health metrics to assess women's cardiovascular risks (27). This guideline was initially developed and published by the AHA in 2010, and includes advice on diet, physical activity, smoking cessation, body mass index (BMI), blood pressure (BP), total cholesterol (TC), and fasting glucose reduction, specifically tailored for women (28). 1.1.3 Family history and genomics Family history can be an essential factor contributing to the development of CVD. Genetic CVDs may manifest themselves in the form of chromosomal disorders (such as congenital 13 heart defects or congenital heart disease) or single-gene diseases (i.e., cardiomyopathies (CMPs) or heritable aortic diseases); it can also show itself in form of multi-gene disorders such as IHD, atherosclerosis and diabetes. Research has shown that when a first-degree male relative has suffered a heart attack before the age of 55, or if a first-degree female relative has suffered from a heart attack before the age of 65, the patient is at increased risk of CVD development (29). In cases where both parents have suffered from heart disease before the age of 55, the patient has an increased risk of developing heart disease of up to 50%. In terms of treatment options also genetic testing can be used to identify the patient's unique variation and suggest the best preventative or treatment approach. However, genetic testing for individual susceptibility to CVD is not yet available broadly, especially at primary care level setting such as community pharmacies (CPs); neither is someone’s genotype the only determinant factor in the development of heart disease. Other factors such as environment can also impact the individual CVD risk profile (30). 1.1.4 Ethnicity The terms race and ethnicity are used interchangeably among scientists. However, each plays a different role in the predisposition of an individual toward CVD. The Oxford Dictionary has defined race as the biological variation among individuals based on physical characteristics or shared ancestry. Ethnicity refers to people’s cultural expression and identification; it is determined by many factors including race, national and tribal origin, religious background, linguistic abilities, and cultural and family background. Ethnicity is a widely used term as a health determinant of an individual but is indeed a manifold and complex issue to be considered. In today's world where relocation for work, migration and interracial marriage are quite common, the real risk that human diversities can impose upon an individual’s 14 cardiovascular health can not only be defined by their country of origin but also by other factors such as religion, cultural background, linguistic abilities, socioeconomic situation, biology, geographical location and race (31-33). According to the most recent “Health System Review”, in Spain 86.4% of the population are Spanish registered citizens, 1.8% are from Morocco, 1.3% are Romanians, another 10.5% are from many diverse ethnicity (34). Each of these backgrounds carries dissimilar risks of developing CVDs due to various factors, including inequalities with regards to health provision (35). The same report disclosed that the general health status indicator1 for CVD among Spanish residents is 4% and in foreign residents is worse (9%) (36). 1.2 Modifiable risk factors 1.2.1 Hypertension Hypertension, also known as the “silent killer”, is the most prevalent CVR factor and a growing public health problem. It is associated with increased risk of morbidity and mortality. Hypertension is characterised by a persistently systolic blood pressure (SBP) over 140 mmHg and diastolic blood pressure (DBP) over 90 mmHg recorded in 2 separate measurements (37, 38). Uncontrolled BP can put at risk heart, brain, kidney, and other organs (involvements and injury) (37, 38). According to Di@bet.es, a population-based cross-sectional study, 42% of the Spanish adult population aged over ≥ 18 (years) suffered from hypertension, of which 49% were men. This article has stated that among the hypertensive individuals, 67% were prediabetics, and 79% were people with diabetes. Another interesting finding of this ongoing study was that there were 37% of Spaniards with undiagnosed hypertension, which was 1 General health status indicators are defined by five elements: morbidity, mortality, and disability data, quality of life or functional status. For example, physical functioning, mental and emotional well-being, social functioning, general health perceptions been used. 15 observed more amongst men (43%). Furthermore, they identified that 88% of the hypertensive patients were receiving drug therapy, but only 30% of them were well- controlled and there was a higher proportion of women (24%) (39). This study has highlighted the need for an interventional program in Spain to target the unidentified hypertensive individuals in the community. This study claims that there is a move to improve medication compliance among diagnosed hypertensive patients. Despite the national attempt to diagnose and treat hypertension in Spain, some patients may present elevated BP in the clinic but normal ones at home. This is known as white-coat syndrome and should be taken into count by pharmacists who provide interventional services to reduce a patient’s CVR. On the other hand, it has long been known that there is a group of patients who present a normal clinic BP but elevated ambulatory or home measurements. This phenomenon is known as masked hypertension. The European Society of Cardiology’s 2018 guideline defined the BP cut-off value of 135/85 mmHg for out-of-office daytime or home BP and 130/80 mmHg for 24-h BP for clinical decision making (38). The prevalence of masked hypertension in Spain was investigated by the study of masked hypertension (ESTHEN). The researcher has identified a 48% (95%CI 42-53) prevalence of this syndrome among Spaniards. The risk factors that caused the masked hypertension were abdominal obesity (39%), smoking (24%), relatives with premature CVD (22%), and diabetes (11%) (40). Similarly, a more recent study in the geriatric population also found masked hypertension syndrome among 43% of the study cohort (41). Another review article looked at studies with a total of 51,573 hypertensive patients included in the Spanish ambulatory blood pressure monitoring (ABPM) Registry. Their results suggested a daytime variation of more than ≈20/10 mmHg when comparing office and 24 h BPs, lending additional support to the previous study findings (42). 16 Furthermore, one meta-analysis reported subjects with masked hypertension have a higher risk of cardiovascular accidents (hazard ratios: 1.92 (1.51–2.44)) than normotensive subjects (43). There is abundant evidence for the benefit of provision of the (ABPM) devices that recognise hypertensive patients and provide appropriate treatment options. However, this will be associated with a high cost for the healthcare system. The Spanish ABPM Registry was developed in 2004 to promote the use of ABPM in primary care settings. However, pharmacists have not been utilized by the Spanish healthcare system in making a contribution to the ABPM Registry (44, 45). 1.2.2 Obesity Individuals diagnosed with obesity ( BMI ≥30 kg/m2) or being overweight (BMI 25-29.9 kg/m2) are at an amplified risk of diabetes, hypertension, dyslipidaemia, and CHD (46). On the other hand, men and women who have waist circumferences greater than 102 cm and 88 cm, respectively, are considered to be at greater risk of cardiometabolic disease (47). Waist circumference measurement used to monitor the effectiveness of interventional services provided by the community pharmacy for overweight and obese patients results in improvement of anthropometric, clinical and therapeutic parameters in patients (48). A recent study revealed an estimate of 39.3% of overweight in the Spanish adult population aged between 25-64 years. Further, there has been a 21.6% general obesity with an increasingly higher trend among men (22.8%). More dangerously the prevalence of abdominal obesity was estimated as 33.4% and was higher among women (43.3%). Both abdominal and general obesity rose with age among the Spanish population (49). Obesity may lead to the development of CVD and diabetes with time depending on patients’ metabolic profile (50). Patients are divided into metabolically unhealthy obese and metabolically 17 healthy obese. Research revealed that the metabolically unhealthy obese were subjected to higher risk of developing type 2 diabetes mellitus (T2DM) and other comorbidities such as CVDs (51). Metabolically healthy obese individuals were defined by BMI ≥30 kg/m, Homeostatic Model of Assessment-Insulin Resistance Index (HOMA-IR) <90 %, HDL >40 mg/dL in men and HDL>50 mg/dL in women, TG <150 mg/dL, fasting blood glucose (FBG) <110 mg/dL, and BP ≤140/90 mmHg (52). Although patients with metabolically healthy obesity have a lower risk of developing other comorbidities, their risk remains high and increases with time (53). Childhood obesity is another major public health challenge in Spain. Children from families with a lower level of education (35%) and immigrants (19%) have a higher level of unhealthy weight (54). 1.2.3 Dyslipidaemia Recent research has revealed that 1 in 2 Spaniards have high TC serum levels and more than 44.9 % suffer from elevated levels of low-density lipoprotein cholesterol (LDL-C ≥130mg / dL or drug treatment), irrespective of their gender (55). Elevated TC of >200 mg/dl and LDL-C >70 mg/dl have been shown to act as an independent risk factor of CVD (56). Therefore, early identification and management of these parameters among the Spanish population can reduce the burden of CVD significantly. Various trials have investigated the initiation of statins to reduce TC and LDL-C impact on the development of CVD (57). Initially the West of Scotland Coronary Prevention Study (WOSCOPS) trial and AFCAPS/TexCAPS proved the positive impact of pravastatin and lovastatin use on the primary prevention of coronary artery disease (58) (59). Later the ASCOT-LLA trial proved that statin reduced the rate of nonfatal myocardial infarction (MI) and coronary artery disease-induced mortality in hypertensive patients (60). Dyslipidaemia can be described as a number of conditions, such as: 18 1. Hypercholesterolaemia (presence of high concentrations of TC in the blood, typically including elevated low-density lipoprotein cholesterol (LDL-C)). 2. Hypertriglyceridemia (presence of elevated triglyceride (TG) levels in the blood). 3. Mixed dyslipidaemia (elevations in LDL-C, TC and TG levels accompanied by low levels of high-density lipoprotein cholesterol (HDL-C). 1.2.4 Diabetes mellitus Diabetes mellitus is a chronic metabolic disease caused by the inability of pancreatic cells to produce enough insulin which causes a permanent rise in blood glucose level. In Type 1 diabetes mellitus the body is unable to synthesis insulin genetically whereas in T2DM the body is resistant to the use of insulin. Research has shown high prevalence of diabetic and prediabetic state among patients newly diagnosed with an acute MI (61). The International Diabetes Federation report suggested that by 2045 we will have a 15% increase in diabetes among the 20-79 age group across Europe (62). The Finnish diabetes prevention study has shown that a weight reduction of >5% by decreasing the fat intake by <30% and the saturated fat consumption by <10% of energy intake, a fibre intake of ≥ 15g/1000kcl along with regular exercise 4 times a week or more can prevent T2DM in high-risk patients by more than half (63). Another interesting investigation demonstrated that the cumulative incidence of developing T2DM and weight reduction is lower in patients who have received education and metformin in comparison with the control group (64). All this evidence emphases the importance of a plan for patient education, support, and personalised care. The American Diabetes Association guidelines have suggested that primary care professionals must routinely screen CV patients at high risk of developing T2DM by measuring their FBG and glycated haemoglobin (HbA1c). However, EUROASPIRE IV, a cross-sectional survey of patients 19 aged 18-80 years with coronary artery disease in 24 European countries, suggested that an oral glucose tolerance test (OGTT) is a better indicator of impaired glucose tolerance (IGT) with established coronary artery disease. 4004 of the patients in this study had no reported history of diabetes (65). Table 1 outlines the diagnostic criteria for diabetes mellitus and pre- diabetes according to the 2019 American Diabetes Association recommendations. However, pharmacists must consider the possible variation and limitation that HbA1c has, such as increase in the result due to haemoglobin variants and anaemia (66). Table 1. Diagnostic criteria for diabetes mellitus Parameters Values Diabetes mellitus HbA1c ≥6.5% (48 mmol/mol) FBG ≥7.0 mmol/L (126 mg/dL) Diagnose impaired glucose tolerance (IGT) FBG <7.0 mmol/L (<126 mg/dL) 2hPG ≥7.8 to <11.0 mmol/L (≥140–199 mg/dL) 1.2.5 Other comorbidities Different comorbidities are associated with CVD occurrences. Poor vision, diabetes, back/neck problems, osteoarthritis, chronic obstructive pulmonary disease, and cancer are significantly more associated with CVDs when compared with patients without those cardiovascular conditions (67, 68). A large number of publications have also reported the increased association of arterial stiffening and vascular aging with physiological conditions such as low birth weight (69), menstrual cycle (70), metabolic syndrome (71), rheumatoid 20 arthritis (72), systemic lupus erythematosus (73), etc. Risk-reducing strategies for ASCVD must incorporate the patient’s comorbidities in the estimation of lifelong risk. The 2019 ACC/AHA guidelines asked practitioners to pay special attention to patients who have a family history of premature ASCVD (males aged <55 years; females aged <65 years), primary hypercholesterolemia (LDL-C = 4.1-4.8 mmol/L); (HDL-C = 4.9-5.6 mmol/L), metabolic syndrome, elevated TG (>150 mg/dL), elevated BP, raised glycemia, and low HDL-C (<40 mg/dL in men; <50 mg/dL in women), chronic kidney disease (CKD), chronic inflammatory conditions (psoriasis, rheumatoid arthritis, lupus, or human immunodeficiency virus), a history of premature menopause (before age of 40) and pregnancy-associated disorders (preeclampsia) and persistently raised primary hypertriglyceridemia (≥175 mg/dL) during risk estimation (46). 1.2.6 Mental health Empirical research done by cardiologists Friedman and Rosenman (1976) argued that patients with a “Type A personality” typically characterised by a competitive, ambitious, work-driven, easily stressed, anxious, time-conscious, and aggressive personality are at higher risk of CHD (74). This claim was later scientifically proved by the Western Collaborative Group Study and the Framingham study (75-77). However, mental health aspects were not later included in the Framingham cardiovascular risk CVR estimation tool. Stress as one of the most common psychological problems in the modern world is an influencing factor directly linked with CVDs. Stress can be acute (e.g., natural disasters) or long term (e.g., occupational stress). In a report by Gullette et al. negative emotions such as tension, sadness and frustration, which lead to chronic stress are directly correlated with double the risk of myocardial ischemia (MI) subsequently (78). 21 The research indicates that emotional stress can cause an upsurgence of the sympathetic nervous system, damages endothelial function and create favours coagulation in the vascular system, resulting in MI or sudden death (79). Similarly, researchers have found that stress triggers the consumption of a higher amount of calorie-rich food such as sweet and fatty foods. That in turn causes a lower amount of micronutrient consumption beneficial to the individual’s health & and causes a higher rate of cardiovascular incidents (80, 81). One of the suggested approaches for managing the prevention of CVD caused by stress and other psychological risk factors is routine screening for early detection and timely management. A number of studies have proved the positive impact of CPs’ services on early detection and management of stress (82). One of these studies used a 4-item screen for the detection of post-traumatic stress disorder in the community pharmacy setting. The investigation provided evidence on the effectiveness of CP’s screening and identification of stress among service users (83). On the other hand, patients with mental health conditions have a low adherence rate with their medication. CPs can give them support to in order to increase their compliance (84). The prevalence of psychological distress in Spain has decreased slightly. Variations are observed in psychiatric abnormalities in Spain based on location and gender where women showed poorer outcomes (85). 1.2.7 COVID-19 It was initially thought that Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) only targets pulmonary epithelial cells, it was later scientifically proven that this virus does indeed infect many other cell types causing systematic inflammation with cytokine release and vascular damaging (86). The endothelial induced end-organ complications of the SARS- CoV-2 are most recently reported to be vasoplegia, acute respiratory distress syndrome, 22 myocardial injury, thromboembolism, and immune system collapse (87). Furthermore, it has been proven that SARS-CoV-2 affects the lipid cholesterol biosynthesis and decreases the level of total, HDL-C, and LDL-C as COVID-19 progresses in patients, but the long-term impact of this mechanism is still unknown (88). The pathophysiological explanation for developing these abnormalities is beyond the scope of this thesis. However, COVID-19 cases have been reported to be associated with some modifiable and non-modifiable risk factors. Surveillance data has shown that the modifiable risk factors associated with COVID-19 were obesity, smoking, slow walking pace indicative of lower fitness/activity and use of BP medication for hypertension (89). Also, those of an older age, male gender, low socio-economical level and from an ethnic minority were reported to be at greater risk of developing COVID-19 infections (90). It seems there is an overlap of risk factors that predispose patients to the development of both COVID-19 and cardiovascular abnormalities. Before the COVID-19 outbreak, it was expected that more than 30% of the total Spanish population would be over the age of 64 by 2050 (91). This requires the government to develop an action plan to prevent CVD and premature mortality in this population. However, recent statistics have shown the high mortality rate among those aged from 60-90 compared to their younger counterparts, since the pandemic. In the 60-69 age group, 5.1%; in the 70-79 age group 14.5%; in the 80-89 age group 21.2% and over 90s had a more than 22.2% mortality rate during the pandemic (92). According to Oxley, the increasing incidence of vascular endothelial dysfunction and large- vessel stroke has been reported in patients younger than 50 years of age with the COVID-19 infection (93). Another remarkable article by professor Libby et al states that direct viral infection and the inflammatory response elicited causes myocardial injury, which may or may not be reversible (94). However, this will raise the question that perhaps in the era post COVID-19 healthcare professionals (HCPs) should widen the age range of patients to 23 determine the actual risk of developing future CVD, since the pandemic has affected various age groups. Another possibility could be that patients who acquired this virus recently or in the past, may carry an additional risk of developing CVDs, and this risk should be included when calculating the VA of the patients. However, the statistical weight of risks contributing to future CVD is yet to be determined by long term follow-up clinical trials. 1.2.8 Smoking Smoking is a most important modifiable risk factor in developing CVD (95). A smoker can be defined as a person who has smoked at least 1 year in his or her life and has smoked within the last month (96). Smoking also harms many other major organs in the body as shown in Figure 1. BP is increased in active smokers or non-smokers exposed to passive smoking. Upon initial exposure, nicotine causes vasoconstriction and an instant increase in SBP. Then the depressant effects of nicotine cause a decrease in BP. However, carbon monoxide present in the cigarette acts directly on the vascular wall causing irreversible vascular stiffening (97). This functional alteration of vascular structure leads to long-term BP and increased heart rate (98, 99). Similarly, smoking reduces the amount of oxygen that reaches the body's tissues, increasing the risk of clot formation and doubling the risk of stroke (100). Smoking is also known to decrease the level of HDL-C, total HDL, and large HDL particles, especially in women (101). In contrast, smoking was not found to affect LDL-C (101). 24 Figure 1: Impact of smoking on major organs in the body Harm from smoking can vary in individuals according to their pack history. Pack history is a calculation of cigarette smoking employed to measure a person's exposure to tobacco. Smokers can be divided into heavy smokers who consume ≥15-20 cigarettes per day, moderate smokers who use 10-19 cigarettes per day, and light smokers who smoke <10 cigarettes per day. This can be used by primary care practitioners to assess the patient’s risk of developing CVDs. Pack history is used for inclusion in smoking cessation programmes funded by Social Security in Spain. A recent systematic review showed that substantial reduction in smoking can reduce the CVD risks (102). In the light of the current COVID-19 pandemic, new studies have demonstrated that smokers have a weaker immune system (103). Smokers are at greater risk of getting acute respiratory Heart Double the risk of having a heart attack Circulation Increase the blood pressure and heart rate Brain Increase the risk of having a stroke Kidney Smoking may cause kidney damage by its effect on sympathetic nervous system BP 25 infections and furthermore, their infection may last longer (104). Smoking is a major risk factor in provoking severe infection and even death from severe acute respiratory syndrome coronavirus (SARS-CoV-2). Epidemiological studies claim that active smoking is correlated with an increased severity of disease and death in hospitalized COVID-19 patients. The pathophysiological mechanism involved is that smoking can upregulate the angiotensin- converting enzyme-2 receptor. This receptor is used by the SARS-CoV-2 virus to enter the human cell. This not only causes an infection but may also activate a 'cytokine storm' which can potentially worsen the outcome in COVID-19 patients (105). Research has shown that smoking can add 10 years extra to the patient’s VA, lending additional support to the hypothesis that smoking may increase the rate of mortality in patients with CVD. Quitting smoking should be promoted among patients by healthcare practitioners including pharmacists, especially during the COVID-19 pandemic. Investigation established that three quarters of smokers have a tendency to quit. However, only one third (39%) make an attempt to quit each year of whom only 5% quit successfully (106). Adequate behaviour change promoted by CPs can develop an understanding of the negative impact of smoking in patients. Smokers who quit smoking with HCPs support and medication are up to three times more likely to stop successfully compared to smokers without professional support (107). Practical intervention will make a significant difference in patients’ lives through becoming permanent ex-smokers. Intervention by CPs should be tailored to match the smoker. Evidence shows that a combination of behavioural support and pharmacotherapy can increase a smoker’s chances of stopping by up to four times (108). 26 1.2.9 Diet The primary protective measure which can be implemented on a community level for primary or secondary prevention of CVD is a cardio-protective diet. Various diets have been associated with lower cardiovascular incidents. There is abundant evidence for the cardio-protective mechanisms of the Mediterranean diet (MedDiet). The ATTICA study suggested that adherence to a MedDiet can play a significant role in CVD risk reduction (109). The MedDiet mainly consists of fruit, vegetables, fish, and whole grains. It is high in unsaturated fats such as olive oil, nuts, and seeds. Moreover, it contains less saturated fats such as red meat and full fat dairy products. The traditional food pattern of the Spanish population has long been known to follow the MedDiet (110). However, recent nutritional surveillance studies suggest that nutrition intake has changed markedly in the last few years across Spain (111). This surveillance study has found that a new dietary pattern among the younger generation in Spain is now more focused on meat and that consumption of cereals, fruit and vegetables, and pulses does not meet the national recommendations for the Spanish population (111). Furthermore, this study has reported that the use of traditional Mediterranean foods (olive oil) has dramatically declined over the last forty years in light of the dietary recommendations by the Spanish Society of Community Nutrition (SENC) (112). This might be the explanation for the increasing obesity trends in Spain reported in the WHO NCDs report (7). Another aspect that dictates today’s diet across the world and in Spain may be socio- economic factors as well as climate change. A new published study in 2019 known as the Eat- Lancet report suggested that individuals can save the planet as well as reduce their risk of developing NCDs by following a planetary health diet. This universal healthy reference diet suggests that individuals mostly base their diet on plant-based food to save the planet (113). 27 Similarly, the community based cohort study known as the ARIC (Atherosclerosis Risk in Communities) study, that followed up patients from 1987 to 2016, lends additional credibility to the hypothesis of a planetary health diet benefits in reducing CVD (114). Dietary approaches to stop hypertension (DASH) diet is another healthy eating guideline also known to prevent and control CVDs. The DASH diet mainly consists of whole grains, fruits and vegetables, low-fat dairy products, and nuts. On the other hand, consumption of sweets, sodium, and red meats are reduced as part of this dietary habit. The focus of the diet is on reduction of sodium intake which has proved to significantly reduce SBP both in individuals with and without hypertension (115, 116). Furthermore, this DASH diet has been associated with a lower risk of all-cause mortality (117-119). A recent systematic review revealed that the DASH dietary pattern related to a decreased rate of CVD, CHD, stroke, and diabetes mellitus, lower SBP and DBP, as well as reduced TC, LDL-C, HbA1c, fasting blood insulin, and body weight in controlled trials (120). Evidence from a cross-sectional study conducted in 2008-2010 among 12,948 Spanish individuals with hypertension revealed only 17.3% (95% confidence interval (CI) 15.4-19.2%) were following a DASH diet and 17.2% (95% CI 15.4- 19.1%) had a MedDiet (121). This lends additional support to the urgent need for health education to be given to patients with existing CVD or high-risk groups. A calorie restriction diet that reduces calorie consumption during the day is proven to be beneficial to the CV system as well. Similarly, intermittent fasting with a special focus on timing can reduce CVR factors too. The intermittent fasting regimens range from 12 to 16- hour daily fasts to 5:2 strategy (24-hour fasts followed by a 24-hour eating period that can be done a few times a week). Thus, the benefit of one type of intermittent fasting regimen over another remains uncertain (122). The benefits of intermittent fasting for the CV system are the reducing of weight, hypertension, dyslipidaemia and glycemia (123). The mechanism 28 behind the benefit of this two-dietary restriction on CVD is not fully understood. However, there are three main proposed theories: 1. Oxidative stress hypothesis: reduction in energy intake reduce free radicals’ generation by mitochondria and thus, their deleterious effect on the heart (124). 2. Circadian rhythm hypothesis: it states that insulin levels should be kept lower later in the day. Therefore, late dinners can deregulate the body circadian mechanisms and lead to chronic disease such as diabetes (122). 3. A ketogenic state occurs after 6–8 hours of fasting where the body produces ketone bodies by breaking down fatty acids and ketogenic amino acids. Increased ketone level converts the body into a state of fat utilization with a decrease in LDL-C and an increase in HDL-C levels (125). 1.2.10 High alcohol consumption The well-recognised effect of moderate alcohol consumption especially red wine was first introduced by Renaud and de Lorgeril in his French paradox phenomena (126). The study compared the annual mortality from CHD and related risk factors in MONICA study cohorts, with the French patient's data. The results demonstrated long-term cardiovascular benefits of moderate alcohol consumption (20-30 g per day) among the French population despite high consumption of saturated fat (126). This study was later criticized due to its design because of patient genetical predisposition, the lack of control of potential confounding factors, and considering similar alcohol consumption levels for all participants rather than actual individual intake. However, it had triggered an avalanche of further studies on the effect of alcoholic beverage, in particular wine, on CVD development. Advance research showed that the presence of flavonoids in red wine has a protective effect on the heart. 29 Alcohol-related harm can have an important personal and social impact. This is a major public health problem. In conclusion, the effect of alcohol on CV system has been explained as having a J-shaped curve, in which low-to-moderate consumption is correlated with less risk than heavy drinkers who have the highest risk. High alcohol consumption on a continual basis can greatly increase the risk of dementia, disability, and frailty as well (127). The ACC/AHA guideline for preventing CVD suggested moderation in alcohol consumption. They further defined ≤2 units of alcohol a day in men and ≤1 unit of alcohol a day in women. In the United States, 1 unit is defined as 14 g of pure alcohol, which is typically found in 12 oz of regular beer (usually about 5% alcohol), 5 oz of wine (usually about 12% alcohol), and 1.5 oz of distilled spirits (usually about 40% alcohol) (46). However, the value attributed to for the standard drink unit (SDU) varies from country to country. In Spain, one SDU is equivalent to 10g for wine, 9 g for beer and 20 g for spirits (128). Although one study found variation in SDU definition in various Spanish states, primary care uses 10 g that is equivalent to a single consumption of wine or beer and a half consumption of liquors on the national level for clinical practice (129). The National Institute for Health and Care Excellence (NICE) recommended no more than 14 units per week of alcohol for both men and women (130, 131) . Pharmacists can help individuals make informed choices on their alcohol consumption and personalised interventional measures. 1.2.11 Caffeine Coffee is metabolized by the polymorphic cytochrome P450 1A2 (CYP1A2) enzyme. Individuals with the CYP1A2*1A allele are rapid caffeine metabolizers, whereas carriers of the CYP1A2*1F are slow caffeine metabolizers (132, 133). Cardiovascular incidence rate varies depending on the patient’s caffeine metabolism level (134) . Drinking coffee is prevalent in 30 Spain and its consumption is positively associated with educational level, greater BMI (≥30), tobacco smoking, higher alcohol, and energy intake (135). A sport cardiologist reported that consumption of 200 to 300 mg of caffeine, improves endothelial cell function and causes vasodilation at rest (136). The same research argued that consumption of a similar amount of caffeine one hour prior to aerobic exercise disrupts the normal physiological mechanisms that help increase myocardial blood flow by blocking the adenosine receptors. This can have an adverse effect on cardiac functioning specially in the younger population (136). Similarly, a recent study which looked at the collective results of the Framingham Heart Study, CHS (Cardiovascular Heart Study), and the ARIC study (Atherosclerosis Risk in Communities) reported a decreased incidence of heart failure in individuals with a higher consumption of caffeine (137). However, this is not to say caffeine can prevent other types of CVD. Collective literature may suggest that caffein impact on the heart varies in the individual depending on their genetic predisposition (137). 1.2.12 Poor medication compliance One of the principal difficulties in the treatment of long-term conditions such as CVD is medication non-compliance. Health organizations have reported that approximately 50% or more of the patients on long-term treatment, are non-complaint or do not take medication appropriately (138). Patient habits in taking medication can be better understood via three various terms compliance, concordance, and adherence. The term compliance refers to whether or not the patient takes their medicine as directed by the prescriber (138, 139). Traditionally doctors used to demand the use of medicines in a particular manner without any prior negotiation with patients. However, in recent years this classic model has been replaced by a more holistic approach known as concordance. Concordance alternatively is a 31 mutual agreement between patients and doctors, a two-way agreement where patients take an active part in the decision-making process according to their preference, beliefs, and abilities. Conscious decision making can empower the patient and improves medication compliance. Estimates of compliance or adherence for cardiovascular medications vary widely across Spanish studies. According to one recent research paper the mean rate of adherence in patients with cardiovascular abnormalities was 45.8% (140). Adherence can be achieved when a healthcare professional accepts the patient's preferences and prescribes accordingly. Patient medication adherence can be determined in numerous ways (141). Some studies use direct medication counting or determine adherence through serum drug concentration. Others rely on administrative data such as the self-report Morisky-Green questionnaire first published in 1986 (142). Medication-possession ratio or portion of days covered are other possible methods. However, they only indicate the patient's possession of their medication not their compliance (141). With the advancement of science, in recent years the use of predictive analytics software has been suggested to predict the patient's compliance patterns. These machine-learning approaches use the patient's compliance history to predict their future adherence behavior. The limitation of this approach is that the patient's compliance in one type of medication, for instance pain killers with immediate benefit to the patient's health, may be different to preventative medication where they might not feel any difference instantly. Another drawback of these machine-learning methods could be that most healthcare systems do not have access to the patient's compliance information history, and it might take years before the healthcare professional will have access to such valuable data. Therefore, the Morisky-Green questionnaire is applicable and currently the best possible indicator of patient's medication adherence (143). 32 Various studies have demonstrated that a multidisciplinary approach and direct involvement of pharmacists can play a vital role in facilitating patient adherence to their medication (144). The pharmacy office in Spain proposes the preparation of weekly pill dispensers, Personalized Dosage System known as sistemas personalizados de dosificación (SPD) in Spain, to improve patients with chronic disease compliance. However, SPD is still in the implementation phase and there are important differences between the different regions (145). A collaborative work between the Daroca health center and the CPs investigated the effectiveness of SPD system on improvement of patient’s compliance. Out of 37 CPs located in the area of the study (Madrid) only 13 pharmacies offered the SPD preparation service (35.1%), and only 5 of them prepared pill dispensers. The remaining 8 pharmacies have not yet started preparing SPD, despite the adequate training or infrastructure (145). The finding of this research indicated SPD is useful in improving patient’s adherence to medication but only a few CPs offer these services. Further, SPD is not fully known among doctors and nurses (145). A recent systematic review and meta-analysis on the impact of Spanish CPs' intervention to improve patient adherence to statin therapy demonstrated better patient compliance (143). One of the limitations of this study was that the researchers did not investigate the reduction in lipid levels in the studies included in the systematic review due to a variation in lab results. However, the results obtained from the Morisky-Green scales demonstrated the positive impact of CPs' intervention on patient medication adherence. One of the obstacles in using the Morisky-Green scale is that it works well when assessing single medication or a monotherapeutic regimen but may be less accurate in patients with complex regimens presented in the form of polypharmacy. However, the practicality and ease of Morisky-Green makes it a suitable tool for community pharmacy use (141). 33 1.2.13 Pharmacological treatments Some prescription medications (e.g., doxorubicin, daunorubicin, epirubicin, idarubicin for cancer treatment, antipsychotic such as clozapine, chlorpromazine, fluphenazine, haloperidol, risperidone, anabolic steroids, for example testosterone and methyltestosterone etc) and other over the counter (OTC) treatments (e.g., nonsteroidal anti-inflammatory drugs (NSAID), etc.) have a negative impact on the heart. For example, antipsychotics (chlorpromazine, haloperidol, droperidol, quetiapine, olanzapine, amisulpride, thioridazine), type IA antiarrhythmics (quinidine, procainamide, disopyramide), type IC antiarrhythmics (flecainide, encainide), class III antiarrhythmics (sotalol, amiodarone, tricyclic antidepressants, amitriptyline, doxepin, imipramine, nortriptyline, desipramine and other antidepressants (citalopram, escitalopram, venlafaxine, bupropion), antihistamines, diphenhydramine, astemizole, loratadine, terfenadine etc. cause drug-induced QT prolongation and dangerous life-threatening ventricular arrhythmias (146). A literature review in medication consumption in Spain reported a similar number of medicines used in comparison with other European countries except for the higher consumption of antiulcer drugs, anxiolytics and peripheral vasodilators (147). The CPs in some parts of the Spain have limited access to the patient’s medical record and electronic prescription. Although recent clinical trials proved CP could contribute to the improvement of patients' health status and to reduce their problems related with the incorrect use of medicines or ADR (148). This wide access to the patient’s medical record is not fully implemented in Spanish CPs and it lack communication with the medical doctors. This is found to be a major limiting factor in provision of pharmaceutical care in the privet retailing pharmacy throughout Spain and potential cause of ramifications (149). 34 1.2.14 Physical activity Regular physical activity can reduce the CVR significantly. According to guidance on primary prevention of CVD published in 2019, individuals should perform physical activity including resistance exercise for at least 150 minutes per week of moderate-intensity or 75 minutes per week of vigorous-intensity (46). However, Spain’s National Health Monitoring and Surveillance System published a report under supervision of the Spanish Ministry of Health. This Spanish National Health Survey (Encuesta Nacional de Salud de España (ENSE) has shown that 66.4% of adults and 68.1% of older adults engage in regular physical activity in accordance with the WHO) recommendations on physical activity (150). Similar to the 2019 ACC/AHA Guideline on the primary prevention of CVD, the WHO has specific advice for the prevention of a sedentary lifestyle and obesity among adults aged 18-64. The WHO also has guidelines for adults 65 years of age and above, pregnant and postnatal women, patients with chronic conditions and disable individuals as well (151). 1.2.15 Health Inequalities Health Inequalities can be defined as unequal opportunity of an individual on a social level to have a better access to health amenities, health education and other factors that can establish one’s physical and mental health. There are five interlinked domains that are the cause and consequence of health inequalities: 1. Social determinants of health are strongly rooted in unequal economic, and environmental conditions (low income, unemployment, poor housing conditions, poor education). 2. The intrapersonal and interpersonal situation dictates the distribution of power and resources (age, sex, race, sexual orientation, disability). 35 3. Vulnerability (immigration, being part of a social minority, language barrier, mental health issues). 4. Cultural and behavioural differences. 5. The geographical location of an individual causes them to be subject to a different political and economic climate (urban and rural living location) (152). One of the studies that used the postcode to link the level of deprivation with patient’s VA was the Joint British Societies (JBS3)-derived heart age tool. In this study the residential location was used to identify areas with patients at higher risk of developing CVDs. These data were then employed to develop strategies to focus CP’s interventional services to reduce CVD (153). Other major study performed in Scotland measured the cardiovascular outcomes in the Scottish Heart Health Extended Cohort against the Framingham CVD score. They concluded that considering the social gradients in CVD is essential because the patient likelihood to develop CVD are influenced by unattributed risk from inequalities mentioned above (154). On one hand, a perfect healthcare model tries to facilitate the patient’s access to health by creating a fully integrated community-based care programme not subject to the five domains mentioned above. In this case patients will all receive an equal service regardless of location, socio-economical or intrapersonal characteristics. In this health model primary care including CPs or local general practitioners are well trained and supported to provide the best of care for their patients. Communication among practitioners is a key element of this model. All healthcare practitioners are valued by the health system for their service provision and get paid sufficiently to motivate them further to provide world class services. It is evident that creating empanelment (1.6) can breach the gap between primary and secondary care. It also serves to reduce inequalities by reaching a wider range of patients who have limited access. 36 1.2.16 Climate change Climate change is a global phenomenon that negatively impacts the health of the population (155). Numerous studies have indicated that a higher rate of cardiovascular-related hospital admissions or emergency cases is seen due to an increase in regional temperature (156). Similarly, data from the Disease Surveillance Point System of China, revealed higher CVD, CHD and ischaemic and haemorrhagic stroke due to changes in the climate (157). Another study in Iran also showed similar findings (158). On the other hand, chronic exposure to ozone causes thickening of the carotid artery and formation of carotid plaque. This in turn leads to higher CVD rate and stroke (159). The extent of CVD due to outdoor pollutant exposure is greater in populations with a low socioeconomic status which HCPs often have no control over (160, 161). 1.3 Cardiovascular health in Spain Life expectancy in Spain is one of the highest in Europe (7), although the 2019 WHO report revealed the decreasing trend in Spanish life expectancy since 2018 (6). NCDs are estimated to account for 91% of all deaths in Spain. CVD with 28% prevalence, is one of the top causes of mortality. Regarding the lifestyle factors affecting cardiovascular health, consumption of tobacco is reported high in Spain, with 24% smokers, 22% daily smokers and quarter of the population as former smokers in 2020. The population in Valencia and Andalucía are the highest consumers of tobacco. On the other hand, alcohol consumption in the Spanish population between 1990 and 2019 has been variable. In recent years, beer has replaced wine as the preferred alcohol beverage and binge drinking among the younger generation has been reported (162, 163). A recent analysis of national consumption data has revealed a decrease of 4.5% per year from 2006 to 37 2011, and a period of no change in alcohol consumption from 2011 onwards (163). However, psychological distress triggered by the current pandemic, an upsurge in unemployment and the economic crisis may trigger higher alcohol consumption (164). Another theory is that regular consumption of alcohol may decrease as people give priority to other expenses. This is followed by binge drinking of cheap alcohol to cope with emotional distress (165). Obesity and overweight are other considerable risk factors of CVD in Spain. Statistics revealed that 62.0% of the adult population (> 20 years old) in Spain were overweight and 26.6% were obese. The prevalence of overweight was higher among men (67.7%) than women (56.6%). Childhood obesity is another big challenge for the Spanish National Health System (SNS). A recent systematic review revealed that between 1987 and 2014, the prevalence of overweight and obesity increased in men by 0.28% (P=0.004) and 0.50% (P <0.001) accordingly per year. In women also the incidence of overweight rose by 0.10% (P=0.123) and obesity 0.25% (P=0.078) each year. This led to expenditure of more than 2% of the 2016 health budget in Spain. This excess medical cost is predicted to be 58% if the government does not implement a national health strategy to tackle the issue (166). Possible causes of this increasing trend of obesity among Spanish population could be physical inactivity and poor diet. Nevertheless, the government needs to promote early prevention and management of this ongoing problem (167). High BP, high salt/sodium intake, diabetes and air pollution are other risk factors for CVD in the Spanish population (7). 1.4 Cardiovascular Risk estimation In 1839, William Farr recognised that "diseases are more easily prevented than cured, and the first step to their prevention is the discovery of their existing causes" (168). Early identification of the multifactorial predisposition of individuals can help us identify possible 38 susceptibility to the development of CVD. Early identification of these variations is being used in modern healthcare systems as CVD preventive measures. The National and international health agencies have suggested that risk estimation, prevention, and early treatment of the causes of CVDs can reduce the effect on the individual's health and reduce the cost to the healthcare system and society. According to the WHO analysis in 2010, reducing risk factors in young adults and maintaining an optimum risk profile until the age of 50 could prevent 90% of CVD rate (169). Preventative interventional measures are performed by HCPs in three phases of the patient's life. Primordial prevention identifies habits and lifestyle choices that prevent the development of CVR factors and educates the individuals on how to avoid them. It targets individuals from as early as in utero, follows them up through infancy, childhood, adolescence, and adulthood. It mainly focuses on tobacco avoidance, adequate daily activity, a healthy diet, and weight management. Primary prevention is defined as a health measure targeted at individuals with risk factors, who have not yet developed clinically manifest CVD. Finally, secondary prevention is targeting patients with pre-existing CHD, cerebrovascular disease and peripheral vascular disease and attempting to reverse the CVD or slow down its progression. This prevention of CVDs throughout the lifespan model was suggested by Strasser in 1978 (170). This study aimed to ascertain the real impact and efficacy of CPs' intervention in primary and secondary prevention of CVD across the Spanish cohort. The development of CVD in the general population is due to a cluster of genetic predisposition and environmental risk factors as explained in detail above (171, 172). The economic burden of CVD on the Spanish healthcare system and the population is described to be enormous (35). According to a recent study which has looked at the global burden of diseases, out of 5 leading causes of death 14.6% belonged to IHD and 7.1% was due to stroke (35). 39 1.4.1 Relative risk calculation Risk in the Oxford Dictionary is defined as the probability of encountering an adverse or beneficial event. The risk factor of an event can be calculated by cohort or longitudinal studies such as randomised controlled trials (RCT) (173). In these studies, the investigator determines the strength of association of each risk factor with CVD incidents (174). Relative risk (RR) or risk ratio is obtained by dividing the risk (incidence of CVD) in group one with the risk (incidence proportion) in group two (175). The two groups are normally differentiated by demographic factors. The formula for RR calculation is: !! = !"#$ &' ("#)*#) "+ ,-&./ &' /-"0*-1 "+2)-)#2 !"#$ &' ("#)*#) "+ 3&0/*-"#&+ ,-&./ RR=1.0 indicates similar risk among the two groups. A relative risk greater than 1.0 shows an increased risk for the group in the numerator, usually the exposed group. A result of less than 1.0 indicates a decreased risk for the exposed group (175). However, evidence clearly indicates that RR should not be employed for decision-making regarding a patient. This is because relative risk only considers a single factor and dismisses other cofounders (variable that is associated with both the exposure and the outcome of interest) (176). 1.4.2 Absolute risk calculation The best tool for CVR assessment for effective decision-making is the absolute risk calculator which estimates the probability of heart attack or stroke. Absolute risk is calculated by the rate of an event occurring in a pre-defined population over a specified time. This estimation is useful because although patients might have certain parameters in the range, they have more than one CVR factor and absolute risk takes into account the cumulative association of age, sex, smoking habits, BP, lipid concentrations and diabetes (177). The first study that looked at factors that contribute to CVD development in a large cohort was the Framingham 40 Heart Study (FHS) in 1990. FHS employed the Cox regression2 on data obtained from a long- term surveillance of an adult population in Framingham, Massachusetts to calculate the absolute CVR (172, 178). This on-going study further investigated multigeneration predisposition and various racial groups. These findings led to the creation of a Pooled Cohort Equations CV Risk Calculator to be used at primary care level to estimate a patient’s 10-year ASCVD risk. This calculator which evolved over years considered additional risk factors such as patient’s age, sex, race, TC, HDL-C, SBP, use of BP lowering medication, smoking and diabetes status, all required to estimate ASCVD. As Lloyd-Jones et al 2018 clearly explained, this form of risk calculation allows health care practitioners to estimate the patient’s prognosis and identify individuals with higher risk to initiate treatment earlier for the benefit of individuals and to reduce total cost to the healthcare system (179). However, scientific advance showed that the Framingham risk estimation cannot be used indiscriminately for the Europeans. Risk attribution varies with location. For instance, in the USA the attributed risk for IHD is hypertension and dyslipidemia (180, 181), whereas in Spain, obesity and smoking are the most significant risk factors (182). It appeared that the Framingham chart overestimated the risk in the European population (183). Consequently, the Systematic Coronary Risk Evaluation (SCORE) project gathered data from 12 European cohort studies with a total of 205,178 subjects in order to understand the regional variation in risk across Europe (184). Nevertheless, one limitation of the SCORE system is that in the middle-aged population absolute risk is not high even though the relative risk may be high and may lead to delay in preventative treatment (185). One solution in order to overcome this limitation is the use of percentile risk in which each person will be compared to the individuals without 2 Cox regression (or proportional hazards regression) is a method for assessing the impact of several variables (risk factors) upon the time a CV event takes to happen. It assumes that the effects of the variables upon the patient’s survival are constant over time. 41 risk with the same age and gender (186). Similarly, population-based data from general practices in England provided data for the QResearch database which led to the creation of a risk estimation tool known as the QRISK (187, 188). Although in the SCORE project, data from the Catalonia Cohort Study (Barcelona Multifactorial Trial and Factory Heart Study; a total of 4701 participants with an age range of 25-68) were incorporated, the researcher admitted that the overall accuracy for persons whose risk falls in the 2%-5% (low risk) category is uncertain (184). Therefore, the researchers adopted the Framingham table for the Spanish cohort in 2003 (183, 189, 190). Thereafter, the REGICOR study (Registre Gironí del COR) was validated to allow a 5-year coronary event risk estimation in the Spanish population aged 35- 74 years. However, the current updated version of the calculator estimates the 10-year risk for patients. The REGICOR calculator uses the sex and age of the patients, smoking and diabetes status, TC (mg/dl), HDL-C (mg/dl), SBP (mmHg) and DBP (mmHg) in creating the most accurate risk estimation (191, 192) . Another Spanish research group designed a model to estimate the lifetime risk of developing CVD (193). Clinical practice guidelines advised primary care professionals to use these calculators for clinical decision-making for primary prevention of CVD. Despite the development of a population specific assessment tool, factors such as patient level of understanding of numerical processes (e.g., %), age, cultural background, etc., dictate the accuracy of their risk perception. Research indicates that visual aids (graphs and diagrams) and repeating health messages through follow-up can help health professionals convey their message more transparently (194, 195). Improving a patient’s perception of their CVR can play a key role in the adaptation of a healthier lifestyle (196). 42 1.4.3 High-risk or population intervention approach The main objective of pharmaceutical services is to improve health among the service users and reduce inequalities. Interventional services can be delivered in two modes: the high-risk approach, which targets and provides intervention for those with the highest CVR and the population approach, which implements strategies to reduce CVR among all individuals (197). Considering that CVD is the number one cause of death across the world, a small shift in the risk the distribution curve has a considerable impact on reducing morbidity and mortality, and so, the population risk approach is the preferred mode of action (198). This theory was first explained by Geoffrey Rose as early as 1985, in an article “Sick individuals and sick populations” (199). CPs are well situated to deliver a population-based approach (200). 1.5 Personalisation of intervention according to patient's risk estimation 1.5.1 Patient's perception of their CVR According to John Dewey "A problem well-defined is a problem half solved". It is essential for HCPs to develop a clear understanding of the patient's perceptions about their specific CVR to facilitate the reduction or prevention of CVD. Most healthcare systems stratify patients into low, moderate, and high-risk groups and focus their primary care resources on patients with moderate to high risk for developing CVD. It is also notable that according to the well- established theory of Kuller and Reisler's published in 1971, the relative importance of each risk factor can be a determinant of pathophysiology for future CVD development in patients (201). This theory emphases that the level of BP, TC and glucose can define subtypes of CVD. Patients better understand their true risk and make an informed decision when information is presented in simple terminology. Research indicates that HCPs can influence patients to 43 make healthier lifestyle choices by focusing on one or two risks at a time. Also, presenting the data in a positive way, employing non-technical language and evaluation including elements such as VA, may improve the patient’s outcome (202). 1.6 Empanelment Empanelment can be defined as the continuous process of patient care where a group of individuals are identified and later assigned to be cared for by a group of healthcare professionals. These HCPs will proactively collaborate as part of wider primary health care in the prevention and management of the patient’s health. Empanelment is a key aspect for population health management and enables health systems to empower patients, reduce costs, and improve health outcomes. The general population is split into groups who get assigned to be cared for by a panel of HCPs based on geographical situation, and by voluntary and insurance-based means (203). Figure 2: Visual display of empanelment in population health management It is crucial that the healthcare panel is appropriately-sized in terms of manpower and specialities to cover the need of all patients (204). 44 Figure 3: Illustration of appropriateness of healthcare panel size 2. Spanish community pharmacy system According to a national statistic in the year 2018, a total of 74,043 pharmaceutical professionals were registered in Spain, with a professional profile of 71.6% female and 45.5% under 44 years of age. The latest reports have shown that there is a ratio of 4.7 pharmacies per 10,000 inhabitants. Out of all the practising registered pharmacists, 87.1% (51,959 pharmacists) worked in CP (205). All community pharmacies are privately owned (149). Spain is divided into 17 communities (149). The regulatory law that determines the principles of community pharmacy operation across Spain is Law num. 16/1997 issued on 25th of April 1997, on the Regulation of Pharmacy Office Services or “Ley 16/1997 de 25 de abril, de Regulación de Servicios de las Oficinas de Farmacia” in Spanish (206). The most up to date version on pharmaceutical care is defined in “Law 29/2006, of July 26, on guarantees and rational use of medicines and health products” or “Ley 29/2006 de de garantías y uso racional de los medicamentos y productos sanitarios” in Spanish. This law defined the safe dispensing of medication, patient counseling services, pharmacotherapy follow-up, making extemporaneous preparations, and pharmacovigilance for all Spanish pharmacies. Furthermore, a consensus written by The General Directorate of Pharmacy and Health Products defined dispensing, a minor ailments scheme, and medication review as key roles of 45 the CPs (207). However, these services are not commissioned by the local or national government. However, although CP are privet services in Spain, the SNS returns to the pharmacies a percentage of the dispensed medication costs, but only for medicines covered by the SNS. COVID-19 highlighted that the Spanish healthcare system does not acknowledge the community pharmacies as healthcare providers but rather as private business entities. Nevertheless, the general public expect CPs to deliver pharmaceutical care without any additional funding or support (208). 2.1 Provision of community pharmacist intervention Pharmacists, as health care professionals, are keen to extend their expertise from the traditional dispensing and medication supply to a more clinical role. This has been clearly demonstrated by the significant outcome of CP intervention across Spain as part of RCTs, e.g., (143, 209-212). Research has shown that the CP’s active involvement in the prevention and early detection of diseases, as part of the primary care system, ease the pressure on urgent care provided by hospitals. It also has a positive health benefit for the patients and saves costs for the healthcare system (211). This is especially valuable in the current pandemic and beyond to prevent the healthcare system collapsing due to unnecessary pressure. Community pharmacies have a strategic location, extended opening hours in the evening and weekends, and accessibility for the elderly, social minorities, and immigrant (213, 214). They are placed in the heart of the community with a high percentage of Spaniards living within walking distance of a pharmacy. Therefore, they are a well-suited avenue for the implementation of public health services in resource-poor locations with disproportionately high rates of CVD. Public healthcare may benefit greatly using the pharmacist’s knowledge and expertise in the better management and prevention of CVD. 46 2.2 Consistency in healthcare provision and coherence in medical records In Spain, CPs do not have access to the patient's medical record. This can cause potential errors in the provision of pharmaceutical services from dispensing medication with drug-drug interactions and beyond. This was recognised as one of the factors leading to inefficiency in the Spanish healthcare model (215). There is an urgent need for building an infrastructure that transfers health records electronically across different care settings in Spain. Although a patient with private healthcare has their clinical record kept and shared across various healthcare settings, pharmacists in the community have no means to access these records unless the patient is a regular customer and has an existing patient medical record on the local pharmacy database. Therefore, future provision of pharmaceutical services across Spain must be supported by an electronic system that not only complies with the Human rights Act 1998, the Data Protection Act, the Code of Practice for confidential information law and GDPR; but also, must facilitate continuity of care between pharmacists and doctors. Effective record- keeping is vital to increase patient safety. Additionally, good quality record keeping can justify the professional decision made by the healthcare professional in the case of investigation for negligence. It should have a section to record the patient’s consent to pharmacists handling patient sensitive medical information. 2.3 Role of community pharmacists in health empanelment in Spain Over the past few months, the importance of empanelment was evident with the pressure that the COVID-19 pandemic had imposed on the healthcare system. Effective empanelment with proactive community pharmacies, with long opening hours, covering their patient panel significantly reduced the pressure on healthcare settings such as hospitals. One of the 47 important components of empanelment is that not only patients but also all members of the care teams including the doctors, recognize pharmacists as partners in care. Empanelment also allows the healthcare model to be shifted from waiting for the patient to develop a particular disease to actively screening and preventing the occurrence of a particular disease. Research showed CPs interventions can improve the cardiovascular health of patients by early screening and better pharmaceutical care management (216). Although the role of the CP in reducing the effect of CVD and their accessibility to the general public is evident, nevertheless many years of commissioned pharmaceutical services are required for building a culture of collaboration among doctors and pharmacists in Spain (217). According to the WHO, 80% of premature CVD are preventable (218). It appears that Spain will have a high percentage of elderly population as a result of low fertility and increased longevity by 2050 (219). The projections for prevalent cases of CVD, for example, obesity, hypertension, diabetes mellitus, smoking, depression, etc., will more than double by 2050. Behavioural risk factors account for more than one-third of the mortality in Spain. Smoking and obesity are major public health problems (220). Health spending accounted for 8.9 % of GDP3 in 2017, below the EU average of 9.8 %. Although Spaniards are covered by statutory health insurance, long waiting times for medical doctor consultation is a persistent issue (220). Health care accessibility can be improved by empowering the CPs who have enough clinical skills and time to assist patients in reducing their CVR. This part of the thesis intends to examine the existing literature on the effectiveness of CP intervention in reducing the burden of CVD throughout Spain. The fundamental preventative risk factors in the development of CVD were discussed above. The research databases4 were assessed to 3 Gross Domestic Product (GDP) is a measure of the market value of all the products and services produced in a specific time period by a country. This is an indicator for a nation´s economic situation. 4 PubMed/Medline (via PubMed and OVID), SCOPUS (via biblioguias.ucm.es), Cochrane Central Register of Controlled Trials (CENTRAL) (via cochranelibrary.com), EMBASE (via OVID), National Regional Database (LILACS BIREME) (via lilacs.bvsalud.org), CINAHL (via 48 identify all randomized/quasi-randomized controlled trials, interventional before-after studies, and cross-sectional methodologies on CP’s intervention for CVD prevention. RCTs are considered as the preferred tool of hypothesis testing. There was a limited body of evidence available on this theme with RCT design, therefore articles with a range of study designs were selected. The search resulted in 489 articles both in English and Spanish. A total of 16 articles met the inclusion criteria5 with a total of 11,262 participants, age ranging from 18 to 85. The research group did not perform a meta-analysis due to substantial variation in studies’ methodologies. The Cochrane risk of bias tool, which is a gold standard measure for systematic review was employed in finding research with minimum risk of bias. This tool considers aspects such as randomization, allocation concealment, blinding of treatment, intention to treat analysis or complete follow-up, as potential source of biases. The Cochrane risk-of-bias (RoB 2) was used to assess RCTs. On the other hand, the ROBINS-I tool was used to assess the non-randomize studies interventions (NRSIs) (221). The Robvis tool was used to summarize risk-of-bias in these 16 articles (Figures 4 and 5) (222). The RoB2 tool considers aspects such as randomization, deviations from intended intervention, missing outcome data, measurement of the outcome, and the selection of the reported result (Figure 4). EBSCO), Pharm-line (via worldcat.org); ClinicalTrials.gov (via clinicaltrials.gov), ISRCTN (via isrctn.com), DOAJ (Directory of Open Access Journals) (via doaj.org/), opengrey.eu International Pharmaceutical Abstracts (IPA) (via ebsco.com), the Spanish National Research Council (CSIC) (via digital.csic.es), the WHO ICTRP (via www.who.int/clinical-trials-registry-platform), SCIELO (via scielo.org/es) and Google Scholar. 5 Eligible studies were set as full-text English and Spanish articles on Spanish population from January 2000 onwards for all services performed by Spanish community pharmacists in community pharmacies settings based in Spain that were designed to improve the CVD via vascular risk reduction. 49 Figure 4: Risk of bias assessment in RCT studies Figure 5: Risk of bias assessment in NRSIs studies 50 The risk of bias tool ROBINS-I considers aspects such as confounding, selection of participants, classification of intervention, deviation from intended interventions, the missing data, measurement of outcomes and selection of the reported result (Figure 5). 2.3.1 Hypertension control Efficient health policies and long-term governmental plans are needed to identify the hypertensive individuals at an early stage (39). Phenomena such as masked hypertension is another pressing factor leaving to hypertensive patients being unnoticed (40, 41). Five studies investigating the impact of community pharmacy services in BP reduction were identified (210, 212, 223-225). The duration of these interventions varied from 2 to 24 months, with a total of 1,211 patients. Long-term interventional services provided by Spanish community pharmacies improved clinical outcomes in patients in terms of their BP, reduced long-term CVR and were shown to save costs for the healthcare system and patients. All specific objectives of the identified studies were in line with the evaluation of pharmaceutical follow- up (PFU), drug therapy monitoring and health education in achieving therapeutic targets for BP in patients. Only one of the studies was a RCT, which is the gold standard method of hypothesis testing (210). The majority of the studies have employed the Dáder Method for Pharmaceutical Care which was first created by the Pharmaceutical Care Research Group at the University of Granada (Spain) in 1999 (226). This methodology is a simple-to-follow operating procedure which aims at detecting, preventing and resolving drug-related problems as well as achieving therapeutical targets (226). In relation to the impact of community pharmacy intervention in achieving of therapeutic targets for BP, four looked at the direct impact on SBP and DBP (210, 212, 224). In relation to masked hypertension detection, only one study looked at nocturnal BP using ABPM (225). Two studies reported 51 lowering of SBP and DBP (210, 224). One has reported controlled BP and a change of treatment by doctors (225). All the studies clearly defined their outcome measures, key elements of study designs, CP setting criteria, participant selection process, data analysis, protocols, etc. A limitation of the studies was that the cluster of CVR factors were targeted by CP intervention which may have impacted the BP outcomes. However, according to the population strategy theory by Geoffrey Rose published as early as 1985, in an article “Sick individuals and sick populations”, the distribution curve of a single risk factor impacts an entire population and causes a greater reduction on mortality rates than does treating only people with high levels of a single risk factor. Therefore, targeting the cluster of risk factors by CP may reduce patient’s CVD on a larger scale. In conclusion, there is a strong body of evidence that proves PCS offered by CPs to reduce BP and the rate of CVDs in Spain. Thus, a better homogeneous study design (RCT) could lend additional support to this hypothesis. 2.3.2 Weight management by community pharmacist via diet and lifestyle advice As explained in a previous section, the prevalence of obesity is increasing in Spain (227). According to the 2019 ACC/AHA Guideline on the Primary Prevention of CVD patient with high waist circumference have a higher risk of CVD and diabetes, especially if the patient falls into a metabolically non-healthy phenotype (46, 52). Similarly, the prevalence of childhood obesity is also reported high, lending additional support to the urgent need for developing national health strategies to tackle this ongoing problem. Spain went through a financial crisis also known as the Great Recession between 2008 and 2014. The current pandemic also caused on 11% contraction in Spanish economy (228). The economic crisis and unemployment were found to trigger poor mental health problems. This in turn caused modification in nutritional status and increased obesity (229). This places Spain at a tipping 52 point where if no further action is taken by the health authority to control obesity, it will get out of control. The research group identified four recent studies in which Spanish CPs provided interventional services for weight management (212, 230-232). The intervention of these studies was aligned with providing personalized nutritional advice and promoting regular physical exercise to reduce patient’s weight (212, 230, 231). Other guidance on diet was provided as a secondary outcome (143). Although all these studies were limited in the sense that they relied on the patient’s own reporting for data collection, they revealed a significant improvement in the patient’s CVR due to CPs’ services. No study was found on CPs intervention that would address obesity in children or those under 18. Data collection was based on patients’ reports on dietary habits or exercise, which may be a potential limitation. Another limitation was that these studies only included patients with obesity (BMI≥30 kg/ m2) or metabolic syndrome with waist circumference greater than 102cm for men or 88cm for women. As discussed previously in the introduction, this is known as high-risk group prevention technique but intervention which targets a wider range of the population is preferred. Although the population level approach requires more resources initially, it prevents delay in action for patients in overweight categories and it is cost saving in the long term. Similar cost-effective results were reported from country-specific data in Denmark, France, Germany, Italy, Poland, and the United Kingdom, saving €14,903 per quality-adjusted life year (QALY)6 (233). Offering health checks only to higher-risk (obese) individuals saved €10,200 per QALY (234). 6 Quality-Adjusted Life Year (QALY) is a measure of health outcomes in terms of the quality and the quantity of life lived. 53 Another factor impacting patient’s weight is their level of physical activity. Three studies were identified in the systematic review that investigated the advice given on a patient’s physical activity by community pharmacies (231, 235, 236). One looked at the impact of regular physical activity on a patient’s cardiovascular medication compliance (236). Another looked at the prevalence of metabolic syndrome and the patient’s sedentary level (231). Only one of the studies compared physical activity, health education and PFU intervention in patients with a CVR factor. This study measured patient’s BP, TC, weight and BMI and found that patients in the drug therapy monitoring (DTM) group improved their parameters better than those in the health education (HE) group (235). 2.3.3 Dyslipidaemia management Four studies looked at the impact of CP’ interventional programs on reducing TC and adjusting the lipid profile in the Spanish cohort, to reduce CVD (143, 210, 223, 235, 237). Studies were of varying quality and methodologies. For instance, the Amariles et al. randomized control trial used the Dáder Method for Pharmaceutical Care dealing with control of TC in outpatients with existing CVD or CVR. This study showed a statistically significant reduction in the TC (210). Similarly, Oñatibia-Astibia et al. investigated the difference between standard care or tailored pharmaceutical intervention in adherence to statins, lending additional support to the hypothesis that CP intervention improves statin adherence and reduces TC (143). Furthermore, another study by Rodriguez-Chamorro reviewed the effectiveness of PFU in the control of hypertension and TC as a secondary outcome and that showed after 6 months of continuous PFU, patients had achieved adequate therapeutic targets for TC (223). Correspondingly, the FISFTES-PM study investigated the impact of HE and DTM in patients with CVR factors (CVRF). TC levels decreased in all study subjects, suggesting that community pharmacies delivering a combination of HE and DTM have a positive impact on CVR (235). 54 Thus, from existing literature it seems likely that the CP’ interventional program can improve CV health in the Spanish cohort. 2.3.4 Diabetes control The review identified five studies on diabetes control and patient education (209, 210, 230, 235, 236). Two had a long follow-up time of 13 M (209) and 24 M respectively (230). One employed the Dáder methodology (209) and the other used Pharmafit protocol (230). Pharmafit protocol seems to provide a most rigorous monitoring and patient support with its monthly patient’s visit. One researcher monitored the patient’s body weight, BMI, fata mass, TC, LDL-C, HDL-C, TG as well as glucose and HbA1c (230). This protocol also measured REGICOR CVR estimate, tailored for the Spanish population (238). The other group measured five main variables monthly, metabolic control (HbA1c, FBG, TC, HDL-C, LDL-C, albumin/creatinine), BP, weight and BMI, patient’s knowledge, and drug-related problems (209). Both studies communicated with physicians to improve the patient’s glycaemic control. One study also reported the provision of foot care (209). A multidisciplinary approach to diabetes care can prevent macrovascular and microvascular complication. 2.3.5 Smoking cessation Smoking is another public health challenge in Spain. A total of four studies were identified for smoking cessation services in Spain (239-242). Although primary objective of these studies was to promote the stop smoking, many of the other studies in the systematic review had smoking cessation as a secondary outcome (231, 235). Evidence showed that the promotional campaign for smoking cessation services delivered by the CPs increases the number of patients who stop smoking (239). Similarly, another study showed that patients who used nicotine replacement therapy offered by CPs were more likely to be successful in quitting smoking (240). Also, the Cesación tabáquica desde farmacia comunitaria (CESAR) program 55 offered by the Society of Community Pharmacists in Spain (Sociedad Española de Farmacia Familiar y Comunitaria, SEFAC) showed significant improvements in patients’ sense of taste and smell, lung capacity, cardiac function (HR and BP), TC and physical activity (241). One of the major drawbacks of the identified studies was lack of referral to doctors for prescription medicines e.g., varenicline (Champix®), bupropion (Zyban®) to stop smoking. Although, in case of the patient’s compliance with varenicline, smoking cessation services will be funded by SNS in Spain. Two of the investigations used the Fagerström nicotine dependency test to identify the patient's physical dependence on nicotine (239, 240). Thereafter, they used motivational interviewing to help patients quit smoking. One study used CO oximetry as an aid to quit smoking (239). One research group provided smoking cessation advice as a secondary outcome to improve BP (212), another group as part of health education and pharmaceutical care (235) and a third group as part of medication reconciliation services (236). Smoking is found to be associated with lower medication compliance (236). Further studies present a gold standard smoking cessation service that involves the whole with healthcare team, regular reviews to assess the failed attempts to stop smoking. This holistic approach may reveal whether CPs can reduce the burden of CVD in Spain, or not. 2.3.6 Alcohol advice A high level of alcohol consumption has been identified as a major CVR factor. A recent study assessing the data from Global Information System on Alcohol and Health showed that alcohol consumption in Spain has shifted from wine to beer and binge-drinking7 is a common practice (163). They reasoned that these new behavioural patterns may be due to a pro-cyclic 7 European Health Interview Survey (EHIS) defined binge drinking as five or more drinks for men and four or more drinks for women, at least once a month over the past year. 56 theory8 also observed in other countries due to the economic crisis (243). A narrative review was conducted to identify the community pharmacy consultation service on alcohol consumption. Although there was one study on the alcohol advice services of CPs in Spain, the findings must be interpreted with caution due to the short duration of the intervention (2 months) and simultaneous provision of patient education on other CVR factors9 that led to a reduction of the patient’s CVR (212). 2.3.7 Medicine reconciliation Improving patient’s medication compliance and detecting ADRs are key roles of community pharmacy services. The researcher critically reviewed the literature for pharmaceutical services on the detection of polypharmacy or ADRs and the medication review service in the Spanish CP, especially for geriatric patients. A broad automated literature search on published articles and a manual review of their references revealed six studies on medication review services in CPs (211, 235, 236, 244, 245). The articles originated in various regions in Spain and were in English or Spanish. A patient’s treatment adherence was measured by various ways which made pooled analysis difficult. One study used the Morisky-Green Levine test as well as a blood test (TC) to assess patient’s adherence to their statin (143). Another relied on the Morisky-Green test only (236). As explained before, Spain has a high percentage of older people so one might assume that the increasing number of research studies are targeted at the geriatric population. But the researchers found it difficult to encounter medicine reconciliation services directed only at cardiovascular medicines in the geriatric population during the literature search. Although the review revealed some studies such as the REVISA project that focused on improvement of the elderly’s compliance and the patient’s knowledge 8 Economic fluctuation causes individuals to spend less money on alcohol, which explains the decrease in daily alcohol consumption, but may bring about an increase in binge drinking of cheaper alcoholic beverage. 9 Diet, salt intake and physical exercise 57 regarding their medication, they were not focused on cardiovascular medicines. The REVISA project reported high patient satisfaction and a wiliness to pay for service delivery by the public, as well as an improvement in doctor-pharmacy relations (246). Similarly, a cluster RCT looked at the cost-effectiveness ratio (ICER) of a medication review with follow-up service for older adults with polypharmacy in Spanish community pharmacies. Although the medication review with follow-up was not only for cardiovascular medicines, it also reported an improvement in the quality of life of the elderly and cost effectiveness of the services (247). Although, there is abundant evidence for the importance of the CP’s intervention in achieving therapeutic goals and preventing unwanted ADRs, the finding must be interpreted with caution. There is a need for more studies with similar data collection methods to draw a conclusion. 2.3.8 Telepharmacy This new modality of pharmacy practice can be defined as the patient’s access to pharmaceutical services via telecommunication tools, including telephones, smartphones, and mobile wireless devices, with or without a video connection (248). Telepharmacy comes under telemedicine which originated back in 1950 when a Nobel Prize winner, Dutch physician Willem Einthoven transmitted an electrocardiogram created in hospital conditions to his laboratory over 1 km away via telephone cables (249). Remote pharmaceutical services and intervention advanced rapidly during the pandemic especially in rural areas (250). One of the advancements in pharmaceutical care delivery during pandemic was that the distribution of medication and access to the patient’s medical record was given to CP through patient’s identification code (Código de Identificación Personal Autonómico; CIPA). The main benefit of this new response strategy was to increase patient access and enable the convenient delivery of healthcare (251). Pharmaceutical counselling regarding the VA can act as a tool for 58 telepharmacy to reduce the rate of contamination and increase the access of patients to pharmaceutical care. 3. Vascular age calculator (VAC) As once said by Thomas Sydenham (1624–1689): “Man Is as Old as His Arteries”(252). One form of CVR presentation is comparing individual’s VA with their chronological age, that is easy for the patients to understand. Various VA tools have been launched across the world to empower patients to proactively manage their risk factors. In England, a calculator based on QRisk data was first introduced in 2014 by the Joint British Societies guideline for the prevention of CVD (JBS3) (253). It was then made available for public use without supervision of HCP in 2015. However, the research group investigating the data from this calculator reported some limitations. For example, if patients did not know their anthropometric, metabolic, and biochemical values, the national average was applied, thus introducing errors in the data collection. This study also reported that although there was a high level of public interest in knowing their CVR, 80% of the participants did not know their TC and 50% their BP level. They have recommended the use of this risk measurement in the presence of trained health professionals to fill the knowledge gap (153). The high proportion of users unaware of their risk was also reported in other studies (254). Evidence from this study and other similar research has shown that VA has a greater emotional impact on patients which may lead to behaviour changes (255). Although the benefit of VA calculator over 10-year risk estimates was proven previously, Patel et al. 2016 demonstrated that this version of VA results may provide false security because of unknown data being replaced by the national average (153). 59 HYPOTHESIS AND OBJECTIVES 60 Research hypotheses The VA tool employed under the supervision of CPs, has the potential to improve the patient's understanding of their particular risk of long-term CVD. Furthermore, the CP's intervention in the areas of BP, TC, diabetes, and weight management, smoking cessation, alcohol consumption, as well as medicine reconciliation in cardiovascular medicines, can influence the cardiovascular health of the patient by personalising a plan and continuous support via motivational interviewing. General objectives To develop a tool in the form of an interactive VA calculator and educational modules embedded on the website to support CPs in reducing VA in Spain. Specific objectives 1. To create an accessible and accurate tool to be used by CPs (a) To develop a better understanding in patients of their actual CVR factors and long- term impact on their heart. (b) To assess the Spanish patient's CVRs. 2. To determine the CPs' perceptions about the usefulness of the tool created. 3. To determine CP's perception about the feasibility of measuring CVD risks in patients at community level. 4. To identify possible barriers faced by the Spanish CPs in using VA as a tool to improve vascular health in patients. 61 MATERIALS AND METHODS 62 Materials and methods 1.1. Literature search A webpage was developed in the form of an interactive VAC and educational modules for HCPs and information for the patients, to be used as a tool by CPs. The webpage was designed with assistance of the Audience Talking Support company. For data extraction electronic bibliographic databases including PubMed/Medline (via PubMed and OVID), SCOPUS (via biblioguias.ucm.es), EMBASE (via OVID), the Spanish National Research Council (CSIC) (via digital.csic.es) and SCIELO (via scielo.org/es) were searched. A comprehensive search was performed to identify most up-to-date guidelines. The keywords: cardiovascular disease, diabetes, community pharmacist(s)/pharmacy(ies), pharmaceutical services, Spain, Spanish, diet, smoking cessation, blood pressure, cholesterol, hypertension, hypercholesterolemia, dyslipidaemia, metabolic syndrome, alcohol consumption and medication reconciliation were used. All cited guidelines from journals, dissertations, selected conference proceedings, standards of practice, and book chapters were screened. The Boolean search operators “AND, OR and NOT” were used to include relevant studies or impose limits on the search. Eligible guidelines were set as full-text English and Spanish evidence-base that were designed to improve the CVD via CVR reduction. English and Spanish guidelines published by the Spanish Society of Cardiology for CVD prevention, Spanish Society of Endocrinology and Nutrition, European society of Cardiology, the National Institute for Health and Care Excellence (NICE) and American College of Cardiology/American Heart Association Clinical Practice Guidelines were considered. The search was restricted to guidelines published between January 2010 and June 2021. Also, the authors searched through the citations of the guidelines to identify additional materials. 63 1.2. Vascular age questionnaire The questionnaire designed to assess the vascular age and is accessible on the website, has been based on the algorithm used to calculate the vascular age on the Systematic Coronary Risk Evaluation (SCORE) risk estimation tool with additional categories, which is valid for women and men aged 35-74. The survey consisted of 34-items that explored the patient’s CVR via a mixture of close-ended questions. The first section of the questionnaire investigated the sociodemographic characteristics of the participants. The subsequent sections explored i) the patient’s anthropometric and biochemical values on weight, height, TC, HDL-C, LDL-C, TG, glucose, HbA1C, SBP and DBP; ii) smoking; iii) pregnancy and breastfeeding in women; iv) comorbidities; v) medication use; vi) physical activity; vii) alcohol consumption; viii) air pollution exposure; ix) stress level; x) food consumption habits and social connection status xi). The questionnaire is further explained in result section. 1.3 Algorithm for vascular age calculator VA can be defined as an age that an individual would have if they were to have the same absolute risk but controlled risk factors. The CVR estimation across Europe is mostly based on the Systematic Coronary Risk Evaluation (SCORE) test which was first acknowledged by the cardiovascular prevention and management of dyslipidaemia guidelines in 2016 (256). Later, a researcher from Palencia in Spain used this SCORE data to create a vascular speeding or aging formula by including the Spanish cohort's low-risk profile (185). The scoring table is displayed in the Figure 6. The researcher Francisco Javier Manzano Lista has developed a VAC embedded in Microsoft Excel, using the risk percentile based on low-risk countries. The calculator handles the variables in two different ways: on one hand, the variables of sex and smoking are assigned a binary coding. In the case of sex as the variable the following coding 64 of (female=1, male=0) has been used. Furthermore, code 1 has been employed for yes and code 0 for no in relation to smoking status. On the other hand, the variables of TC and SBP are coded according to intervals. A range between 116 and 310 mg/dl (codes 4 to 8) for TC, and between 100 and 180 mmHg (codes 1 to 4) for BP were assigned to these parameters. In this manner of coding for variables such as sex, smoking, TC and SBP, the calculator locates the coordinates in the matrix (through horizontal and vertical search functions) and establishes a VA based on the CVR factors, as previously established by Cuende et al. (185). Figure 6: Vascular age calculated based on the SCORE system Once the factor is located, the programme multiplies this value by the biological age of the patient to obtain the VA. The assignment of the 10-year CVR has been done according to the established VA in Spain. The programme, based on the established age ranges obtained from the CVR table of Cuende et al., assigns a coding (from 0 to 5) discriminating according to the patient's gender. Subsequently, this code is assigned a percentage increase in CVR and a 65 colour tone that is established by means of a conditional format previously established on the screen that shows the result of the VAC. 1.4 Ethical approval The Ethical Committee Board of San Carlos Hospital in Madrid (CEIC Hospital Clínico San Carlos) has approved the VA study and registered it with the registration number 19/446-E. You can find a copy of the ethical approval letter in section 5 in the "Documentación" section under the sub-category “Dictamen favorable comité de ética” demonstrated in Figure 7. A copy of the ethical approval letter might be found in appendices I. Figure 7: Ethical approval documents location on the website 1.5 Patient confidentiality Patient Confidentiality is a legal duty of the researcher and service providers. The research team will maintain patient confidentiality by anonymising the data collection. Only the CPs can identify the patients from the unique number given to them on the questionnaire's initial section, as shown in Figure 8. The CP oversees keeping this number confidential and can use the number later during follow-up. 66 Figure 8: Patient’s confidentiality by anonymizing the participants 1.6 Informed consent The word consent can be defined as giving permission. Consent is an essential aspect of complying with the person’s right in providing patient-centred care. Also, obtaining consent is a legal and professional duty of all HCPs. There are two types of consent: explicit and implied. The researcher will use the exact consent form throughout this study to give specific permission in written format. Before initiating the service delivery, the researcher will clearly describe the study's nature to the pharmacists. The researcher will obtain written informed consent for participation in a contract from all CPs involved. The CPs will then actively obtain explicit consent from the patients to participate in the study. Also, the pharmacists delivering the intervention will require the patient's agreement to use the information for the research. Further, the CPs will need the patient's agreement to discuss the patient’s data with doctors as part of the referral scheme to receive more advanced care or prescribed medicines. Collecting of data, including biochemical samples, will be with the full consent of the patients. Patients must have the mental capacity to give support, act voluntarily, have sufficient information about the study to make their decision, and make use of the information provided by the pharmacists. All study procedures will be in full compliance with the ethical principles for medical research involving humans specified in the Declaration of Helsinki (257). 67 1.7 General Data Protection Regulation (GDPR) compliance The General Data Protection Regulation (EU) 2016/679 (GDPR) is a regulation on patient’s data safety and confidentiality in the European Union and the European Economic Area. The researcher will process the patient’s information data collected by the VAC in compliance with the data protection legislation, including the GDPR updated on May 25th, 2018, the Human Rights Act 1998, and Data Protection Act (2018). The GDPR includes roles such as lawfulness, fairness, transparency, purpose limitation, data minimisation, accuracy, storage limitation, integrity, and confidentiality (security) and accountability that set guidelines for the collection and processing of personal information from patients who live in the European Union (EU). The researcher follows the Spanish patient’s confidentiality laws regulated by Spain's data protection authority, also known as “Agencia Española de Protección de Datos (AEPD)” (258). Therefore, the researcher made the personally identifiable information (PII) anonymous for the pilot study of the pharmacists’ view from the webpage. Further, the CPs will camouflage the patient’s data (with the patient’s identity substituted by a number) for follow-up purposes. 1.8 Data storage and handling The researcher will securely store the data collected from the study at the University of the Complutense database, and only the research team and service provider will have access to them. 1.9 Study pilot among community pharmacists eHealth is a new phenomenon that can facilitate providing CPs with interventional services to improve cardiovascular health. However, there may be some barriers involved in its use. 68 The researcher consulted the webpage user’s opinion via an online survey. The researcher created a 26-item self-completion questionnaire to be distributed online among CPs using the Google forum. The researcher used open and closed questions to gain a wide range of replies and an in-depth understanding. The research members assessed the questionnaire and re- drafted it to create an assessment tool. The pilot was made available online on 1st August 2020. The questionnaire was live for seven months before closing on the 31st of February 2021. Twenty-five pharmacists were randomly selected to try the website and provide their opinion. An email preceded by the link to the questionnaire was designed so that participants could make an informed decision about their participation. Although the survey responses were collected anonymously, participation in the survey was taken as their consent to participate in the study. The questionnaire was divided into three sections, one covering demographic units, including age, gender, and location. The following section explored the pharmacists’ formation, experience, and prior training in providing pharmaceutical care to the patients. The final section asked about the pharmacists’ view concerning the webpage. The complete questionnaire can be found in the Appendix I. To protect the project's originality, the pilot study to evaluate the website was only performed within a limited number of CPs. 1.10 Pilot survey analysis Statistical analyses were performed with the STATA package version 12.0 (StataCorp LP, College Station, TX, USA). Descriptive statistics were used for the demographic findings and the close-ended questions such as NVivo qualitative data analysis software; QSR International Pty Ltd. Version 12 was used for analysing the open-ended questions at the end of the survey. 69 Furthermore, the Chi-square test was employed to find the correlation between the categorical variables. Statistical significance was set at P <0.05. 1.11 Adoption of QR barcode for the website and the questionnaire The SARS-CoV-2 pandemic has made delivering healthcare intervention very difficult. The protocol has been adopted to reduce the need for direct contact with the participant. Therefore, a QR barcode has been generated for pharmacists to access the webpage faster and more efficiently. The researcher can also track the scanning activity anonymously for statistical purposes. The QR code to access the VA webpage is displayed below in Figure 9. Figure 9: QR barcode for the vascular age website The website can be accessed using the following URL: https://edad-vascular.ucm.es/ Furthermore, CPs may use this barcode to facilitate the intervention process. They share the barcode with the patients to directly enter their data if they deem it necessary and later provide their patient the interventional services of the pharmacy based on VA. 70 RESULTS 71 1. Gender § Male § Female § Transgender § Other 2. Age 3. Level of the education § No education § Primary education § Secondary education § University studies 4. Ethnicity: § Caucasian § Hispanic § Black § Asian § Mixed (specify) 5. Region of residence eg. La Rioja, Galicia … 6. Postcode 1. Creating a data collection tool A novel website to act as a valuable tool for the Spanish CP’s interventions has been developed. The website includes the original questionnaire, the VAC, a detailed protocol for the pharmacist’s intervention and the patient’s information leaflets on CVR factors. 1.1 Questionnaire A questionnaire of 35 items was designed to assess each participant's different CVR profile. Questions are presented with concrete and straightforward options to select from, with open fields for numerical inputs. According to the Spanish national guideline (259), the author displayed uniform units for biochemical values to facilitate data entry. Patients must consent before providing data to the pharmacists. That will be kept anonymous, before the questionnaire is filled in. Therefore, pharmacists need to initially enter the patient’s national identity number (DNI or NIE) into the database. The interventionist will later use this number for the patient’s follow up purposes. Initially, the patient’s demographical data is requested in the first section of the questionnaire, as exhibited in Figure 10. Figure 10: Questions 1- 6 of the vascular age tool 72 7. Weight (Kg): ______ 8. Height (m): ______ 9. Total cholesterol (mg/dL): _______ 10. HDL cholesterol (mg/dL): _______ 11. LDL cholesterol (mg/dL): _______ 12. Triglyceride (mg/dL) _______ 13. Fasting glucose (mg/dL) _______ 14. HbA1c (mmol/mol) _______ 15. Systolic blood pressure (mmHg): _______ 16. Diastolic blood pressure (mmHg): _______ It is noteworthy that we would like to collect the patient’s province and postal code for possible future epidemiological interpretation of regional differences in VA in Spain. This data may allow us to assess affluence based on the patient’s location and draw possible conclusions about the social determinants of CVD, such as inequalities. Thenceforth the questions will take pharmacists onto anthropometric and biochemical values including weight, height, TC, HDL-C, LDL-C, TG, FBG, HbA1c and SBP, DBP as demonstrated in Figure 11. Figure 11: The anthropometric and biochemical values section of the vascular age tool Thereafter, the questionnaire focuses on the individual’s risk behavioural profile. The question moves on to ask about the smoking habits of the patients by calculating the pack- years, considering that there are 20 cigarettes in a pack. This explores patient’s smoking exposure, considering how long and how much they have smoked within the last ten years. Initially it is presented in a simple yes/no format but later asks about the details of pack-years. Another factor contributing to development of CVD is silent exposure to the toxic substance 73 17. Are you a smoker? § Yes § No Þ Pack history § I smoke less than 1 pack per day § I smoke more than 1 pack a day Þ Smoking history § I quit less than 10 years ago § I quit more than 10 years ago 18. Have you been exposed to tobacco smoke or high pollution? (Yes, no, I Don't remember) Þ Stage of exposure § Childhood § Adulthood § Housing in a place with high levels of pollution 19. Have you ever been pregnant, if so, please indicate the number of children you have: § No previous pregnancy § 1 § 2 § 3 § 4 § more than 4 20. Have you ever breastfed a child? § Yes § No Please Indicate the cumulative months of breastfeeding by counting all the children: § Up to 6 months § Between 6 and 12 months § Over 12 months 21. Have you reached menopause? § Yes § No of tobacco or pollution (Figure 12). This factor has been dismissed in previous research but plays a huge part in patient’s CVD risk profile. Figure 12: The smoking status question Subsequently, the next part of the questionnaire is only applicable for women. It focuses on women-specific risk factors, by recognizing female differences in CVD manifestation and the huge need for the CP to provide specific intervention for prevention, and management of risks in accordance with the history of patient’s reproductive health. This part explores client history about maternity, breastfeeding and menopause status (Figure 13). Figure 13: Women specific risk factor or protective elements data collection 74 22. Do you have a family history of cardiovascular disease? § Yes § No Next the interview moves on to investigate the individual’s family history of premature CHD (Figure 14). This is to identify the cohort of patients with higher risks of developing future CHD in the proximity of the community pharmacy and later use the VA tool to develop a better understanding in patients about their true CVRs profile. Correspondingly, CPs will proactively provide a personalised intervention to prevent patient’s premature morbidity and mortality. Figure 14: The question on family history of premature CHD The subsequent section investigates the patient’s comorbidity and medication history. This is to indicate past medical history as well as regular medication use that constitute a subsequent increase in CVR on patients. A strong body of evidence indicates that there is a potential association between these comorbidities or medicine consumption with the cardiovascular state as explained in section 1.2.5 of the introduction. This section of questions is also designed for identifying the potential confounding factors when interpreting the association between categories of comorbidities (e.g., migraine) or medicine use (antipsychotics) and the VA (Figure 15). The complete explanation about the meaning of confounder can be found in the introduction section. The next part of the questionnaire explores the physical activity level in patients in terms of frequency and intensity (Figure 16). This will allow the CP to measure patient’s activity habits and demonstrate its direct impact on VA. 75 24. Have you suffered a heart attack? § Yes § No 25. Are you currently taking any of the following groups of medicines? § Antihypertensive § Oral antidiabetic or insulin § Anti-inflammatory § Anti-migraine § Antipsychotics § Tricyclic § Antidepressants § Amiodarone § Levofloxacin § Digoxin § Thyroid Hormones § Oral contraceptives § Corticoids § Nutritional supplements: § Hormone replacement therapy, please indicate the type of HRT 26. How often do you exercise (more than 30 minutes)? § Daily § 1-2 days per week § 3-5 days a week § Never 27. With what degree of intensity? § light (walking) § moderate (swimming, cycling, running, Pilates, yoga, etc.) § intense (weights, spinning, etc.) 23. Do you have any of the following pathologies? § Cardiovascular diseases § Atrial fibrillation § Ictus § Angina § Intermittent claudication (tired legs) § Heart failure § Hypertension § stenosis, valvular insufficiency § Erectile dysfunction § Chronic renal failure § Thyroid disease § Polycystic ovary syndrome § Migraine § Gout § Autoimmune diseases Depression § Lupus erythematosus § Alzheimer's disease § Diabetes § COVID-19 Figure 16: The physical activity question in vascular age tool Figure 15: Medical and medication history of the patient 76 28. How often do you drink alcohol? Consider the last year. Þ Quantity § Daily § 1 or 2 glasses § More than 3 glasses Þ Frequency § More than 3 times/week § Less than 3 times/week § Never 29. What type of alcohol do you consume? § Beer § wine § liquors 30. Do you consider that you usually have a high level of stress? § Yes § No The questionnaire then focuses on the alcohol consumption of the individual. It surveys the frequency of alcohol consumption and the type of alcohol being consumed (Figure 17). More than 14 units a week of alcohol on a regular basis are proven to increase risk of developing of CVD. These questions and their relation to VA can assist the pharmacist to plan an intervention for the patient to achieve drink-free days. Figure 17: Alcohol habits assessment Stress has a major contribution in triggering many diseases including cardiovascular abnormalities (260). Therefore, the level of the patient’s stress will be also assessed (Figure 18). Figure 18: Stress assessment test The next part of the questionnaire investigates midday sleeping patterns, since some of the Spanish individuals have a short nap in the early afternoon (Figure 19). It has been shown that a 20- minute midday nap is associated with better cardiovascular health, where a longer one has a negative impact on the heart (261). 77 31. Do you take regular naps? § Yes § No § Please indicate the usual duration 32. Do you often add salt to meals? § Yes § No 33. Which of the following food groups do you regularly consume? Type of food Daily 2-3 times a week > 3 times a week Fruits and vegetables Red meat Pork Chicken Fish Seafood Pulses Dry fruits Olive oil Carbohydrates (pasta, rice, bread) Dairy Soft drinks, biscuits, snacks Fast food 34. Level of sociability: § I have few but very good friends and I spend time with them § I have quite a few friends and I spend time with them § I spend time with people, but I don't consider them my friends § I have no friends Figure 19: Spanish midday nap habit test Dietary habits amongst the Spanish population are known to be similar to MedDiet patterns (262). However, this part of the survey tends to investigate food consumption patterns in terms of macronutrient and micronutrient intake based on age and gender (Figure 20). Figure 20: Dietary habits of Spanish population The final part of the questionnaire assesses the level of social connections and relationships of the individuals across the wider society (Figure 21). Figure 21: Social interaction assessment 1.2 Vascular age calculator and interpretation of the results for patients In order to calculate the VA, the SCORE (Systemic Coronary Risk Estimation) risk assessment equation adapted to the Spanish population published in 2010 was used (185). This is a form 78 of a multivariable modelling equation based on patient’s age, gender, smoking status, lipid profile including TC and HDL-C as well as SBP. In the questionnaire embedded inside the website, these parameters are mandatory and marked with * for VA calculation. In the case where one of the mandatory sections is not filled, VA results cannot be displayed and the sentence “please complete this section” will appear to promote rectification of the problem. After completion of the questionnaire, the website will allow the service provider to store and print the results. This will allow the patient’s medical record and lifestyle habits to be available at CP’s fingertips. The printed hard copy can be used by the pharmacists to easily perform a PFU. Pharmacists are encouraged to fill out all questions fully and arrive to the patient’s VA by pressing the “enviar” option whereby the VA will be calculated and displayed on the next page. In any case after estimation of a VA for the patient by the CP, patients will be offered the service of PFU. Therefore, and based on both the VA and the information included in the questionnaire, the pharmacist will design an intervention plan aimed at reducing the CV age/risk by promoting changes in patients’ lifestyle and pharmacotherapeutic treatment if required. Research has shown that cardiovascular health is better perceived by patients when presented in the form of VA. To enhance patients understanding in relation to their particular risk factors CPs can display a patient’s VA using various models. For example, let’s say Mrs Gonzales who is a 55-year-old smoker with BP of 140 mmHg and TC of 220 mg/dL arrives at the community pharmacy. Her initial VA which is 9 years and 4 months higher than her chronological age will be displayed as below (Figure 22): 79 Figure 22: Illustrate how vascular age tool can improve patient’s comprehension In this case the pharmacist will assess the risk profile of the patient. There are many possible means for improvement for this patient. The pharmacist will tackle each CVR individually to demonstrate the true impact of each risk on the patient’s VA. Initially the pharmacist can encourage patients to quit smoking. Pharmacists will then use the VA tool to demonstrate that without tobacco use Mrs Gonzales will gain six more years of potential VA as shown by the automated calculator below (Figure 23). Figure 23: Vascular age tool improves smoking cessation Smokin g Blood pressure 140 mmHg Blood cholesterol 220 mg/dL Blood cholesterol 220 mg/dL Blood pressure 140 mmHg 80 Another case scenario can be that pharmacists try to encourage Mrs Gonzales to have a healthier diet and exercise regularly. These measures can reduce parameters such as weight, BP, and TC. To make the patient comply with the suggested health measures, pharmacists can adjust her current results on the calculator to aid her visualization and understanding of the tremendous effect this will have on her VA. Let’s say Mrs Gonzales only succeeds in reducing her BP from 140 to 120 mmHg. Her VA will improve by more than 4 years as shown below (Figure 24). Figure 24: Blood pressure reduction by vascular age tool Furthermore, pharmacists can suggest that if Mrs Gonzales complies with a healthy diet and manages to reduce her TC then again, her VA will be reduced as shown in Figure 25. In addition, pharmacists can refer the patient to doctors in the case where prescriptions are required for pharmacological treatments such as anti-hypertensives or lipid-lowering medication, among others. In the case of existing BP or cholesterol medication, the pharmacist can assess Mrs Gonzales’ medication compliance and promote a better adherence if required. Blood pressure 120 mmHg Blood cholesterol 220 mg/dL 81 Figure 25: Blood cholesterol reduction by vascular age tool Finally, the CPs can explain to Mrs Gonzales that if she quits smoking, improves her diet, exercise regularly, avoids salt and stress, reduces her alcohol consumption, etc. she will improve her VA significantly as displayed below in Figure 26. Figure 26: Improvement of patient’s comprehension by vascular age tool This method of visual aid to enhance a patient’s understanding is a milestone and the webpage can act as an excellent tool to assist the pharmacist in performing the best intervention to improve patients’ lives. Blood cholesterol 180 mg/dL Blood cholesterol 180 mg/dL Blood pressure 120 mmHg Blood pressure 120 mmHg 82 1.3 Study protocol A clear protocol was designed to make uniform the interventional services delivered by pharmacists. The study protocol is exhibited in the “Metodología Estudio” section of the webpage and is also shown in Figure 27. Figure 27: Methodology of the study 83 1.4 Study design The VA study will use intervention control before and after the CP’s intervention methodology. A simple design methodology in which many patients from a multicentre are recruited and subjected to intervention might seem appealing. The problem with simple design methodology is that it has less precision in estimation. Due to the enrolment of a heterogeneous sample of patients with less control over the service provider's training and standardisation of the intervention, bias in results is inevitable. Therefore, intervention control before and after study design is preferred. Another issue involved in the design of the study is masking the treatment to reduce bias in the outcome. However, in interventional studies such as a weight loss program, the researcher cannot hide the intervention from the participants. However, in the case where the primary outcome of the pharmacist’s intervention is objective measures (weight loss, reduction in BP or TC), it is not essential to mask. The individual perception of the treatment is less likely to influence objective outcome measures such as biochemical blood results. As is demonstrated above, initially pharmacists will identify potential volunteers to participate in the interventional program. The patients will be recruited if they fall into the inclusion criteria. The inclusion and exclusion criteria are described below. 1.5 Inclusion criteria Participants must be between 34 and 75, men or women living in Spain, and with at least one of the following criteria based on ACC/AHA 2019 Guideline on the Primary Prevention of Cardiovascular Disease: • Patients who are regular smokers (individuals who have more than one cigarette a day during the last month). • Overweight (BMI 25-29.9 kg/m2) or obese individuals (BMI 30-40 kg/m2). 84 • Patients who drink more than 14 units of alcohol per week. • Patients with hypertension (SBP ≥ 140 mm Hg or DBP ≥ 90mmHg) as well as individuals under antihypertensive treatments. • Patients with dyslipidaemia or familial hypercholesterolemia (full lipid profile including TC, HDL-C, LDL-C, and TG concentrations should be considered). • Individuals with a family history of premature CHD (defined as MI or sudden death before 55 years of age in a male first degree relative, or before 65 years of age in a female first degree relative). 1.6 Exclusion criteria Patients with the following criteria are not eligible to take part in the study: • Individuals with a history of previous CVD such as acute myocardial infarction (AMI), atrial fibrillation (AF), angina, CHD, heart failure, stroke (ischemic, haemorrhagic, or transient ischemic attack), or peripheral artery diseases or any other known cardiovascular comorbidities. • Patients with chronic inflammatory disease (e.g., HIV). • Individuals with cognitive disabilities with difficulties in communication or understanding pharmacists’ advice in relation to possible intervention. • Individuals with a history of previous CKD which has been classified as stage 3, 4 or 5. • Patients who are either pregnant or breastfeeding. 1.7 Patient recruitment All patients aged between 35-74 who comply with the inclusion criteria, do not fall into exclusion categories, and express interest in participation in the VA study, can be recruited by the CPs to participate in the study. Pharmacists are encouraged to provide these interventional services for patients whose calculated VA is higher than their chronological age 85 or have one or more CVR factors. This approach, also known as the high-risk interventional approach, has been explained in the section 1.4.3 of this thesis. Patient recruitment can be performed directly by pharmacy staff via oral invitation or through a poster presentation in the pharmacy premises. A request for a copy of the poster to be sent to a pharmacy can be made directly via email to the principal investigators; those details can be found below in the home section of the webpage, as shown in Figure 28. Figure 28: Principal investigator contact details in webpage home section Pharmacists are responsible for giving correct and sufficient information about this cardiovascular health campaign before signing an agreement with the participants. The following factors should be discussed, and patients should be given time to understand the study and process what it involves in terms of the follow-up. All patients' doubts should be clarified before initiating the study. 1. Voluntary participation: the pharmacist must explain to the patients that they are invited to take part in the study to estimate their VA and to improve their CVRs. Emphasis must be placed on the voluntary nature of the study. It should be explained to the patients that they have the right to withdraw consent at any time, without altering the relationship with their pharmacist. However, the data collected previously from the patients cannot be retrieved due to the anonymous nature of the data collection techniques. 86 2. The objective should be explained clearly to the patients. It should be emphasized the aim of this study, which is to calculate the patient's VA. Based on risk factors personalised intervention will be designed to try to reduce the patient's risk. The patient's progress will be evaluated during a maximum period of 12 months. Patients must agree to visit the pharmacy once a month. 3. The pharmacist must explain the implication of the FarmaFit protocol in detail for patients. They must include what patients' participation will involve: • Providing the pharmacist with the necessary information to calculate VA including, i) anthropometric parameters (weight, height, waist circumference and percentage of fat mass), (ii) BP, iii) fasting plasma determinations (TC, HDL-C, LDL-C, TG, glycaemia and HbA1c). This data may be determined by the pharmacist or provided by the patients from a recent analysis within the last month. • Provide the pharmacist with information on their personal health habits (diet, exercise, alcohol consumption or tobacco use, level of social interactions, stress, etc.). • Answering questions in relation to the patient's adherence to the pharmacological treatments. • Pharmacists must notify smokers that their participation in the study will involve answering a questionnaire to evaluate the degree of dependency on and motivation to stop smoking. • Patients will be given a monthly prior appointment as well as a 6 and 12 month visit under which patients personal progress will be monitored based on their personalised plan. • Possible risks involved in participation in the study must be discussed by pharmacists with patients. 87 • The time determined to fill out the questionnaire has been estimated to be no more than 10-15 minutes for each of the planned visits. • Pharmacists must clarify that participating in this study means compliance with the monthly visits as indicated by the pharmacists and agreeing to take part in the study activities as clearly explained above. • It should be explained to the patients that participation is voluntary, and they will not receive any financial return. The benefit of the involvement in this study will be to improve the CVR profile and quality of life of the patients on a long-term basis. • Patients must be assured that their personal data is fully protected. The researcher is committed to fully complying with the requirements of the Protection of Personal Data and guarantee of digital rights Organic Law 3/2018, of December 5. Pharmacists must further explain to the patients that their identity will not be disclosed to any person except in the case of a medical emergency to the doctor via a referral form or legal requirement. Study subjects will be identified only by a code, traceable only by the pharmacist responsible for follow-up purposes. • Finally, contact details of principle investigators and pharmacists in charge should be provided to the patients in case of questions. The above information can be found in section ‘3. Hoja de información al paciente" of the "Documentación" as in Figure 29. Patients who agree to participate in the study should sign a copy of the patient's consent form, which will be kept by the participating pharmacies during the survey. The patient's consent form will be collected by the researcher after the data collection period (12 months) and kept by the university for five years after the study. The patient's consent form can be found in the "Documentación" section under sub-category "4. Consentimiento informado" 88 as shown in Figure 29. The detailed copy of the patient's consent form is demonstrated in Figure 30. Figure 29: Webpage snapshot on study documents 1.8 Sample size It has been estimated that the VA study requires 385 participants to produce statistically valid results. The Cochrane equation was employed: N = 45 (7)! )! N is the minimum sample size for a statistically significant result. P is the proportion in the population possessing the characteristic of interest (risk of CVD), Q is 1-P, Z is a type I error equal to 1.96 found on the Z table. In statistical hypothesis testing, a type I error is the rejection of a true null hypothesis. E is the margin of error of 5%. To estimate the effect of CP’s intervention on patients' VA reduction in Spain; maximum variability of half of the population in Spain with CVD has been assumed; therefore, (p = 0.5). A 95% confidence intervals was used. This gives us Z values of 1.96 on the Z table, ((1.96)2 (0.5) (0.5)) / (0.05)2 = 385, therefore a random sample of 385 patients across Spain should provide the confidence levels required for a statistically significant result. 89 Figure 30: Patient’s consent form 1.9 Standard Operating Procedure (SOP) for patient’s consultation After recruiting of the patients as explained above inviting them for a private consultation in the community pharmacy; pharmacist and patients will sit in the consultation room while 90 complying with all infection control procedures. The pharmacist must wash their hands using the seven-step technique. Table 2: Initiating consultation by using I2C6 technique Initiating consultation using I2C6 technique Patient’s identity must be confirmed Pharmacist must introduce themselves to the patients and ask for their full name and date of birth. Explain the study process Pharmacist can briefly explain to patients that the vascular age study involves taking patients through medical history, medication history, family history as well as lifestyle. Finally, the must explain what kind of biochemical test will be taken from patients in case they did not test their blood parameters have not been tested recently. Gain patient consent Patients must sign a copy of the consent form presented in Figure 21. This consent form must be kept in the pharmacy until the end of the study period (5 year). Confidentiality Pharmacist must explain to the patients that all information obtained from them will remain confidential and anonymous. Patient’s carer Pharmacist can ask patients if they wish to be accompanied by another person whilst being interviewed by pharmacist. Patient comfort and privacy Pharmacist must take all steps possible to ensure patient comfort and protect their privacy during vascular age study. Subsequently the pharmacist will sign into an allocated computer to access the VA questionnaire. Pharmacists can follow the universal I2C6 consultation technique for the initiation of the interview. Table 3 demonstrates a template of I2C6 and suggests this uniform initiation of a conversation with patients for all service providers. The procedure checklist is 91 intended as an aide memoire to proficient CPs performance. It can also standardise the interviews across multiple community pharmacy centres. After completion of the consent form and initiation of the consultation with the patient using the I2C6 technique, the pharmacist can start by monitoring and recording patient’s anthropometric (height, weight, BMI, waist circumferences and biochemical data (TC, TG, HDL-C, LDL-C, FBG, HbA1c and BP) as shown in the protocol in Figure 27. The pharmacist then uses the collected data to complete the VA questionnaire explained in detail below and generate a chronological VA by using calculator embedded inside the website. The pharmacist should develop a personalized care plan depending on the patient’s calculated VA and biochemical parameters. After pharmacists enter the mandatory information marked with * in the questionnaire on the website the VAC will display a chronological VA result. According to this result pharmacists can generate a personalised care plan for patient intervention according to their risk factor profile. The full timetable for patient’s follow-up can be observed in a table presented in Figure 31 as below. This table can also be found in the “Metodología Estudio” section of the webpage under the study protocol. Figure 31: Study follow-up schedule 92 As explained in Figure 31, patients will visit the pharmacy once a month. During these monthly visits the anthropometric values such as weight, height (from which BMI will be calculated) waist circumference and BP will be measured. Patients will visit the pharmacy on month 3,6,9, and 12 after initiation of the study to monitor the biochemical values such as TC, TG, HDL-C, LDL-C, FBG and HbA1c. On the other hand, patient’s VA will only be monitored every six months. Also, pharmacists will fill out the ADHFARM questionnaire as shown in Figure 32 below, as an integral part of the intervention. In the ADHFARM questionnaire the first section examines the patient adherence to the pharmacist’s intervention offered to them on their initial visit (e.g., diet and alcohol intake, physical activity, and patient’s mental health such as stress level). The second part of the ADHFARM questionnaire provides suggested advice for pharmacists depending on the patient’s respond to the pharmacist’s questions in section one. The last section is a visual display and an evaluation table of the patient’s risk profile as well as the VA results taken every six months. Figure 32: ADHFARM questionnaire for patient follow-up 93 Before the pharmacists initiate the intervention process, a certain framework is to be followed with the aim of achieving coherent provision of intervention through community pharmacies. This is to advocate the advancement of community pharmacy services from conventional dispensing towards providing advice and assisting patients closely in improving their cardiovascular health. The following conditions must be met by pharmacists to support and promote behaviour change in patients as part of the VA study. 1.10 Premises requirements for pharmacies and pharmacist The criteria to be met by the pharmacies to be able to participate in this cardiovascular health campaign is defined on the website. This can be found under the sub-category "1. Criterios para las farmacias participantes" in the "Documentación" section of the webpage, as demonstrated in Figure 29. The actual document is presented in Figure 33. Figure 33: Criteria for pharmacies that participate in the cardiovascular health campaign 94 As shown in Figure 33, the eligible pharmacy must have an allocated consultation area marked clearly as private in which the interviewing pharmacist and patients can sit together. In Spain this area is normally marked as “Zona de atención personalizada”. Pharmacists are responsible for complying with sanitary requirements suggested by the WHO. The consultation area must be a place in which both parties can talk at average speaking volumes without being overheard by others on the premises. Finally, pharmacists are advised to place a computer in the consultation area for ease of access to the questionnaire or VAC. The pharmacist must fulfil certain conditions for VA service provision. Firstly, to consolidate the advice to be given to patients, participating pharmacists should attend a training day at the Universidad Complutense de Madrid presented by the "Grupo para el Estudio de la Salud Cardiometabólica” group for cardiometabolic health studies" (GESCAMET) before the beginning of the service. In this session, the GESCAMET group will address medication reconciliation techniques, specific healthy living advice on diet, alcohol consumption, physical activity, stress avoidance and smoking cessation. Pharmacies that complete this training will be granted a certificate issued by the GESCAMET. Secondly, all participating pharmacists are obligated to keep the patient's data safe to avoid a possible data breach. If they fulfil these two conditions pharmacists can participate in the service provision for which they need to sign a contract. This is a written agreement between the provider of the intervention and the researcher team. The contract can be accessed by pharmacists from the "Documentación" section under the sub-category "2. Contrato con las farmacias participantes" as demonstrated in Figure 29. A copy of the signed contract must be sent to the researcher via post or by email. The research group will keep this copy for the duration of the study and five 95 years after to meet the national legal requirements. Figure 34 shows the contract for the CPs who are eligible to participate in the study. DATOS DE LA FARMACIA Nombre de la farmacia Dirección de la farmacia Dirección de correspondencia (si es diferente de la anterior) Dirección de correo electrónico del farmacéutico Número de teléfono del farmacéutico ACEPTACIÓN DE PARTICIPACIÓN EN EL ESTUDIO v Adjunto una copia del certificado de formación en promoción de la salud cardiovascular para el farmacéutico que realiza la actividad. v He comprendido mi papel en el estudio y acepto participar en el mismo. En Madrid, a _____ de ___________ de 2020. Firma del farmacéutico Firma del responsable del proyecto Figure 34: Pharmacists' contract for participation location 1.11 Telepharmacy The beginning of the global pandemic has influenced our medical practice in such a way that patients are encouraged to visit the medical practices including pharmacists only if essential. That has prompted the researcher to think of alternative means for data collection and delivery of CPs’ service and the form of interventions. Initially, CP must sign a written consent with the patient to have their data, in this case, the mobile phone or any communication address with the patient. This requirement is to comply with the Data Protection Service of the Pharmacy Office10 law in Spain. Therefore, participating pharmacists can perform the intervention and patients interview via telephone or a video call. The strength and weaknesses of this technique will be further explored in the discussion section of this thesis. Participating pharmacists need to give a prior appointment to the patients to avoid time 10 Reglamento 2016/679/UE 96 overlapping with their other daily tasks. The interview over the phone should also be performed in the consultation area to maintain the patient's confidentiality. 1.12 Record management The patient information data obtained from the questionnaire on the website must meet the following requirements 1. Authenticity: The medical data created in the system is anonymous and only accessible for the CPs’ follow-up purposes. Furthermore, each pharmacy staff member using the system to enter patient data is advised to have a designated username and password. 2. Reliability: The information in the record is full and accurate. It is going to be entered by the trained healthcare professionals. Biochemical parameters are going to be either measured by HCPs at the patient interview or are being extracted from patients' own statements. 3. High integrity: The VA and the patient's data cannot be modified afterwards on the database. 4. Operational: Data can be kept in the printable format for future follow-up purposes. 1.13 Data collection process CPs are recruited randomly from a cohort of pharmacists specialised in pharmaceutical care. Participating pharmacists are required to follow six initial steps before starting the data collection from the patients as part of the VA online assessment questionnaire. These steps are: 1. Complete the pharmacist contract demonstrated in Figure 34 and return it to the GESCAMET research group. 97 2. They will be given a webpage address and pharmacy specific ID to use as username and password to enter the webpage, upon receipt of the contract by the GESCAMET research administrator. The welcome page of the webpage is displayed in Figure 35 below. Figure 35: Pharmacists access to the Vascular age calculator Pharmacists must initially register their username and password by clicking the icon "Check- in" on the "Access Form" of the home page. This form is shown in Figure 36. After this point the user can utilize the same data for re-entering the VA questionnaire. Figure 36: initial registration of the pharmacy in the database 3. Confirm a person to act as Data Collection Officer. This pharmacist will be appointed by the Technical Director of the Pharmacy Office after approval of the project. This 98 person will be the only person with access to the webpage and will be responsible for keeping patient information data confidential, interviewing the patients, and recording the data correctly on the webpage. The same person will later be responsible for dealing with any conflicts that might arise during the study and communication with study group. 4. Pharmacists must ensure that personal emails are not used in transferring patient information. 5. It is obligatory for pharmacy contractors to select one of the staff to take responsibility for protecting the confidentiality of patients and making sure that pharmacy premises meet all the requirements in the service specification. Also, the data collected from the patients is only used for the purpose of pharmacist’s interventions dealing with the VA study and follow-up. 6. All staff involved in the VA study must attend training before the initiation of the study. The research group encourage the pharmacists to hold a briefing with other pharmacy staff and explain the purpose and procedures involve in the VA research. Furthermore, pharmacists can delegate some of their daily tasks to the staff to help reduce the pressure on them whilst performing the study. 1.14 Referral to the Doctor CPs are providing many interventional services in Spain. They have the potential to detect and manage NCDs at an early stage. However, to achieve continuity of care a multidisciplinary approach is required. Continuity of care means that pharmacists should work collaboratively with other HCPs to provide ongoing and consistent care. There is a great need in Spain for a joint electronic database 99 which all healthcare professionals, including CPs involved in the care of patients, have access to. This eHealth record can allow HCPs to be aware about any changes in patient's medication or state of health immediately. Transferring the data by digital means is not yet possible in Spain. According to the study protocol, it is essential for pharmacists to contact the patient's doctor by letter if any of the below issues arise during the VA study. A template for this communication letter is presented in Figure 37. Farmacia ………………….. Ldo. ………………. Nº Colegiado: …… Estimado Dr. ……………….: Me pongo en contacto con usted porque el …….(FECHA)…………… detectamos la aparición de un problema relacionado con la medicación de su paciente, D/Dña. ……………….. Dicho paciente se encuentra actualmente en tratamiento con …………………………………………………………………………………………………………………………………………… ………………………… y desde hace unos días refiere ……………………………………………………………………….., lo cual considero que puede estar relacionado con dicho tratamiento, tras haber descartado otras posibles causas que pudieran justificar dichos síntomas. Lo dejo en sus manos para que tome las medidas que usted estime oportunas. En cualquier caso, quedo a su entera disposición si necesita de mi colaboración. Un cordial saludo, En Madrid, a … de ……………. de 2020 Fdo. Ldo. …………. Datos analíticos recientes (si es necesario): …………………………………………………. Figure 37: Doctor referral form 100 This document can be accessed in the "Documentación" section under sub-category “6. Formulario para derivar al medico” as shown in Figure 29. The inclusion criteria for referral to the doctors are: 1. Raised BP 140/80 in three consecutive reading and patient on no BP medication. 2. Those with a family history of premature ASCVD (males, age < 55 years and females age < 65 years), Primary hypercholesterolemia (LDL-C, 160–189 mg/dL (4.1–4.8 mmol/L); non–HDL-C 190–219 mg/dL (4.9–5.6 mmol/L)* with no medications such as statins. For initiation of primary prevention in patients age over 75, please refer to the introduction section. 3. Those with metabolic syndrome which can be detected by the presence of three of the following symptoms (increased waist circumference by ethnically appropriate cutpoints, elevated TG (>150 mg/dL, nonfasting), elevated BP, elevated glucose, and low HDL-C <40mg/dl in men and <50 mg/dl in women; should be referred to a doctor for further cardiovascular health screening and preventative medicines such as statins, antithrombotic agents like Aspirin®. 4. VA more than ten years above chronological age with raised BP or TC and patient with no preventative medicines. 5. Patient request for varenicline (Champix) or bupropion. This can be obtained by prescription from the pharmacy for smoking cessation services. 6. Client request for prescription-only medicines (benzodiazepine) to alleviate their stress. 7. Individual with BMI of more than 30. 8. Patients who drink more than 14 units of alcohol per week on a continual basis. 101 9. Patient who has reported noncompliance due to a drug-related problem such as side effects to a specific medicine. 1.14.1 Red flag symptoms in referral to a doctor The pharmacist should be aware of symptoms that may indicate more serious medical conditions requiring urgent referral to the doctor. They must encourage patients to seek immediate medical advice if they encounter any of these symptoms whilst interviewing the patients during VA study. A broad range of symptoms may suggest the onset of cardiovascular abnormalities. Red flag symptoms include: § Clammy, unwell patient. § Sudden onset of chest pain with increased intensity over 5-10 min may suggest MI. § Heavy, tight, pressure on the chest is typical for ischaemia. § Pain radiating to left arm, right shoulder or both arms may suggest MI. Radiation from the back, abdomen or legs may suggest aortic dissection. Furthermore, exacerbated pain relieved by rest may suggest angina. § Breathlessness, nausea or vomiting with one or more of the above symptoms could suggest MI. CPs must take into consideration the onset, site, character, radiation, severity, exacerbating and relieving factors as well as duration and associated symptoms of red flags on a case-to- case basis before referral. Red flag symptoms where there is a known history of coronary artery disease or a family history of premature coronary artery disease in an immediate family member or of the male sex may suggest acute coronary syndromes and needs immediate referral to the relevant doctor or emergency unit. 102 1.15 Detailed pharmacist intervention protocol Consultation can be defined as a discussion or advice given by the pharmacist to the patient. This is the opportunity for the pharmacist to make a difference in the patient’s life. Traditionally, HCPs made decisions during consultation with little or no input from the patients. This paternalistic approach has been replaced by shared decision-making between patient and HCP; based on the patient’s beliefs, evidence-based information and advice given by HCP. Pharmacists are advised to take a holistic approach towards a patient’s cardiovascular health. They must consider social, physical, psychological, and behavioural aspects of a patients’ life that may impact on their health. Therefore, during their consultation, the CP should: 1. Explore the patient’s agenda (get to know your patients to help them better by more personalised advice). 2. Consider patient views and beliefs about CVD and medications. 3. Involve patients as a true partner in the discussion. Patients must be at the centre of their own healthcare and take an active part in decision making. 1.15.1 Management of patients with obesity Pharmacist advice on weight management is available on the “Protocolos de Intervención” section under sub-category “obesidad” as shown in Figure 38. The pharmacist can use the WHO scale shown in Table 4 to identify the degree of overweight or obesity in patients. 103 Figure 38: Webpage snapshot of pharmacist’s intervention guide for obesity control Table 3: WHO classification for BMI (kg/m2) measures in white Caucasian adult Classification BMI (kg/m2) white Caucasian adult Underweight 18.5 or less Healthy weight 18.5-24.9 Overweight 25-29.9 Obesity I 30-34.9 Obesity II 35-39.9 Obesity III 40 or more (morbid obesity) 40 or more BMI measures an individual’s total weight (Kg) relative to their height (m). It determines the degree of overweight or obesity in patients. However, BMI is non-specificity for body fat. Athlete individuals have above average muscle mass and weigh more, therefore their BMI results should be interpreted with caution. Waist circumference indicates the distribution of body fat known as central adiposity. Patients with greater central obesity have higher risk of developing CVD and diabetes. Pharmacists should practice their clinical judgment when considering patients from diverse ethnic backgrounds. 104 Table 4: Classification of patient’s risk based on waist circumference in cm Classification waist circumference cm Low waist circumference Men – less than 94 cm Women- less than 80 cm High waist circumference Men- 94-102 cm Women- 80-88 cm Very High waist circumference Men- more than 102 cm Women more than 88 cm Pharmacist can use the risk classification suggested by the NICE clinical guideline 189 on obesity management (263). Table 7 shows appropriate types of intervention based on a patient’s CVR factors. Table 5: Classification of patient’s risk by BMI, waist circumference & comorbidities BMI (kg/m2) Waist circumference (cm) Patient with comorbidities Low Hight Very high Overweight 1 2 2 3 Obesity (Class I) 2 2 2 3 Obesity (Class II) 3 3 3 4 Obesity (Class III) 4 4 4 4 Table 6: The choice of intervention adequate for patient’s risk Risk level according to BMI, waist circumference and comorbidities 1 General advice on healthy weight and lifestyle 2 Diet and physical activity 3 Diet and physical activity; consider referral 4 Diet and physical activity; consider referral 105 The pharmacist must agree with the patient about the choice of intervention most adequate according to their preferences and lifestyle. Realistic goals and a plan to achieve this must be drawn up by taking into consideration the patient’s opinion. The pharmacist must provide support and regular follow-up for the patients. General advice provided in the intervention section of the website that can be given to the patients are 1. Healthy weight loss is no more than 0.5 - 1kg/week. 2. Recommended caloric intake for women is 1200-1500 Kcal per day and for men is 1500-1800 Kcal per day. 3. The pharmacist must come to an agreement with the patient to try to achieve a weight loss of between 5-10% of the initial weight or until a BMI of 20-25kg/m2 is reached. The pharmacist can give the following diet advice focused on weight loss to their patients: 1. Eating five servings of fruit and vegetables a day. 2. Daily consumption of legumes, nuts (small amounts) and whole grains. 3. Three portions of fish per week. 4. Avoid eating fast food, foods high in saturated fat. 5. Reducing salt intake. 6. Limit the intake of red and processed meat. 7. Reduce the intake of carbonated and sweetened drinks. 8. Use extra virgin olive oil preferably for cooking. 9. Preferably grilled, steamed, or baked food. Furthermore, pharmacists can provide personalised advice for patients based on the information obtained as part of the VA questionnaire and the patient’s ability to maintain an active lifestyle. Pharmacists should provide personalized advice that consists of 106 recommended frequency, intensity, time (duration), and type of exercise for each individual. CPs must advice against sedentary behaviours. Physical activity counselling in line with the ACC/AHA Guideline on the Primary Prevention of CVD is as follows: 1. At least 150 minutes per week of accumulated moderate-intensity aerobic physical activity or 75 minutes per week of vigorous-intensity aerobic physical activity (or an equivalent combination of moderate and vigorous activity) to minimize the patient’s specific CVR. 2. Longer duration of exercise of ≥10-minute is beneficial to reduce CVRs. Moreover, a patient information leaflet (PIL) was designed by the researcher for visual displays. The best interventional procedures are the ones where verbal information is backed up with written information. This PIL can be printed from the webpage in the “Consejos” section under sub-category “obesidad” as shown in Figure 39. The actual leaflet is displayed in Figure 40. Figure 39: Webpage snapshot of PIL on obesity prevention 107 Figure 40: Patient information leaflet on obesity This PIL can be used as an aid for clinical discussion and to facilitate a person's understanding of the importance of lifestyle modification and risk factor reduction. Photos are used to reach out more to the patient and convince them of the importance of change. It also can assist Consejos nutricionales enfocados a la pérdida de peso 1. Ingesta de cinco porciones de frutas o verduras al día 2. Consumo diario de legumbres, frutos secos (pequeñas cantidades) o cereales integrales 3. Tres porciones de pescado a la semana. 4. Evitar la ingesta de comida rápida, snacks y alimentos con alto contenido en grasas saturadas 5. Reducir la ingesta de sal 6. Cocinar preferentemente a la plancha, vapor o al horno 7. Evitar el consumo de bollería y dulces Déjenos ayudarle a perder peso Consulte a su farmacéutico 8. Utilizar aceite de oliva virgen extra prefentemente para cocinar 9. Limitar la ingesta de carne roja y procesada 10. Reducir la ingesta de bebidas gaseosas y edulcoradas • Pédida de peso saludable (no más de 0.5 - 1kg/semana) • Ingesta calórica recomendada: mujeres (1200-1500 Kcal/día); hombres (1500-1800 Kcal/día) • Recomendamos a realización de ejercicio físico moderado al menos 5 días/semana durante 30’ minutos donde su corazón late más rápido . Características del plan de pérdida de peso ¿Para quién está dirigido este servicio? Adultos (18 años o más) que desean ayuda y apoyo para su control de peso y que estén dispuestos a acudir a citas regulares cada 3 meses de seguimiento. El objetivo es perder entre el 5 y el 10% de su peso corporal actual, hasta alcanzar el objetivo final de reducir su IMC por debajo de 25kg/m2 y/o su perímetro de cintura por debajo de los siguientes valores: • < 94 cm en hombres • < 80 cm en mujeres . El Servicio de Control de Peso para Adultos ofrece apoyo y asesoramiento a las personas que desean perder peso de una manera controlada y saludable. Podemos ayudarle a mejorar su salud y bienestar, así como apoyarle para mantener el peso que pierde. Al bajar de peso puedes mejorar tu salud, bienestar emocional y disminuir el riesgo de diabetes y de enfermedades cardiovasculares. Servicio de Control de Peso para Adultos 108 patients in remembering the pharmacist’s advice after an intervention session in “Protocolos de Intervención” section. 1.15.2 Management of patients with Dyslipidaemia One of the major risk factors associated with CVD is high blood TC. Pharmacist advice on cholesterol management is available in the “Protocolos de Intervención” section on the designed web page; under sub-category “Dislipemia” as shown in Figure 41. Figure 41: Webpage snapshot of pharmacist’s intervention guide for lipid measurement and control Furthermore, a PIL was created by the researcher to improve a visual display for the patient. Also, the webpage gives the pharmacist the ability to print a PIL from the “Consejos” section under sub-category “Dislipemia” as shown in Figure 42. The actual PIL is presented in Figure 43. Figure 42: Webpage snapshot of patient information leaflet for lipid measurement 109 Figure 43: Patient’s information leaflet in relation to hypercholesteremia 110 The pharmacist should offer cholesterol monitoring and management to patients without regard to their age categories. Effective primary CVD prevention requires attention to ASCVD risk factors such as dyslipidemia at any stage of the life cycle. The pharmacist can measure the patient’s cholesterol in a community pharmacy setting with the following consultation skills. Before pharmacist conduct any clinical assessment procedures they must: • Check the expiry dates on all equipment before conducting the measurement. Please note that it is suggested that Percentage of fat mass be measured using a lipocaliber bioimpedance (Tanita Innerscan Dual RD-953) device and TC, HDL-C, LDL-C and TG should be determined by Cobas B-101 (Roche Diagnostics, Barcelona, Spain) to ensure uniformity of data across all service providers. • Wash hands and sterilize with alcohol gel. • The pharmacist must introduce themselves, explain their role and confirm patient identity. • Full explanation of the clinical assessment and procedure involved in measuring the lipid profile. • Gain verbal consent from the person for the pharmacist to perform the TC measurement. • Ask if the patient has any question or concern. • Consider whether the patient likes to have a chaperone with them during the clinical assessment. After the clinical assessment procedures, the pharmacist should: • Advise the patient that the cholesterol check is finished and thank them for participating in the study. 111 • Document the test results obtained. • Clean up the test site by alcohol and sterilized cotton wool, if appropriate. • Dispose of the needle used safely in the yellow needle box. • The pharmacist must wash their hands and sterilize the room for the next patient appointment. All the chemical waste should be disposed in line with the legislation of the Official College of Pharmacists of Madrid with an agreement signed with SRCL Consenur company. The waste management form for CP in Madrid can be found in the Annex V. • Check with patients if they have any question. The pharmacist can place the patient’s risk into categories of normal, high and very high risk by considering the patient’s clinical metric and age with special emphasis on abnormal LDL-C level in accordance with the 2019 ACC/AHA Guideline on the Primary Prevention of CVD and 2020 ESC/EAS Guidelines for the management of dyslipidaemias (46, 264) . According to the patient’s risk, the pharmacist can decide on the appropriate course of action. Figure 44 states the TC, LDL-C, HDL-C, and TG level which indicates the patient’s risk stratification. And Figure 45 plans out an appropriated course of action. Figure 44:TC, LDL-C, HDL-C and triglyceride level and related risk of CV 112 Figure 45: Pharmacist course of action depends on patient’s LDL-C, total cholesterol, HDL-C, triglyceride level and other comorbidities 113 The pharmacist can give the following dietary advice focused on cholesterol control to their patients: • Recommend an intake of at least 2 portions of fish a week, including a portion of oily fish (such as herrings, sardines, mackerel, or salmon). A portion is measured to be about 140 g (a fillet of fresh fish or a small tin). • Eating at least 5 portions of fruit and vegetables a day. A portion is about 80 g (for example, an apple or 3 heaped tablespoons of peas). • Avoid products containing saturated fat (for example, fatty meat, whole fat dairy such as margarine and cheese). Substitute these with mono-unsaturated fats (such as olive oil) and polyunsaturated fats (e.g., corn oil and sunflower oil). • Avoid consumption of sweetened products, processed foods. • Recommend the patient prepares the meals in the oven or grill instead of frying them. Also suggest they use healthy ways of cooking by adding flavour using spices, herbs, and lemon juice instead of using buttery, cheesy or creamy sauces, which tend to be high in fat. • Suggest patients use wholegrain food including wholegrain rice and pasta. • Promote the use of at least 4 to 5 portions of unsalted nuts, seeds, and legumes (such as peas and beans) a week. 1.15.2.1 Referral to doctor Patients with two or more elevated TC parameters (see below) and existing ASCVD risk, should be referred to the doctor (letter is presented in Figure 37). Þ Patient with TC>240 mg/dl. Þ Patient with LDL-C> 160 mg/dl. 114 Þ Men with HDL-C < 35 mg/dl and women with HDL-C < 40 mg/dl whose lifestyle did not elevate the HDL-C parameter. Þ Patient with TG level of > 150 mg/dl. 1.15.3 Management of patients with diabetes Pharmacist advice on diabetes management is shown in the “Protocolos de Intervención” section under sub-category “Diabetes” as shown in Figure 46. Figure 46: Webpage snapshot of pharmacist’s intervention guide for diabetes management and control Printable PIL to provide the patient a visual display on diabetes control is also available on the webpage. The PIL is available from the “Consejos” section under sub-category “Diabetes” as shown in figure 47. The actual PIL is also presented in Figure 48. Figure 47: Webpage snapshot of patient information leaflet for diabetes intervention 115 Figure 48: Patient’s information leaflet in relation to diabetes management and control 116 Although this interventional service is focused on improving CVR factors, diabetes is highly linked with increasing of CVD in the general population as a separate risk factor or in combination with other comorbidities such as CKD. Therefore, CPs can offer a personalized intervention to patients with elevated blood glucose highlighted by the VA intervention. The WHO has divided diabetes into four categories. Our intervention is going to be focused on T2DM and patients with diabetes due to the use of other medicines (glucocorticoids, thiazides, beta-blockers, nicotinic acid, ciclosporin, tacrolimus, atypical antipsychotics, and protease inhibitors) or comorbidities (pancreatitis, neoplasia and cystic fibrosis hyperthyroidism and genetic syndromes such as Cushing’s syndrome). The pharmacist should carry out an appropriate screening in individuals in one of the categories below to aid early diabetes detection and time management. The categories of people in whom it may be beneficial to screen for diabetes include the following: 1. Patients with a family history of diabetes in first degree relatives. 2. Patients in ethnical groups with a higher prevalence of diabetes. 3. Overweight (BMI>25 kg/m2) or obese (BMI>30 kg/m2) patients. 4. Patients with abdominal obesity (waist circumference >80 cm in women and >94 cm in men). 5. Patients over 40 years of age. All diabetic and pre-diabetic individuals should exercise regularly, stop smoking and improve their diet as shown in Figure 49. 117 Diabetes control • Adopt a diet rich in fruit and vegetables at least 5 portions a day. • Suggest patient cuts down on saturated and trans fats (butter, margarine, cheese) and chooses unsaturated & monounsaturated fats or oils (olive oil), more than 2 portions of oily fish a week and low-fat dairy products. • Advice on reduction of salt intake to less than 6g per day. • Limit sugar and sugary foods. Avoid soft drinks with added sugars. • Restrict the consumption of fruit with a high glycaemic index: grapes. • Advice on starchy carbohydrate with each meal; lower glycaemic index foods are preferable, including pasta, basmati rice, grainy breads, porridge oats. • Advice on daily activity. Total of 150 minutes of moderate- intensity activity, or 75 minutes of vigorous activity, in bouts of 10 minutes or more over a week. • Encourage patient to lose 5% to 10% of their weight. Low Risk Drinking Guidelines • Advice on no more than 14 units a week on a regular basis. • Advice on spreading drinking evenly over 3 or > days • Encourage patient to have drink- free days • Suggest BMI <25kg/m2 • a waist size of <80 cm in women and <94 cm in men to prevent abdominal obesity Figure 49 : Diabetes control protocol 118 1.15.3.1 Referral to doctor The following group of patients with two or more elevated glucose parameters and existing symptoms should be referred to the doctor. Þ Patients with FBG ≥7.0 mmol/L (126 mg/dL). Þ Patients with HbA1c ≥6.5% (48 mmol/mol). Þ Patients presenting excessive osmotic diuresis (polyuria), extreme thirst (polydipsia), tingling hands, visual disturbances, or recurrent genital thrush due to candidiasis. Þ Diabetic patients who report recurrent candidiasis, bacterial urinary tract infections, foot ulceration due to lack of sensation in the toes, feet, legs (peripheral neuropathy), erectile dysfunction or change in vision, should be investigated for medication compliance, given information on lifestyle, and then referred to the doctor. Þ The pharmacist should note that referral in suspected diabetes individuals is crucial. Confirmation of the diagnosis should be based on plasma glucose samples measured by the laboratory as it is more accurate than the capillary samples. Þ The pharmacist should provide information and advice on lifestyle to patients with FBG of 6.1 mmol/L – 6.9 mmol/L (110 – 125 mg/dl) and monitor them frequently. Pre- diabetes is a state of increased risk of progressing to diabetes. It increases patient’s risk of developing CVD and CKD. There are two categories, impaired glucose tolerance and impaired fasting glucose. Pre-diabetes should also be referred to the doctor to re- affirm the diagnosis and provide early management. 119 1.15.4 Smoking cessation services Pharmacist advice on quitting smoking is shown in the “Protocolos de Intervención” section under sub-category “Deshabituación Tabáquica” as shown in Figure 50. Figure 50: Webpage snapshot of pharmacist’s intervention on smoking cessation A printable PIL to improve the visual display on smoking cessation for patients is also available on the webpage. The PIL is available from the “Consejos” section under sub-category “Deshabituación Tabáquica” as shown in Figure 51. Figure 51: Webpage snapshot of patient information leaflet on smoking cessation 120 The actual PIL is also presented in Figure 52. Figure 52: Patient information leaflet in relation to diabetes management and control 121 1.15.4.1 Pre-quit smoking Smoking is influenced by the patient’s environment and social habits therefore smoking cessation services should be offered as part of a community-based program which is more accessible for patients. 30 seconds of CP time can save a patient’s life and transform someone ‘s future for the better by preventing premature death caused by lung cancer or CVD. The power and effectiveness of the three simple steps of Ask, Advice and Act campaign was first stablished by the SNS in the United Kingdom has been proved in clinical practice. Pharmacists initially need to establish if the patients are active smokers. It can be difficult to build a rapport with patients and not make them feel not judged. However, CPs are an active part of the community and patients who are smokers trust them. Therefore, building on that relationship and reaching out to smokers to provide services can be easier. The pharmacist can then record the smoking status of the patients on their system. It is essential to explain the health benefits of quitting smoking for the patients. Clarify that research has shown that the best method to quit smoking is to receive a combination of support and pharmaceutical treatment (e.g. nicotine replacement therapy). Discuss further that the choice is theirs, but they can always receive personalized smoking cessation services and support free of charge from the community pharmacy. Finally ask if that is something that interests them, and if they would like to book an appointment. In the case where the patient shown interest, set a date for them to quit smoking. Take note of the date, patient name and their telephone number in a confidential manner. The pharmacist is to give the patient a call one day prior to the appointment to ensure their attendance. On the initial visit explain to the patients that weekly contact of the pharmacist with patients is extremely important. They will have six support sessions over six weeks, once before quitting, once on the day they quit, and then 122 once a week for four weeks after that date. Figure 53 demonstrates the suggested protocol for smoking cessation services. Figure 53: protocol for smoking cessation services Behavioral support requires creating an understanding in patients about the pathophysiological nature of nicotine dependency in simple words. Correct understanding of nicotine dependency can further support patient in quitting. It will create a realistic expectation of what an attempt to give up will involve. On the initial visit it is advised that CPs establish the patient pack history, in Spanish “Historia de fumador”. In order to support the patient fully the pharmacist is required to understand the patient’s past and current history of smoking and their previous attempts to stop smoking. The CPs can ask the following questions: 1. When did you first start smoking? 2. How many cigarettes a day do you usually smoke? Initial visit •Preparation visit. Establish a pack history, meaasure motivation level by Richmond test, dependency level by Fagerström Test, CO2 level by carbon monoxide breath test , determine anthropometric values and BP. agree with patients on a date to stop smoking. Explain treatment options and advice patients on craving symptoms. Second appointment •Patient quits smoking on this day. Advice on pharmaceutical treatment available (e.g. nicotine patch) Supportive sessions • 3 – 8 days after the initial visit •15 days after the initial visit •30 days after the initial visit Follow up visits •6 months after the initial quitting date •1 year after the initial date they stopped smoking 123 3. What do you smoke and where do you buy them? 4. How many times have you tried to quit smoking before? In the case whose patients who have had a previous attempt to quit smoking, it is essential to establish if they have tried any specific medication and their experience related to using that medication (e.g., rash with nicotine patch). This will allow the pharmacist to evaluate whether the smoker has used medication correctly in the past, and what expectations they have of the medication. The pharmacist can ask: 1. What medication have you used to stop smoking and how was it? In some cases, patients have failed attempts to stop smoking. The CPs must ensure the patients with previous failed attempts demonstrate their commitment to quit smoking and it will increase the chance of quitting smoking this time. Finally, the CPs must consider that the attempt to stop smoking and behavioral support of the patients may be influenced by the patient’s comorbidities such as a history of depression. In patients with a history of mental health disorders, general health advice and support should be paired with referral to a doctor in the case of worsening of mental health symptoms. Thereafter, complete a short questionnaire to measure the patients’ levels of motivation and cigarette dependency, using the brief Richmond motivational questionnaire shown in Figure 54 as on the website. Research has shown the higher the score of the patient’s Richmond test, the greater the chances of success. 124 Figure 54: Richmond test Thereafter, the CP must assess patients’ nicotine addiction level. The Fagerström Test for Nicotine Dependence (FTND) can be used as a tool to establish the level of patients’ dependency. This test can be seen as presented on the website in Figure 55. This test includes questions such as: 1. How many cigarettes per day do you smoke? 2. How soon after waking do you have your first cigarette of the day? 3. Do you wake up in the middle of the night to smoke? 125 Figure 55: Fagerström Test for Nicotine Dependence (FTND) 1.15.4.2 Carbon monoxide breath test To increase the patient’s level of motivation and assess their success in their attempt to stop smoking, the carbon monoxide breath test at every visit is scientifically proven to be highly motivational. Carbon monoxide (CO) has a short half-life and is usually undetectable around 24 hours after the last cigarette. Smokers may underreport their smoking habits; therefore, a quick exhaled air test can confirm this. The CP must follow the following procedure when using the carbon monoxide device: • The patient must be instructed to inhale deeply, hold their breath for 15 seconds, then exhale slowly aiming to completely empty the lung. • The results are instantly available on monitor screen. The CO measuring kit gives a CO reading in parts per million (ppm). 9 ppm2 is generally considered to be the highest 126 acceptable level of CO in the exhaled breath of an individual who reported not smoking. NICE recommends that success in stopping smoking should be validated by a CO monitor reading of less than 10 ppm2 at the four-week point after the quit date. A patient with the following may demonstrate a higher CO result despite absence of smoking: 1. Chronic obstructive pulmonary disease levels up to 11 ppm2. 2. Exposure to CO fumes from a faulty gas boiler or car exhaust. 3. Lactose intolerance where the high reading is a consequence of consuming dairy products. 4. Passive smoking. 5. Unusually high ambient CO concentrations due to air pollution. • The CP must sterilize the device after each patient and use a fresh mouthpiece. The device must be calibrated initially and monthly thereafter unless it is a device that does not require a calibration. Figure 56 demonstrates the flow chart on the website on CO carboxyhaemoglobin (CO-Hb) exhaled in 15 seconds and its relationship with cigarette consumption. Figure 56: Direct relation between carbon monoxide (CO) carboxyhemoglobin (CO-Hb) exhaled in 15 second and smoking 127 The CP should then measure the patients’ anthropometric values including BP, HbA1c and record the result in a confidential manner for the follow-up visit. The quitting date should be agreed with patients. The pharmacist should explain to the patients that they might experience depression, irritability, restlessness, difficulty concentrating, increased appetite, cough, constipation, weight gain, and in some cases mouth ulcers. Most of these symptoms can be resolved by using drugs such as NRT, bupropion or varenicline, though they might also completely disappear after a few weeks. However, increased appetite may last longer. Advice on healthy diet should also be offered as well as an information leaflet. The hydrocarbon agents in cigarette smoke stimulates a liver enzyme responsible for metabolizing drugs such as antipsychotics, antidepressants, and anxiolytics. Therefore, the pharmacist should refer the patient on this medication who quits smoking to a doctor to adjust the dose of their medication to achieve the same drug level and therapeutic effect. This process is explained clearly on the website as demonstrated in Figure 57. Figure 57: Demonstrate the smoking cession protocol for initial visit 128 Possible first line therapeutical options for patients could be: • Varenicline (Champix®) • Nicotine replacement therapy (NRT) • Transdermal Patches • Gum • Lozenges • Sublingual • Inhaler • Bupropion Þ It is important to note that patients who require a medical prescription for varenicline or bupropion should be referred to the doctor. One or a combination of these treatments can be used for smoking cessation purposes. The treatment choice depends on patient’s preference but mainly on the level of dependence (e.g., night crave) shown in Figure 58 and Table 8 on the website. Figure 58: Patient treatment options according to their level of dependency 129 Table 7: Suggested regimen for therapeutical treatment protocol In addition, pharmacists are encouraged to reinforce the positive health outcome of the smoking cessation to the patients to increase motivation in quitting smoking and improve their adherence to medication. To do so, the following advantages of stopping smoking might be useful (Figure 59). Figure 59: Exhibit the advantages of stopping smoking During the follow-up visits it is suggested that the pharmacist follow the protocol shown in Figure 60. 130 Figure 60: Smoking cessation protocol for the community pharmacist After a month of abstinence from smoking, it is advised that the pharmacist ask patients to visit the pharmacy after six months and a year. This is intended to assess how effective the community pharmacy services are as well as measure patients’ success in quitting smoking. Figure 61 shows the guideline to follow on the 6 month and one-year follow-up visit. Figure 61: Protocol for follow up on STOPPING smoking services at 6 months and one year Measure CO level, weight, BP, HbA1c in diabetic patients Advise patients on risk of relapse and suggest possible ways to avoid it. Reinforce the positive impact stopping smoking has on their health. (CO measure to motivate patients) Discuss difficult situation that arises (relapse or attempts) Evaluate patient medication adherence (possible side effect) Confirm patient abstinence Draw positive conclusion by using vascular age calculator and demonstrating how one year stopping smoking improve the vascular age by 10 years. Do not blame patients if they had a relapse offer help and advice again Ask patients if they have any relapse or temptation to smoke Reinforce the positive impact this had on patient. Confirm abstinence from smoking (use CO measure and patients’ self-report) 131 1.15.4.3 Remote consultation for smoking cessation Although as part of the essential services provided by CPs, the pharmacy team have been in direct contact with patients, the current state of the pandemic in Spain demands the reduction of pharmacist and patients’ face-to-face interactions. CPs must continue to provide education and support via healthy lifestyle intervention to patients to reduce CVD. Smoking has been identified as one of the significant risk factors for COVID-19. Therefore, patients may need smoking cessation services more than before. Therefore, pharmacists must continue to provide this service to patients by phone or pre-arranged video-based communication. 1.15.5 Medication reconciliation One of the main reasons for patients’ uncontrolled BP, TC or worsening diabetes can be lack of medication compliance. CP can play a huge part in improving patients’ adherence to their medication, detecting unwanted side effects, and referring the patients to the doctor for alternative treatment options. Pharmacist advice on medication adherence is shown on the “Protocolos de Intervención” section of the website under sub-category “Adherencia al tratamiento” as in Figure 62. Figure 62: Webpage snapshot of pharmacist’s intervention on medication adherence 132 The different types of medication review that can be performed by the CP are the following: 1. Providing information to the patient on their medication including indications, correct use, side effects. 2. Refer the patients to the doctors to obtain an alternative medicine due to unwanted side effects, ineffectiveness of medication or polypharmacy. 3. Notification to the pharmacovigilance system any safety incidents such as a life- threatening or serious side effects. 4. Medication optimization by ensuring medicines provide the greatest possible benefit to the patient by medication review. It is suggested the pharmacist performs a structured medication review by taking a patient- centred approach. A tool such as the Morisky-Green test provided on the website (Figure 63) can be used to establish the level of a patient’s medication compliance. Figure 63: Morisky-Green test 133 Morisky Green test consists of four item tests. The patient who answers yes to the first two questions and no to the following two are compliant with their treatments. This test can be accessed from the “Protocolos de Intervención” section as shown in Figure 64 under “Descargar test de Morisky-Green”. Figure 64: Adopted Morisky Green test for assessing patients’ medication compliance Another available and valid test such as the Brief Medication Questionnaire (BMQ) may also be used to access patients’ compliance, but it may take longer. CPs continually face lack of time to perform patient-centred intervention, therefore this project has adopted a short version of the Morisky Green test to facilitate the pharmacist service delivery. 1.15.6 Hypertension control Hypertension is a silent cause of cardiovascular morbidity and mortality among patients. The protocol for CPs’ intervention on hypertension is presented in the “Protocolos de Intervención” section of the website under sub-category “Hipertensión” as in Figure 65. 134 Figure 65: Webpage snapshot of pharmacist’s intervention on hypertension In this section pharmacists are advised to target SBP below 120 mmHg and DBP below 80 mmHg in the patients. Furthermore, the following advice are included in this section to assist patients in maintaining optimal BP: 1. The pharmacist can advise patients to maintain the DASH diet which is known to lower BP. This includes intake of five portion of fruit and vegetables daily. A diet rich in whole grains is also recommended as is consumption of lean meats (chicken, turkey), fish and pulses instead of red meat. Reduction in daily salt intake to <6g daily and reduction in daily sugars and saturated fat intake are recommended. Pharmacists must advice the patient to avoid alcohol or reduce their consumption to less than 14 units per week. Furthermore, advise patients to avoid salty snacks and processed foods. Daily intake of at least 2L of water can improve their kidney function and in turn reduce their BP. Research has shown that keeping a daily food diary by patients means 135 pharmacists can provide continuous and personalised support to improve the patients’ diet and reduce patient’s BP greatly. 2. Pharmacists must advise the patient to maintain an active lifestyle by performing at least 150 minutes per week of accumulated moderate-intensity aerobic physical activity or 75 minutes per week of vigorous-intensity aerobic physical activity (or an equivalent combination of moderate and vigorous activity) to minimize CVR. Exercise of ≥10-minutes can reduce CVRs. Exercise in geriatrics must be personalised according to their age, exercise experience, functional capacity, safety, co-morbidities, and lifestyle habits. According to the European guidelines on sport cardiology, the elderly population are advised to perform aerobic, strength or flexibility and balance exercises as in Table 9 below. Table 8: Exercise protocol in the elderly Type of exercise Frequency Intensity Duration Aerobic Þ Moderate exercise (e.g., walking or riding a bicycle on ground level) for 5 days per week Þ Vigorous exercise (e.g., jogging or running, swimming fast) for 3 days per week • 5-6 points from 10-point Borg scale • 7-8 points Borg scale 30 minutes per day for moderate or at least 20 minutes for continuous exercise Strength training (all major muscle groups) At least twice a week 8-10 exercise 10-15 repetitions Flexibility and balance Twice a week 3. The pharmacist can advise patients to stop smoking. 4. Patients diagnosed with BP who age on medications for uncontrolled hypertension, can benefit from medication optimization and review to increase adherence to 136 treatment. This is an opportunity for pharmacists to identify any unwanted ADRs and increase patients’ understanding about the state of their health. 5. The pharmacist can demonstrate the benefit of the above healthy lifestyle in patients by performing monthly BP monitoring. 6. Pharmacists must refer the patients to a doctor if SBP ≥ 140 mmHg, DBP ≥ 90 mmHg by considering the patient’s age and other contributing factors (in at least 3 consecutive measurements). The pharmacist can provide the PIL to patients to increase their understanding of their state of health and encourage habitual changes. This PIL designed by the researcher (Figure 67) can be found in the “Consejos” section under sub-category “Hipertensión” as shown in Figure 66. Figure 66: Webpage snapshot of patient information leaflet about hypertension 137 Figure 67: Patient information leaflet in relation to hypertension management 138 1.15.7 Advice on reduction of alcohol consumption Excessive alcohol intake over a long term can result in poor cardiovascular health outcomes such as an increase of heart rate, high BP, weakened heart muscles causing heart failure, irregular heartbeat, and stroke in addition to alcohol-related accidents and hospital admission. The community pharmacy is part of the primary care umbrella, with high accessibility to patients due to its unique location, based in the heart of the community. Intervention on reduction of alcohol consumption is presented in the “Protocolos de Intervención” section of the website under sub-category “Consumo de alcohol” as in Figure 68. Figure 68: Webpage glimpse of pharmacist’s intervention on reduction in alcohol use One unit of alcohol can be defined as: 25 ml of spirit ½ pint of beer ½ glass of wine 139 Figure 69: Guide to unit of alcohol definition The pharmacist must take every opportunity to talk to the patient about safe drinking habits. Pharmacists can display posters or patient information leaflets in the pharmacy to encourage patients to have a short conversation about this major public health issue. Pharmacists must use the evidence-based preprepared conversation to discuss alcohol consumption with patients. Pharmacists can start by explaining the negative impact that drinking of alcohol drinking has on health as shown in Figure 70. They can use three simple questions to give a score to patients’ alcohol consumption as in Table 10 to motivate and support the individual to think about changing their drinking behaviour. CPs should provide advice to the patient with a score higher than 5 using the PIL available in the “Consejos” section of the website under sub-category “Consumo de alcohol” as in Figure 71 and Figure 72. Furthermore, patients with a score higher than 10 should be referred to the addiction center or medical doctors. 140 Figure 70: Alcohol misuse health implications Figure 71: Webpage snapshot on patient information leaflet about alcohol consumption Heart disease High blood pressure Liver Cirrhosis & liver cancer & Pancreatitis Reduced fertility Stroke & depression Harm to the fetus Breast cance r Cancer of mouth & throat, oesophagus & larynx 141 Never Monthly or less 2-4 times per month 2-3 times per month More than 4 times per week How often do you have a drink containing alcohol? 0 1 2 3 4 0-2* 3-4* 5-6* 7-8* 10+* How many units do you drink on a typical day when you are drinking? 0 1 2 3 4 Never Less than monthly Monthly Weekly Weekly Daily or almost daily How often have you had 6 or more units if female, or 8 or more if male, on a single occasion in the last year? 0 1 2 3 4 *Score 0-4 is associated with low risk *Score 5-10 is associated with medium CVD risk give patient advice and PIL *Score above 10 is associated with high risk provide support and advice, refer patient to doctor Table 9: Scoring system to quantify the patients’ risk based on their weekly alcohol consumption 142 Figure 72: Alcohol consumption Patient information leaflet 1.15.8 Other CVD intervention The material provided for pharmacists on the website and the eHealth interactive tool in relation to risk factors for CVD development is an endless list and pharmacists do not have the time or adequate tools to possibly provide advice on all. However, some other risk factors such as mental state and stress level (Figure 73), woman’s health (Figure 74) and healthy aging (Figure 75) are also covered on the website in the form of educational material for the patient. Pharmacists can provide advice and support on these matters to the patients to improve their cardiovascular health. 143 Figure 73: Stress and mental state patient information guide 144 Figure 74: Women & cardiovascular health patient information guide 145 Figure 75: Aging and cardiovascular health patient information guide 146 1.16 Website validation by the community pharmacist A total of 24 pharmacists from Madrid were included in the pilot study, of whom 54% were female as shown in Figure 76. Figure 76: Gender distribution for vascular age pilot participants. Data are expressed in percentage of the total number of participants. Most participants were in the 20-29 (50%) age group (Figure 77). Figure 77: Age distribution for vascular age pilot in community pharmacies. Data are expressed in percentage of the total number of participants. The gender distribution of the participants according to their age group is shown in Table 11. Table 10: Age and gender distribution for vascular age pilot participants Age categories (years) Men n (%) women n (%) 20-29 8(33%) 4(16%) 30-39 1(4%) 3(12%) 40-49 1(4%) 3(12%) 50-59 1(4%) 2(8%) 60-69 0 1(4%) Total 11(45%) 13(54%) Data are expressed in frequency and percentage (in brackets) of the total number of participants. 147 66% of the participants had prior training or been accredited for the provision of PCS (Figure 78). Figure 78: Ratio of community pharmacists accredited for the provision of pharmaceutical care. Data are expressed in percentage of the total number of participants. Among the 24 participants, only six (25%) have claimed to be actively involved in providing PCS, of whom 16 (66%) were formally accredited in addition to their pharmacy degree for provision of pharmaceutical care and 9 (37%) were trained in motivational interviews with some overlap between these two groups. Eleven pharmacists with training in the pharmaceutical care plan did not participate in the provision of interventional services. Six pharmacists with training in motivational interviews did not provide services to the patients. The relation between CPs training in pharmaceutical care or motivational interviewing and their true participation on a daily basis in provision of PCS can be seen in Table 12. Table 11: Stratification of pharmacists according to the age group, level of training and provision of pharmaceutical care Age Provision of pharmaceutical care (n) Trained in pharmaceutical care* Trained in motivational interviews * 20-29 3 7 4 30-39 2 4 3 40-49 1 4 2 50-59 0 1 0 60-69 0 0 0 * 9 pharmacists were trained in both pharmaceutical services and motivational training. Data are expressed in frequency. 148 Training bodies used by CPs varied, 28% of them received pharmaceutical care training in the form of an internship. The distribution of the various accreditation is shown in Figure 79. Figure 79: Community pharmacist’s various form of accreditation for providing pharmaceutical care. Data are expressed in percentage of the total number of participants. The majority of these courses are provided by accredited universities across Spain (57%) or by the Official Associations of Pharmacists in Spain (14%) as demonstrated in Figure 80. Figure 80: Accreditation bodies for pharmaceutical care across Spain. Data are expressed in percentage of the total number of participants. In response to the open questions (Appendices I), most of the CP claimed that it is straightforward to use (95%). They all also reported the design and protocols to be easy to follow and use (75% strongly agree, 25% somewhat agree). Notably, all 6 pharmacists who provide pharmaceutical care for patients strongly agreed the website is easy to use and simple to understand. 70% strongly agreed and 29% somewhat agree that the patient information designed is appropriate in terms of language and content. 149 In terms of protocols used to control the various risk factors in improving VA, on a scale of 1 to 5, 54% gave the score of 5 (all providers of PCS and 37% gave the score of 4, which reveals the appropriate use of up-to-date protocols. Nevertheless, the participants were given the opportunity to express their view in the last section of the survey. In terms of the VA questions, 62% of pharmacists, all in the PCS provider group, strongly agreed that the time to fill out the VA questionnaire is reasonable. On a scale of 1-5, 62% gave the score of 5 and 29 % gave the score of 4 for the clarity and adequacy of responses to the VA survey. It is noteworthy that 87% strongly agreed and 12 % somewhat agreed to recommend the VA tool to their colleagues to improve a patient’s vascular health. Interestingly all regular provider of PCS (n=6) claimed that they recommend the website to their colleagues. We also explored the barriers pharmacists face in providing such services to the patient and their perception towards providing pharmaceutical services. The majority of the respondents claimed that providing pharmaceutical services to obtain VA has the potential to improve their sense of job satisfaction (62% said it will significantly improve 33% it will slightly improve). Furthermore, 83% believed that their professional image with patients will improve significantly and 12% said slightly. On the other hand, a large number of participants thought that the VA tool may improve the pharmacist’s relation with medical doctors, 37% said significantly, 37% claimed slightly although some alleged that it will not make any differences (20). Very interestingly 79% claimed that VAC will improve pharmaceutical care delivery. The details of the community pharmacies responses in relation to a patient’s visiting time at the CP in relation to VAC can be found in Figure 81. 150 Figure 81: Patient’s visiting time from community pharmacy with vascular age services. Data are expressed in percentage of the total number of participants. It is noteworthy most of the participants claimed that VA will improve the quality of the cardiovascular care significantly (75%). However, a majority of the pharmacists were concerned that VA interventional services may increase the community pharmacy workload as shown in Figure 82. Figure 82: Relation between community pharmacists’ increase in workload and vascular age intervention. Data are expressed in percentage of the total number of participants. In the final section of the questionnaire, 79% of the pharmacists believed that the VA tool will help significantly to improve the patient’s cardiovascular health and 20% said slightly. Also, 66% responded that collaboration between pharmacists and doctors will help reduce the health care costs for both the patient and the health care system significantly and 33% said slightly. In conclusion 79% of the CPs who participated in the VA study strongly believed that this tool can be a key component in cardiovascular health promotion services. 151 1.17 Reflexive thematic analysis results: An open-ended final question gave the participants the possibility to express their opinion to obtain an in-depth insight. The question was “Do you have any possible suggestions regarding the questionnaire or parameters to be included as part of this CP's intervention?” or in Spanish “¿Tiene alguna posible sugerencia en relación con el cuestionario o los parámetros que se incluirán como parte de la intervención de este farmacéutico comunitario?”. Fifteen participants expressed their opinion in detail and others said there is nothing extra they would like to add. The reflective thematic analysis with the NVivo qualitative data analysis software; QSR International Pty Ltd. Version 12 was used for evaluating the open-ended question. Initially common words were used for coding. Thereafter, what is known as a “fully realised” coding was used. That involves using a shared meaning underpinned by a central concept from which various themes will emerge (Figure 83). Figure 83: Reflective thematic analysis for qualitative research The word cloud generated from the pharmacists’ responses is illustrated in Figure 84. Familarizati on •Responces were read •Codes were developed according the the literature review or close ended questions used in the qualitative section (Q1-Q25). Meaning • Domains and sentences were summerised. Code •Open codes (common words) were merged into categories. Themes •The categories was then used to create themes. 152 Figure 84: Vascular age pilot from community pharmacist’s viewpoint world cloud 153 DISCUSSION 154 Discussion CVD with a 28% prevalence, is one of the top NCDs and causes of mortality in Spain (7). Obesity, smoking and high BP are among the most common risk factors in this Mediterranean country (36). The INTERHEART study stated that 80% of the premature death due to CVD are preventable by the adoption of a healthier lifestyle and risk factor prevention (265). One of the key problems with engaging patients in CVD prevention programmes is the lack of a clear perception about true CVR factors. Patients are often found to underestimate their risk and have difficulty understanding absolute risk percentage (266). In response to this challenge the VA concept was introduced. VA was proven effective in communicating a patient’s true risk and better comprehended by patients. It is widely used by healthcare providers to inform patients and motivate them to participate in adopting a healthier lifestyle (174, 267). A greater comprehension of risk and protective factors by which they may influence the development of CVD is a first step to prevention. The conventional VAC normally uses the population specific risk score along with patient’s age, gender, ethnicity, BP, TC, comorbidities such as AF, CKD, rheumatoid arthritis, diabetes, etc., smoking status, BMI, family history and medication history to provide an estimation for the VA of the patients (153). However, more in-depth assessment of the literature provides evidence of other possible CVR factors which were not explored by the Spanish scientists in cluster form before. The explicit objective of this thesis was to create a patient-centred tool to be used by CPs to estimate the patient’s VA and in turn analyse risk factors in patients. The current existing VA tools across the world does not incorporate all risk factors that lead to developing CVD, neither do they consider the protective factors that slow down vascular ageing. However, the questionnaire created for this thesis tried to incorporate the risk factors that can be targeted by the CP services. Although this list may not be inclusive and future scientific advancement 155 may shed light on additional factors the author believes that they should not be dismissed in the risk calculation process. Pharmacists and other HCPs are responsible for the health information they provide to patients and therefore an incomplete risk calculation might result in over or underestimation of the results. Furthermore, this research aims to facilitate the CP’s service delivery in Spain by providing a common training framework for the CPs and patients in Spain. Clear standard operating procedures, a safe, confidential, and reliable platform to record patient data and a clear follow-up procedure based on patient medication history and biochemical results was created. The author admits that previously in Spain some methods such as Dáder or Pharmafit existed, but this thesis and research is hoping to put all the tools and more together, so pharmacists can benefit from them on a national level. To meet the first objective of this thesis, an accessible tool in form of a website has been created to be used by CPs to develop a better understanding of patient’s CVR factors. Regarding the VA tool, in the first section, demographic data was explored. The British version of the heart age calculator considered inequalities presented by a patient’s unequal economic, environmental conditions (employment status, education level) and geographical location that subject the individuals to a different political and economic climate (urban and rural living location). The Public Health service in England made this data widely available in the form of a “Health Inequalities Dashboard” map. This Dashboard can be used to dictate an efficient use of health resources including pharmacists as viable health workers. It can further help in future planning of CVD preventative programmes in poor economic areas (268). The unique Spanish healthcare model with 17 distinct states and various legislative powers in relation to the operation of community pharmacies and the CVD preventative health policy arises health inequalities throughout Spain which makes it worth exploring to detect areas with greater needs. 156 A pool analysis was identified that accessed 11 studies conducted in the first decade of the 21st century, in Spain. They identified that CVD prevalence is greater in the Islas Canarias, Extremadura, and Andalucía. However, this pool analysis which was performed in 2011 did not link this high rate of CVD with the socioeconomical status in these regions which may initiate future planning of health measures (269). Therefore, new data is required in respect of CVD prevalence specially post COVID-19, at different local levels in Spain. To fill the gap in the existing knowledge, the demographic section of the questionnaire explored the patient’s education level and their location. The author was hoping to link this data with variable VA in the Spanish cohort to assist future planning of community pharmacy interventional services. Another limitation found in the existing VAC across the world is that it is normally performed without considering disparities in sexual orientation. This method of risk estimation is biased since it overlooks the additional risks that a homosexual individual may have by taking hormonal therapy. New investigation revealed that gay and bisexual men had significant elevations in DPB, and pulse rate. Also, lesbians and bisexual women had more risk factors for CVD including smoking, heavy alcohol consumption, and higher BMI (270). Therefore, a gender-stratified VA questionnaire was developed. However, some individuals might hesitate to share their sexual orientation with the HCPs due to fear of discrimination, embarrassment, breaches in confidentiality and more factors beyond scope of this discussion (271, 272). Expert advice HCPs to provide this opportunity for the patients to disclose information about sexual orientation using an open and accepting language. Further, provision of services in a consultation area where patient’s voice cannot be overheard by others can facilitate this moment of disclosure (271). Prior work has suggested that the anthropometric and biochemical values, smoking history, exercise, alcohol intake, family history of CVD, comorbidities, medication use and finally diet 157 can negatively influence VA (153, 174) . These aspects were included in our VA questionnaire. In addition, there is growing evidence on the benefits of maternal health on CVD outcome. New scientific advancement has revealed that the short-term beneficial effect of breastfeeding for more than six months in women leads to improvements in metabolic health, lipid & glucose homeostasis, and insulin sensitivity (273, 274). On the other hand, breast feeding is associated with a lower risk of diabetes, hypertension, obesity, and metabolic syndrome and (275-277). Similarly, evidence showed that breastfeeding ≥5 months in at least one pregnancy seemed to decrease the risk of coronary artery disease in later life (277).These protective aspects were incorporated in the VA questionnaire but a longitudinal study over a large period of time can shed light on the number of years these factors add to the VA. One of the other elements observed in Spanish society is a midday nap. Evidence suggests that a habitual long siesta (> 60 min/day) increases the risk of CVD and metabolic disorders and the risk of mortality compared to the daily short and infrequent siesta, which was considered by the authors (278). Further, chronic stress has been linked to higher prevalence of CVD (279). This factor has also been included in the questionnaire since the CPs can provide counselling to patients on OTC medicines for stress or refer the patients to the appropriate HCPs for stress management (280). Another key determinant of vascular health which is often missed out is individual level of social interaction. Studies have found that social interaction protects individuals from all-cause and CVD-specific mortality and reduces the risk of CVD incidence (281). In conclusion, one cannot attempt to solve and eradicate CVD unless by clearly defining the problem from the original, although the author does not claim that the VA questionnaire is inclusive of all causes. However, it can be a steppingstone and a sound theoretical framework for future advancements. 158 The feasibility of the provision of VA services was assessed by looking through existing literature. A systematic review showed that pharmacist interventions in CVR reduction can significantly improve the cardiovascular health in patients by improving medication adherence, reducing BP, TC, glucose level and weight management. More research studies are needed to explore the community pharmacy interventional services on smoking cessation and alcohol consumption. Furthermore, identified intervention varied in data collection and methodology. Therefore, uniform protocols can assist in drawing a better conclusion on the impact of CP intervention on improving cardiovascular health in Spain. The systematic review of the literature also revealed that, in the past few years the traditional model of community pharmacy practice has shifted from dispensing only towards delivering a more comprehensive services to improve population health. This historical shift can be a steppingstone for future changes in the pharmaceutical care delivery model throughout Spain. The creation of a tool such as the VA webpage can unify the pharmaceutical care provision. Further research should explore the impact of delivering VA services on the pharmacist’s workload. Additionally, the research team must plan adequate training11 for the service providers. Another issue is that the pharmacist cannot provide adequate pharmaceutical care unless they have access to patient’s full medication history. Future health policies in Spain should consider pharmacies as an integral part of the healthcare setting rather than a commercial entity. 1.1 Provoking factors for vascular aging in the Spanish population Despite the high prevalence of risk factors in the Spanish cohort, there is an unexpectedly low incidence of CVD observed in the countries of the Mediterranean area of southern Europe in 11 Training day with official accreditation 159 comparison to the rest of the world. This may be explained by the protective effect of “southern European paradox”. Three possible theories have been proposed to support the low incidence of CHD observed in the Spanish cohort (282). One is underestimation of the mortality rate, another is national delay in the consumption of fatty food which delayed the appearance of raised serum TC concentrations in Southern Europe and thirdly, the MedDiet and lifestyle. The second theory is contradictory with no significant changes in CHD rate despite the high population exposure to an animal fat diet within the last 40 years (283). The high content of olive oil (rich in oleic acid (55%-80% of total fat), monounsaturated fatty acid and linoleic acid (5%-20% of total fat), polyunsaturated omega-6 fatty acid, and several antioxidants such as polyphenols) in the MedDiet could explain the cardiovascular benefits associated with its consumption. The level of HDL-C and vitamin D has also been found high in Spanish individuals (284). Although Spaniards live the longest in the EU, many report CVD in old age. The WHO European health policy framework endorsed by the 53 member states of the WHO European Region in 2012 (9), and places particular focus on reducing health inequalities and strengthening health systems using a people-centered approach (10). 1.2 Interpretation of findings of the vascular age questionnaire A cross-sectional observational method was performed with CPs to study inaccuracy of the VA tool. It further aimed to explore the CP's perception about the feasibility of measuring VA and added value of webpage, assessing the CVR profile and identifying possible barriers faced in using VA tool. The online survey was selected as a preferred mode of data collection due to being cost-effective, convenient for participants due to automation, not time-consuming, broader geographical accessibility, design flexibility and responder's anonymity 12 (285). 12 Respondents may be more willing to share information 160 Confidentiality of the VA webpage limited the number of respondents. The survey consisted of 32-items with a mixture of open and close-ended questions presented in the form of cloud- based Google Forms. The result of the survey showed that half of respondents were aged between 21-29 years with a slightly higher percentage of female (54% vs 46% of men). All the participants were based in Madrid. A plausible explanation for this high portion of young respondents based in Madrid can be the snowball convenience sampling technique within the researcher's social network via email for the study. The author suggests the use of randomizing sampling techniques to overcome this shortcoming and increase the external validity of the results for future research. The stratification of the respondents by accreditation and age demonstrated that a large proportion of trained pharmacists were younger than 50 years. Most of those who were accredited in pharmaceutical care were also trained in motivational interviewing. These data may suggest the shift of the community pharmacy role from dispensing to clinical care and diagnostic. Nevertheless, these results must be interpreted with caution and further studies with a larger sample size is required. But shift from traditional role of CP in dispensing medicines only into provision of more pharmaceutical services, has also been observed among other EU countries and England. For instance, the process of the "Hub and Spoke dispensing model" in community pharmacies is being used in some EU countries13. As part of this model, prescriptions are collected from a "spoke" pharmacy, medication is prepared centrally in a "hub" with centralized dispensing and then delivered back to the "spoke" pharmacy, which provides it to the patient (286). Therefore, the CPs have more time to provide pharmaceutical care for the patients. On the other hand, the General Pharmaceutical Council (GPhC), which is the independent regulator 13 Belgium, Germany, Sweden, Finland and Netherland 161 for pharmacists in Great Britain, decided that in future, all graduate pharmacists will be independent prescribers at the end of five years Master of Pharmacy course (287). This may indicate that the advancement in technology and automation will demand a more clinical role of the CP in the near future. The next section of the questionnaire explored the perception and experiences of the pharmacist from the VA interface. There is a wide range of online health information available to HCPs. However, credibility and up to datedness of online resources plays a fundamental role. Performing a pilot among the service users was a crucial step in this thesis. It created an opportunity for pharmacists to interact with the information available on the website. That allowed the author to understand the functionality and practicality of the webpage design as well as health promotional protocols on the community level. The questionnaire considered other aspects beyond the visual display of the website. Subsequently, pharmacist's views can assist the research group to improve the webpage. This section of the survey explored the ease of navigation and accomplishment of the pharmacist goal in health promotion. It appears that the majority of pharmacist found the website straightforward to navigate. The next section assessed visual display (colour, framework, and layout) and information architecture (visual organization of information) of the interface. Seventy-five per cent found the design inspiring and protocols adequate. Seventy per cent strongly agreed, and twenty- nine per cent slightly agreed that the PIL designed are appropriate in terms of language and contents. However, improvement in quality of care is only possible if patient's perceptions are also considered for contextual quality of PIL or method of service delivery. Miscommunication and information gap will negatively impact the patient's adaptation to a healthy lifestyle (288). Further studies are required to give a patient a voice by exploring the patient’s views. 162 Pharmacist stratification according to their accreditation status14 indicated that all six trained pharmacists could navigate through the website easily. The next part of the survey assessed the pharmacist's views on the credibility of the contents of the interface. In terms of protocols, the majority15 indicates the trust they had in the quality of information being shared. Noteworthy individuals who trusted in the information of the interface were all trained in PCS. However, further qualitative measures such as open-ended question or interview with participants are needed to gain insight and more in-depth knowledge in protocols improvements. Thereafter, the pilot explored the user experience in a real-world situation. Sixty-two per cent responded that the time to fill out the VA questionnaire is reasonable. Previous studies indicated that if service provision is time-consuming, HCPs will not participate in the service (289). Therefore, a key consideration for designing and deploying the VA questionnaire was to identify if the tool is optimal layout to prevent time constraints in practice. Regarding health information sharing habits among CPs, our results indicated that recommending an eHealth tool to a professional network is common practice among the participants. Eighty-seven per cent of the respondents strongly agreed that they would recommend the VAC to their colleagues to adopt in their daily pharmaceutical care. The author noted that skilled pharmaceutical care providers (n=6) were more likely to share and recommend health promotion tools to their colleagues. The barriers and facilitators pharmacists faced in using the VA questionnaire was then assessed. Most of the respondents claimed that providing pharmaceutical services in the form of VA has the potential to improve their sense of job satisfaction. A recent systematic review 14 Pharmaceutical care or motivational training 15 A 54% gave the score of 5, and 37% gave the score of 4 163 which examined satisfaction in the pharmacist workforce stated that factors such as amount of work, stress level, development opportunities, job security, independence, equality in the workplace, colleagues and boss attitude and job atmosphere are determinant factors in pharmacists' job satisfaction (290). However, some of the respondents claimed that vascular health promotion in pharmacy in the form of VA might increase their workload. Nevertheless, it appears that factors such as better attributes of professional image enhanced pharmacist's relation with medical doctors and improve pharmaceutical care delivery, which in turn can lead to the development of new opportunities for pharmacists, can increase pharmacists' work satisfactions. Most significantly, respondents claimed that a VA webpage could improve the quality of cardiovascular care. This is because the VA website is made for a CP to monitor patient's CVR factors, improve their lifestyle by patient-centred care and continual education, improve adherence to pharmacotherapy by surveillance and motivate them to increase their physical activity, eat healthily and quit smoking and reduce their alcohol intake. In the last question of the survey, fifteen pharmacists expressed their opinion in detail about the VA tool. The reflective thematic analysis with the NVivo software was used for evaluating the open-ended question. The summary of this analysis can be accessed in the Annex. In relation to the visual display of the tool, many positive themes were mentioned by the pharmacists (complete, good, innovative, attractive, important tool, comprehensive, etc.). In terms of information architecture, two of the repliers asked for the breakdown of the survey into different pages. However, the research group believes that a one-page display may be less time consuming for completion. This result must be interpreted with caution due to the small sample size, and further study is required to explore the practicality of this display mode. Some of the responses suggested adding additional components to the VA questionnaire, such as alanine aminotransferase (ALT) and aspartate transaminase (AST) values, indicators 164 of chronic liver disease. Because the liver is responsible for the production of lipoproteins (HDL-C and LDL-C), that are directly related with atherosclerosis and CVD (291). This is a valid comment that the research group will implement in the revised version of the questionnaire. Other suggested adding QR code to the website to facilitate the intervention process during the pandemic. This suggestion was also implemented in the study protocol. Other respondents proposed to add other drugs that influence the plasma TC and TG concentration, such as antivirals and isotretinoin. This suggestion will also be implemented in the questionnaire. These detailed and additional suggestions are a clear indication of the high- level clinical knowledge and expertise of the CPs, which is not being utilized by the healthcare system. This remarkable tool can be employed by the CP throughout Spain to assess, support, and educate patients on their personal risk of developing CVDs. 1.3 Implication of the eHealth vascular age tool on pharmacy practice in Spain Although, the Spanish SNS provides free access to healthcare for the general population, health spending in Spain is lower than the EU average (36). Another pressing issue is a high percentage of an older population in Spain, as older population will suffer more from CVD. Careful allocation of health resources is a critical step in disease prevention. Continuous assessment of risk factors and vascular status in form of VA may decrease the burden of CVD and reduce related health costs and slowing declining quality of a patient’s life. The concern for lack of pharmacist time to implement pharmaceutical care and promote healthy lifestyle as well as lack of time and eHealth user difficulties within pharmacists was address by the research pilot. Although the finding should be interpreted with caution and larger scale webpage audit is still required. These problems can be also addressed with proper 165 pharmacists training and service reorganization. The strategic locations of the pharmacies with extended opening hours, and ease of public accessibility and the pharmacists’ undeniable expertise in pharmaceutical care, make these centres strategic places for implementing interventional services. 1.4 Limitation One of the greatest limitations in this research was the COVID-19 pandemic. The original plan of the author was to pilot the VA tool among the general public, but risk of contamination had stopped the large-scale data collection. The research group is hoping that with time and the help of vaccination, COVID-19 will be controlled which will allow the investigation to be carried out. The plan will be to initially launch the webpage as a pilot to include the patient’s voice (participation) and later to assess the VA of the patient. This future plan itself stopped the investigator from piloting the webpage on a larger scale. The pilot was performed among a small network of pharmacists with a convenient sampling, which may limit generalization to other jurisdictions. Moreover, the pilot was performed anonymously to increase the reliability of the results. 166 CONCLUSION Conclusions • The vascular age calculator constitutes a novel tool to improve the patients understanding and consciousness about their cardiovascular risk and might contribute to improve the patient’s attitude and implication in their self-care. 167 • The vascular age webpage is inclusive, easy to use and provides the appropriate intervention protocols and advises for patients. It can be a useful tool for community pharmacists to facilitate the follow-up and management of the patient’s cardiovascular risk, thus contributing to improve their cardiovascular outcomes. • The vascular age website might favor the communication and coordination among different healthcare professionals involved in the integral patient care, such as pharmacists, doctors, nurses, nutritionists, etc. • The assessment of the vascular age website in the general population would be required to properly validate it, so that its use might be generalized in pharmacotherapeutic follow- up services provided by community pharmacists. • Once validated, the vascular age tool might contribute to improve the community pharmacist’s recognition as an integral part of the healthcare system rather than a commercial entity in Spain. 168 REFERENCE 1. National Institute for Health and Care Excellence. 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Seleccione el tipo de formación recibida: § Cursos de formación continuada on-line § Cursos de formación continuada presenciales § Máster Universitario en Atención Farmacéutica § Realización de prácticas en un Servicio de Atención Farmacéutica § Otro 8. Indique el organismo que le proporcionó dicha formación: § Universidades § Consejo General de Colegios Oficiales de Farmacéuticos § Colegio Oficial de Farmacéuticos § Farmacia particular § Otro Descripción de la página web Por favor, entre en nuestra página web https://edad-vascular.ucm.es/ y después de familiarizarse con la herramienta web proporcionada, responda a las siguientes preguntas. Para responder dispone de una puntuación del 1 al 5 de gradiente ascendente conforme el grado de acuerdo es mayor. Por tanto, el 1 representa el total desacuerdo y el 5 el total acuerdo 9. El manejo de la web es sencillo § 1 § 2 § 3 § 4 § 5 187 10. Encontré lo que necesitaba fácilmente § 1 § 2 § 3 § 4 § 5 11. Los documentos de información al paciente son apropiados § 1 § 2 § 3 § 4 § 5 12. Los protocolos de actuación recomendados son apropiados § 1 § 2 § 3 § 4 § 5 13. El tiempo que se emplea en rellenar el Cuestionario es razonable § 1 § 2 § 3 § 4 § 5 14. Las opciones que se ofrecen como respuestas al cuestionario son adecuadas § 1 § 2 § 3 § 4 § 5 15. Recomendaría la web a mis compañeros § 1 § 2 § 3 § 4 § 5 Impacto de la web en la práctica farmacéutica Por favor, tómese su tiempo para responder a las siguientes preguntas. 16. Su sensación de satisfacción laboral § Mejorará notablemente § Mejorará ligeramente § No cambiará § Empeorará ligeramente § Empeorará notablemente 17. Su imagen profesional de cara al paciente § Mejorará notablemente 188 § Mejorará ligeramente § No cambiará § Empeorará ligeramente § Empeorará notablemente 18. Su relación con los médicos § Mejorará notablemente § Mejorará ligeramente § No cambiará § Empeorará ligeramente § Empeorará notablemente 19. Esta intervención mejorará sus servicios de atención farmacéutica § Mejorará notablemente § Mejorará ligeramente § No cambiará § Empeorará ligeramente § Empeorará notablemente 20. El tiempo de las visitas de los pacientes § Aumentará notablemente § Aumentará ligeramente § No variará § Se reducirá ligeramente § Se reducirá notablemente 21. La calidad de la atención al paciente § Aumentará notablemente § Aumentará ligeramente § No variará § Se reducirá ligeramente § Se reducirá notablemente 22. Su carga de trabajo § Aumentará notablemente § Aumentará ligeramente § No variará § Se reducirá ligeramente § Se reducirá notablemente Impacto socioeconómico de la herramienta de la edad vascular Por favor, tómese su tiempo para responder a las siguientes preguntas. 23. La herramienta para calcular la edad vascular contribuirá a mejorar la salud del paciente § Totalmente de acuerdo § Ligeramente de acuerdo § Ligeramente en desacuerdo § Absolutamente en desacuerdo 24. La colaboración entre farmacéuticos y médicos contribuirá a reducir el gasto sanitario tanto para el paciente como para el sistema de salud § Totalmente de acuerdo § Ligeramente de acuerdo § Ligeramente en desacuerdo 189 § Absolutamente en desacuerdo 25. Esta herramienta es otro componente clave para sus servicios continuos de promoción de la salud cardiovascular § Totalmente de acuerdo § Ligeramente de acuerdo § Ligeramente en desacuerdo § Absolutamente en desacuerdo 26. ¿Tiene alguna posible sugerencia en relación con el cuestionario o los parámetros que se incluirán como parte de la intervención de este farmacéutico comunitario? 190 Appendix II: Community pharmacist responses in Spanish for question 26 of the pilot. 1. El cuestionario es bastante completo. Sí que trabajaría en los protocolos de intervención. Como están ahora, son una serie de recomendaciones generales, que se pueden dar incluso a la población general, lo cual está bien, pero me parece insuficiente para el paciente diabético o hipertenso, por ejemplo. Los trabajaría para acompañar al paciente en el cambio de hábitos de vida, elaborando una herramienta que nos permita marcar objetivos realistas para cada paciente en función de su situación actual y el objetivo que queremos alcanzar. Como ejemplo, en el protocolo de adherencia terapéutica, al margen de hacer el test de Morisky-Green, estudiaría ofrecer servicios de seguimiento farmacoterapéutico protocolarizado y en caso necesario elaborar SPDs para el paciente. También estudiaría la posibilidad de facilitar en la sección de documentación, una carta de presentación del proyecto para entregar al médico/s de atención primaria de la zona, para intentar establecer una comunicación fluida entre médico y farmacéutico. 2. Creo que se incluyen todos los parámetros, pero añadiría otra pregunta donde señalar el tipo patología en antecedente familiar como (ictus, IAM, hipercolesterolemia, diabetes, etc.) detallar algo más la patología del familiar. 3. Hay algún campo que revisar en el formulario, pero me parece una web, una herramienta y un proyecto bastante importante y significativo para la salud de los pacientes y poder contribuir desde la farmacia comunitaria en este aspecto. 4. En mi opinión sería interesante la vinculación a entidades como el COFM, el Consejo, SEFAC, CENTROS DE SALUD, etc. de esta campaña del cálculo de la edad vascular para aumentar la difusión en beneficio del paciente y reducción del gasto sanitario. 5. Simplemente como comentario: es necesario hacer hincapié en la confidencialidad de los datos, cara al paciente. Figura en el aviso legal, pero creo que debe quedarle más claro, quizás encabezando el texto de información. 6. Valorar la posibilidad de incluir los valores de ALT y AST con relación al colesterol y el riesgo cardiovascular. 7. La posibilidad de añadir en el algoritmo de trabajo un pequeño seguimiento, en lugar de excluir al paciente completamente del estudio. Así, si el ve que su edad cardiovascular va empeorando, quizás se anima. 8. Dividir el formulario en diversos apartados que se vayan completando por fases (datos personales, antecedentes familiares, datos analíticos, hábitos alimentarios y de estilo de vida, etc. 9. La cumplimentación del formulario podría agruparse en bloques: datos personales; hábitos higiénicos-salud (fumar, ejercicio, comida), parámetros analíticos (bioquímica), antecedentes personales (enfermedades, tratamientos...). 10. Página web muy intuitiva y visualmente atractiva. 11. No, está bastante bien. 12.Tratar de implicar al mayor número posible de oficinas de farmacia en el proyecto. 13. Integrating with QR code 14. Yo pondría referencias para los protocolos 15. Incluir otros fármacos que influyen en el colesterol y los triglicéridos plasmáticos, como isotretinoína (tratamiento del acné) y antirretrovirales. 191 Appendix III: The themes that merged from the pharmacist’s responses coding Respondents Questions Protocols Benefits for pharmacy sector Benefit to the patients Other benefits How to improve the protocols or questions Other tool or protocols which can be added to the services 1 Complete -Can be improved -Cover generalize cardiovascular advice. -It is good -Insufficient for patients with diabetes and hypertension. - - - Personalize patient intervention plan is needed to support patient change their lifestyle habits. - Tool to set realistic targets for each patient based on their current situation and the goal. - Assessment test to identify patient’s compliance such as Morisky-Green* or Therapeutic drug monitoring (TDM). - Clear documentation -Pre-designed referral letter to communicate with the doctor. 2 -Inclusive -must include an option for patient to specify the family history for CVD in detail (e.g., Stroke, diabetes, hypercholesteremia) - - - - - - 3 - Some part of the questionnaire needs revising. -Important tool and significant project - Involves community pharmacists’ in reducing the CVD risks. Improves cardiovascular health among patients significantly. - - - 4 - - - Improves cardiovascular health in patients significantly. Reduce the cost in healthcare system. - Collaborative work with COFM, the Council, SEFAC, HEALTH CENTRES 5 Clarify that patient information is secure. 192 6 This participant asked the research group to include ALT and AST values in relation to cholesterol and cardiovascular risk. 7 Adding control group to the study for patients who don’t want to participate but can use vascular age tool. 8 Divide the form into different sections 9 Divide the form into different sections 10 Webpage is very innovative and attractive 11 Good website 12 Involve many pharmacists. 13 Use QR code for webpage 14 Add more references 15 other drugs that influence plasma cholesterol and triglycerides, such as isotretinoin (acne treatment) and anti- retroviral. 193 Appendix IV: NVivo analysis of the vascular age website pilot word repetition Word Cou nt Weighte d Percenta ge Percenta ge communication 2 3,57% 0.5% divide 2 3,57% 0.5% form 2 3,57% 0.5% health 2 3,57% 0.5% adherence 1 1,79% 0.2% algorithm 1 1,79% 0.2% alt 1 1,79% 0.2% ast 1 1,79% 0.2% attractive 1 1,79% 0.2% benefit 1 1,79% 0.2% campaign 1 1,79% 0.2% centres 1 1,79% 0.2% changing 1 1,79% 0.2% cholesterol 1 1,79% 0.2% cofm 1 1,79% 0.2% comprehensive 1 1,79% 0.2% confidentiality 1 1,79% 0.2% contribute 1 1,79% 0.2% council 1 1,79% 0.2% cvd 1 1,79% 0.2% drugs 1 1,79% 0.2% encourage 1 1,79% 0.2% family 1 1,79% 0.2% follow 1 1,79% 0.2% good 1 1,79% 0.2% habits 1 1,79% 0.2% history 1 1,79% 0.2% important 1 1,79% 0.2% inclusive 1 1,79% 0.2% innovation 1 1,79% 0.2% insufficient 1 1,79% 0.2% intuitive 1 1,79% 0.2% legal 1 1,79% 0.2% lifestyle 1 1,79% 0.2% monitoring 1 1,79% 0.2% multidisciplinary 1 1,79% 0.2% notice 1 1,79% 0.2% objectives 1 1,79% 0.2% opportunity 1 1,79% 0.2% personalize 1 1,79% 0.2% pharmacotherap eutic 1 1,79% 0.2% protocol 1 1,79% 0.2% realistic 1 1,79% 0.2% reduce 1 1,79% 0.2% sefac 1 1,79% 0.2% services 1 1,79% 0.2% significant 1 1,79% 0.2% spending 1 1,79% 0.2% therapeutic 1 1,79% 0.2% treatment 1 1,79% 0.2% visually 1 1,79% 0.2% 194 Appendix V: Application for the provision of waste management services, SRCL Consenur company form. Tesis Marjan Manouchehri PORTADA TABLE OF CONTENTS LIST OF FIGURES LIST OF TABLES LIST OF ABBREVIATIONS ABSTRACT RESUMEN INTRODUCTION HYPOTHESIS AND OBJECTIVES MATERIALS AND METHODS RESULTS DISCUSSION CONCLUSION REFERENCE APPENDICES