Adherence and persistence with antihypertensive drugs Boris L.G. van Wijk Cover illustration: Conny Groenendijk (Dienst Grafische Vormgeving, Department of Pharmaceutical Sciences, Utrecht University) Printed by: Gildeprint Drukkerijen, Enschede CIP-gegevens Koninklijke Bibliotheek, Den Haag Van Wijk, B.L.G. Adherence and persistence with antihypertensive drugs Thesis Utrecht – with ref. – with summary in Dutch ISBN-10: 90-393-4395-0 ISBN-13: 978-90-393-4395-1 © Boris L.G. van Wijk No part of this thesis may be reproduced, stored in a retrieval system, or transmitted in any form or by any means without permission of the author, or when appropriate, of the publishers of the publications. Adherence and persistence with antihypertensive drugs Therapietrouw met antihypertensiva (Met een samenvatting in het Nederlands) Proefschrift ter verkrijging van de graad van doctor aan de Universiteit Utrecht op gezag van de rector magnificus prof. dr. W.H. Gispen ingevolge het besluit van het college voor promoties in het openbaar te verdedigen op woensdag 6 december 2006 des middags te 12.45 uur door Boris Leonard Gijsbert van Wijk geboren op 16 oktober 1977 te Nijmegen Promotor: Prof. dr. A. de Boer Co-promotoren: Dr. O.H. Klungel Dr. E.R. Heerdink This thesis was funded by the Dutch Board of Health Insurance Organizations (College voor zorgverzekeringen). The Netherlands Organization for Scientific Research (NWO) is gratefully acknowledged for their travel grant. The Stichting KNMP-fondsen is gratefully acknowledged for their financial support for the publication of this thesis. Voor mijn ouders Contents Chapter 1 Introduction and objective 9 Chapter 2 Methodological aspects 19 2.1 Indications for antihypertensive drug use in a prescription 21 database 2.2 Different definitions of the maximum allowed treatment 31 gaps lead to different rates of refill persistence Chapter 3 Adherence with antihypertensives as a predictor of 49 medication events 3.1 The association between adherence with antihypertensive 51 drugs and modification of antihypertensive drug regimen 3.2 Initial non-adherence with antihypertensive monotherapy is 67 followed by complete discontinuation of antihypertensive therapy Chapter 4 Adherence and persistence with antihypertensives in 81 daily practice 4.1 Rate and determinants of 10 year persistence with 83 antihypertensive drugs 4.2 Rates and determinants of reinitiating antihypertensive 99 therapy after prolonged stoppage: a population based study 4.3 A cross-national study of persistence of antihypertensive 121 medication use in the elderly 4.4 A comparison of two multiple characteristics decision 143 making models for the comparison of antihypertensive drugs: Simple Additive Weighting and Technique for Order Preference by Similarity to an Ideal Solution Chapter 5 Intervening in patients using chronic treatment 163 5.1 Effectiveness of interventions by community pharmacists to 165 improve patient adherence with chronic medication: a systematic review 5.2 Effectiveness of a community pharmacist-led intervention to 189 increase adherence in patients with hypertension: a randomized controlled study 5.3 Generic substitution of antihypertensive drugs: does it affect 201 adherence to therapy? Chapter 6 General discussion 215 Chapter 7 Summary 243 Chapter 8 Samenvatting 253 Dankwoord 263 List of publications 267 Curriculum Vitae 269 Chapter 1 Introduction and objective CHAPTER 1 Scope of this thesis Hypertension is an important risk factor for the development of cardiovascular morbidity and mortality. In 2002, 10.9% of all deaths in the developed countries were attributable to hypertension, making it the second major risk factor of overall death just below tobacco use (12.2%) but over high cholesterol (7.6%), alcohol use (9.2%) and obesity (7.4%)1. In addition, about half of all cardiovascular disease (mortality and morbidity combined) is attributable to high blood pressure. Fortunately, it is widely considered as one of the most preventable causes because of the availability of effective antihypertensive drugs. In 2003, $30 billion was spend on antihypertensive drugs in the US, which is about 18% of the costs of all prescription drugs1. This is in line with Dutch findings, that in 2004, €916.490 was spent on drugs to treat patients with antihypertensives, which is more than 21% of the total budget of pharmacological treatment in The Netherlands2. Using these drugs effectively, every 20 mmHg decrease of systolic blood pressure and 10 mmHg decrease of diastolic blood pressure could potentially lead to a 50% reduction of the risk of cardiovascular disease according to the World Health Organization, although other non-blood pressure related effects of pharmacological treatment may alter these figures1. Compared to no treatment, antihypertensives have demonstrated to reduce the risk of major cardiovascular events with 27%, the risk of cardiovascular mortality with 16% and the risk of all cause mortality with 10%3. The number needed to treat for elderly patients is 190 for major cardiovascular events, 221 for cardiovascular mortality and 244 for all cause mortality1. Although high blood pressure has long been identified as an important medical condition, until 1964, the most important strategy for decreasing a patient’s blood pressure was a low salt diet4. Introduction of pharmacological treatment for hypertension In his book “The Rise and Fall of Modern Medicine”, James le Fanu describes how in 1964, Michael Hammilton and Eileen Thompson, doctors at the Helmsford Hospital in the United Kingdom were the first to demonstrate the protective effect of pharmacological treatment with chlorothiazide on major cardiovascular events in patients with hypertension5,6. Before 1964, pharmacological treatment in general was in most cases aimed to treat acute disorders resulting in relatively short duration of treatment. In 1967, the Veterans Affairs Health Cooperation on Antihypertensive Agents Study confirmed their finding7. In this study among US military veterans with severe hypertension, twelve out of seventy patients, who 10 Introduction and objective used a placebo, experienced a major cardiovascular event compared to only one out of seventy-three patients who were treated with high doses of chlorothiazide. From that point forward, more than forty different randomized clinical trials have been performed to further develop our insights in the pharmacological treatment of hypertension, although a derivative of that first antihypertensive, hydrochlorothiazide is still widely considered the first choice in the treatment of hypertension, supported by good evidence3,8. In the years preceding 1964, various other pharmacological antihypertensive strategies, such as pentaquine, hydralazine, methyldopa, guanetidine and clonidine have been used. Although these compounds all demonstrated the ability to reduce blood pressure, the side- effects were unacceptable for patients, who in the period preceding treatment experienced no symptoms and suddenly were confronted with a dry mouth, dizziness and impotence. These side-effects are especially unappealing considering the chronic nature of the disease. However, as Le Fanu stated in his book, with the discovery of the diuretic chlorothiazide and the beta-blocker propranol, hypertension had become a “treatable disease” because “these new drugs interfered so little with a person’s life” that hypertensive patients who start with the treatment with antihypertensive drugs “are prepared to take them for longer periods”6. Are they? Adherence vs. persistence The use of antihypertensives for long consecutive periods is important because incorrect use will lead to a less effective treatment in daily practice than observed in RCTs. This thesis focuses on two aspects of “using antihypertensives correctly” namely adherence and persistence. Although these issues are conceptually linked together, and even interchanged in medical literature, they refer to a different problem. Adherence or compliance are both used to define the extent to which a patient “takes his medication as prescribed”, or more theoretically, “to which a patient’s dosing history corresponds to the prescribed regimen”, as defined by Urquhart9,10. The term is usually expressed as a percentage or fraction of doses taken as scheduled. In this context, non-adherence or non-compliance refers to problems such as missing doses, intentionally or not, or short periods of so called drug holidays, periods during which patients consciously do not take medication, but restart thereafter. This means that in case of non-adherence, a patient does have the intention to use treatment for longer periods, but not always as prescribed. The long-term consequence is that the full benefit of treatment cannot 11 CHAPTER 1 be obtained making the patient sub-optimally protected. In addition to the long- term risk associated with non-adherence, Psaty et al. demonstrated that there is also an acute risk associated with non-adherence. Patients who missed doses of beta-blockers had a 4.5 times increased risk of ischemic heart disease11. The term persistence, or continuation, is used to characterize patients that continue for a defined period, e.g. one year. In case of non-persistence, patients completely discontinue the use of a certain drug or treatment regimen, in contrast to non- adherence where only some doses are omitted. Therefore, non-persistence constitutes an even greater barrier to attain treatment goals. Use of prescription databases to elucidate patterns of drug use