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Nsaids and Cardiovascular Drugs in Neurodegenerative and Cerebrovascular Diseases

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Nsaids and Cardiovascular Drugs in Neurodegenerative and Cerebrovascular Diseases NSAIDs and Cardiovascular Drugs in Neurodegenerative and Cerebrovascular Diseases Mendel Haag ACKNOWLEDGMENTS The work presented in this thesis was conducted at the Department of Epidemiology at Erasmus MC, Rotterdam, the Netherlands. The Rotterdam Study of the Department of Epidemiology at the Erasmus MC is supported by Erasmus MC and Erasmus University Rotterdam, the Netherlands Organisation for Scientific Research (NWO), the Netherlands Organisation for Health Research and Development (ZonMW), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry of Health, Welfare and Sports, the European Commission (DGX II) and the Municipality of Rotterdam. The Rotterdam Scan Study of the Department of Epidemiology at Erasmus MC is supported by grants from the Netherlands Organisation for Scientific Research (NWO) and the Netherlands Heart Foundation, Erasmus MC and Erasmus University Rotterdam, the Netherlands. The author gratefully acknowledges the collaboration with the Department of Neurology (Prof.dr. P.J. Koudstaal), the Department of Radiology of Erasmus MC and the inhabitants, general practitioners and pharmacists participating in The Rotterdam Study. The publication of this thesis was financially supported by the Department of Epidemiology at Erasmus MC and Erasmus University, Rotterdam, the Netherlands. Addtional financial support for publication of this thesis was granted by: Alzheimer Nederland AstraZeneca Internationale Stichting Alzheimer Onderzoek Pfizer bv Cover design by Mendel Haag and Printpartners Ipskamp, Rotterdam. Lay-out by Legatron Electronic Publishing, Rotterdam. Printed by Printpartners Ipskamp, Enschede. ISBN: 978-90-9023916-3 © Mendel Haag, 2009 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 publication. NSAIDs and Cardiovascular Drugs in Neurodegenerative and Cerebrovascular Diseases NSAIDs en cardiovasculaire medicatie in neurodegeneratieve en cerebrovasculaire aandoeningen Proefschrift ter verkrijging van de graad van doctor aan de Erasmus Universiteit Rotterdam op gezag van de rector magnificus Prof.dr. S.W.J. Lamberts en volgens besluit van het College voor Promoties. De openbare verdediging zal plaatsvinden op vrijdag 13 februari 2009 om 15:45 uur door Mendel Digna Margarete Haag geboren te Amsterdam PROMOTIECOMMISSIE Promotoren: Prof.dr. M.M.B. Breteler Prof.dr. B.H.C. Stricker Overige leden: Dr. A.H. van den Meiracker Prof.dr. H.G.M. Leufkens Prof.dr. P.J. Koudstaal CONTENTS Introduction 7 Chapter 1. Nonsteroidal anti-inflammatory drugs (NSAIDs) 17 1.1 NSAIDs and risk of Stroke 19 1.2 NSAIDs and risk of Transient Ischemic Attack 35 1.3 NSAIDs and risk of Parkinson disease 47 1.4 NSAIDs and risk of Alzheimer disease 57 Chapter 2. Cardiovascular drugs 73 2.1 Statins and risk of Alzheimer disease 75 2.2 Antihypertensive drugs and risk of Dementia 91 2.3 Antihypertensive drugs and progression of White Matter Lesions 111 2.4 Antithrombotic drugs and presence of Cerebral Microbleeds 127 General discussion 145 Summary 163 Samenvatting 167 Dankwoord 173 About the author 179 MANUSCRIPTS AND PUBLICATIONS BASED ON THIS THESIS Chapter 1.1 Haag MDM, Bos MJ, Hofman A, Koudstaal PJ, Breteler MMB, Stricker BHC. Cyclooxygenase Selectivity of Nonsteroidal anti-inflammatory drugs and Risk of Stroke. Arch Intern Med. 2008;168(11):1219-1224. Chapter 1.2 Haag MDM, Bos MJ, Hofman A, Koudstaal PJ, Breteler MMB, Stricker BHC. Nonsteroidal Anti-inflammatory Drugs and Risk of Transient Ischemic Attack. Chapter 1.3 Bornebroek M, de Lau LM, Haag MDM, Koudstaal PJ, Hofman A, Stricker BHC, Breteler MMB. Nonsteroidal Anti-inflammatory Drugs and the Risk of Parkinson disease. Neuroepidemiology. 2007;28(4):193-196. Chapter 1.4 Haag MDM, van Oijen M, de Jong FJ, Hofman A, Koudstaal PJ, Stijnen T, Stricker BHC, Breteler MMB. Amyloid-β42 Modulating Properties of Nonsteroidal Anti-Inflammatory Drugs and the Risk of Alzheimer Disease: a population-based cohort study. Submitted. Chapter 2.1 Haag MDM, Hofman A, Koudstaal PJ, Stricker BCH, Breteler MMB. Statins are associated with a Reduced risk of Alzheimer disease regardless of Lipophilicity. The Rotterdam Study. JNNP. October 17, 2008, Epub ahead of print. Chapter 2.2 Haag MDM, Hofman A, Koudstaal PJ, Breteler MMB, Stricker BHC. Duration of Antihypertensive Drug Use and Risk of Dementia, a Prospective Cohort Study. Neurology. Accepted for publication. Chapter 2.3 Haag MDM, Van Dijk EW, Prins ND, Ikram MA, Hofman A, Breteler MMB, Stricker BHC. Antihypertensives and Progression of White Matter Lesions. The Rotterdam Scan Study. Submitted. Chapter 2.4 Vernooij MW*, Haag MDM*, van der Lugt A, Hofman A, Krestin GP, Stricker BHC, Breteler MMB. Use of antithrombotic drugs and presence of Cerebral Microbleeds. The Rotterdam Scan Study. Archives of Neurology. Accepted for publication. Introduction Introduction Neurodegenerative and cerebrovascular diseases are frequent in elderly populations and comprise primarily of dementia (mainly Alzheimer disease (AD)), Parkinson disease (PD) and stroke. The prevalence of these neurological disorders rises with older age. From 55 years to 90 years and above, the prevalence of dementia increases from less than 1% to over 40%.1-3 For PD, the prevalence increases over the same age range from less than 0.5% to more than 4%,4,5 and for stroke from approximately 1% to nearly 10%.6,7 Similar age-related patterns are observed for incidence figures.8-11 In the Netherlands, the population of persons of 65 years and older is expected to increase from 2.4 million in 2007 to 3.9 million in 2050.12 At a global level, 2 billion persons above 65 years are expected by 2050.13 As a consequence of the aging population the incidence and prevalence of age-related neurological diseases will increase accordingly. Moreover, these neurological disorders all constitute highly disabling diseases, with appreciable impact on quality-of-life at the patient level, but also on society, both economically and socially.12,14-17 Currently, there is no effective cure for AD18, PD19 or the consequences of stroke.20 Hence, identification of determinants of these neurological diseases and development of preventive strategies is of paramount importance. This search is, in part, directed at currently available drugs which target established risk factors of neurological disease, or that have, in in vivo or in vitro studies, shown to interfere with more specific elements of the supposed pathogenic pathway of disease. Two drug groups commonly used by elderly are of interest, namely nonsteroidal anti-inflammatory drugs (NSAIDs) and cardiovascular medication. The general objective of this thesis was to study the role of these drugs as determinants of neurodegenerative and cerebrovascular diseases. NONSTEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDS) NSAIDs are among the most widely prescribed drugs worldwide owing to their anti- inflammatory, antipyretic and analgesic properties.21 Registered indications relevant to the elderly population include mild to moderate pain and symptomatic relief in musculoskeletal and joint diseases. In the early 1970’s, a decade after their market introduction, it was discovered that NSAIDs mediate their anti-inflammatory effects through inhibition of the cyclooxygenase (COX) enzyme.21 COX is the enzyme required for the conversion of arachidonic acid to prostaglandins, a group of compounds with extensive functions in human physiology. At least two isoforms of COX to date have been identified, COX1 and COX2.22-24 NSAIDs differ with respect to relative selectivity 8 Introduction for either of the COX-enzymes.25 The ‘traditional’ NSAIDs are mostly non-selective and inhibit both COX-enzymes concurrently. Due to their inhibition of COX1, which is involved in gastric mucosal defence, the ‘traditional’ NSAIDs are known for their gastrointestinal adverse effects.26-28 In order to reduce these adverse events, the more recently developed compounds selectively inhibit COX2. However, in September 2004, a COX2-selective NSAID was voluntarily withdrawn from the market as a result of concerns regarding its cardiovascular safety based on clinical trial data.29-31 It was thought that selective COX2-inhibition, without concomitant inhibition of COX1, causes platelet aggregation and thereby induces a prothrombotic state.32,33 Retrospective analyses of observational series and non-cardiovascular clinical trials suggested, however, that cardiovascular events may also occur with non-selective NSAIDs. Hence, it was debated whether the cardiovascular risk is restricted to the COX2-selective compounds.28,34-36 Furthermore, it is unclear whether NSAID use poses similar risks for different cardiovascular and cerebrovascular events. We investigated the association between NSAID use and risk of stroke in Chapter 1.1 and transient ischemic attack (TIA) in Chapter 1.2 and determined whether associations differed for the different NSAID groups, based on their COX-selectivity. NSAIDs have been a focus of pharmacoepidemiological research in neurodegenerative disease.37,38 Inflammation is a process that has been related to the onset of numerous neurodegenerative disorders.39,40 Findings from epidemiological studies have repeatedly suggested that anti-inflammatory drugs, particularly NSAIDs, could protect against AD and possibly against PD.37,41,42 Initially, it was thought that the anti-inflammatory
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