Antiplatelet Drugs for Secondary Prevention of Cardiovascular Diseases: Drug Utilization, Effectiveness, and Safety

Tags: ischemic stroke, secondary prevention, Dr, antiplatelet drugs, clinical practice, clopidogrel, Alfi Yasmina Noorsyahdy, Cardiovascular Diseases, Utrecht Institute for Pharmaceutical Sciences, Utrecht Cardiovascular Pharmacogenetics, Yasmina Noorsyahdy, Drug Utilization, Utrecht University, Akhmad Noor Abb, antiplatelet drug, PhD position, pharmacogenetic testing, platelet reactivity, CAD patients, aspirin, carbasalate calcium, genetic polymorphisms, cost-effectiveness studies, PhD students, methodological questions, Olaf Klungel, epidemiological methods, genetic studies, Prof
Content: Antiplatelet Drugs for Secondary prevention of cardiovascular diseases: Drug Utilization, Effectiveness, and Safety Alfi Yasmina Noorsyahdy
All the research presented in this PhD thesis were conducted at: ­Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, the Netherlands ­Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, the Netherlands Printing of this thesis was kindly supported by: Utrecht Institute for Pharmaceutical Sciences, Utrecht University, the Netherlands Alfi Yasmina Noorsyahdy Antiplatelet Drugs for Secondary Prevention of Cardiovascular Diseases: Drug Utilization, Effectiveness, and Safety Thesis Utrecht University ­ with summary in English, Dutch, and Bahasa Indonesia ISBN: 978-90-393-6725-4 Layout and printing: Off Page, Cover photo: Renny Aditya, Akhmad Noor Abb, Anshorullah Al Faruqi Copyright © 2017 by A.Y. Noorsyahdy. All rights reserved. For articles published or accepted for publication, the copyright has been transferred to the respective publisher. No part of this book may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, without prior permission of the author, or when appropriate, the publisher of the manuscript.
Antiplatelet Drugs for Secondary PrEvention of Cardiovascular Diseases: Drug Utilization, Effectiveness, and Safety Trombocytenaggregatieremmers als secundaire preventie bij cardiovasculaire aandoeningen: toepassing, effectiviteit en veiligheid (met een samenvatting in het Nederlands) Obat antiplatelet untuk pencegahan sekunder penyakit kardiovaskular: penggunaan obat, efektivitas dan keamanan (dengan ringkasan dalam bahasa Indonesia) Proefschrift ter verkrijging van de graad van doctor aan de Universiteit Utrecht op gezag van de rector magnificus, prof. dr. G. J. van der Zwaan, ingevolge het besluit van het college voor promoties in het openbaar te verdedigen op maandag 13 maart 2017 des middags te 2.30 uur door Alfi Yasmina Noorsyahdy geboren op 4 oktober 1974 te Banjarmasin, Indonesiл
Promotoren: Copromotor:
Prof. dr. A. de Boer Prof. dr. O. H. Klungel Dr. V. H. M. Deneer
6.1 Summary
Antiplatelet drugs are the mainstay of treatment for several diseases in which the pathophysiology is associated with platelet aggregation and atherosclerosis, including acute coronary syndrome (ACS), transient ischemic attack (TIA), ischemic stroke, and peripheral artery disease. Antiplatelet drugs are recommended for secondary prevention of recurrent cardiovascular events in patients who experience these diseases. Despite the recommendations in the guidelines by the cardiology and neurology societies, the utilization of antiplatelet drugs varies widely between countries. Furthermore, the efficacy and safety of antiplatelet drugs demonstrated in the randomized controlled trials (RCTs) are not expected to be completely similar in daily clinical practice. Aspirin and clopidogrel are two antiplatelet drugs most commonly associated with drug response variability. Various factors have been shown to influence the effectiveness and safety of aspirin and clopidogrel. In this thesis, we aimed to evaluate the time trends of prescriptions of antiplatelet drugs after a myocardial infarction (MI), ischemic stroke, and TIA; and to assess the effectiveness and safety of antiplatelet drugs as secondary prevention for cardiovascular diseases in daily practice, taking into account genetic and non-genetic factors either as confounders or effect modifiers. Chapter 1 provides the general introduction for this thesis. In Chapter 2, we evaluated antiplatelet drug utilization as secondary prevention for cardiovascular diseases. In Chapter 2.1, we assessed antiplatelet drug use patterns after a first MI and evaluated the determinants of antiplatelet non-persistence. We selected 4,690 MI patients diagnosed during 1986-2010 from the Utrecht Cardiovascular Pharmacogenetics (UCP) cohort and followed them for a maximum of 10 years. A dynamic pattern of antiplatelet drug use after the first MI was observed, with many discontinuations and restarts during follow-up. A large proportion (89.3%) of patients with a first MI still used antiplatelet drugs after 10 years. The frequent discontinuations after MI are alarming, because the discontinuations are expected to reduce the effectiveness of antiplatelet drugs as secondary prevention of cardiovascular diseases. Diabetes, hypertension, hypercholesterolemia, and a more recent MI diagnosis period were associated with a lower risk of antiplatelet drug non-persistence, while vitamin K antagonist co-medication was associated with an increased risk. The time trend of antiplatelet drug use in 90 days after a first ischemic stroke or TIA during 1998-2013 was assessed in 21,064 patients selected from the United Kingdom (UK) Clinical Practice Research Datalink (CPRD) (Chapter 2.2). Antiplatelet drug use was increased by 2.0% and 1.8% annually after a first ischemic stroke and TIA, respectively. Based on the type of antiplatelet regimen used, clopidogrel monotherapy was more commonly used in recent years, after a recommendation by the National Institute for Health and Care Excellence (NICE) in the UK. Sex, smoking habit, diabetes, history of heart failure, year of diagnosis, previous use of antiplatelet drugs and oral anticoagulants were determinants of non-use of antiplatelet drugs after a first ischemic stroke; while age, hypertension, history of heart failure, year of diagnosis, previous use of antiplatelet drugs and oral anticoagulants were determinants of non-use of antiplatelet drugs after a first TIA. Chapter 3 presents the results of effectiveness and safety studies on antiplatelet drugs in daily clinical practice. The comparative effectiveness and safety of antiplatelet regimens as secondary prevention after a first ischemic stroke or TIA are described in Chapter 3.1. We conducted a retrospective cohort study in the CPRD database with 20,542 patients who were hospitalized for ischemic stroke or TIA who started an antiplatelet drug within 90 days
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after the diagnosis. Aspirin-only (HR 1.19, 95%CI 1.05-1.34) and clopidogrel-only (HR 1.21, 1.05-1.40) regimens were less effective compared to aspirin-dipyridamole in reducing the risk of ischemic stroke, while the aspirin-clopidogrel regimen was not statistically different (HR 1.13, 0.93-1.37). Clopidogrel-only (HR 1.41, 1.17-1.70) and aspirin-clopidogrel (HR 1.66, 1.29-2.13) regimens were associated with a higher risk of major bleeding compared to aspirin-dipyridamole in patients without previous major bleeding. Aspirin-dipyridamole regimen appears to have a favourable benefit-risk profile for secondary prevention after a first ischemic stroke or TIA compared to the other antiplatelet regimens. A matched case-control study was conducted in the AmsteRdam REsuscitation STudies (ARREST) dataset and the Dutch PHARMO record linkage System to assess the association between the use of antiplatelet drugs and out-of-hospital sudden cardiac arrest with ventricular tachycardia/ventricular fibrillation (VT/VF-OHSCA) in patients with coronary artery diseases (CAD) (Chapter 3.2). Current use of antiplatelet drugs as a group was not associated with the risk of VT/VF-OHSCA (OR 1.00, 95%CI 0.75-1.32) compared to no antiplatelet drug use. Current use of aspirin monotherapy was significantly associated with a lower risk of VT/VF-OHSCA (OR 0.72, 0.53-0.98), while current use of carbasalate calcium monotherapy was associated with a higher risk (OR 1.35, 1.01-1.82) compared to non-use. Carbasalate calcium is converted rapidly to acetylsalicylic acid after absorption, and the pharmacokinetics of carbasalate calcium is the same as aspirin from that point. Therefore, the higher risk of carbasalate calcium might be caused by residual confounding. In addition, the use of carbasalate calcium is declining in the Netherlands. This finding strengthens the basis of recommendation for the lifelong use of aspirin in CAD patients. Chapter 4 contains studies assessing the role of genetic factors in the effectiveness of antiplatelet drugs as secondary prevention of cardiovascular diseases. The pharmacogenomics of oral antiplatelet drugs in the treatment of CAD was reviewed in Chapter 4.1. A large number of studies and several meta-analyses have been published on this topic, but until recently, there have been no clear conclusions and no definite guidelines on the clinical use of pharmacogenetic testing before prescribing antiplatelet drugs for CAD. There are no genetic polymorphisms consistently associated with the effect of aspirin. For clopidogrel, the most consistent results are shown for the CYP2C19 genetic polymorphism. The CYP2C19 loss-of-function (LOF) alleles have been shown to be consistently associated with stent thrombosis events when patients are treated with clopidogrel. Meanwhile, there are no genetic polymorphisms associated with prasugrel and ticagrelor. Despite the consistent results with clopidogrel, there is no formal recommendation to genotype patients before starting clopidogrel treatment. In the near future, we expect a more certain recommendation can be provided when more results are available from cost-effectiveness studies comparing genotypeguided antiplatelet therapy with standard therapy in patients with CAD who undergo percutaneous coronary intervention (PCI) and stenting. The associations between on-treatment platelet reactivity and the CYP3A4*22 allele and genetic variations of the PPAR- gene (G209A and A208G) were investigated in 1126 clopidogrel-treated patients undergoing non-urgent PCI with stenting (Chapter 4.2). Platelet reactivity was measured using the VerifyNow® P2Y12-assay. A recessive model was used for all associations. CYP3A4*22 was not associated with platelet
reactivity. PPAR- genetic variants were significantly associated with platelet reactivity (PPAR- G209A AA: -23.87 PRU [-43.54, -4.19]; PPAR- A208G GG: -23.70 PRU [-43.13, -4.27]). The influence of co-medication with clopidogrel and statin/fibrate on these associations was also evaluated. In patients who were co-treated with clopidogrel and statin/fibrate, these PPAR- genetic variants were associated with a lower platelet reactivity (-29.74 PRU [-50.94, -8.54], and -29.38 PRU [-50.26, -8.49], respectively), while those who were treated with clopidogrel without statin/fibrate co-medication did not show a significant change in platelet reactivity (13.00 PRU [-39.79, 65.80]). It can be concluded that the genetic variants in PPAR- (G209A and A208G) were associated with lower platelet reactivity in patients with non-urgent PCI and stenting co-treated with clopidogrel and lipid-lowering drugs. In Chapter 4.3, the interaction between PPAR- G209A genetic variant and co-use of clopidogrel and statin/fibrate in reducing the risk of recurrent cardiovascular event (MI, unstable angina, or ischemic stroke) was evaluated in 907 patients with ACS. This explorative retrospective cohort study was conducted in patients from the UCP cohort who had a first diagnosis of ACS during 1998-2009. The exposure was clopidogrel and statin/fibrate co-use, assessed as a time-dependent variable. A recessive model was used for the association. The homozygous carriers of PPAR- G209A minor allele who co-used clopidogrel and statin/fibrate had a lower risk of recurrent cardiovascular events compared to the heterozygous or non-carriers who did not use both drugs (HRint 0.25, 95%CI 0.03-2.32), but the association was not Statistically Significant. It can be concluded that there was no interaction between the PPAR- G209A genetic variant and co-use of clopidogrel and statin/fibrate in reducing the risk of recurrent cardiovascular events in patients with ACS. This study had a small Sample Size with low power. A study with larger sample size is needed to evaluate the association with adequate statistical power. Afterwards, if the results of this larger study appear to be statistically significant, a replication study is needed to confirm the results. Chapter 4.4 presents a review on the application of routine electronic health record (EHR) databases for pharmacogenetic research. The review described the concept of pharmacogenetics, gene selection, and study design for pharmacogenetic research; summarized the potential of linking pharmacoepidemiology and pharmacogenetics, along with its strengths and limitations; and provided examples of pharmacogenetic studies utilizing EHR databases. Three models of the EHR database use were suggested: (1) subjects are selected from EHR in which information on drug use and medical diagnoses are available, and then the subjects are invited to provide lifestyle and genotype data, (2) subjects are invited for a pharmacogenetics study, the information on lifestyle and a biological sample for genotyping are collected directly, and then information on drugs and morbidity is obtained from EHR, (3) information on lifestyle and genotype is obtained from a biobank (from previous large cohort/ case-control/RCTs, ongoing population health surveys, or routine genotyping data in hospitals), and then information on drugs and morbidity is collected from EHR. In Chapter 5, the main findings of our studies are summarized, the methodological issues in conducting observational studies on antiplatelet drugs as secondary prevention are discussed, and lastly, the knowledge we obtained from our studies are brought to a practical clinical perspective and directions for future research are recommended.
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Acknowledgements Bismillahirrahmanirrahim. Alhamdulillahi rabbil alamin. First of all, I want to thank Allah SWT for all the blessings and guidance during my whole life, and particularly during the exciting, sometimes frustrating, but also enjoyable, PhD years. I could not get this far without the help and guidance from my supervisors. Prof. Ton de Boer, I still remember how kind and helpful you were when I sent you an email in 2010, asking about a PhD position in your Division. You were willing to help me to apply for various scholarships, until finally I secured a scholarship from the Dikti-Neso to start the PhD journey in 2012. During the journey itself, you were not only a (very) perfectionist supervisor for my research (and publications), but also an advisor and, most of the times, problem solver for other issues outside of the research work. Prof. Olaf Klungel, the beginning of learning of (pharmaco-)epidemiological methods really started when I was under your supervision. I started as a very clueless PhD student in methods, looking blank when you're suggesting some analyses I had never heard of, and then went back to my desk and studied everything about those methods so that I could give you some results at the next meeting. I might be still clueless right now, but at least I can answer some of your methodological questions. I am still awed by your breadth of knowledge, your on point critics, and your sunny personality. Dr. Vera Deneer, as a hospital pharmacist and an expert in genetic studies you have access to past and ongoing genetic studies in your hospital. I feel so lucky that I was given the opportunity to write a review with you and conduct research on one of the many genetic study cohorts in your hospital. As a supervisor, you are very patient, critical, and thorough; and you were always worried of whether I liked and enjoyed what I was working on (which I of course did!). To all three of you, thank you for willing to deal with my dumb questions and dramatic attitude, and thank you for being the academics I aspire to become. I would like to thank the members of my reading committee, Prof. dr. B. Wilffert, Prof. dr. Y. van der Graf, Prof. dr. F.W. Asselbergs, Prof. dr. H.G.M. Leufkens, and Prof. dr. M.L. Bouvy for reading my thesis book and become the members of the committee. I would also like to thank Norazida Ab Rahman, dr. Thomas O. Bergmeijer, Dr. Marieke T. Blom, Dr. Rolf H. H. Groenwold, Dr. Christian M. Hackeng, dr. Paul W. A. Janssen, Prof. Anke-Hilse Maitland-van der Zee, Dr. Han L. Tan, Dr. Jurrien M. ten Berg, Prof. Tjeerd P. van Staa, and dr. Gerrit J. A. Vos for their valuable contribution in the studies and articles in this thesis. Also a considerable gratitude for Dr. Patrick Souverein, without whose kind help I would not have been able to do some of the studies in this thesis: from your input on the protocol, data collection, program writing, data analysis, to your criticism for the article drafts. I practically buried you in thousands of questions, and you patiently explained everything, sometimes more than once because I am so forgetful. Thank you very much for Dr. Svetlana Belitser who was willing to sit with me at my desk to discuss the time-dependent analysis with R. I would like to extend special gratitude to Prof. dr. Iwan Dwiprahasto, Prof. Mustofa, and Dr. Erna Kristin for all the inspiring motivation and advice these whole years. 269
I do not know how to thank these two persons enough: my paranimfen and my best friends, Adi and Bakhri. Adi has started his PhD journey together with me in September 2012, coming to the Netherlands with lots of luggage and thousands of worries on whether we had made the right decision (which now we think we did!); but our friendship (which includes many quarrels) seemed to start since I was born, because I do not remember how I lived before we met. Bakhri started the PhD journey a year later, adding one more best friend to rely on. Without the two of you, I might have still finished my PhD, but with a lot of mental damage. To my good friends in the Netherlands: Julia, Putri, Eko, Tom, Yared, and Nina. Julia, I miss our gossip talks and fangirling over K-drama and TV series, see you soon! Putri, that New Year party in your apartment really rocked! We should do it again sometime, but now in some nice secluded and relaxing place in Eastern Indonesia. Eko, I miss traveling with a semi-pro photographer following me around! Tom, my best bookworm buddy in the Netherlands, who kept arguing everything I said. Go finish your PhD quickly, so we can visit you in your home country. Yared, I am still amused by your astoundingly eclectic knowledge of everything: music, movies, books, places, and practically anything. Chatting and traveling with you are both entertaining and enlightening. Nina, I enjoy eating out, going to cinemas, or just sitting down and listening to your hilarious quips! To the amazing ladies in the Secretariaat of the Division: Suzanne, Ineke and Anja, thank you for your kindness and patience dealing with my many requests during my studies, including booking dates and lecture rooms while I was a DIMI master. I have enjoyed working, talking, and having lunch with my fellow PhD students and postdocs: Ali, Arif, Delphi, Fariba, Fawaz, Geert, Gert-Jan, Hamid, Hedy, Heshu, Jamal, Jet, Joost, Joris, Katerina, Lotte, Lourens, Mariette, Nilufar, Paul, Renate, Rianne, Richelle, Sanni, Sulmaz, Susanne, Teresa, Turki, Veronica, Yaser, and Yumao. A very big thanks to Sander who wrote the translation of my thesis title; I really enjoyed and missed having you as my deskmate, you're so funny and sarcastic! Special thanks to Andhyk who spared his valuable time to help me during the end of my PhD studentship. I will also not forget the international PhD students who used to sit on the flex desks behind me: Verica, Claudia Vargas Pelaez, Julien, Rasmus, and Claudia Spatari; three of them already obtained their PhDs. Hail to the fellow Dikti-Nesoers 2012: Bu Lili, Ajeng, Galuh, and Pak Budi; plus Richo, who is actually Diktiers 2012 but he's always in the Dikti Nesoers mailing list. Despite all the problems we had to deal with, we've finally made it (for Richo) or almost made it (for the others)! After this, I guess nothing can beat us, yes? I am very grateful to my wonderful landlord/landladies and housemates: Bu Dewi, the Yigit's family, Jip's family, and Sander-Marianne-Anoek, who are the nicest young Dutch I ever lived with. The Netherlands feels like home because of the enjoyable time spent with the Indonesian students and families: Ariyadi, Andi Yani, Sugih, Tante Nanda & Oom Richard, Mas Andi's family, Mas Arie's family, Ceu Rina, Vita's family, Ari Susanti & Mas Raymond, Ary Savitri's family, the IMPOMErs (Ismi, Cici, Ronal, Said, Wahid, Rudi), Dowty & Opik, Irene, Galih, Widya, Felis, and other Indonesian Utrechtsers. 270
A huge thanks to Renny Aditya, an obstetrician who always has time to take photos, and was willing to volunteer her busy time to make a good cover photo for my thesis. Thank you to those people who listened and made fun of all my complaints and sad/ funny stories of PhD life: the Pharma crew (Anna, Ida, Rina, Jojo, Nisa, Kak Nunuy, Pak Pagan, Hendra, Bu Isna, Pak Agung), Gustaf and the Emergency Room (ex-)crew, the KuBuGil `n friends, the B5ers, and the Plurkians gank. You guys made me laugh when I was feeling down. Of course, the biggest appreciation is for my family. Mom, all my achievements are always dedicated to you, the smartest yet the humblest person on earth. You are my inspiration, my role model, and the lighthouse in my darkest and tempestous times. This thesis is for you. I am so proud of you and Grandma who, in the community who is not used to have their female family members attend higher education, always support all my choices and let their daughter/granddaughter travel far and wide to study and experience other cultures. I am also grateful for the continuous love and support from the rest of the Asykiyah family: my sister Nunus & family (Khair, Nabilah, Latifah), Acil Ati & family (Nida, Kiki, Nadya, Amat, Athiyya), and the Jember cousins (Ditto, Oddie, Mita). I am back again. 271

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