The Reply

Abstract

We thank Hauch for his interest in our work.1Serebruany V.L. Fortmann S.D. Cherepanov V. Litvinov O. Kim M.H. Marciniak T.A. Excess ticagrelor mortality in the Food and Drug Administration Adverse Event Reporting System: time to recount PLATO trial deaths.Am J Med. 2017; 130: e245-e246Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar First, there is an obvious conflict for the retired pharmaceutical outcome expert employed with the ticagrelor manufacturer for over 15 years, and now running a private consultant business, to defend the questionable drug. This looks like a fishing expedition to generate more business from the former employer. Second, the numbers of death reports, and the built-in-stone fact of consistent excess of ticagrelor fatalities in the FDA [Food and Drug Administration] Adverse Event Reporting System (FAERS) from launch until 2016 are not being challenged. The rest are differences in data interpretation, which are debatable but not critical for the comprehension of the real-life woeful survival risk after ticagrelor. Suggesting that the FDA-ruled international uniformed unbiased repository requiring mandatory death reporting contains random unreliable evidence, incapable of picking up true outcome trends, is either naïve or heavily biased. Third, we anticipated the continuation of vicious critique from staff ticagrelor defenders; therefore, we hired independent statisticians focusing exclusively on FAERS, to avoid the ground for unnecessary clashes. Indeed, there are advanced specifics in applied FAERS statistics, but we deliberately excuse ourselves from these tasks. Fourth, assessing the totality of the evidence with regard to ticagrelor mortality, the industry proponents always limit their analyses exclusively to the Platelet Inhibition and Patient Outcomes (PLATO) study and the Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies (SWEDEHEART), as if there are no other neutral or even negative randomized trials. In fact, such gross cherry picking is deliberate and misleading, because no other data suggest any benefit, or even a slight trend for better survival after ticagrelor. The SWEDEHEART registry shows one fact clearly—that in Sweden, ticagrelor is used in much lower-risk patients than clopidogrel. Should Swedish cardiologists truly believe in ticagrelor mortality benefit, then clopidogrel patients will not be 4 years older, experience more cancer, repeated myocardial infarctions, coronary artery bypass grafting, heart failure, and stroke than ticagrelor patients,2Sahlén A. Varenhorst C. Lagerqvist B. et al.Outcomes in patients treated with ticagrelor or clopidogrel after acute myocardial infarction: experiences from SWEDEHEART registry.Eur Heart J. 2016; 37: 3335-3342Crossref PubMed Scopus (123) Google Scholar making the FAERS results even more compelling. It is also unclear why prasugrel data are consistently not reported in SWEDEHEART, potentially indicating bias. We summarized the totality of evidence in the Table, which is not impressive for ticagrelor. To make things even worse, all studies were heavily controlled by the ticagrelor sponsor, challenging the declared benefit, in contrast to independent FAERS data. Finally, the expert is right, that verifying PLATO death numbers is a top priority, and a canary is not yet caught. Again, this is not the eCRFs or other trial-related paperwork, but physical patient recount and confirmation of an extreme 506 clopidogrel fatalities in PLATO,3Serebruany V.L. Paradoxical excess mortality in the PLATO trial should be independently verified.Thromb Haemost. 2011; 105: 752-759Crossref PubMed Scopus (64) Google Scholar which is even more justified now after PARTHENON program failures.TableAll-Cause Mortality and TicagrelorStudyTicagrelor (N/ACM; %)Control (N/ACM; %)ComparatorDISPERSE663/13; (2.0)327/4; (1.2)ClopidogrelPLATO9333/399; (4.5)9291/506; (5.9)ClopidogrelPEGASUS7050/326; (4.6)∗For 180 mg/daily arm.7067/326; (4.6)AspirinPHILO401/10; (2.5)400/7; (1.75)ClopidogrelEUCLID6930/628; (9.1)6955/635; (9.1)ClopidogrelSOCRATES6589/68; (1.0)6610/58; (0.9)AspirinSWEDEHEART (2010-2013)11,954/?†Exact number of deaths is not reported.; (5.8)33,119/?; (12.7)ClopidogrelFAERS (2015)2607/382; (14.7)2927/151; (5.2)Prasugrel13,234/1,156; (8.7)ClopidogrelFAERS – Total9860/1222; (12.4)7562/635; (8.4)Prasugrel108,081/12,538; (11.6)ClopidogrelACM = all-cause mortality; N = number of patients; % = per cent of fatalities.∗ For 180 mg/daily arm.† Exact number of deaths is not reported. Open table in a new tab ACM = all-cause mortality; N = number of patients; % = per cent of fatalities. Excess Ticagrelor Mortality: Reporting Bias or a Canary in the Coal Mine?The American Journal of MedicineVol. 130Issue 8PreviewThe commentary by Serebruany et al1 published online February 1, 2017 uses the US Food and Drug Administration (FDA) Adverse Event Reporting System repository to evaluate data on comparative mortality risks linked to the oral P2Y12 platelet inhibitors clopidogrel, prasugrel, and ticagrelor. Full-Text PDF