Excess Ticagrelor Mortality: Reporting Bias or a Canary in the Coal Mine?

The commentary by Serebruany et al1Serebruany 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; ([e-pub ahead of print])https://doi.org/10.1016/j.amjmed.2016.12.037Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar 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. The authors reported that for 2015, the rate of ticagrelor deaths was about 40% higher compared with clopidogrel, and almost tripled compared with prasugrel, “providing strikingly significant P-values.” To support the integrity of the analysis, the authors stated:1.The number sufficient to validate the analysis.2.The quantity of FAERS reports for each drug is clearly a reflection of the current clinical utilization of oral P2Y12 antiplatelet agent.a)This would only be correct if the reporting rate can be assumed to be identical across the 3 products. With 20, 8, and 6 years,2U.S. Food & Drug Administration[email protected]: FDA approved drug products.http://www.accessdata.fda.gov/scripts/cder/daf/Google Scholar respectively, and a different adverse event profile, this assumption could introduce bias. The only conclusion that can be drawn from the presented analysis is that the rate of fatal vs nonfatal adverse events for the 3 products is highly statistical different. The authors call for real-world evidence to be used for regulatory decisions. However, real-world evidence needs to be based on well-designed, prospective protocols and analyzed with appropriate statistical methods controlling for the relevant confounders. The largest reported real-world evidence study of the relative death rate in acute coronary syndrome patients treated with clopidogrel or ticagrelor was published by Sahlén et al,3Sahlén 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 who reported that a cumulative risk of death from any cause over 24 months was significantly lower in the ticagrelor group (5.8% vs 12.9%, adjusted hazard ratio 0.83; 95% confidence interval, 0.75-0.92). In the Editorial, Pareek and Bhatt4Pareek M. Bhatt D.L. Ticagrelor for patients with acute coronary syndromes: PLATOnic affair or lasting SWEDEHEART?.Eur Heart J. 2016; 37: 3343-3346Crossref PubMed Scopus (9) Google Scholar wrote: “Sahlén et al should be commended on their report, which expertly uses registry data from SWEDEHEART to provide real-world confirmation of the findings from PLATO with respect to the benefits of ticagrelor in patients with acute coronary syndrome.” The finding by Serebruany et al1Serebruany 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; ([e-pub ahead of print])https://doi.org/10.1016/j.amjmed.2016.12.037Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar could be “a canary in the coal mine,” and their call for regulatory action by the FDA and statement: “Sometimes admitting a mistake and fixing the problem saves lives and reputation” is justified. However, if the mortality benefit in the PLATO study as the SWEDEHEART study seems to support is correct, then restriction of ticagrelor use would be detrimental to patient outcome. Serebruany and co-authors ought to heed their own advice. The ReplyThe American Journal of MedicineVol. 130Issue 8PreviewWe thank Hauch for his interest in our work.1 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. Full-Text PDF The ReplyThe American Journal of MedicineVol. 130Issue 8PreviewWe have a long history of disagreements regarding the comprehension of the Platelet Inhibition and Patient Outcomes (PLATO) trial results with the same group of authors. Considering that all our opponents receive substantial monies from the ticagrelor sponsor, it is always challenging to triage propaganda from sincere scientific debate. There are numerous examples of misunderstanding or deliberate misrepresentations of our work. In fact, death reporting in the FDA [Food and Drug Administration] Adverse Event Reporting System (FAERS) is not “voluntary,” and 2015 isn't a cherry-picked year without justification. Full-Text PDF Unreliable Observations from a Confounded Analysis of a Skewed DatabaseThe American Journal of MedicineVol. 130Issue 8PreviewSerebruany et al1 report on all-cause mortality rates in an observational US Food and Drug Administration (FDA) database, based on voluntary reporting of adverse events, and compare fatalities reported in patients treated with clopidogrel, prasugrel, and ticagrelor. Using this database, and examining unadjusted death rates with no attempt to adjust for any of the obvious major differences between groups likely to confound the comparisons made, they claim that patients receiving ticagrelor had a death rate 40% higher than those treated with clopidogrel and triple that of patients receiving prasugrel. Full-Text PDF