ABSTRACT
BACKGROUND: Excess vascular deaths in the PLATO trial comparing ticagrelor to clopidogrel have been repeatedly challenged by the Food and Drug Administration (FDA) reviewers and academia. Based on the Freedom of Information Act, BuzzFeed won a court order and shared with us the complete list of reported deaths for the ticagrelor FDA New Drug Application (NDA) 22-433. This dataset was matched against local patient-level records from PLATO sites monitored by the sponsor. STUDY QUESTION: Whether FDA death data in the PLATO trial matched the local site records. STUDY DESIGN: The NDA spreadsheet contains 938 precisely detailed PLATO deaths. We obtained and validated local evidence for 52 deaths among 861 PLATO patients from 14 enrolling sites in 8 countries and matched those with the official NDA dataset submitted to the FDA. MEASURES AND OUTCOMES: Existence, precise time, and primary cause of deaths in PLATO. RESULTS: Discrepant to the NDA document, sites confirmed 2 extra unreported deaths (Poland and Korea) and failed to confirm 4 deaths (Malaysia). Of the remaining 46 deaths, dates were reported correctly for 42 patients, earlier (2 clopidogrel), or later (2 ticagrelor) than the actual occurrence of death. In 12 clopidogrel patients, cause of death was changed to "vascular," whereas 6 NDA ticagrelor "nonvascular" or "unknown" deaths were site-reported as of "vascular" origin. Sudden death was incorrectly reported in 4 clopidogrel patients, but omitted in 4 ticagrelor patients directly affecting the primary efficacy PLATO endpoint. CONCLUSIONS: Many deaths were inaccurately reported in PLATO favoring ticagrelor. The full extent of mortality misreporting is currently unclear, while especially worrisome is a mismatch in identifying primary death cause. Because all PLATO events are kept in the cloud electronic Medidata Rave capture system, securing the database content, examining the dataset changes or/and repeated entries, identifying potential interference origin, and assessing full magnitude of the problem are warranted.
Subject(s)
Acute Coronary Syndrome/mortality , Cause of Death , Data Accuracy , Platelet Aggregation Inhibitors/administration & dosage , Acute Coronary Syndrome/complications , Acute Coronary Syndrome/drug therapy , Clinical Trials, Phase III as Topic , Clopidogrel/administration & dosage , Clopidogrel/adverse effects , Datasets as Topic , Drug Approval , Humans , Platelet Aggregation Inhibitors/adverse effects , Randomized Controlled Trials as Topic , Ticagrelor/administration & dosage , Ticagrelor/adverse effects , Treatment Outcome , United States , United States Food and Drug Administration/legislation & jurisprudence , United States Food and Drug Administration/standardsABSTRACT
BACKGROUND AND OBJECTIVES: Placement of drug-eluting stents (DES) can be complicated by stent thrombosis; prophylactic antiplatelet therapy has been used to prevent such events. We evaluated the efficacy of cilostazol with regard to stent thrombosis as adjunctive antiplatelet therapy. SUBJECTS AND METHODS: A total of 1,315 patients (846 males, 469 females) were prospectively enrolled and analyzed for the frequency of stent thrombosis. Patients with known risk factors for stent thrombosis, except diabetes and acute coronary syndrome, were excluded from the study. All patients maintained antiplatelet therapy for at least six months. To evaluate the effects of cilostazol as another option for antiplatelet therapy, triple antiplatelet therapy (aspirin+clopidogrel+cilostazol, n=502) was compared to dual antiplatelet therapy (aspirin+clopidogrel, n=813). Six months after stent placement, all patients received only two antiplatelet drugs: treatment either with cilostazol+aspirin (cilostazol group) or clopidogrel+aspirin (clopidogrel group). There were 1,033 patients (396 in cilostazol group and 637 in clopidogrel group) that maintained antiplatelet therapy for at least 12 months and were included in this study. Stent thrombosis was defined and classified according to the definition reported by the Academic Research Consortium (ARC). RESULTS: defined and classified according to the definition reported by the Academic Research Consortium (ARC). RESULTS: During follow-up (561.7+/-251.4 days), 15 patients (1.14%) developed stent thrombosis between day 1 to day 657. Stent thrombosis occurred in seven patients (1.39%) on triple antiplatelet therapy and four patients (0.49%) on dual antiplatelet therapy (p=NS) within the first six months after stenting. Six months and later, after stent implantation, one patient (0.25%) developed stent thrombosis in the cilostazol group, and three (0.47%) in the clopidogrel group (p=NS). CONCLUSION: During the first six months after DES triple antiplatelet therapy may be more effective than dual antiplatelet therapy for the prevention of stent thrombosis. However, after the first six months, dual antiplatelet treatment, with aspirin and cilostazol, may have a better cost benefit ratio for the prevention of stent thrombosis.
