Mortality and Antithrombotics: Focus on FAERS Repository

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Presentation transcript:

Mortality and Antithrombotics: Focus on FAERS Repository Victor Serebruany, MD, PhD Owner, HeartDrug™ Research LLC; Johns Hopkins University; Busan, December 10, 2016

Limitations of Clinical Trials Small sample size; Heavily selective population; Lack of elderly, children, pregnancy, co-morbidities, impaired renal function; Narrow indications; Short duration, no chronic use; Potential industry bias

FDA Postmarketing Surveillance Drug Utilization data External databases: Passive Surveillance (FAERS) Active Surveillance Background Incidence Rates

FAERS FDA Adverse Event Reporting System (FAERS) Voluntary, “spontaneous” reporting system Sponsors required to report (21CFR314.80) Computerized database Origin 1969; > 7.5 million reports Contains human drug and “therapeutic” biologic reports Exception - vaccines (VAERS)

FAERS Strengths Open to public Includes all U.S. marketed products Simple, inexpensive reporting system Detection of events not seen in clinical trials (“signal generation”) Especially good for events with rare background rate, short latency Case series evaluation: identification of trends, drug indication, population, and other clinically significant emerging safety concerns Open to public

FAERS Limitations Duplicate reporting; Extensive underreporting; Quality of report is variable; Reporting biases; Difficult to attribute events with a high background rate, confounders, long latency outcomes; Hard to mine effectively

FDA should monitor FAERS Daily “in-box” review of reports All serious unlabeled reports; Serious directreports; Periodic and “enhanced pharmacovigilance” reports Periodic safety reports Main mission: identify and monitor “Safety Signals” Work with epidemiologists, and medical officers

Objective: Assess mortality with antithrombotics in FAERS Clopidogrel vs. Prasugrel vs. Ticagrelor NOACs vs. Warfarin Dabigatran vs. Rivaroxiban vs. Apixaban vs. Edoxaban vs. Warfarin

Total fatalities co-reported with oral P2Y12 inhibitors in FAERS Drug Cases (n) Deaths (n/%) Chi-square p-value PRR (95%-CI) ROR (95% - CI) _________________________________________________________________________________________ Clopidogrel 108,081 12,538; 11.6% 5.59 0.018 0.935 (0.885- 0.988) 0.927 (0.870- 0.987) Prasugrel 7,562 635; 8.4% 71.35 < 0.00001 0.678 (0.619- 0.742) 0.648 (0.586-0.717) Ticagrelor 9,860 1.222; 12.4% - - 1.000 1.000

Annual 2015 deaths co-reported with oral P2Y12 inhibitors in FAERS Drug Cases (n) Deaths (n/%) Chi-square p-value PRR (95%-CI) ROR (95% - CI) _________________________________________________________________________________________ Clopidogrel 13,234 1,156; 8.7% 86.33 <0.00001 0.596 (0.535- 0.664) 0.558 (0.492- 0.631) Prasugrel 2,927 151; 5.2% 93.49 < 0.00001 0.425 (0.355- 0.508) 0.386 (0.317-0.471) Ticagrelor 2,607 382; 14.7% - - 1.000 1.000

Death events co-reported with NOACs and warfarin in FAERS. Drug Total Cases (n) Deaths (n;%) chi-square p-value PRR (95% CI) ____________________________________________________________________________ Dabigatran 46,250 6,989 (15.11%) 185.2 3.61e-42 0.838 (0.817 - 0.860) Rivaroxaban 64,512 6,318 (9.79%) 359.4 3.72e-80 1.293 (1.259 - 1.328) Apixaban 17,789 1,693 (9.52%) 145.8 1.43e-33 1.331 (1.269 - 1.395) Edoxaban 755 53 (7.02%) 21.2 4.18e-06 1.804 (1.391 - 2.340) All NOACs 128,267 14,917 (11.63%) 70.0 6.05e-17 1.089 (1.067 - 1.111) Warfarin 153,911 19,493 (12.67%) - - 1.000

Conclusions: Total and 2015 annual fatalities in FAERS are higher after ticagrelor than with clopidogrel, challenging PLATO trial results Prasugrel is linked to remarkably less deaths than ticagrelor NOACs appear to be associated with a mild mortality benefit over warfarin Among NOACs FAERS reveals favorable trends for factor-Xa inhibitors (apixaban, rivaroxaban, and edoxaban), but unfavorable signal for the direct thrombin inhibitor (dabigatran)