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Mortality and Antithrombotics: Focus on FAERS Repository

Mortality and Antithrombotics: Focus on FAERS Repository. Victor Serebruany, MD , PhD Owner, Heart Drug ™ Research LLC; Johns Hopkins University; Busan, December 10, 2016. Limitations of Clinical Trials. Small sample size; Heavily selective population;

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Mortality and Antithrombotics: Focus on FAERS Repository

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

  2. 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

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

  4. 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)

  5. FAERS Strengths • 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

  6. 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

  7. 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, andmedical officers

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

  9. Total fatalities co-reported with oral P2Y12 inhibitors in FAERS DrugCases (n) Deaths (n/%) Chi-square p-value PRR (95%-CI) ROR (95% - CI) _________________________________________________________________________________________ Clopidogrel 108,081 12,538; 11.6%5.590.0180.935 (0.885- 0.988) 0.927 (0.870- 0.987) Prasugrel7,562635; 8.4%71.35 < 0.000010.678 (0.619- 0.742) 0.648 (0.586-0.717) Ticagrelor9,8601.222; 12.4%- - 1.000 1.000 _________________________________________________________________________________________

  10. Annual 2015 deaths co-reported with oral P2Y12 inhibitors in FAERS DrugCases (n) Deaths (n/%) Chi-square p-value PRR (95%-CI) ROR (95% - CI) _________________________________________________________________________________________ Clopidogrel 13,234 1,156; 8.7%86.33<0.000010.596 (0.535- 0.664) 0.558 (0.492- 0.631) Prasugrel2,927 151; 5.2%93.49 < 0.00001 0.425 (0.355- 0.508) 0.386 (0.317-0.471) Ticagrelor2,607382; 14.7%- - 1.000 1.000 _________________________________________________________________________________________

  11. Death events co-reported with NOACs and warfarin in FAERS. • Drug Total Cases (n) Deaths (n;%) chi-square p-value PRR (95% CI) • ____________________________________________________________________________ • Dabigatran46,250 6,989 (15.11%) 185.23.61e-42 0.838 (0.817 - 0.860) • Rivaroxaban 64,512 6,318 (9.79%) 359.43.72e-80 1.293 (1.259 - 1.328) • Apixaban 17,789 1,693 (9.52%) 145.81.43e-33 1.331 (1.269 - 1.395) • Edoxaban755 53 (7.02%) 21.24.18e-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 • ____________________________________________________________________________

  12. 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-Xainhibitors (apixaban, rivaroxaban, and edoxaban), but unfavorable signal for the direct thrombin inhibitor (dabigatran)

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