Impact of Bleeding on Myocardial Infarction, Stroke and Death During 12-months Dual Antiplatelet Therapy After Acute Coronary Syndrome


      • The overall annual bleeding rate for dual antiplatelet therapy is alarming 20.3%, exhibited in 19.2% patients with acute coronary syndrome;
      • Total bleeds were associated with almost twice less deaths and myocardial infarctions, while stroke risks were identical;
      • There was no statistical correlation between bleeding severity and outcomes or differences between ticagrelor and clopidogrel.



      Bleeding remains complication during dual antiplatelet therapy (DAPT) for acute coronary syndrome (ACS). Some data suggest a link between bleeding and worsened vascular outcomes. However, this association is unclear, due to omitting of minor bleedings when applying conservative scales. In contrast, Platelet Inhibition and Outcomes (PLATO) trial classification utilized broad realistic capturing of all bleedings.


      Access was gained to the FDA-issued adjudication dataset on which post hoc analyses of bleeding, MI, stroke and death was conducted. Bleeding was defined as minimal, minor, major and life-threatening or fatal (LTOF) as per the original PLATO scale.


      Among 18,624 enrollees, 10,705 adjudicated events occurred across 7,171 patients. There were 618 minimal, 1,412 minor, 1,216 major and 536 LTOF bleedings for the total of 3,782 events reported in 3,387 patients. There were 938 deaths, 2,751 MI's and 359 strokes. The overall bleeding was 20.3%, exhibited in 19.2% patients. Total bleeds were associated with less deaths (OR (95% CI): 0.55 (0.47 – 0.63)) and MI 0.47 (0.41 – 0.54; p < 0.001 for both). There were no differences in deaths (1.11 (0.93-1.34); p = 0.24), but less MI's (0.72 (0.59 – 0.86); p < 0.001), and more strokes (2.17 (1.64 – 2.88); p < 0.001) after LTOF. Major, minor and minimal bleeds were associated with less deaths and MI but not strokes.


      These large uniformly adjudicated data reveal that within 12-months of DAPT, one out of five patients experiences bleeding. Overall, bleeding was associated with diminished incidence of death and MI, but not strokes.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to The American Journal of Medicine
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Giustino G
        • Baber U
        • Sartori S
        • Mehran R
        • Mastoris I
        • Kini AS
        • Sharma SK
        • Pocock SJ
        • Dangas GD.
        Duration of dual antiplatelet therapy after drug-eluting stent implantation: a systematic review and meta-analysis of randomized controlled trials.
        J Am Coll Cardiol. 2015; 65: 1298-1310
        • Watanabe H
        • Domei T
        • Morimoto T
        • et al.
        for STOPDAPT-2 Investigators Effect of 1-Month Dual Antiplatelet Therapy Followed by Clopidogrel vs 12-Month Dual Antiplatelet Therapy on Cardiovascular and Bleeding Events in Patients Receiving PCI: The STOPDAPT-2 Randomized Clinical Trial.
        JAMA. 2019; 321: 2414-2427
        • Valgimigli M
        • Frigoli E
        • Dik Heg D
        • et al.
        for MASTER DAPT Investigators. Dual Antiplatelet Therapy after PCI in Patients at High Bleeding Risk.
        N Engl J Med. 2021; 385: 1643-1655
        • Mauri L
        • Kereiakes DJ
        • Yeh RW
        • Driscoll-Shempp P
        • Cutlip DE
        • Steg PG
        • Normand SL
        • Braunwald E
        • Wiviott SD
        • Cohen DJ
        • Holmes Jr, DR
        • Krucoff MW
        • Hermiller J
        • Dauerman HL
        • Simon DI
        • Kandzari DE
        • Garratt KN
        • Lee DP
        • Pow TK
        • Ver Lee P
        • Rinaldi MJ
        • Massaro JM
        DAPT Study Investigators. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents.
        N Engl J Med. 2014; 371: 2155-2166
        • Kamran H
        • Jneid H
        • Kayani WT
        • Virani SS
        • Levine GN
        • Nambi V
        • Khalid U.
        Oral Antiplatelet Therapy After Acute Coronary Syndrome: A Review.
        JAMA. 2021; 325: 1545-1555
        • Trifan G
        • Gorelick PB
        • Testai FD.
        Efficacy and Safety of Using Dual Versus Monotherapy Antiplatelet Agents in Secondary Stroke Prevention: Systematic Review and Meta-Analysis of Randomized Controlled Clinical Trials.
        Circulation. 2021; 143: 2441-2453
        • Simonsson M
        • Wallentin L
        • Alfredsson J
        • Erlinge D
        • Hellström Ängerud K
        • Hofmann R
        • Kellerth T
        • Lindhagen L
        • Ravn-Fischer A
        • Szummer K
        • Ueda P
        • Yndigegn T
        • Jernberg T
        Temporal trends in bleeding events in acute myocardial infarction: insights from the SWEDEHEART registry.
        Eur Heart J. 2020; 41: 833-843
        • Alexander D
        • Ou FS
        • Roe MT
        • Pollack Jr,, CV
        • Ohman EM
        • Cannon CP
        • Gibler WB
        • Fintel DJ
        • Peterson ED
        • Brown DL
        American College of Cardiology/American Heart Association. Use of and in-hospital outcomes after early clopidogrel therapy in patients not undergoing an early invasive strategy for treatment of non-ST-segment elevation myocardial infarction: results from Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the American College of Cardiology/American Heart Association guidelines (CRUSADE).
        Am Heart J. 2008; 156: 606-612
        • Serebruany V
        • Rao SV
        • Silva MA
        • Donovan JL
        • Kannan AO
        • Makarov L
        • Goto S
        • Atar D.
        Correlation of inhibition of platelet aggregation after clopidogrel with post discharge bleeding events: assessment by different bleeding classifications.
        Eur Heart J. 2010; 31: 227-235
        • Chew DP
        • Bhatt DL
        • Sapp S
        • Topol EJ.
        Increased mortality with oral platelet glycoprotein IIb/IIIa antagonists: a meta-analysis of phase III multicenter randomized trials.
        Circulation. 2001; 103: 201-206
        • Bhatt DL
        • Topol EJ.
        Current role of platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes.
        JAMA. 2000; 284: 1549-1558
        • Wallentin L
        • Becker RC
        • Budaj A
        • et al.
        Ticagrelor versus Clopidogrel in Patients with Acute Coronary Syndromes.
        N Engl J Med. 2009; 61: 1045-1057
      1. The FDA ticagrelor review of complete response. Available for download at: (Accessed February 4th, 2022)

      2. Brilinta Prescription Information: (Accessed February 4th, 2022)

      3. Plavix Prescription Information: (Accessed February 4th, 2022)

        • Rao AK
        • Pratt C
        • Berke A
        • Jaffe A
        • Ockene I
        • Schreiber TL
        • Bell WR
        • Knatterud G
        • Robertson TL
        • Terrin ML.
        Thrombolysis In Myocardial Infarction (TIMI) trial—phase I: hemorrhagic manifestations and changes in plasma fibrinogen and the fibrinolytic system in patients treated with recombinant tissue plasminogen activator and streptokinase.
        J Am Coll Cardiol. 1988; 11: 1-11
        • The GUSTO investigators
        An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction.
        N Engl J Med. 1993; 329: 673-682
        • Serebruany VL
        • Atar D.
        Assessment of bleeding events in clinical trials – proposal of a new classification.
        Am J Cardiol. 2007; 99: 288-290
        • Mehran R
        • Rao SV
        • Bhatt DL.
        • et al.
        Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium.
        Circulation. 2011; 123: 2736-2747
        • Marciniak TA
        • Cherepanov V
        • Golukhova E
        • Kim MH
        • Serebruany V.
        Drug Discontinuation and Follow-up Rates in Oral Antithrombotic Trials.
        JAMA Intern Med. 2016; 176: 257-259
        • Eikelboom JW
        • Mehta SR
        • Anand SS
        • Xie C
        • Fox KA
        • Yusuf S.
        Adverse impact of bleeding on prognosis in patients with acute coronary syndromes.
        Circulation. 2006; 114: 774-782