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Dual Antiplatelet Therapy in Patients With Prior Myocardial Infarction: The Twilight of Prolonged DAPT Duration? Free Access

Editorial Comment

J Am Coll Cardiol Intv, 15 (3) 294–296
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Introduction

For the past 2 decades, dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor inhibitor has become the standard antithrombotic regimen for patients with acute coronary syndromes (ACS) or undergoing percutaneous coronary intervention (PCI). Yet despite a vast amount of clinical research, the optimal duration of DAPT after ACS or PCI is still controversial. Two key factors in determining the recommended DAPT duration for an individual patient are bleeding risk and thrombotic risk. High bleeding risk (HBR) criteria for patients undergoing PCI have been recently defined and well validated.1,2 Development of thrombotic risk scores with consistent predictive performance has been more challenging, and most scores have displayed moderate levels of discrimination for thrombotic events.3,4 However, several clinical factors have been consistently shown to confer high risk for thrombotic events after PCI, including prior myocardial infarction (MI) or PCI, ACS presentation, diabetes, and renal dysfunction.3-5

Patients who have had MI are at increased long-term risk for recurrent atherothrombotic events.6,7 This increased risk is partly mediated by enhanced platelet reactivity and a proinflammatory state. For this reason, prolonged DAPT strategies have been advocated for patients with prior MI. The PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin–Thrombolysis In Myocardial Infarction 54) trial, as well as a large meta-analysis that followed it, showed that extended DAPT in patients with prior MI reduced the risk for ischemic events, including recurrent MI, stroke, and cardiovascular death, but increased the risk for major bleeding.8,9 Thus, extended DAPT strategies may apply to some patients with histories of MI, especially those with low bleeding risk.

In this issue of JACC: Cardiovascular Interventions, Chiarito et al10 add important information regarding DAPT in this unique subgroup of patients. They report a prespecified subgroup analysis of the TWILIGHT (Ticagrelor With Aspirin or Alone in High-Risk Patients After Coronary Intervention) trial,11 focusing on patients with histories of MI. The TWILIGHT trial examined high-risk patients who underwent PCI and completed 3 months of DAPT and showed that ticagrelor monotherapy reduced the risk for bleeding without an increase in ischemic events compared with continued DAPT. The present analysis shows that about 30% of the original TWILIGHT study cohort had previous MI, and indeed, their rate of ischemic events (death, MI, or stroke) at 1 year after randomization was almost twice as high as among those without previous MI (5.7% vs 3.2%). Despite the overall higher risk for ischemic events, the results of the present subanalysis reflect very closely the results of the whole TWILIGHT study, with a significant reduction in the risk for Bleeding Academic Research Consortium type 2, 3, or 5 bleeding (3.4% with ticagrelor monotherapy vs 6.7% with continued DAPT), with no difference in ischemic events (6.0% vs 5.5%). The same balance between reduced bleeding without a difference in ischemic events was also maintained in patients with prior MI who met the PEGASUS-TIMI 54 inclusion criteria.8

Several limitations are important to note regarding this study. First, the original TWILIGHT study was not powered to detect differences in ischemic events (the analysis was based on a prespecified noninferiority hypothesis), so the present subgroup analysis with a smaller sample size is definitely not powered for this endpoint. Therefore, the “ischemic cost” of ticagrelor monotherapy in post-MI patients needs further evaluation in larger studies. The small sample size also limits the ability to detect clinically relevant differences in rare but important adverse events such as stent thrombosis and ischemic stroke. Despite these limitations, the study highlights the potential benefit of ticagrelor monotherapy after 3 months of DAPT in patients with prior MI. It is rather unexpected that this high-risk group of patients, often considered for extended antithrombotic regimens,5 appears to benefit from an abbreviated DAPT protocol.

Ticagrelor has unique pharmacodynamic properties that may facilitate its use as single-antiplatelet therapy without coadministration with aspirin. In contrast to clopidogrel, the phenomenon of low response to the drug is practically nonexistent with ticagrelor.12 In fact, ticagrelor therapy overcomes nonresponse to clopidogrel.12 Furthermore, the overall hemostatic effect of ticagrelor alone appears to be comparable with that of the combination of ticagrelor and aspirin. In healthy subjects, ticagrelor alone reduced parameters of hemostatic system activation, such as β-thromboglobulin and prothrombin fragment 1.2 to a similar degree as ticagrelor and aspirin.13 In patients undergoing PCI, ticagrelor alone compared with ticagrelor plus aspirin was associated with similar levels of inhibition of most platelet activation pathways.14 These pharmacodynamic and hemostatic studies support the use of ticagrelor monotherapy as an alternative to prolonged DAPT.

In patients with HBR, abbreviated DAPT protocols of 1 to 3 months following PCI have been shown to substantially reduce the risk for major bleeding, without an increase in ischemic events,15,16 and are therefore clinically recommended.5 In other patients, including those with increased thrombotic risk, the optimal DAPT duration and the type of single-antiplatelet therapy afterward (aspirin or P2Y12 inhibitor) are still debatable. It should be noted that the TWILIGHT study population by definition was at high risk for ischemic or bleeding events.11 Recent meta-analyses of DAPT duration following PCI have generally shown that 1 to 3 months of DAPT followed by P2Y12 inhibitor monotherapy is associated with lower major bleeding and similar risk for ischemic events compared with prolonged DAPT, across a wide range of risk profiles.17 Furthermore, in a recent large pooled dataset, compared with short DAPT durations, 1 year of DAPT was not associated with reduced ischemic events in any risk stratum (including ACS) but was associated with increased bleeding events in patients with HBR.18 The present study lends support to a strategy of short DAPT duration followed by P2Y12 inhibitor monotherapy in patients with histories of MI, generally considered to be at high risk for thrombotic events. The pendulum thus appears to be swinging toward shorter DAPT duration not only in patients with HBR but in other populations as well. Future approaches will need to further refine and personalize the decision-making process for antiplatelet therapy duration following PCI.

Funding Support and Author Disclosures

The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

References

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Footnotes

The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center.