Net Adverse Clinical Events With Antiplatelet Therapy in Acute Coronary Syndromes

“Clopidogrel, prasugrel, and ticagrelor are oral platelet P2Y12 receptor inhibitors that decrease the risk of platelet-mediated coronary artery thrombosis.

[..] A 1-year composite end point of death, MI [myocardial infarction], and stroke is often used to evaluate efficacy in ACS [acute coronary syndrome] trials. However, death can be defined as all-cause death, cardiovascular death, or death from vascular causes (cardiovascular plus cerebrovascular deaths). Although ticagrelor was associated with a reduction in death in the PLATO trial, no subsequent trial with ticagrelor and no trials with clopidogrel or prasugrel have shown a mortality benefit with DAPT [dual antiplatelet therapy] compared with antiplatelet monotherapy, so it is not clear that death is a relevant end point in DAPT trials. Similarly, MI can variably be defined by international, professional society, or clinical trial definitions. The most recent debate concerns whether periprocedural MI detected by high-sensitivity troponin values is equivalent to spontaneous MI as a prognostic end point. Since there is no difference among antiplatelet agents in preventing ischemic stroke, and since hemorrhagic stroke risk is higher with ticagrelor and prasugrel compared with clopidogrel, stroke might better be a safety end point than an efficacy end point in DAPT trials. Therefore, the only consistent favorable efficacy outcome in DAPT trials has been reduction in MI rates across the different definitions of MI.

[..] major bleeding has also been defined differently in trials, with at least 10 definitions used, making it more difficult to compare studies. For instance, in PLATO, there was no difference in major bleeding when coronary artery bypass graft surgery–related bleeding was included, but there was a difference when coronary artery bypass graft surgery–related bleeding was excluded. Another trial reported benefit for a genotype-guided strategy for choosing oral P2Y12 receptor inhibitors in primary PCI when major and minor bleeding were combined as the primary end point, but there were no differences in the more traditional end point of major bleeding using 3 different definitions or in transfusion rates.

[..] Some clinical trialists oriented toward demonstrating efficacy have argued against this composite variable [adverse net clinical event rate in DAPT trials – the numerical difference between ischemic events avoided and excess bleeding events] based on the challenges in how to define events, the differential severity of events, and the high probability of a null value when combining efficacy and safety end points in antithrombotic therapy trials. Conversely, this equation is important to patients and clinicians in shared decision making, as are minor bleeding events and the copayment price for a drug prescription.

In this issue of JAMA, You and colleagues evaluated the net adverse clinical events associated with ticagrelor or clopidogrel among patients with ACS undergoing PCI in routine clinical practice. The authors performed a retrospective, propensity-matched, cohort analysis of 62,580 patients enrolled in 2 US electronic health-record databases and 1 nationwide South Korean administrative claims database. Net adverse clinical events were defined as a composite outcome of ischemic events (recurrent MI, revascularization, or ischemic stroke) and hemorrhagic events (hemorrhagic stroke or gastrointestinal bleeding). At 12 months, there was no difference in the primary outcome of net adverse clinical event rates between treatment groups (ticagrelor patients, 15.1% [3484/23 116 person-years] vs clopidogrel patients, 14.6% [3290/22 587 person-years]; summary hazard ratio, 1.05 [95% CI, 1.00-1.10]). In secondary analyses, there were no significant differences between treatment groups in the risk of all-cause mortality (2.0% in ticagrelor patients vs 2.1% in clopidogrel patients) or composite ischemic events (13.5% in ticagrelor patients vs 13.4% in clopidogrel patients), but ticagrelor was associated with significantly more hemorrhagic events (2.1% in ticagrelor patients vs 1.6% in clopidogrel patients), and more drug-related dyspnea (27.3% in ticagrelor patients vs 22.6% in clopidogrel patients).

[..] complete and accurate ascertainment of events and miscoding are uncorrectable limitations in such studies [like the You study]. Their conclusion of no added benefit associated with ticagrelor is consistent with prior studies from Canada, Korea, Japan, China, and the Netherlands that used different study designs to reach the same conclusion without attracting much clinical attention.

These results challenge the conventional wisdom promoted in clinical guidelines and communicated by thought leaders and in the media that ticagrelor is more effective than clopidogrel in DAPT. The interpretation of 2 randomized clinical trials that tested DAPT with ticagrelor against aspirin monotherapy for secondary prevention helps illustrate the clinical conundrum. Both of these trials reported 3-year outcomes instead of 1-year outcomes. One study enrolled 21,162 patients 1 to 3 years after MI with high-risk characteristics and concluded that DAPT compared with aspirin monotherapy was efficacious—a message amplified in multiple subsequent sub-study reports. However, the annualized efficacy benefit with ticagrelor, 90 mg, was 4.0 ischemic events prevented per 1000 patients treated or 4.2 ischemic events prevented per 1000 patients treated with ticagrelor, 60 mg. The annualized safety risk with ticagrelor, 90 mg, was 4.1 excess major bleeding events per 1000 patients treated or 3.1 excess major bleeding events per 1000 patients treated with ticagrelor, 60 mg. Minor bleeding and transfusion rates were 3- to 4-fold higher with ticagrelor (eg, transfusion occurred in 2.43% of patients who received 90 mg 2.09% with 60 mg vs 0.72% who received aspirin).

Another trial enrolled 19,220 patients with type 2 diabetes and high-risk characteristics and concluded that there was no significant difference in net adverse clinical events between DAPT with ticagrelor vs aspirin alone. The annualized efficacy benefit with ticagrelor compared with aspirin was 2.14 ischemic events prevented per 1000 patients treated, and the annualized safety risk was 2.73 major bleeding events per 1000 patients treated. The minor bleeding rate was increased with ticagrelor compared with aspirin (0.83% vs 0.30%), and there was an excess of intracerebral hemorrhage events (0.7% vs 0.5%; hazard ratio, 1.71; 95% CI, [1.18-2.48]). However, a prespecified sub-study analysis that included 58% of the patients who underwent prior PCI was published the same year and widely promoted as proving the benefit of DAPT despite being a sub-study report of a neutral trial. The US Food and Drug Administration has approved long-term DAPT with ticagrelor for secondary prevention in high-risk patients based on these trial results.

Efficacy results can be magnified by increasing trial sample sizes, extending the timeframe of the primary end point determination, reporting relative risk reductions (rather than absolute risk differences), and emphasizing the P value result (rather than point estimates and CIs). Efficacy results can be minimized by reporting 1-year absolute risk reductions and calculating the number needed to treat to prevent 1 event. Similarly, bleeding risk can be magnified by including more events in the bleeding definition or by including minor and nuisance bleeding. Bleeding risk can be minimized by limiting the types of bleeding events in the definition or by only counting major bleeding as significant. Whereas some have suggested that different events should be weighted differently in interpreting net adverse clinical event rates (ie, net clinical benefit), others have suggested that MI and major bleeding, the important efficacy and safety end points in DAPT randomized clinical trials, have equivalent prognostic value.

Ticagrelor has a more favorable pharmacodynamic profile than clopidogrel. However, compared with clopidogrel and prasugrel, ticagrelor may not demonstrate greater clinical benefit because of adverse effects (dyspnea), inconvenience (twice-daily dosing), or higher cost (clopidogrel and prasugrel are generics), which may decrease medication adherence. The pragmatic clinical recommendation, yet to be proven in randomized trials, may be to prescribe ticagrelor (or prasugrel because it was more effective than ticagrelor in one randomized trial) for patients with ACS, if the patient tolerates and can afford this medication, and to consider de-escalating to clopidogrel at 1 month after the greatest ischemic risk period has passed to decrease subsequent bleeding risk and cost. At 12 months, DAPT can be transitioned to low-risk aspirin monotherapy for secondary prevention.”

Full editorial, Bates ER. JAMA 2020.10.27