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
Selected in JAMA by D. Giacoppo
Results of the STOPDAPT-2 randomized clinical trial
References
Authors
Watanabe H, Domei T, Morimoto T, Natsuaki M, Shiomi H, Toyota T, Ohya M, Suwa S, Takagi K, Nanasato M, Hata Y, Yagi M, Suematsu N, Yokomatsu T, Takamisawa I, Doi M, Noda T, Okayama H, Seino Y, Tada T, Sakamoto H, Hibi K, Abe M, Kawai K, Nakao K, Ando K, Tanabe K, Ikari Y, Hanaoka KI, Morino Y, Kozuma K, Kadota K, Furukawa Y, Nakagawa Y, Kimura T; STOPDAPT-2 Investigators
Reference
JAMA. 2019 Jun 25;321(24):2414-2427
Published
June 2019
Link
Read the abstractReviewer
My Comment
Why this study – the rationale/objective?
Very short dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) with second-generation drug-eluting stent (DES) is an attractive option. Randomized clinical trials comparing DAPT regimens have generally shown an increased risk of bleeding after prolonged DAPT with possible implications on survival.
However, evidence supporting the comparable ischemic protection of very short and prolonged DAPT is limited. In addition, current evidence about short versus prolonged regimens mostly refers to DAPT versus aspirin monotherapy following P2Y12 platelet receptor inhibitor interruption.
The STOPDAPT-2 trial sought to compare 1 month of DAPT followed by clopidogrel monotherapy with 12 months of DAPT in patients undergoing PCI with second-generation DES.
How was it executed – the methodology?
The STOPDAPT-2 trial was a multicenter, open-label, adjudicator-blinded, randomized study comparing in a 1:1 ratio 1 month of DAPT (n = 1500) with 12 months of DAPT (n = 1509) in patients undergoing cobalt-chromium durable-polymer everolimus-eluting stent implantation. Randomization was performed during index hospitalization.
DAPT comprised of aspirin (81-200 mg once daily) and clopidogrel (75 mg once daily) or prasugrel (3.75 mg once daily) for the first month.
At 1 month (30-59 days), patients in the experimental group interrupted aspirin and continued clopidogrel as monotherapy. In both groups, when originally prescribed, prasugrel was switched to clopidogrel after 1 month. Patients in the control group received DAPT with aspirin and clopidogrel from 1 to 12 months.
The primary endpoint was a composite of cardiovascular death, myocardial infarction, definite stent thrombosis, ischemic or hemorrhagic stroke, or Thrombolysis in Myocardial Infarction (TIMI) major or minor bleeding.
The major secondary endpoints included the composite of the ischemic endpoints of cardiovascular death, myocardial infarction, definite stent thrombosis, ischemic or hemorrhagic stroke, and the safety endpoint of TIMI major or minor bleeding.
The primary hypothesis was that 1 month of DAPT followed by clopidogrel monotherapy was noninferior to 12 months of DAPT in terms of primary endpoint at 12-month follow-up with a margin equivalent to a 50% variation in the expected hazard ratio.
What is the main result?
Complete 12-month follow-up was achieved in 98.8% of patients. Endovascular imaging, mainly intravascular ultrasound, was performed in almost all PCIs.
At 12 months, the primary endpoint occurred in 2.4% of patients assigned to 1 month of DAPT and 3.7% of patients assigned to 12 months of DAPT. Short DAPT not only met criteria for noninferiority compared with prolonged DAPT (pnoninferiority < 0.001) but resulted also to be superior (psuperiority = 0.04) and associated with a 36% relative risk reduction (HR 0.64, 95% CI 0.42-0.98). The sensitivity analyses according to the per-protocol (p = 0.004) and as-treated (p = 0.015) principles confirmed the noninferiority of 1 month of DAPT compared with 12 months of DAPT but did not reveal also a superiority.
The analysis of the major ischemic secondary endpoint did not show significant differences between groups (2.0% vs. 2.5%, p = 0.34; HR 0.79, 95% CI 0.49-1.29), while in the analysis of the other major secondary endpoint of TIMI major or minor bleeding significant differences emerged between regimens, with patients assigned to 12 months of DAPT showing a higher risk compared with those assigned to 1 month of DAPT (0.4% vs. 1.5%, p = 0.004; HR 0.26, 95% CI 0.11-0.64).
No significant differences in other composite endpoints, individual ischemic endpoints (i.e. death, myocardial infarction, stroke, and stent thrombosis), and specific subtypes of each of these outcomes were observed. Differences in TIMI major or minor bleeding were mainly driven by TIMI major events (0.2% vs. 1.1%, p = 0.01; HR 0.19, 95% CI 0.05-0.65).
Reclassification of bleeding events according to the Bleeding Academic Research Consortium (BARC) and Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) scales did not change these conclusions (BARC Type 3-5: 0.5% vs. 1.8%, p = 0.003; HR 0.30, 95% CI 0.13-0.65; GUSTO moderate or severe: 0.4% vs. 1.5%, p = 0.004; HR 0.26, 95% CI 0.11-0.64), but differently from the TIMI bleeding scale analysis moderate severity events drove the lower incidence of bleeding observed in the short DAPT group compared with prolonged DAPT group (BARC type 3: 0.5% vs. 1.6%, p = 0.004; HR 0.29, 95% CI 0.13-0.68; BARC type 5: 0.1% vs. 0.2%, p = 0.34; HR 0.34, 95% CI 0.03-3.23; GUSTO moderate: 0.1% vs. 0.8%, p = 0.02; HR 0.17, 95% CI 0.04-0.75; GUSTO severe: 0.3% vs. 0.7%, p = 0.09; HR 0.37, 95% CI 0.12-1.15).
Intracranial haemorrhage was not significantly different between groups but gastrointestinal bleeding occurred more frequently in patients assigned to 12 months of DAPT than in those assigned to 1 month of DAPT (0.4% vs. 1.3%, p = 0.01; HR 0.32, 95% CI 0.13-0.79).
Landmark analyses showed overall consistent results over time across the inspected outcomes.
Subgroups analyses with respect to the primary endpoint revealed a significant interaction in terms of chronic kidney disease. Interestingly, the stratification of patients according to the PARIS and CREDO-Kyoto thrombotic and bleeding risk scores did not show significant heterogeneity, though a substantial dilution of the sample size across classes might have mitigated dissimilarities.
Critical reading and the relevance for clinical practice
The STOPDAPT-2 trial shows the noninferiority of 1 month of DAPT followed by clopidogrel monotherapy compared with 12 months of DAPT after second-generation DES implantation in terms of a net composite endpoint including individual ischemic and bleeding outcomes at 12-month follow-up.
Of note, noninferiority was met also for the major secondary endpoint of cardiovascular events and the superior safety of 1 month of DAPT compared with 12 months of DAPT in terms of TIMI major or minor bleeding was noticed.
After inspection of bleeding events subtypes and reclassification according to the BARC and GUSTO scales results were generally confirmed. A post-hoc analysis showed that a substantial advantage of 1 month of DAPT followed by clopidogrel monotherapy compared with 12 months of DAPT is the significant decrease in the risk of gastrointestinal bleeding.
The results of the STOPDAPT-2 trials should be viewed in light of some consideration. Firstly, although no significant heterogeneity across subgroups was observed with the exception of chronic kidney disease status, this type of analysis entails the unavoidable reduction of the statistical power.
Importantly, some influential clinical subgroups and complex coronary artery disease patterns were underrepresented in the study. In particular, most of patients were single-vessel and the number of stent implanted per patient was limited. In addition, the extensive use of endovascular imaging may have improved the safety of short DAPT.
Secondly, the results may be not translated to other subsets since the study was based on a specific population of Japanese patients who underwent PCI with cobalt-chromium durable-polymer everolimus-eluting stent.
Thirdly, the study was open-label and randomization was performed at index hospitalization implying a certain risk of bias. Finally, the number of events was lower than expected and the study was designed for a net composite endpoint, thus conclusions on the composite of ischemic events and each individual components as well as on the bleeding endpoints need to be confirmed in larger trials.
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