Controversy remains regarding the optimal antiplatelet regimen in patients with acute coronary syndrome (ACS). This study sought to investigate the efficacy and safety of P2Y12 inhibitor monotherapy compared with conventional dual antiplatelet therapy (DAPT) and aspirin monotherapy in patients with ACS undergoing percutaneous coronary intervention. Data on 4,453 patients were pooled from SMART-DATE and SMART-CHOICE randomized trials. Antiplatelet therapy regimens were categorized as P2Y12 inhibitor monotherapy (P2Y12 inhibitor monotherapy after 3-month DAPT), conventional DAPT (12-month or longer DAPT), and aspirin monotherapy (aspirin monotherapy after 6-month DAPT). The primary endpoint was major adverse cardiac and cerebrovascular events (MACCE, a composite of all-cause death, myocardial infarction, and stroke). Inverse-probability of treatment-weighted (IPTW) analysis was performed. At 1 year, patients in the P2Y12 inhibitor monotherapy had a comparable risk of MACCE compared with those in the conventional DAPT (IPTW-adjusted hazard ratio [HR], 0.655; 95% confidence interval [CI] 0.393 to 1.094; p = 0.106), and tended to have a lower risk of MACCE than those in the aspirin monotherapy (IPTW-adjusted HR, 0.606; 95% CI, 0.347 to 1.058; p = 0.078). The adjusted hazard for the Bleeding Academic Research Consortium (BARC) type 2 to 5 bleeding was significantly lower in P2Y12 inhibitor monotherapy than in conventional DAPT (IPTW-adjusted HR, 0.341; 95% CI, 0.190 to 0.614; p < 0.001) and in aspirin monotherapy (IPTW-adjusted HR, 0.359; 95% CI, 0.182 to 0.708; p = 0.003). In conclusion, among patients with ACS undergoing PCI, P2Y12 inhibitor monotherapy after 3-month DAPT reduced risk of bleeding compared with conventional DAPT and aspirin monotherapy after 6-month DAPT without increasing MACCE.
Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 inhibitor is the cornerstone of treatment after percutaneous coronary intervention (PCI). The current international guidelines recommend DAPT for at least 12 months after the implantation of drug-eluting stents in patients with acute coronary syndrome (ACS). , However, conventional DAPT for 12 months or longer after ACS increases the bleeding complications that counterbalance the benefit from preventing ischemic events. , Recently, an abbreviated DAPT strategy followed by a P2Y12 inhibitor monotherapy has emerged as a potential alternative to conventional DAPT regimens, aiming to reduce an excess of bleeding risk associated with the addition of aspirin while maintaining an anti-ischemic efficacy. However, the ischemic and bleeding risks of an abbreviated DAPT strategy followed by a P2Y12 inhibitor monotherapy compared with conventional or 6-month DAPT in patients with ACS remain uncertain. To address these issues, we performed an analysis of the pooled data of the Smart Angioplasty Research Team-Safety of 6-Month Duration of Dual Antiplatelet Therapy After Percutaneous Coronary Intervention in Patients with Acute Coronary Syndrome (SMART-DATE) and Smart Angioplasty Research Team: Comparison Between P2Y12 Antagonist Monotherapy vs Dual Antiplatelet Therapy in Patients Undergoing Implantation of Coronary Drug-Eluting Stents (SMART-CHOICE) trials to investigate the efficacy and safety of P2Y12 inhibitor monotherapy after 3 months of DAPT strategy after DES implantation in patients with ACS.
Methods
The SMART-DATE was a multicenter, randomized, open-label trial to investigate whether a 6-month duration of DAPT would be non-inferior to the conventional 12-month or longer duration of DAPT in patients with ACS after coronary stenting. The SMART-CHOICE trial was a multicenter, randomized, open-label trial designed to test the non-inferiority of P2Y12 inhibitor monotherapy compared with aspirin plus a P2Y12 inhibitor after mandatory 3-month DAPT in patients undergoing PCI with current-generation drug-eluting stents. Among 5,705 patients included in the pooled data, 4,453 patients who underwent PCI for ACS were selected, comprising the population used in the present analysis. The antiplatelet therapy regimens were categorized as P2Y12 inhibitor monotherapy (P2Y12 inhibitor monotherapy after 3-month DAPT); conventional DAPT (12-month or longer DAPT); and aspirin monotherapy (aspirin monotherapy after 6-month DAPT); and we compared clinical endpoints among three antiplatelet therapy regimens. e-Figure 1 in the Supplementary Data displays the network of antiplatelet regimens used in the present analysis. An independent institutional review board at each study center approved two clinical trials, and all patients provided written informed consent.
In the SMART-DATE trial, all patients received 300 mg of aspirin and a 300 or 600 mg clopidogrel loading dose orally at least 12 hours before PCI unless they had previously received these antiplatelet medications. After December 2014, prasugrel and ticagrelor became available in Korea. Since then, prasugrel or ticagrelor could be used instead of clopidogrel during the course of the SMART-DATE trial. After the procedure, aspirin (100 mg orally once daily) was used indefinitely and clopidogrel (75 mg orally once daily) was maintained according to the randomization scheme (6 months vs 12 months or longer). In the SMART-CHOICE trial, patients received DAPT with aspirin 100 mg once daily plus clopidogrel 75 mg once daily or prasugrel 10 mg once daily or ticagrelor 90 mg twice daily for 3 months in both groups after the procedure. The administration of aspirin was stopped at 3 months after the index procedure in the P2Y12 inhibitor monotherapy group but was continued indefinitely in the DAPT group. A P2Y12 inhibitor was prescribed continuously in both groups. It was recommended that all patients receive optimal pharmacologic therapy, including statins, β-blockers, or renin-angiotensin system blockade, if indicated, following clinical guidelines. , At follow-up, data from patients, including clinical status, all interventions, endpoint events, and adverse events, were recorded. In particular, information on the use of aspirin and a P2Y12 inhibitor was assessed at each follow-up. Patients who discontinued antiplatelet therapy as a result of clinically significant active bleeding or for other procedures were monitored carefully for cardiac events, and, once they were stabilized, their allocated antiplatelet therapy was restarted as soon as possible. An independent clinical event adjudication committee, whose members were masked to the study group assignments, assessed all clinical endpoints.
In this pooled analysis, the primary endpoint is major adverse cardiac and cerebrovascular events (MACCE), defined as a composite of all-cause death, myocardial infarction (MI), and stroke at 12 months after the index procedure; secondary endpoints were individual components of the MACCE and the Bleeding Academic Research Consortium (BARC) type 2 to 5 bleeding at 12 months after the index procedure. In both trials, all clinical outcomes are commonly defined according to the Academic Research Consortium. The BARC bleeding was defined as reported previously.
The primary analysis was done according to an intention-to-treat principle. Because the follow-up duration of the SMART-CHOICE trial was 1 year, patients enrolled in the SMART-DATE trial were censored at 12 months in the current study. The cumulative rate of clinical events was evaluated by Kaplan-Meier analyses and the significance level was assessed with the Log-rank test. To compare the clinical endpoints, the hazard ratios (HRs) of three antiplatelet regimens were calculated by a Cox proportional hazards model. An extended description of the statistical analysis is presented in the Methods of Supplementary Data . Categorical variables are presented as numbers of events and percentages and were compared using the chi‐square test or Fisher’s exact test. Continuous variables are presented as mean ± standard deviation or median (interquartile range, in the case of a non-normal distribution), and were compared using the t test or Mann Whitney test. All probability values were 2-sided and p values < 0.05 were considered statistically significant. For all analyses, we used SPSS software version 20.0 (SPSS Inc, Chicago, IL) and R software (version 3.3; “MatchIt” and “survival” packages; R Foundation for Statistical Computing, Vienna, Austria) for Windows for the statistical analyses.
Results
Out of a total population of 4,453 ACS patients, 870 (19.5%) patients were treated P2Y12 inhibitor monotherapy, 2,226 (50.0%) with conventional DAPT, and 1,357 (30.5%) with aspirin monotherapy. Baseline characteristics according to the different treatment regimens are shown in Table 1 and Table 2 . Compared to patients in the conventional DAPT group and the aspirin monotherapy group, patients in the P2Y12 inhibitor monotherapy group were older, had a higher prevalence of diabetes, hypertension, dyslipidemia, chronic renal failure, and previous coronary revascularization. Beta-blocker was less frequently prescribed at discharge in the P2Y12 inhibitor monotherapy group than in the conventional DAPT group and the aspirin monotherapy group. After adjustment with the use of inverse probability of treatment weighted (IPTW), clinical characteristics were well balanced except age, left ventricular ejection fraction, ST-segment elevation MI as a presentation, trans-radial approach for PCI, and potent P2Y12 inhibitor prescription at discharge.
| Variable | Unadjusted data | Adjusted date with the use of IPTW | ||||||
|---|---|---|---|---|---|---|---|---|
| P2Y12 inhibitor monotherapy (n = 870) | Conventional DAPT (n = 2,226) | Aspirin monotherapy (n = 1,357) | p value | P2Y12 inhibitor monotherapy | Conventional DAPT | Aspirin monotherapy | p value | |
| Age (year) | 64.4 ± 11.3 | 63.0 ± 11.6 | 62.0 ± 11.5 | <0.001 | 64.2 ± 10.0 | 63.1 ± 11.5 | 62.9 ± 11.4 | 0.028 |
| Gender | 629 (72.3%) | 1677 (75.3%) | 1016 (74.9%) | 0.210 | 73.1% | 74.5% | 73.7% | 0.816 |
| Body Mass Index (Kg/m 2 ) | 24.4 ± 3.3 | 24.5 ± 3.1 | 24.3 ± 3.2 | 0.299 | 24.3 ± 2.9 | 24.4 ± 3.2 | 24.5 ± 3.2 | 0.331 |
| STEMI as Presentation | 164 (18.9%) | 664 (29.8%) | 509 (37.5%) | <0.001 | 22.3% | 29.4% | 30.3% | 0.019 |
| Diabetes | 318 (36.6%) | 698 (31.4%) | 365 (26.9%) | <0.001 | 31.1% | 31.4% | 30.7% | 0.926 |
| Hypertension | 530 (60.9%) | 1175 (52.8%) | 669 (49.3%) | <0.001 | 56.2% | 53.7% | 51.7% | 0.227 |
| Dyslipidemia | 420 (48.3%) | 755 (33.9%) | 322 (23.7%) | <0.001 | 37.7% | 34.1% | 32.7% | 0.126 |
| Current smoker | 306 (35.2%) | 783 (35.2%) | 506 (37.3%) | 0.400 | 33.1% | 35.7% | 35.3% | 0.549 |
| History of CVA | 52 (6.0%) | 105 (4.7%) | 52 (3.8%) | 0.065 | 3.9% | 4.9% | 4.2% | 0.472 |
| History of CRF | 25 (2.9%) | 32 (1.4%) | 13 (1.0%) | 0.001 | 1.6% | 1.7% | 1.4% | 0.770 |
| History of previous MI | 34 (3.9%) | 60 (2.7%) | 30 (2.2%) | 0.056 | 2.4% | 2.7% | 2.2% | 0.616 |
| Previous revascularization | 79 (9.1%) | 147 (6.6%) | 65 (4.8%) | <0.001 | 6.4% | 6.5% | 5.7% | 0.628 |
| LVEF (%) | 58.2 ± 11.2 | 56.7 ± 10.5 | 55.7 ± 10.6 | <0.001 | 57.9 ± 9.9 | 56.7 ± 10.7 | 56.5 ± 10.6 | 0.028 |
| Variable | Unadjusted data | Adjusted date with the use of IPTW | ||||||
|---|---|---|---|---|---|---|---|---|
| P2Y12 inhibitor monotherapy (n = 870) | Conventional DAPT (n = 2,226) | Aspirin monotherapy (n = 1,357) | p value | P2Y12 inhibitor monotherapy | Conventional DAPT | Aspirin monotherapy | p value | |
| Multi-vessel disease | 435 (50.0%) | 1069 (48.0%) | 591 (43.6%) | 0.005 | 47.0% | 47.4% | 45.9% | 0.788 |
| Trans-radial access | 569 (65.4%) | 1203 (54.0%) | 637 (46.9%) | <0.001 | 63.1% | 54.0% | 53.3% | 0.001 |
| Use of IVUS | 217 (24.9%) | 582 (26.1%) | 311 (22.9%) | 0.096 | 23.6% | 24.9% | 24.3% | 0.856 |
| PCI for calcified lesion | 110 (12.6%) | 291 (13.1%) | 165 (12.2%) | 0.727 | 11.6% | 12.5% | 12.8% | 0.730 |
| PCI for thrombotic lesion | 100 (11.5%) | 434 (19.5%) | 325 (23.9%) | <0.001 | 13.5% | 19.3% | 19.7% | 0.062 |
| Bifurcation PCI | 110 (12.6%) | 227 (10.2%) | 124 (9.1%) | 0.028 | 9.3% | 10.3% | 10.5% | 0.659 |
| Treated vessel | ||||||||
| LM | 11 (1.3%) | 37 (1.7%) | 29 (2.1%) | 0.287 | 0.9% | 1.6% | 1.7% | 0.235 |
| LAD | 507 (58.3%) | 1370 (61.5%) | 767 (56.5%) | 0.009 | 62.5% | 59.7% | 59.5% | 0.424 |
| LCx | 249 (28.6%) | 561 (25.2%) | 331 (24.4%) | 0.068 | 24.6% | 25.7% | 24.5% | 0.810 |
| RCA | 311 (35.7%) | 817 (36.7%) | 504 (37.1%) | 0.799 | 33.0% | 36.6% | 38.1% | 0.111 |
| Multi-vessel PCI | 199 (22.9%) | 506 (22.7%) | 263 (19.4%) | 0.041 | 20.4% | 21.7% | 22.4% | 0.657 |
| Degradable polymer DES | 282 (32.4%) | 697 (31.3%) | 391 (28.8%) | 0.146 | 30.8% | 31.4% | 30.1% | 0.821 |
| Total Stent Length (mm) | 37.6 ± 21.6 | 35.1 ± 21.4 | 32.3 ± 18.1 | <0.001 | 34.8±18.1 | 34.5±20.4 | 34.5 ± 20.4 | 0.923 |
| No. of stent implanted | 1.46 ± 0.72 | 1.46 ± 0.77 | 1.39 ± 0.75 | 0.004 | 1.37±0.63 | 1.44±0.74 | 1.46 ± 0.81 | 0.051 |
| Discharge medications | ||||||||
| Statin | 840 (96.6%) | 2064 (92.7%) | 1212 (89.3%) | <0.001 | 94.3% | 92.6% | 92.1% | 0.535 |
| Beta-blocker | 531 (61.0%) | 1509 (67.8%) | 961 (70.8%) | <0.001 | 66.1% | 67.9% | 68.1% | 0.642 |
| RAAS blocker | 538 (61.8%) | 1430 (64.2%) | 929 (68.5%) | 0.003 | 66.4% | 64.54% | 65.7% | 0.730 |
| Potent P2Y12 Inhibitor | 305 (35.1%) | 541 (24.3%) | 275 (20.3%) | <0.001 | 29.8% | 25.1% | 23.7% | 0.028 |
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