Abstract
Aims
To compare early de-escalation of dual antiplatelet therapy (DAPT) (1–3 months) to monotherapy with either P2Y12 inhibitor or aspirin vs. 12 months DAPT after percutaneous coronary intervention (PCI) with drug-eluting stent (DES).
Methods and results
Electronic databases of Medline, Embase, and Cochrane library were searched through February 2020 to identify randomized controlled trials. A Bayesian network meta-analysis was conducted with random effects model. The main endpoints of interest were cardiovascular mortality and total bleeding events. Among seven trials (35 821 patients), 52.6% patients were presented with acute coronary syndrome. A total of 3359 patients and 14 530 patients were de-escalated to aspirin and P2Y12 inhibitor monotherapy, respectively. At a median follow-up of 12 months, compared with 12 months of DAPT, there was no significant difference in cardiovascular mortality between 1-month DAPT followed by P2Y12 inhibitor monotherapy [hazard ratio (HR) 0.84 (95% credible interval 0.29–2.43)], 3 months of DAPT followed by P2Y12 inhibitor monotherapy [HR 0.74 (0.39–1.46)], or 3 months of DAPT [HR 1.00 (0.54–1.86)] followed by aspirin monotherapy. Except for de-escalation of DAPT to aspirin monotherapy after 3 months [HR 0.75 (0.43–1.20)], de-escalation to P2Y12 inhibitor monotherapy after 1 month [HR 0.28 (0.10–0.83)], or 3 months [HR 0.57 (0.33–0.98)] were associated with significant decrease in total bleeding events. There were no significant differences in terms of ischaemic endpoints among different DAPT strategies.
Conclusion
Early de-escalation of DAPT (1–3 months) to monotherapy with a P2Y12 inhibitor instead of aspirin might be a safer and equally effective approach compared with 12 months of DAPT in patients with PCI and DES.
Keywords: Drug-eluting stent, Network meta-analysis, Percutaneous coronary intervention
Introduction
Despite numerous clinical trials and meta-analyses, duration of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) with drug-eluting stent (DES) remains controversial.1 Both the European Society of Cardiology (ESC) and the American College of Cardiology/American Heart Association (ACC/AHA) guidelines recommend at least 6 months of DAPT (aspirin and a P2Y12 inhibitor) following PCI for stable coronary artery disease (CAD) and 12 months of DAPT in the setting of acute coronary syndrome (ACS).2,3 While both professional guidelines suggest extension of DAPT for patients with low bleeding and high thrombotic risk; the ESC guidelines recommend early cessation of DAPT at 1–3 months and the ACC/AHA guidelines recommend interruption of DAPT at 3 months for high bleeding risk patients.2,3 Both societies recommend indefinite continuation of aspirin therapy after DAPT. Recently, a number of clinical trials sought to examine the novel approach of early de-escalation of DAPT (1–3 months) to monotherapy with a P2Y12 inhibitor instead of aspirin.4–7 However, what remains uncertain is that whether this strategy offers the optimal balance of safety and effectiveness after PCI with DES, compared with longer duration of DAPT. To answer this question, we performed a network meta-analysis to compare early de-escalation of DAPT at 1–3 months followed by P2Y12 inhibitor or aspirin vs. 12 months of DAPT after PCI with DES.
Methods
The network meta-analysis followed the Cochrane Collaboration guidelines and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA).8–10
Data sources and searches
Two independent investigators (M.Z.K and M.S.K) performed the literature search using electronic databases (Medline, Embase, and the Cochrane library) through February 2020. We also queried online resources of TCTMD, ClinicalTrials.gov, Clinical Trial Results (http://www.clinicaltrialresults.org), and proceedings of major cardiovascular conferences. Following key search terms were used: ‘dual antiplatelet therapy’, ‘drug eluting stents’, ‘Biolimus Eluting Stent’, ‘Everolimus Eluting Stent’, ‘Paclitaxel Eluting Stent’, ‘Sirolimus-Eluting Stent’, ‘Zotarolimus Eluting Stent’, ‘percutaneous coronary intervention’, ‘cardiovascular outcomes’, and ‘mortality’ (Supplementary material online, eTables 1–3). We removed the duplicates and two independent authors (M.Z.K and M.S.K) screened the remaining articles at the title and abstract level and then at full text based on the pre-determined selection criteria.
Study selection
The pre-determined inclusion criteria were: (i) randomized controlled trials comparing shorter-term DAPT (1–3 months) in patients undergoing PCI with DES; (ii) sample size ≥1000 patients and follow-up duration of at least 1 year; and (iii) reporting on outcomes of interest. We excluded studies focused on pharmacokinetic and pharmacodynamics of the drugs or if a minority of patients received DES.
Quality assessment and data extraction
Two authors (M.S.K and M.Z.K) were involved in data abstraction and adjudication of the data. Any conflicts related to data were resolved by third author’s (S.U.K) opinion.8,10–12 The following information was abstracted: baseline clinical and procedural characteristics of the trials and participants, crude point estimates, number of events and sample sizes, and follow-up duration (Tables 1–2 and Supplementary material online, eTables 4–11). We abstracted the data according to the intention-to-treat principle. The risk of bias assessment was performed at trial level using the Cochrane Risk of Bias Tool (Supplementary material online, eTable 12). Following groups were compared: 1-month DAPT and 3-month DAPT followed by P2Y12 inhibitor therapy; 3-month DAPT followed by aspirin therapy; and 12-month DAPT.
Table 1.
Baseline characteristics of participants and trials
| % |
||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Trial | DAPT (months) | Age (years) | Women | ACS | Diabetes | DLD | HTN | Smoker | LVEF | Prior PCI | Prior CABG | MVD |
| RESET18 | 3/12 | 62.4/62.4 | 35.6/37.1 | 55.5/53.7 | 29.8/28.8 | 57.7/59.9 | 62.3/61.4 | 25.2/22.8 | 64.2/63.9 | 3.5/3.0 | — | 43.1/42.9 |
| OPTIMIZE19 | 3/12 | 61.3/61.9 | 36.5/36.9 | 5.4/5.4 | 35.4/35.3 | 63.2/63.7 | 86.4/88.2 | 18.6/17.3 | — | 20.9/19.1 | — | — |
| REDUCE17 | 3/12 | 61.0/60.0 | 17.4/22.7 | 100/100 | 21.6/19.5 | 46.3/44.9 | 50.7/50.7 | 42.1/42.7 | — | 11.7/9.8 | 2.8/2.8 | 36.1/33.8 |
| GLOBAL LEADERS6 | 1/12 | 64.5/64.6 | 23.4/23.1 | 47.0/46.8 | 25.7/24.9 | 69.3/70.0 | 74.0/73.3 | 25.9/26.3 | — | 32.7/32.7 | 5.6/6.2 | — |
| SMART-CHOICE7 | 3/12 | 64.6/64.4 | 27.3/25.8 | 58.2/58.2 | 38.2/36.8 | 45.1/45.5 | 61.6/61.3 | 28.4/24.5 | 59.9/60.0 | — | — | 50.1/49.0 |
| STOPDAPT-25 | 1/12 | 68.1/69.1 | 21.1/23.5 | 37.7/38.6 | 39.0/38.0 | 74.4/74.8 | 73.7/74.0 | 26.6/20.6 | 59.8/59.7 | 33.5/35.1 | 2.8/1.1 | — |
| TWILIGHT4 | 3/12 | 65.2/65.1 | 23.8/23.9 | 63.9/65.7 | 37.1/36.5 | 60.7/60.2 | 72.6/72.2 | 20.4/23.1 | NR/NR | 42.3/42.0 | 10.2/9.8 | 63.9/61.6 |
ACS, acute coronary syndrome; CABG, coronary artery bypass grafting; DAPT, dual antiplatelet therapy; DLD, dyslipidaemia; HTN, hypertension; LVEF, left ventricular ejection fraction; MVD, multivessel disease; PCI, percutaneous coronary intervention.
Table 2.
Effects of treatment on outcomes in clinical trials
| Months of DAPT | Participants | Cardiovascular mortality | All-cause mortality | Myocardial infarction | Stroke | Definite/probable stent thrombosis | MACE | NACE | Total bleeding | Major bleeding |
|---|---|---|---|---|---|---|---|---|---|---|
| Interruption of DAPT followed by Aspirin monotherapy | ||||||||||
| RESET18 | ||||||||||
| 3 | 1059 | 2 | 5 | 2 | 6 | 2 | 40 | NA | 5 | 2 |
| 12 | 1058 | 4 | 8 | 4 | 6 | 3 | 41 | NA | 10 | 6 |
| OPTIMIZE19 | ||||||||||
| 3 | 1563 | 29 | 43 | 49 | 5 | 13 | 87 | 93 | 35 | 3 |
| 12 | 1556 | 32 | 45 | 42 | 5 | 12 | 78 | 90 | 45 | 12 |
| REDUCE17 | ||||||||||
| 3 | 751 | 13 | 23 | 26 | 2 | 12 | 64 | 85 | 24 | 3 |
| 12 | 745 | 8 | 16 | 22 | 4 | 6 | 66 | 88 | 29 | 12 |
| Interruption of DAPT followed by P2Y12 inhibitor monotherapy | ||||||||||
| GLOBAL LEADERS6 | ||||||||||
| 1 | 7980 | NA | 224 | 248 | 80 | 64 | 362 | NA | 163 | 1 |
| 12 | 7988 | NA | 253 | 250 | 82 | 64 | 416 | NA | 169 | 12 |
| SMART-CHOICE7 | ||||||||||
| 3 | 1495 | 11 | 21 | 11 | 11 | 3 | 42 | 65 | 28 | 3 |
| 12 | 1498 | 13 | 18 | 17 | 5 | 2 | 36 | 81 | 49 | 12 |
| STOPDAPT-25 | ||||||||||
| 1 | 1500 | 9 | 21 | 13 | 8 | 4 | 38 | 35 | 8 | 1 |
| 12 | 1509 | 11 | 18 | 11 | 16 | 1 | 32 | 55 | 27 | 12 |
| TWILIGHT4 | ||||||||||
| 3 | 3555 | 26 | 34 | 95 | 16 | 14 | 135 | NA | 141 | 3 |
| 12 | 3564 | 37 | 45 | 95 | 8 | 19 | 137 | NA | 250 | 12 |
MACE, major adverse cardiovascular events; NA, not available; NACE, net adverse cardiovascular events.
Outcome measures
The main outcomes of interest were cardiovascular mortality and total bleeding events. The secondary endpoints were all-cause mortality, myocardial infarction (MI), stroke, definite or probable stent thrombosis, major bleeding events, major adverse cardiovascular events (MACE), and net adverse clinical events (NACE). The outcomes are defined in Supplementary material online, eTables 4–8.
Statistical analysis
The Bayesian network meta-analysis was performed with a random effects model.13,14 Outcomes were reported as hazard ratio (HR) with 95% credible intervals (Cr Is). The 95% Crs that did not cross one were considered statistically significant.15 For studies reporting HRs, the log HRs and corresponding standard errors were extracted for analysis. Otherwise, the number of events and length of follow-up (in person-years) for each group were extracted to permit comparison of studies with different durations of follow-up, assuming a constant event rate over time in these trials.15 Summary estimates were generated from each network using a Poisson likelihood and log link, incorporating both data from event counts and from HRs.15 Non-informative vague priors were used for all parameters. The Markov Chain Monte Carlo method was used with 5000 adaptation iterations followed by 100 000 iterations of four chains.13–15 Convergence was examined using the Brooks–Gelman–Rubin, using a cut-off of 1.05. Consistency assessment was not applicable since direct comparison in trials was limited to short-term DAPT with 12-month DAPT only and rest of the comparisons between aspirin and P2Y12 inhibitor monotherapy were generated based on indirect evidence.16I2 statistic was used to determine heterogeneity, with a cut-off of ≤0.25 consistent with low heterogeneity. The SUCRA metric was used to compare hierarchy of effectiveness and safety of the intervention (Supplementary material online, eFigure 10). SUCRA values vary between 0% and 100%, i.e. higher the value, the higher the likelihood that a therapy is in the top rank or highly effective.13–15 To assess consistency of the results, sensitivity analysis was performed by removal of REDUCE, which was exclusively performed in ACS.17 We used gemtc package in R (version 3.4.1) and JAGS (version 4.3.0) for all analyses.
Results
Of 11 805 records screened, 112 trials were assessed for eligibility. Additional 105 articles were removed based on the a priori study selection criteria. Ultimately, seven trials (35 821 patients) were included in the network meta-analysis (Figure 1). For direct comparisons, two trials (18 977 patients) compared 1-month DAPT followed by P2Y12 inhibitor therapy with 12-month DAPT, two trials (10 112 patients) compared 3-month DAPT followed by P2Y12 inhibitor therapy with 12-month DAPT, and three trials (6732 patients) compared 3-month DAPT followed by aspirin therapy with 12-month DAPT. A total of 3359 patients and 14 530 patients were deescalated to aspirin and P2Y12 inhibitor monotherapy, respectively. Overall, the proportion of patients presented with ACS was 52.6% and the median follow-up duration across all trials was 12 months (interquartile range 12–18). The baseline characteristics of trials and participants are reported in Table 1 and Supplementary material online, eTables 9–11. Among the seven included trials, 28% had low risk of bias for allocation concealment, 57% had high risk of bias for blinding, and 42.8% had low risk of detection bias (Supplementary material online, eTable 12).
Figure 1.
PRISMA diagram showing study selection process.
Outcomes
Cardiovascular mortality
The risk of cardiovascular mortality was similar in patients who received 1-month DAPT followed by P2Y12 inhibitor monotherapy [HR 0.84 (0.29–2.43)], 3 months of DAPT followed by P2Y12 monotherapy [HR 0.74 (0.38–1.43)], and 3 months of DAPT followed by aspirin monotherapy [HR 1.00 (0.54–1.86)] compared with 12 months of DAPT (Figure 2).
Figure 2.
Network meta-analyses for cardiovascular mortality and total bleeding events. Outcome is reported in hazard ratios for treatment vs. the comparator and 95% credible intervals. The comparator groups are de-escalation of dual antiplatelet therapy after 1-month to P2Y12 inhibitor monotherapy [1-month DAPT (P2Y12 inhibitor)], after 3 months to P2Y12 inhibitor monotherapy [3 months DAPT (P2Y12 inhibitor)], after 3 months to aspirin monotherapy [3 months DAPT (Aspirin)], and 12 months dual antiplatelet therapy.
Total bleeding
The use of 1-month DAPT followed by P2Y12 inhibitor monotherapy [HR 0.28 (0.10–0.81)] and 3-month DAPT followed by P2Y12 monotherapy [HR 0.57 (0.33–0.98)] were associated with lower risk of total bleeding compared with 12 months of DAPT (Figure 2). However, there was no significant difference between 3 months of DAPT followed by aspirin monotherapy [HR 0.75 (0.45–1.25)] vs. 12 months of DAPT.
All-cause mortality
The risk of all-cause mortality was similar in patients who received 1-month DAPT followed by P2Y12 inhibitor monotherapy [HR 0.82 (0.45–1.49)], 3 months of DAPT followed by P2Y12 monotherapy [HR 0.89 (0.54–1.53)], or 3 months of DAPT followed by aspirin monotherapy [HR 1.02 (0.63–1.62)] compared with 12 months of DAPT (Supplementary material online, eFigure 3).
Myocardial infarction and definite or probable stent thrombosis
The risk of MI was similar in patients who received 1-month DAPT followed by P2Y12 inhibitor monotherapy [HR 0.80 (0.47–1.51)], 3-month DAPT followed by P2Y12 monotherapy [HR 0.90 (0.49–1.49)], or 3-month DAPT followed by aspirin monotherapy [HR 1.12 (0.64–1.82)] compared with 12 months of DAPT (Supplementary material online, eFigure 4). Similarly, the risk of definite or probable stent thrombosis was similar among patients who received 1-month DAPT followed by P2Y12 inhibitor monotherapy [HR 1.47 (0.55–5.41)], 3-month DAPT followed by P2Y12 monotherapy [HR 0.85 (0.29–2.96)], and 3-month DAPT followed by aspirin monotherapy [HR 1.24 (0.48–3.15)] compared with 12 months of DAPT (Supplementary material online, eFigure 5).
Stroke and major bleeding
The risk of stroke was similar in patients who received 1-month DAPT followed by P2Y12 inhibitor monotherapy [HR 0.86 (0.39–1.61)], 3 months of DAPT followed by P2Y12 monotherapy [HR 2.09 (0.87–4.95)], and 3 months of DAPT followed by aspirin monotherapy [HR 0.86 (0.35–2.08)] compared with 12-month DAPT (Supplementary material online, eFigure 6). In terms of major bleeding, the risk was similar with 1-month DAPT followed by P2Y12 inhibitor monotherapy [HR 0.63 (0.14–1.53)], 3-month DAPT followed by P2Y12 monotherapy [HR 0.60 (0.21–1.97)], and 3-month DAPT followed by aspirin monotherapy [HR 0.71 (0.24–1.69)] compared with 12 months of DAPT (Supplementary material online, eFigure 7).
Major adverse cardiovascular events and net adverse clinical events
The risk of MACE was similar in patients who received 1-month DAPT followed by P2Y12 inhibitor monotherapy [HR 0.79 (0.59–1.06)], 3 months of DAPT followed by P2Y12 monotherapy [HR 1.03 (0.77–1.41)], and 3 months of DAPT followed by aspirin monotherapy [HR 1.03 (0.77–1.33)] compared with 12 months of DAPT (Supplementary material online, eFigure 8). In terms of NACE, the risk was similar with 1-month DAPT followed by P2Y12 inhibitor monotherapy [HR 0.64 (0.36–1.14)], 3-month DAPT followed by P2Y12 monotherapy [HR 0.81 (0.48–1.35)], and 3 months of DAPT followed by aspirin monotherapy [HR 0.98 (0.73–1.33)] compared with 12-month DAPT (Supplementary material online, eFigure 9).
There were no significant differences among 1-month or 3-month DAPT followed by P2Y12 inhibitor monotherapy and 3 months of DAPT followed by aspirin monotherapy in terms of ischaemic or bleeding endpoints.
Sensitivity analysis
After removal of trial performed exclusively in the setting of ACS,17 the risk of cardiovascular mortality or ischaemic endpoints was similar in patients who received 1-month DAPT or 3-month DAPT followed by P2Y12 inhibitor monotherapy or aspirin monotherapy compared with 12 months of DAPT (Supplementary material online, eTable 14). The risk of total bleeding events was significantly lower with 1-month DAPT or 3-month DAPT followed by P2Y12 inhibitor monotherapy compared with 12 months of DAPT. Moreover, 1-month DAPT followed by P2Y12 inhibitor monotherapy was also associated with lower risk of total bleeding events compared with 3-month DAPT followed by aspirin monotherapy [HR 0.38 (0.14–1.09)].
Net clinical benefit
Figure 3 illustrates the risk of total bleeding vs. cardiovascular mortality of different DAPT strategies compared with 12 months of DAPT. Overall, net clinical benefit favoured 1–3 months DAPT followed by P2Y12 inhibitor monotherapy for superior safety (fewer total bleeding events) and similar cardiovascular mortality compared with 12 months of DAPT.
Figure 3.
Net clinical benefit. Hazard ratios of different de-escalation strategies compared with 12-month dual antiplatelet therapy (reference) and associated 95% credible intervals are plotted. Total bleeding is on the x-axis and cardiovascular mortality is on the y-axis.
Discussion
This network meta-analysis showed that in patients who underwent PCI with DES, at a median follow-up of 12 months, early de-escalation of DAPT (1–3 months) to P2Y12 inhibitor monotherapy instead of aspirin was associated with lower risk of total bleeding events compared with 12 months of DAPT. This benefit was achieved without increasing the risk of mortality or ischaemic outcomes. The net clinical benefit favoured 1–3 months of DAPT followed by P2Y12 inhibitor in patients with PCI and DES.
Aspirin monotherapy constitutes the foundation of secondary prevention after discontinuation of DAPT in patients with PCI with DES.1,20 Recently, four clinical trials have tested a new approach of early de-escalation of DAPT (1–3 months) to P2Y12 inhibitor monotherapy and have unanimously showed superior safety in terms of bleeding events compared with 12 months of DAPT.4–7 The rationale behind an early disruption of DAPT followed by P2Y12 inhibitor monotherapy instead of aspirin carries some theoretical justifications. Clinical trials and meta-analyses have suggested that the benefits of lower risk of bleeding events with short-term DAPT followed by aspirin monotherapy were counter-balanced by higher rates of stent thrombosis.21,22 However, the head to head trials between P2Y12 inhibitor vs. aspirin have shown better effectiveness in terms of ischaemic endpoints and superiority in terms of bleeding endpoints with P2Y12 inhibitor.23,24 In the CAPRIE trial, clopidogrel was found to be superior to aspirin in reducing composite endpoint of death, MI, or stroke and was associated with lower rates of gastrointestinal bleeding in patients with history of recent MI, stroke, or peripheral artery disease.23 In the TASS trial, ticlopidine was associated with lower risk of death or stroke and had lower risk of gastrointestinal bleeding compared with higher doses of aspirin (1300 mg).24 Moreover, since the use of contemporary stents and transcatheter technologies have resulted in significantly lower risk of stent thrombosis, 1–3 months of DAPT followed by P2Y12 inhibitor monotherapy might offer an optimal balance for safety and effectiveness after PCI with DES.20
We compared our results with previous meta-analyses. Giustino et al. (10 trials, 32 125 patients) showed that compared with 12 months of DAPT, short-term DAPT (3–6 months) was associated with higher odds of stent thrombosis [odds ratio (OR) 1.71 (1.26–2.32)] and lower rates of clinically significant bleeding [OR 0.63 (0.52–0.75)].21 However, the hazardous effect of short-term DAPT on stent thrombosis was attenuated with the use of second-generation DES. In another patient-level meta-analysis of six clinical trials (11 473 patients), 3 months of DAPT was associated with higher risk of stent thrombosis and MI in ACS patients, but not in the setting of stable CAD.22 However, to our knowledge, no previous meta-analysis had compared short-term DAPT de-escalation followed by P2Y12 inhibitor.
Limitations
This meta-analysis has several limitations. The study population was a mix cohort of both acute and stable CAD; and due to lack of access to patient-level data, we could not perform subgroup analyses in ACS and stable CAD. Therefore, the current meta-analysis arguably constitutes evidence for both conditions. This is also important in the context of considerable heterogeneities across the trials related to study designs, baseline demographic, and clinical characteristics of patients, indications for PCI, types of stents, types of P2Y12 inhibitors, definitions of clinical outcomes, and durations of trials. For instance, trials of aspirin monotherapy enrolled relatively younger patients compared with that of P2Y12 inhibitor monotherapy. Lower than anticipated rates of ischaemic events resulted in limited statistical power for ischaemic and mortality outcomes in most of the included trials. Many trials had restrictive inclusion and exclusion criteria and excluded high ischaemic risk patients and enrolled patients with low bleeding risk. Comparisons between 1 and 3 months P2Y12 inhibitor monotherapy and 1-month aspirin monotherapy were generated based on indirect evidence, hence should be considered exploratory. Finally, despite a rigorous study search and selection process, a degree of potential selection or publication bias cannot be ignored.
Conclusion
Among patients undergoing PCI with DES, an early de-escalation of DAPT (1–3 months) followed by P2Y12 inhibitor monotherapy instead of aspirin might offer optimal balance of safety in terms of bleeding and comparable effectiveness in terms of ischaemic endpoints compared with 12 months of DAPT. Future clinical trials, and if feasible individual patient-level meta-analysis can provide further insights on this issue.
Data availability
All supporting data are available within the article (and its online supplementary files).
Supplementary material
Supplementary material is available at European Heart Journal – Cardiovascular Pharmacotherapy online.
Conflict of interest: none declared.
Supplementary Material
References
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