Short Duration vs Standard Duration of Dual-Antiplatelet Therapy After Percutaneous Coronary Intervention With Second-Generation Drug-Eluting Stents – A Systematic Review, Meta-Analysis, and Meta-Regression Analysis of Randomized Controlled Trials

Abstract: Background. Current guidelines recommend 12 months of dual-antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) with drug-eluting stent (DES) implantation. Whether the duration of DAPT can be safely shortened with use of second-generation DESs is unclear. Methods. We conducted a meta-analysis of randomized controlled trials comparing short duration (SD) (3-6 months) with standard longer duration (LD) (≥12 months) DAPT in patients treated with primarily second-generation DES implantation. Meta-regression was performed to explore the relationship between acute coronary syndrome (ACS) and the effect of DAPT duration. Results. Six studies were included, with 12,752/13,928 (91.5%) patients receiving second-generation DESs. A total of 5367 patients (39%) had PCI in the setting of ACS. There was no difference in all-cause mortality (1.1% vs 1.2%; odds ratio [OR], 0.86; 95% confidence interval [CI], 0.63-1.18; P=.36) or cardiac mortality (0.9% vs 1.0%; OR, 0.92; 95% CI, 0.61-1.39; P=.69) with SD-DAPT vs LD-DAPT, respectively. Definite/probable stent thrombosis (0.5% vs 0.3%; OR, 1.33; 95% CI, 0.75-2.34; P=.51), myocardial infarction (1.5% vs 1.3%; OR, 1.17; 95% CI, 0.88-1.56; P=.29), and stroke (0.4% vs 0.4%; OR, 1.04; 95% CI, 0.60-1.81; P=.88) were similar between the groups. Compared with LD-DAPT, SD-DAPT was associated with lower clinically significant bleeding (0.9% vs 1.4%; OR, 0.64; 95% CI, 0.46-0.89; P=.01). Meta-regression analysis showed no significant association between the proportion of ACS patients in trials and duration of DAPT for the outcomes of mortality (P=.95), myocardial infarction (P=.98), or stent thrombosis (P=.89). Conclusion. In low-risk patients treated with contemporary second-generation DES implantation, SD-DAPT has similar rates of mortality, myocardial infarction, and stent thrombosis, with lower rates of bleeding compared with LD-DAPT.

J INVASIVE CARDIOL 2016;28(12):E203-E210. Epub 2016 September 15. 

Key words: acute coronary syndrome, atherosclerosis, dual-antiplatelet therapy

Dual-antiplatelet therapy (DAPT) with aspirin and a P2Y₁₂ receptor inhibitor is the cornerstone of treatment to prevent atherothrombotic events in patients with myocardial infarction (MI) and stent thrombosis (ST) in patients undergoing coronary stent implantation. Compared with bare-metal stents, first-generation drug-eluting stents (DESs) reduce in-stent restenosis;^1,2 however, they necessitate longer duration of DAPT due to their increased and prolonged risk of ST. Initially recommended for 3 months after Cypher sirolimus-eluting stents and 6 months after Taxus paclitaxel-eluting stents, the recommended duration of DAPT after DES implantation was extended in 2006 to 1 year or longer to mitigate the sustained risk of ST reported in observational studies^3–6 and meta-analyses of randomized controlled trials (RCTs).⁷ This recommendation, formed by expert consensus, remains endorsed by current American guidelines.⁸ Concerns regarding late ST with first-generation DESs led to the development of second-generation DESs with thinner stent struts, improved vascular healing, and reendothelialization properties.^9,10 These newer-generation DESs have demonstrated superior performance with lower ST rates compared with the first-generation DESs,¹¹  constituting the basis to reconsider abbreviated regimens of DAPT after DES implantation. In this context, several RCTs have recently been performed to evaluate shortening DAPT duration to <1 year following second-generation DES implantation. However, given the low frequency of adverse events, these studies are insufficiently powered to individually detect potential hazard with reduced DAPT duration. 

Despite previous meta-analyses published in the literature,^12,13 there has not been an analysis that focuses specifically on second-generation DESs, and whether acute coronary syndromes affect duration of DAPT. We performed a systematic review and meta-analysis of these RCTs to evaluate the safety and efficacy of abbreviating DAPT duration <1 year after implantation of second-generation DESs. Furthermore, we also employed meta-regression analysis to assess whether the proportion of acute coronary syndrome patients in the respective studies interacted with the duration of DAPT studied to influence ischemic endpoints.

Methods

Study selection and data extraction. We searched Medline, PubMed, and Scopus for relevant studies between 2012 and December 1, 2015 using the following keywords: “dual antiplatelet,” “myocardial infarction,” and “drug-eluting stents.” Abstracts and presentations from major cardiovascular meetings were also searched. No language restriction was imposed. Studies eligible for this meta-analysis were prospective RCTs comparing short-duration (SD)-DAPT (<12 months) with standard longer-duration (LD)-DAPT (≥12 months). Randomized trials comparing 12 months with >12 months DAPT were excluded. Trials were excluded if they were substudies of other included studies, and if they included fewer than 70% patients treated with second-generation DESs (everolimus, zotarolimus, second-generation sirolimus and biolimus-eluting stents). Two authors (AW, HK) independently reviewed the relevant references for inclusion in the meta-analysis and extracted data. A third author (IS) independently reviewed the extracted data and reconciled any discrepant data with the original trial data. 

Endpoints of interest. The endpoints of interest included all-cause mortality, cardiac mortality, MI, ST, stroke, and clinically significant bleeding. All endpoints in each trial were independently adjudicated by a clinical events committee. The endpoint definitions as applied in each trial were incorporated (Appendix A) and reported at the maximum time of follow-up available according to intention-to-treat principle. 

Statistical analysis. Continuous data are expressed as mean ± standard deviation and dichotomous data as absolute values and percentages. The meta-analysis was performed according to the Quality of Reporting of Meta-Analysis statement.¹⁴ Risk of bias was assessed by evaluating randomized sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, and selective reporting. 

The odds ratio (OR) associated with SD-DAPT compared with LD-DAPT from each trial was determined for each endpoint. The summary effect for each endpoint and 95% confidence interval (CI) were calculated by means of random effects meta-analysis according to the method of DerSimonian and Laird.¹⁵ Statistical heterogeneity among studies was assessed with Cochran’s Q-test and the magnitude of heterogeneity was evaluated by the I² statistics, which describe the proportion of total variation due to heterogeneity rather than by the play of chance. I² values indicate heterogeneity (25% low, 50% moderate, and 75% high heterogeneity).¹⁶ Studies were considered statistically heterogeneous if the I² result was ≥50% with P<.05. Analyses were conducted using Review Manager version 5.3 (The Nordic Cochrane Centre, The Cochran Collaboration) and data processing and reporting of results were executed according to accepted principles of systemic review and meta-analysis.¹⁴ We performed two sensitivity analyses to assess consistency of the results: (1) by excluding studies that did not use at least 90% second-generation DESs; and (2) by excluding studies where LD-DAPT was >12 months. Statistical significance was set at a P-value of <.05 and all tests performed were two sided.

Weighted meta-regression analysis was applied to explore the relationship between the percentage of acute coronary syndromes in each trial, and benefit of SD-DAPT vs LD-DAPT on reduction in endpoints of all-cause mortality, MI, and ST. Meta-regression was conducted on comprehensive meta-analysis software using effect size with 95% CI, 2-tailed null test. This random effects regression model was done to explore the association between treatment effect and the study-level covariate of percentage of acute coronary syndromes. 

Results

Study and patient characteristics. A total of 13 RCTs were identified from our review for consideration (Figure 1). Four studies were excluded because they only examined extended duration DAPT beyond 12 months;^17-20 1 study was excluded due to a high proportion of patients (50%) with non-second generation DESs;²¹ and 2 studies were excluded because they were substudies of included studies.^22,23 This resulted in 6 studies, comprising 13,928 patients, that met criteria for inclusion in the meta-analysis.^24-29 

The characteristics of the included studies are summarized in Table 1. The mean age of patients was 63.7 years. Overall, 12,752 patients (91.5%) received a second-generation DES, while 1126 patients (8.1%) received a first-generation DES and 50 patients (0.4%) were treated with a bare-metal stent, balloon angioplasty, drug-eluting balloons, or bioresorbable scaffold. In 3 trials, all patients were treated with second-generation DESs: ITALIC (Is There a Life for DES After Discontinuation of Clopidogrel),²⁵ SECURITY (Second-Generation Drug-Eluting Stent Implantation Followed by Six- Versus Twelve-Month Dual-Antiplatelet Therapy),²⁶ and OPTIMIZE (Optimized Duration of Clopidogrel Therapy Following Treatment With the Zotarolimus-Eluting Stent in Real-world Clinical Practice).²⁷ Second-generation DES use was 88.2% in ISAR-SAFE (Intracoronary Stenting and Antithrombotic Regimen: Safety and Efficacy of 6 Months Dual-Antiplatelet Therapy After Drug-Eluting Stenting)²⁴ and 74.8% in EXCELLENT (The Efficacy of Xience/Promus Versus Cypher to Reduce Late Loss After Stenting).²⁹ In the RESET (Real Safety and Efficacy of 3-Month Dual-Antiplatelet Therapy Following Endeavor Zotarolimus-Eluting Stent Implantation)study,²⁸ second-generation DES use was 100% in the SD-DAPT arm and 68% in the LD-DAPT arm, reserved primarily for patients with acute coronary syndromes, diabetes, and long lesions. The use of everolimus-eluting stents was 38.9%, zotarolimus-eluting stents was 58.2%, biolimus-eluting was 7.4%, and sirolimus-eluting second-generation DES was 4.4%.

Three studies (ISAR-SAFE,²⁴ SECURITY,²⁶ and EXCELLENT²⁹) compared 6 months vs 12 months of DAPT, two trials (OPTIMIZE²⁷ and RESET²⁸) evaluated 3 months vs 12 months of DAPT, and 1 study (ITALIC²⁵) evaluated 6 months vs 24 months of DAPT. In 2 studies (ITALIC and ISAR-SAFE), randomization of SD-DAPT vs LD-DAPT occurred at the end of the SD period (6 months in both studies) (Table 1). Clopidogrel was used in 13,887 patients (99.7%), while 34 patients (0.2%) and 7 patients (0.1%) were treated with prasugrel and ticagrelor, respectively. In total, 4399 of the 13,928 patients (31.6%) had diabetes (range, 24.5%-38.1% between studies) and 5367 patients (39%) had coronary stent implantation in the setting of acute coronary syndromes (range, 23.1%-54.5% between studies). 

Clinical outcomes. There was no difference in all-cause mortality (1.1% vs 1.2%; OR, 0.86, 95% CI, 0.63-1.18; P=.36) or cardiac mortality (0.9% vs 1.0%; OR, 0.92; 95% CI, 0.61-1.39; P=.69] with SD-DAPT vs LD-DAPT (Figure 2). Definite or probable ST (0.5% vs 0.3%; OR, 1.33; 95% CI, 0.75-2.34; P=.51), MI (1.5% vs 1.3%; OR, 1.17; 95% CI, 0.88-1.56; P=.29), and stroke risk (0.4% vs 0.4%; OR, 1.04; 95% CI, 0.60-1.81; P=.88) were also similar between the two groups (Figure 3). Compared with LD-DAPT, SD-DAPT was associated with lower clinically significant bleeding (0.9% vs 1.4%; OR, 0.64; 95% CI, 0.46-0.89; P=.01) (Figure 4).

A sensitivity analysis was performed; both ischemic and bleeding results were consistent with exclusion of studies with <90% second-generation DES use (EXCELLENT and RESET), and with exclusion of studies with LD-DAPT >12 months (ITALIC). 

Meta-regression analysis. Meta-regression analysis was applied to explore the relationship between rates of acute coronary syndromes in each trial and benefit of LD-DAPT vs SD-DAPT on reduction in endpoints of all-cause mortality, MI, and ST. Results are displayed in Figure 5, with the log ratio of SD-DAPT vs LD-DAPT plotted on the y axis and the proportion of study patients having acute coronary syndromes plotted on the x axis. As the rate of acute coronary syndromes increased in the RCT included in this meta-analysis, there was no statistically significant change in the rate of all-cause mortality (P=.95), MI (P=.98), or ST (P=.89) with the use of SD-DAPT vs LD-DAPT.

Discussion

In this meta-analysis of RCTs of 13,928 patients, of which 91.5% were treated with contemporary second-generation DESs with an overall low rate of major adverse cardiac outcomes, we found that short duration (3-6 months) of DAPT was associated with similar rates of all-cause and cardiac mortality, MI, and ST, with lower rates of clinically significant bleeding compared with standard longer duration (≥12 months) of DAPT.  

This meta-analysis is unique in the literature for two reasons. First, this study focuses on a specific question, namely the optimal duration of DAPT in a population with >90% contemporary second-generation DES implantation, and a specific comparison of DAPT (SD 3-6 months vs standard LD >12 months). Second, this study addresses the question of the interaction of acute coronary syndromes on duration of DAPT after PCI with second-generation DESs. Meta-regression analysis was performed, and demonstrated no significant association between proportion of acute coronary syndromes patients in the trials and the efficacy of duration of DAPT.

Several pooled analyses have been performed to study the optimal duration of DAPT after DES implantation.^12,30-32 However, unlike prior meta-analyses, we restricted our study to patients treated with contemporary second-generation DES implantation. Despite heterogeneity in the included patient population, comparator groups, and analytic designs, our study findings are largely in agreement with prior analyses.^12,30,32 Shortening the duration of DAPT from 12 to 3-6 months was associated with less bleeding. This is clinically relevant given data demonstrating bleeding to be an independent predictor of subsequent mortality, equivalent in strength to MI.³³ Despite our study population including a substantial portion of higher-risk acute coronary syndrome patients (40%), shortened 3-6 months of DAPT after implantation of second-generation DES was not associated with an excess hazard of ischemic events including MI and ST. Importantly, the absolute event rates (particularly of ST) were low (0.39%), highlighting the improved performance of second-generation DES in comparison with older first-generation DES. These findings provide further support for the 2014 European guidelines on myocardial revascularization,³⁴ which based upon bleeding hazard associated with DAPT recommend only 6 months of DAPT after DES implantation for a non-acute coronary syndrome indication. The recommended duration of DAPT after acute coronary syndrome, irrespective of stent use, remains 1 year by current guidelines,^34–36 with accumulating data in support for extending DAPT even beyond 1 year,³⁷ particularly among those at low risk of bleeding. A recent review of the factors to consider in choosing duration of DAPT was recently published by Bagai et al.³⁸

The study findings should be considered in the context of a DAPT trial in which 9961 patients who were event-free 12 months after DES implantation were randomized to continuation of DAPT to 30 months vs cessation of DAPT and treatment with aspirin alone.¹⁸ In this study, a differential treatment effect with extended DAPT duration was observed by the type of DES for the composite of death, MI, and stroke, with reduction in outcome observed among those treated with first-generation, but not second-generation DESs. In addition, the absolute reduction in ST with extended DAPT among patients treated with second-generation DES was also smaller compared with patients treated with first-generation DES. Bleeding and non-cardiovascular mortality were increased with extended DAPT irrespective of DES type. A meta-analysis of 10 studies including >31,000 patients also found an increase in non-cardiovascular mortality with extended DAPT, which was not offset by benefit in cardiac mortality.¹² Although the definitive mechanisms of the greater risk of non-cardiovascular mortality remain unclear, these results do not favor routinely extended DAPT in patients treated with current second-generation DESs. 

In the meta-regression analysis of our study, which is unique in the literature, we found no significant association between the proportion of acute coronary syndrome patients in trials and duration of DAPT for the outcomes of mortality, MI, or ST. These findings are interesting, especially in the context of trials such as CURE,³⁹ which showed a 2% absolute reduction in cardiovascular death, non-fatal MI, or stroke with the addition of clopidogrel for up to 12 months, to acetylsalicylic acid in patients who had non-ST elevation MI. While in our study, LD-DAPT did not seem to confer a significant benefit beyond the mandatory minimum duration of SD-DAPT, as the proportion of acute coronary syndrome patients increased in the studies included, prolonging DAPT beyond 12 months may demonstrate reduced rates of atherothrombotic cardiovascular events such as in the DAPT trial. Further trials are needed to test this hypothesis.

Study limitations. Our findings should be interpreted in the context of several limitations. First, summary effects were derived as patient-level data were not available. As such, the findings may not apply to specific subgroups, such as diabetic, or higher angiographic risk patients (left anterior descending, multivessel, or bifurcation stenting). Overall, the event rates were low, and thus caution should be used to extrapolate these findings to higher-risk populations. We used the method of meta-regression to assess the effect of acute coronary syndromes, as patient-level data were not available to directly assess this subgroup. Second, despite having more than 12,500 patients, the absolute rates for events of interest were small, such that our power to detect modest, but potentially clinically and statistically significant differences between SD-DAPT and LD-DAPT remains modest. Third, despite independent adjudication of events by a clinical events committee, with one exception, all studies were open-label trials, introducing potential for observer bias. Fourth, patients included were in general at low risk for bleeding; randomization to longer duration of DAPT occurred at the completion of short duration therapy in 2 studies, thus excluding patients intolerant of DAPT or who suffered recurrent MI. Fifth, treatment crossover, selection bias, and regression to the mean pose problems; a number of patients who were randomized to SD-DAPT remained on DAPT at the end of follow-up (and vice versa). Finally, there is heterogeneity in the type of second-generation DESs used in the trials, and as such, differences in outcomes with SD-DAPT vs LD-DAPT with different second-generation DESs could not be evaluated. 

Conclusion

In this meta-analysis of over 12,500 patients treated with second-generation DES with overall low event rates, there was no excess in ST, cardiac mortality, or MI with SD-DAPT (3-6 months) vs LD-DAPT (≥12 months). SD-DAPT was associated with less bleeding. Accordingly, DAPT for 3 or 6 months may be reasonable in patients undergoing PCI with contemporary second-generation DESs, particularly in patients at risk of bleeding. This may find much wider application henceforth because first-generation DESs are no longer routinely implanted.

References

1.     Stone GW, Ellis SG, Cox DA, et al. A polymer-based, paclitaxel-eluting stent in patients with coronary artery disease. N Engl J Med. 2004;350:221-231.

2.     Moses JW, Leon MB, Popma JJ, et al. Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med. 2003;349:1315-1323.

3.     Iakovou I, Schmidt T, Bonizzoni E, et al. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA. 2005;293:2126-2130. 

4.     Park D-W, Park S-W, Park K-H, et al. Frequency of and risk factors for stent thrombosis after drug-eluting stent implantation during long-term follow-up. Am J Cardiol. 2006;98:352-356.

5.     Airoldi F, Colombo A, Morici N, et al. Incidence and predictors of drug-eluting stent thrombosis during and after discontinuation of thienopyridine treatment. Circulation. 2007;116:745-754.

6.     Daemen J, Wenaweser P, Tsuchida K, et al. Early and late coronary stent thrombosis of sirolimus-eluting and paclitaxel-eluting stents in routine clinical practice: data from a large two-institutional cohort study. Lancet. 2007;369:667-678.

7.     Bavry AA, Kumbhani DJ, Helt TJ, Borek PP, Mood GR, Bhatt DL. Late thrombosis of drug-eluting stents: a meta-analysis of randomized clinical trials. Am J Med. 2006;119:1056-1061.

8.     Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. Circulation. 2011;124:574-651. 

9.     Wijns W, Steg PG, Mauri L, et al. Endeavour zotarolimus-eluting stent reduces stent thrombosis and improves clinical outcomes compared with cypher sirolimus-eluting stent: 4 year results of the PROTECT randomized trial. Eur Heart J. 2014;35:2812-2820.

10.     Baber U, Mehran R, Sharma SK, et al. Impact of the everolimus-eluting stent on stent thrombosis: a meta-analysis of 13 randomized trials. J Am Coll Cardiol. 2011;58:1569-1577.

11.     Dangas GD, Serruys PW, Kereiakes DJ, et al. Meta-analysis of everolimus-eluting versus paclitaxel-eluting stents in coronary artery disease: final 3-year results of the SPIRIT clinical trials program (Clinical Evaluation of the Xience V Everolimus Eluting Coronary Stent System in the Treatment of Patients With De Novo Native Coronary Artery Lesions). JACC Cardiovasc Interv. 2013;6:914-922. 

12.     Palmerini T, Benedetto U, Bacchi-Reggiani L, et al. Mortality in patients treated with extended duration dual-antiplatelet therapy after drug-eluting stent implantation: a pairwise and Bayesian network meta-analysis of randomised trials. Lancet. 2015;6736:1-12.

13.     Navarese EP, Andreotti F, Schulze V, et al. Optimal duration of dual-antiplatelet therapy after percutaneous coronary intervention with drug-eluting stents: meta-analysis of randomised controlled trials. BMJ. 2015;350:h1618. 

14.     Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ. 2009;339:b2535. 

15.     DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177-188. 

16.     Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327:557-560.

17.     Lee CW, Ahn J-M, Park D-W, et al. Optimal duration of dual-antiplatelet therapy after drug-eluting stent implantation: a randomized controlled trial. Circulation. 2014;129:304-312. 

18.     Mauri L, Kereiakes DJ, Yeh RW, et al. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. N Engl J Med. 2014;371:2155-2166. 

19.     Collet J-P, Silvain J, Barthélémy O, et al. Dual-antiplatelet treatment beyond 1 year after drug-eluting stent implantation (ARCTIC-Interruption): a randomised trial. Lancet. 2014;6736:1577-1585.

20.     Park S-J, Park D-W, Kim Y-H, et al. Duration of dual-antiplatelet therapy after implantation of drug-eluting stents. N Engl J Med. 2010;362:1374-1382. 

21.     Valgimigli M, Campo G, Monti M, et al. Short-versus long-term duration of dual-antiplatelet therapy after coronary stenting: a randomized multicenter trial. Circulation. 2012;125:2015-2026.

22.     Garratt KN, Weaver WD, Jenkins RG, et al. Prasugrel plus aspirin beyond 12 months is associated with improved outcomes after Taxus Liberte paclitaxel-eluting coronary stent placement. Circulation. 2015;131:62-73. 

23.     Campo G, Tebaldi M, Vranckx P, et al. Short- versus long-term duration of dual-antiplatelet therapy in patients treated for in-stent restenosis: a prodigy trial substudy (prolonging dual antiplatelet treatment after grading stent-induced intimal hyperplasia). J Am Coll Cardiol. 2014;63:506-512. 

24.     Schulz-Schüpke S, Byrne RA, Ten Berg JM, et al. ISAR-SAFE: a randomized, double-blind, placebo-controlled trial of 6 versus 12 months of clopidogrel therapy after drug-eluting stenting. Eur Heart J. 2015;36:1252-1263. Epub 2015 Jan 23.

25.     Gilard M, Barragan P, Noryani AA, et al. Six-month versus 24-month dual-antiplatelet therapy after implantation of drug eluting stents in patients non-resistant to aspirin: ITALIC, a randomized multicenter trial. J Am Coll Cardiol. 201;65:777-786. Epub 2014 Nov 16.

26.     Colombo A, Chieffo A, Frasheri A, et al. Second-generation drug-eluting stent implantation followed by 6- versus 12-month dualantiplatelet therapy. J Am Coll Cardiol. 2014;64:2086-2097. 

27.     Feres F, Costa RA, Abizaid A, et al. Three vs twelve months of dual antiplatelet therapy after zotarolimus-eluting stents: the OPTIMIZE randomized trial. JAMA. 2013;310:2510-2522. 

28.     Kim BK, Hong MK, Shin DH, et al. A new strategy for discontinuation of dual antiplatelet therapy: the RESET trial (real safety and efficacy of 3-month dual antiplatelet therapy following endeavor zotarolimus-eluting stent implantation). J Am Coll Cardiol. 2012;60:1340-1348. 

29.     Gwon HC, Hahn JY, Park KW, et al. Six-month versus 12-month dual antiplatelet therapy after implantation of drug-eluting stents: the efficacy of Xience/Promus versus Cypher to reduce late loss after stenting (EXCELLENT) randomized, multicenter study. Circulation. 2012;125:505-513. 

30.     Montalescot G, Brieger D, Dalby AJ, Park S-J, Mehran R. Duration of dual antiplatelet therapy after coronary stenting: a review of the evidence. J Am Coll Cardiol. 2015;66:832-847.

31.     Giustino G, Baber U, Sartori S, et al. Duration of dual antiplatelet therapy after drug-eluting stent implantation. J Am Coll Cardiol. 2015;65:1298-1310. Epub 2015 Feb 11.

32.     Pandit A, Giri S, Hakim FA, Fortuin FD. Shorter (≤6 months) versus longer (≥12 months) duration dual antiplatelet therapy after drug-eluting stents: a meta-analysis of randomized clinical trials. Catheter Cardiovasc Interv. 2014;85:34-40.

33.     Berger PB, Bhatt DL, Fuster V, et al. Bleeding complications with dual antiplatelet therapy among patients with stable vascular disease or risk factors for vascular disease: results from the clopidogrel for high atherothrombotic risk and ischemic stabilization, management, and avoidance (CHAR). Circulation. 2010;121:2575-2583. 

34.     Kolh P, Windecker S, Alfonso F, et al. 2014 ESC/EACTS guidelines on myocardial revascularization: the task force on myocardial revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). Developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur J Cardiothorac Surg. 2014;46:517-592. 

35.     Tanguay JF, Bell AD, Ackman ML, et al. Focused 2012 update of the Canadian Cardiovascular Society guidelines for the use of antiplatelet therapy. Can J Cardiol. 2013;29:1334-1345. 

36.     Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC guideline for the management of patients with non-ST elevation acute coronary syndromes: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;64:e139-228. Epub 2014 Sep 23.

37.     Udell JA, Bonaca MP, Collet J-P, et al. Long-term dual antiplatelet therapy for secondary prevention of cardiovascular events in the subgroup of patients with previous myocardial infarction: a collaborative meta-analysis of randomized trials. Eur Heart J. 2016;37:390-399. Epub 2015 Aug 31.

38.     Bagai A, Bhatt DL, Eikelboom JW, et al. Individualizing duration of dual antiplatelet therapy after acute coronary syndrome or percutaneous coronary intervention. Circulation. 2016;133:2094-2098. 

39.     Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345:494-502. 

40.     Chesebro JH, Knatterud G, Roberts R, et al. Thrombolysis in Myocardial Infarction (TIMI) trial, phase I: a comparison between intravenous tissue plasminogen activator and intravenous streptokinase. Clinical findings through hospital discharge. Circulation. 1987;76:142-154. 

41.     Cutlip DE, Windecker S, Mehran R, et al. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation. 2007;115:2344-2351. 

42.     Mehran R, Rao SV, Bhatt DL, et al. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium. Circulation. 2011;123:2736-2747. 

43.     Thygesen K, Alpert JS, Jaffe AS, et al. Third universal definition of myocardial infarction. J Am Coll Cardiol. 2012;60:1581-1598.

From the ¹Terrence Donnelly Heart Center, St. Michael’s Hospital, University of Toronto,Toronto, Ontario, Canada; ²Cardiovascular Division, Women’s College Hospital and Peter Munk Cardiac Centre, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Udell reports grants from Amgen (clinical registry steering committee; research grants; site PI); lecture honorarium from AstraZeneca and Janssen; advisory board member for Boehringer-Ingelheim, Janssen, Merck, Novartis, and Sanofi Pasteur; honoraria from SAGE Publications (Associate Editor, MD Conference Express). Dr Goodman reports grants and personal fees from Eli Lilly (research grant support for observational studies and clinical trials to research centers; advisory board/consultant), AstraZeneca (research grant support for observational studies, clinical trials, and continuing medical education programs to research centers; advisory board/consultant; educational slide set presentations; speaker honoraria), and Sanofi/Bristol-Myers Squibb (research grant support for observational studies, clinical trials, and continuing medical education programs to research centers; advisory board/consultant; educational slide set presentations; speaker honoraria). Dr Bagai reports consulting fees from Astra Zeneca. Dr Yan reports grants from Astra Zeneca.

Manuscript submitted May 25, 2016, provisional acceptance given June 2, 2016, final version accepted June 8, 2016.

Address for correspondence: Akshay Bagai, MD, MHS; Terrence Donnelly Heart Center, St. Michael’s Hospital, University of Toronto, Ontario, Canada. Email: bagaia@smh.ca