Optimal Duration of Dual Antiplatelet Therapy after Drug-eluting Stent Implantation

Saurav Chatterjee, MD

Review

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

Study Design

The authors of a study recently published in Circulation¹ set out to evaluate the hypothesis that dual anti-platelet therapy (DAPT) with aspirin and clopidogrel would be superior to aspirin alone in patients who had undergone PCI at least 12 months earlier. Current guidelines recommend 6 to 12 months of DAPT after drug-eluting stent implantation to minimize the risk of late stent thrombosis.^2,3 However, prolonged DAPT has been associated with excess bleeding events. Hence, it was important to validate the benefits of continuing DAPT beyond the recommended 12 months. The same group of researchers had previously reported that, compared with aspirin alone, continuation of DAPT for >12 months after drug-eluting stent implantation did not translate into improved clinical outcomes.⁴

A total of 5045 patients from 24 centers in South Korea were randomized, 2514 to DAPT and 2531 to aspirin monotherapy. The trial was recruited in successive cohorts. Initially, a total of 2701 patients were randomized (these patients were from 2 smaller trials: 1625 in REAL-LATE and 1076 in ZEST-LATE⁴; the trials had been merged due to slow enrollment). Finally, in a second phase, another 2344 patients were enrolled. Patients were randomly allocated to receive either low-dose aspirin alone (100 mg/d to 200 mg/d) or clopidogrel (75 mg/d) plus low-dose aspirin, in a prospective, multicenter, open-label, randomized design. Follow-ups were scheduled every 6 months. The primary end point was a composite of death resulting from cardiac causes, myocardial infarction (MI), or stroke 24 months after randomization. The secondary end points were death from any cause; MI; stroke; stent thrombosis; repeat revascularization; a composite of death resulting from cardiac causes or MI; a composite of death from any cause, MI, or stroke; major bleeding according to the Thrombolysis in Myocardial Infarction (TIMI) definition; and a composite of death resulting from cardiac causes, MI, stent thrombosis, stroke, or TIMI major bleeding.

Patients’ baseline characteristics were fairly similar between the 2 arms of the study. Approximately 28% had diabetes, 4% had prior MI, and 12% had undergone prior angioplasty. Approximately 38.5% of patients underwent PCI for stable angina, whereas the remainder had acute coronary syndromes, including unstable angina (37%), ST-segment elevation MI (STEMI) (12.5%), and non-STEMI (10.6%). Multivessel disease was noted in approximately 49% of the patients, whereas the left anterior descending artery was revascularized in approximately 50% of the patients. The mean number of stents per lesion was 1.3, with a mean stented length of 30 mm. The majority of drug-eluting stents were sirolimus-eluting stents (44%); others included paclitaxel-eluting stents (20%), zotarolimus-eluting stents (19%), and everolimus-eluting stents (11%).

The median time from index procedure to randomization was 13.3 months, and only 12% of patients were on DAPT beyond 18 months prior to randomization. Although approximately 96% of the patients were still taking aspirin at the end of 2 years of follow-up, only 79.4% of patients in the DAPT arm and 8.1% of the patients in the aspirin arm were taking clopidogrel at the end of 2 years of follow-up.

The incidence of the primary end point (cardiovascular death/MI/stroke) at 2 years (2.6% DAPT arm vs 2.4% in the aspirin-alone arm, P = .75) was comparable in both arms of the trial. No difference was noted when the analysis was conducted separately for each trial, or for each cohort of patients enrolled. At 24 months, there was also no difference between the DAPT vs the monotherapy arms respectively, in the incidence of all-cause mortality (2.0% vs 1.4%, P = .12), MI (0.8% vs 1.2%, P = .23), stroke (0.9% vs 0.9%, P = .98), definite stent thrombosis (0.3% vs 0.5%, P = .34), or need for repeat revascularization (3.5% vs 2.8%, P = .20). TIMI major bleeding was similar between the 2 arms (1.4% vs 1.1%, P = .20).

Commentary

Do results apply to non-Asian population?

Although the risks of late stent thrombosis with drug-eluting stents, especially after cessation of DAPT, are well known; the optimal duration of DAPT following PCI with drug-eluting stents remains dubious. Data from observational studies have been conflicting,⁵ and no randomized trial comparing 12 months of DAPT vs >12 months has yet been reported. This trial thus seeks to answer a very important question. In this trial, patients who had been on DAPT for at least 12 months following PCI with drug-eluting stents were randomized to continuing DAPT for another 2 years, or stopping clopidogrel and continuing aspirin only. The investigators found no difference in the incidence of any of the end points studied, including stent thrombosis.

Prior evidence for prolonged DAPT beyond 1 year remains controversial. The PRODIGY trial showed that 24 months of DAPT was not more effective than 6 months in decreasing the risk of all-cause mortality, MI, or cerebrovascular accident (CVA), but was associated with increased risk of bleeding.⁶ The OPTIMIZE trial randomized 3119 patients undergoing PCI for stable coronary artery disease or low-risk acute coronary syndrome with zotarolimus-eluting stents to 3 vs 12 months of DAPT. The primary end point of net adverse clinical and cerebral events (NACCE; a composite of all-cause death, MI, stroke, or major bleeding) was similar in the 2 arms (6.0% vs 5.8%, respectively; risk difference, 0.17 [95% confidence interval (CI), —1.52 to 1.86]; P = .002 for noninferiority).

There was no difference in NACCE between 91 and 360 days (2.6% vs 2.6%) or stent thrombosis (0.3% vs 0.1%; hazard ratio [HR], 3.97 [95% CI, 0.44 to 35.49]).⁷

One major limitation of the study by Lee et al is that it represents the combination of 2 separate trial phases (the second phase was enrolled after presentation of the first phase). Moreover, the first phase included 2 trials that were merged due to slow enrollment. ZEST-LATE was a continuation of the ZEST trial, which compared zotarolimus-eluting stents to sirolimus-eluting stents, and had slightly different enrollment criteria compared with REAL-LATE, which included a broader patient population. Thus, there may be some heterogeneity between the patients in the 2 trials, although this was not detected with the heterogeneity testing performed by the authors. Further, despite the merger, the overall trial was still underpowered to detect differences in clinical outcomes between the 2 trials, since the event rates were <25% of those anticipated.

It remains unclear whether the results of this trial can be applied to non-Asian populations. Individual variability in response to clopidogrel can be as high as 30% among different ethnic groups, and this has a bearing on ischemic and thrombotic outcomes.⁸

Finally, it should be noted that patients who had experienced a major adverse cardiac event or bleeding after implantation were excluded from this trial. The optimal duration of DAPT in such high-risk patients, such as those with left main coronary artery stents, remains under active investigation.

References

1. Lee CW, Ahn JM, Park DW, et al. Optimal duration of dual antiplatelet therapy after drug-eluting stent implantation: a randomized, controlled trial. Circulation. 2014;129(3):304-312.

2. Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention: executive summary: 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;124:2574-2609.

3. Wijns W, Kolh P, Danchin N, et al. Guidelines on myocardial revascularization. Eur Heart J. 2010;31:2501-2555.

4. Park SJ, Park DW, Kim YH, et al. Duration of dual antiplatelet therapy after implantation of drug-eluting stents. N Engl J Med. 2010;362:1374-1382.

5. Mulukutla SR, Marroquin OC, Vlachos HA, et al. Benefit of long-term dual anti-platelet therapy in patients treated with drug eluting stents: from NHLBI Dynamic Registry. Am J Cardiol. 2012;111:486-492.

6. Valgimigli M, Campo G, Monti M, et al, and the PRODIGY Investigators. Short- vs long-term duration of dual antiplatelet therapy after coronary stenting. Circulation. 2012;125:2015-2026.

7. 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(23):2510-2522.

8. Yin T, Miyata T.Pharmacogenomics of clopidogrel: evidence and perspectives. Thromb Res. 2011;128:307-316.

About the Author

Saurav Chatterjee, MD, is a clinical and research fellow in cardiology at Mount Sinai St. Luke’s Hospital in New York City. He graduated from Calcutta National Medical College with honors and was a Resident in cardiology in Mercy Hospital, Kolkata, India, as well as trial coordinator of the CRESCENDO trial in Kolkata, India. He recently completed his residency in Internal Medicine from Maimonides Medical Center in Brooklyn, NY, and was Clinical and Research Fellow in Preventive Cardiology and Outcomes Research at Brown University and Providence VAMC in Providence, RI. Dr Chatterjee is the recipient of the 2012 Young Investigator Award for Health Outcomes and Population Genetics at the Annual Scientific Sessions of the American College of Cardiology 2012 in Chicago, and also the 2011 American Association of Cardiologists of Indian Origin (AACIO) Young Investigator Award for Interventional Cardiology and Electrophysiology.