ORIGINAL ARTICLE
Optimal Duration of Dual Antiplatelet Therapy After Drug-eluting Stent Implantation: A Meta-analysis of 3 Randomized Controlled Trials Mao Liu, MD,* Jian Chen, MD,* Dan Huang, MB,* Jianting Ke, MD,† Wenyi Tang, MB,* and Wei Wu, MD, PhD*
Purpose: The optimal duration of dual antiplatelet therapy (DAPT) after drug-eluting stent (DES) implantation is still unclear. We conducted a meta-analysis of randomized trials to assess the optimal duration of DAPT after DES implantation.
Methods: Articles were identified through a literature search of EMBASE, Pubmed, Europubmed, and the Cochrane Library until November 2013. Data were independently extracted by 2 reviewers. A random effect model was used to calculate the pooled odds ratios (ORs) with 95% confidence intervals (CIs) of the clinical outcomes concerned.
Results: Three randomized controlled trials with zotarolimus- or everolimus-eluting stents and 6679 patients were included. There were no significant differences between short-term DAPT and standard-term DAPT in the comparison of incidences of cardiac death (OR, 0.84; 95% CI, 0.53–1.35; P = 0.48), myocardial infarction (OR, 1.21; 95% CI, 0.83–1.75; P = 0.32), stent thrombosis (OR, 1.30; 95% CI, 0.50–3.39; P = 0.59), and target vessel revascularization (OR, 1.16; 95% CI, 0.89–1.52; P = 0.26). Short-term DAPT did not increase the risk of all-cause death (OR, 0.86; 95% CI, 0.59– 1.26; P = 0.44), cerebrovascular accidents (OR, 0.88; 95% CI, 0.421.81; P = 0.72), and major bleeding events (OR, 0.59; 95% CI, 0.30–1.15; P = 0.12). Conclusions: The results indicate that short-term DAPT do not increase the risk of cardiac death, myocardial infarction, stent thrombosis, target vessel revascularization, major bleeding, cerebrovascular accidents, and all-cause death at 12 months after implantation of DES compared with current standard-term DAPT. However, only 3 studies with second generation of DES are included in this meta-analysis. Further well-designed studies are still needed. Key Words: drug-eluting stent, dual antiplatelet therapy, myocardial infarction, meta-analysis (J Cardiovasc Pharmacol Ô 2014;64:41–46)
Received for publication December 25, 2013; accepted February 12, 2014. From the Departments of *Cardiology; and †Nephrology, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, China. M. Liu and J. Chen have contributed equally. The authors report no conflicts of interest. Reprints: Wei Wu, MD, PhD, Department of Cardiology, The Fifth Affiliated Hospital of Sun Yat-Sen University, No. 52 Meihua East Rd, Zhuhai 519000, China (e-mail: [email protected]). Copyright © 2014 by Lippincott Williams & Wilkins
J Cardiovasc Pharmacol ä Volume 64, Number 1, July 2014
INTRODUCTION Previous studies have demonstrated that implantation of a drug-eluting stent (DES) reduces the rates of restenosis and associated clinical events compared with the bare-metal stent.1–3 However, the risk of death or myocardial infarction (MI) was reported to be higher after DES than after baremetal stents, which may be because of the different incidences of late or very late stent thrombosis.4–6 Therefore, to reduce the major adverse cardiac events, dual antiplatelet therapy (DAPT, mostly aspirin plus clopidogrel) is widely used after the implantation of stents.7,8 And the current recommendation of the DAPT duration after DES implantation is at least 12 months.7 However, it remains unclear whether short-term (,12 months) DAPT is as safe and effective as the standard-term therapy. Recently, several reports have shown that short-term DAPT is noninferior to the standard DAPT with respect to the occurrence of cardiovascular death, MI, stent thrombosis, and target vessel revascularization (TVR).9–12 In this study, to assess the optimal duration of DAPT after DES implantation systematically, we pooled relevant randomized trials and conducted a meta-analysis.
METHODS We performed an electronic search of Pubmed, Europubmed, EMBASE, and the Cochrane Library from their inception to November 28, 2013. To find the potential studies, we used the following search terms: DAPT, clopidogrel, aspirin, short-term, and randomized trial. The language was restricted to English. Additional articles were identified through searching the reference lists of primary articles and review articles. Titles and abstracts were screened by 2 investigators (W.T. and D.H.) independently. Two investigators (J.C. and M.L.) identified appropriate articles and conducted data extraction independently. Standard-term DAPT in our study was defined as aspirin 100–200 mg/d plus clopidogrel 75 mg/d for 12 months. Short-term DAPT meant that the duration of DAPT was less than 12 months. The selection criteria for eligible studies were as follow: (1) study design: randomized controlled trials; (2) study population: patients received DAPT after DES implantation; (3) grouping: short-term DAPT versus standard-term DAPT; (4) endpoints: all-cause death, cardiac death, MI, stent thrombosis (definite or probable), cerebrovascular accidents, TVR, any bleeding, and major bleeding; and (5) follow-up: at www.jcvp.org |
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were extracted. We assessed the quality of the randomized controlled studies using the Jadad’s scale,13 which evaluated the studies with respect to the method of randomization, adequacy of blinding, and appropriate description of withdrawals. A randomized controlled study can be awarded a highest score of 5. Funnel plot was used to evaluate the publication bias. All quality assessments of articles were performed by 2 reviewers. Inter-rater agreement was assessed using the k statistic. Discrepancies were resolved by contacting a third author.
Statistical Analysis
FIGURE 1. Flow diagram of the systematic review process.
least 12 months. Meeting abstracts, case reports, editorials, and reviews were excluded. All studies included in the analysis were approved by the respective ethics committees. Data extraction was completed independently by 2 investigators (J.K. and J.C.). Study design, country, study population characteristics, inclusion and exclusion criteria of each study, endpoints, number of patients, mean age, stent types, durations of DAPT, and incidences of adverse events were extracted. In case of suspicion of double reporting of the same patient populations, data from the main publication
Cochrane’s Q test and I2 were used to investigate the heterogeneity. The P value for significance of heterogeneity tests was set at 0.10. The I2 values of 0%–25%, 26%–50%, and .50% were considered as low, moderate, and severe statistical heterogeneity, respectively. To reduce the bias, we chose random effect model to calculate pooled odds ratio (OR) in all the analyses progress in this article. ORs with 95% confidence interval (CI) were used as summary statistics. The P value for significance was set at 0.05. All the P values were 2-tailed. All statistical tests were performed with Review Manager 5.1 software (Cochrane Collaboration, Copenhagen, Denmark).
RESULTS A total of 476 relevant publications were evaluated at the beginning. Finally, 3 randomized trials4,9,11 met the inclusion criteria. Flow diagram was shown in Figure 1. In the assessment of inter-rater agreement, the k was 0.88. Two studies4,9 were from Asia and 111 from South America. The loading dose of clopidogrel was 300–600 mg in these studies. The durations of short-term DAPT group were set as 3
FIGURE 2. Funnel plots of the included studies.
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J Cardiovasc Pharmacol ä Volume 64, Number 1, July 2014
Meta-analysis of DAPT Duration
TABLE 1. Main Characteristics of the Included Studies OPTIMIZE Study DAPT duration, mo No. patients Age, yr Males, n (%) BMI, kg/m2 Hypertension, n (%) Diabetes, n (%) Heart failure, n (%) Dyslipidemia, n (%) Current smoker, n (%) ACS, n (%) Stable CAD, n (%) Multi-vessel disease, n (%) Types of DES
Stents per patient, n Publication year Main inclusion criteria
Primary endpoint
Length of follow-up, mo Jadad’s score
RESET
EXCELLENT
Short
Standard
Short
Standard
Short
Standard
3 1563 61.3 6 10.4 992 (63.5) — 1350 (86.4)
12 1556 61.9 6 10.6 982 (63.1) — 1371 (88.2)
3 1059 62.4 6 9.4 682 (64.4) 25.0 (3.2) 660 (62.3)
12 1058 62.4 6 9.8 665 (62.9) 24.9 (3.1) 650 (61.4)
6 722 63.0 6 9.6 470 (65.1) 24.9 (3.1) 525 (72.7)
12 721 62.4 6 10.4 461 (63.9) 25.1 (3.0) 532 (73.8)
554 (35.4) 64 (4.3) 953 (63.2)
549 (35.3) 64 (4.2) 952 (63.7)
316 (29.8) 120 (11.3) 611 (57.7)
305 (28.8) 125 (11.8) 634 (59.9)
272 (37.7) 4 (0.6) 543 (75.2)
278 (38.6) 5 (0.7) 550 (76.3)
290 (18.6)
269 (17.3)
267 (25.2)
241 (22.8)
198 (27.4)
186 (25.8)
494 (31.6) 1069 (68.4) 396 (25.34)
502 (32.3) 1054 (67.7) 413 (26.54)
588 (55.5) 471 (44.5) 456 (43.1)
568 (53.7) 490 (46.3) 454 (42.9)
369 (51.1) 353 (48.9) 375 (51.9)
375 (52.0) 346 (48.0) 375 (52.0)
Zotarolimus
Sirolimus, everolimus, zotarolimus —
Zotarolimus 1.6 6 0.8
Zotarolimus 1.6 6 0.8
—
2013 Stable angina, silent ischemia, low-risk ACS, at least 1 lesion with stenosis .50% located in a native vessel at least 2.5-mm in diameter
2012 Angina, acute MI, stenosis .50% diameter in a coronary artery
A composite of death from any cause, MI, stroke, or major bleeding 12
Cardiovascular death, MI, stent thrombosis, TVR, or bleeding 12
5
4
Everolimus, sirolimus 1.6 6 1.0
Everolimus, sirolimus 1.6 6 0.9
2012 Angina, silent ischemia, recent MI, reversible changes on ECG consistent with ischemia, at least 1 lesion in a native coronary vessel, stenosis .50%, reference diameter is 2.25–4.25 mm A composite of cardiac death, MI, or TVR 12 3
BMI, body mass index; CAD, coronary artery disease; ECG, electrocardiogram; EXCELLENT, Efficacy of Xience/Promus versus Cypher to Reduce Late Loss After Stenting; OPTIMIZE, Optimized Duration of Clopidogrel Therapy Following Treatment With the Zotarolimus-Eluting Stentin Real-World Clinical Practice; RESET, Real Safety and Efficacy of 3-month dual antiplatelet Therapy following Endeavor zotarolimus-eluting stent implantation.
months in 2 studies9,11 and 6 months in the other trial.4 According to the funnel plot shown in Figure 2, the publication bias was acceptable. The types of DESs used in these studies included zotarolimus-eluting stents, everolimus-eluting stents, and sirolimus-eluting stents. Totally, 6679 patients were included in this meta-analysis. Among these patients, about 63.7% of them were men. There were 2896 (43.4%) patients with acute coronary syndrome (ACS), 3344 cases were in short-term DAPT group, and the other 3335 patients received standard-term DAPT. Loss at follow-up was minimal in each study. The main characteristics of included studies are reported in Table 1. In this meta-analysis, adverse cardiac events consisted of the composite of fatal or nonfatal MI, Ó 2014 Lippincott Williams & Wilkins
cardiovascular death, definite or probable stent thrombosis, and TVR. No statistical heterogeneity was found in the heterogeneity test. The pooled results indicated that there was no significant difference between short-term DAPT and standard-term DAPT in the comparison of incidences of cardiac death (0.99% vs. 1.17%; OR, 0.84; 95% CI, 0.53–1.35; P = 0.48), MI (1.91% vs. 1.59%; OR, 1.21; 95% CI, 0.83–1.75; P = 0.32), stent thrombosis (0.63% vs. 0.48%; OR, 1.30; 95% CI, 0.50–3.39; P = 0.59), and TVR (3.68% vs. 3.18%, OR, 1.16; 95% CI, 0.89–1.52; P = 0.26). The pooled composite rates of cardiac death or MI were 2.66% and 2.37%, respectively (OR, 1.13; 95% CI, 0.83–1.54; P = 0.44). Information in detail is shown in Figure 3. www.jcvp.org |
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FIGURE 3. Forest plot illustrating the comparison of adverse cardiac events between short-term and standard-term DAPT.
All-cause death, cerebrovascular accident, any bleeding, and major bleeding were analyzed together to evaluate the safety of short-term and standard-term DAPT. No statistical heterogeneity was found in this analysis (P values for heterogeneity test were 0.62, 0.83, 0.49, and 0.69, respectively). As shown in Figure 4, compared with standard-term DAPT, short-term DAPT did not increase the risk of all-cause death (1.56% vs. 1.80%; OR, 0.86; 95% CI, 0.59–1.26; P = 0.44), cerebrovascular accidents (0.42% vs. 0.48%; OR, 0.88; 95% CI, 0.42–1.81; P = 0.72), any bleeding events (1.32% vs. 1.95%; OR, 0.67; 95% CI, 0.46–1.00; P = 0.05), and major bleeding events (0.42% vs. 0.72%; OR, 0.59; 95% CI, 0.30–1.15; P = 0.12).
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DISCUSSION The DAPT with aspirin and clopidogrel for at least 12 months after implantation of a DES is the mainstay antiplatelet strategy to prevent ischemic events.14,15 However, the optimal or minimal necessary duration of DAPT remains undetermined.4,16,17 The current recommendation is the lack of randomized trial data. It is mainly based on limited trial data and retrospective analyses from registered studies.11,18–20 And the findings of observational studies have been inconsistent.18,21–23 Moreover, DAPT increases bleeding risk and costs compared with aspirin alone.4,24,25 In consequence, the optimal duration of DAPT becomes an interesting and meaningful topic. Ó 2014 Lippincott Williams & Wilkins
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Meta-analysis of DAPT Duration
FIGURE 4. Forest plot illustrating the comparison of safety endpoints between short-term and standard-term DAPT.
Recently, Feres et al11 randomly assigned 3119 patients, with stable coronary artery disease or low-risk ACS treated with zotarolimus-eluting stents, into 2 groups according to DAPT duration: 3-month DAPT (short-term group, n = 1563) versus 12-month DAPT (long-term group, n = 1556). The primary endpoints were net adverse clinical and cerebral events (a composite of all-cause death, MI, stroke, or major bleeding), and the secondary endpoints were major adverse cardiac events (a composite of all-cause death, MI, emergent coronary artery bypass graft surgery, or target lesion revascularization). Between 91 and 360 days, no statistical significance was observed in the comparison of the 2 groups for net adverse clinical and cerebral events, and major adverse cardiac events and stent thrombosis. The results indicated that 3month DAPT was noninferior to standard 12-month DAPT after the implantation of DESs. To assess the benefits and risks of short-term and longterm DAPT after a DES implantation systematically, we Ó 2014 Lippincott Williams & Wilkins
conducted this systematic review and meta-analysis. The results indicate that clinical outcomes of cardiac death, MI, stent thrombosis, and TVR do not differ significantly between patients taking short-term DAPT of 3–6 months compared with the standard 12-month DAPT. Also, short-term DAPT does not increase the risk of major bleeding, cerebrovascular accidents, and all-cause death. In this study, all included studies were randomized controlled trials, and the Jadad’s scores ranged from 3 to 5. According to the funnel plot, the publication bias of this meta-analysis was acceptable. Sensitivity analysis also indicated that no single study significantly altered the summary ORs for each endpoint. Furthermore, we selected random effect model in all the analyses progress to reduce potential bias, although there was no statistical heterogeneity among these studies. Consequently, it suggested a high quality of the evidence in this study. The results of this meta-analysis presented supporting evidence for shortening the duration of DAPT after DES implantation. www.jcvp.org |
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Liu et al
However, several potential limitations should be considered. First, only publications in English were considered in our search process. Studies in other languages were lost inevitably. Second, the number of eligible studies for metaanalysis was relatively few. There were only 3 studies and 6679 subjects included. Besides, 2 of these trials were conducted in Asia. Data from other countries and races are still lacking. Moreover, the number of patients with ACS only accounts for 43.4% of all the included patients, which may lead to a relatively lower risk of adverse cardiac events. In addition, the types of DES in these studies were varied. All 3 studies included second generation of DES (zotarolimus- or everolimus-eluting stents), which may be associated with a reduction in adverse outcomes compared with first generation of DES. But 2 of them4,9 also included first generation of DES. Furthermore, the incidence of adverse events was overall very low, and therefore the analysis is limited in power. All these contributed to the risk of bias in a certain degree. Finally, the comparisons in this study were limited to the duration of 12 months versus 3–6 months. The clinical outcomes in longer durations were not explored. In conclusion, the results of this meta-analysis indicate that short-term DAPT do not increase the risk of cardiac death, MI, stent thrombosis, TVR, major bleeding, cerebrovascular accidents, and all-cause death at 12 months after implantation of DES compared with current standard-term DAPT. However, only 3 studies with zotarolimus- or everolimus-eluting stents are included in this meta-analysis. To confirm the efficiency and safety of short-term DAPT, further well-designed studies are still needed.
8.
9.
10.
11. 12. 13. 14. 15.
16.
17.
REFERENCES 1. Colombo A, Drzewiecki J, Banning A, et al. Randomized study to assess the effectiveness of slow- and moderate-release polymer-based paclitaxel-eluting stents for coronary artery lesions. Circulation. 2003; 108:788–794. 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. Kastrati A, Dibra A, Spaulding C, et al. Meta-analysis of randomized trials on drug-eluting stents vs. bare-metal stents in patients with acute myocardial infarction. Eur Heart J. 2007;28:2706–2713. 4. 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. 5. 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. 6. Migliorini A, Valenti R, Marcucci R, et al. High residual platelet reactivity after clopidogrel loading and long-term clinical outcome after drugeluting stenting for unprotected left main coronary disease. Circulation. 2009;120:2214–2221. 7. O’Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report
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18. 19. 20. 21. 22. 23.
24. 25.
of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;61:e78–e140 Mehta SR, Yusuf S, Peters RJ, et al. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet. 2001; 358:527–533. 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 zotarolimuseluting stent implantation). J Am Coll Cardiol. 2012;60:1340–1348. Fajadet J, Wijns W, Laarman GJ, et al. Randomized, double-blind, multicenter study of the Endeavor zotarolimus-eluting phosphorylcholineencapsulated stent for treatment of native coronary artery lesions: clinical and angiographic results of the ENDEAVOR II trial. Circulation. 2006; 114:798–806. 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. Kandzari DE, Barker CS, Leon MB, et al. Dual antiplatelet therapy duration and clinical outcomes following treatment with zotarolimuseluting stents. JACC Cardiovasc Interv. 2011;4:1119–1128. Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996;17:1–12. Gasparyan AY, Watson T, Lip GY. The role of aspirin in cardiovascular prevention: implications of aspirin resistance. J Am Coll Cardiol. 2008; 51:1829–1843. Mao L, Jian C, Changzhi L, et al. Cytochrome CYP2C19 polymorphism and risk of adverse clinical events in clopidogrel-treated patients: a metaanalysis based on 23,035 subjects. Arch Cardiovasc Dis. 2013;106:517– 527. Bernardi V, Szarfer J, Summay G, et al. Long-term versus short-term clopidogrel therapy in patients undergoing coronary stenting (from the Randomized Argentine Clopidogrel Stent [RACS] trial). Am J Cardiol. 2007;99:349–352. Mulukutla SR, Marroquin OC, Vlachos HA, et al. Benefit of long-term dual anti-platelet therapy in patients treated with drug-eluting stents: from the NHLBI dynamic registry. Am J Cardiol. 2013;111:486–492. 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. 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. Bryniarski L, Pelc-Nowicka A, Zabojszcz M, et al. Dual antiplatelet therapy and antithrombotic treatment: recommendations and controversies. Cardiol J. 2009;16:179–189. Airoldi F, Colombo A, Morici N, et al. Incidence and predictors of drugeluting stent thrombosis during and after discontinuation of thienopyridine treatment. Circulation. 2007;116:745–754. Eisenstein EL, Anstrom KJ, Kong DF, et al. Clopidogrel use and longterm clinical outcomes after drug-eluting stent implantation. JAMA. 2007;297:159–168. Schulz S, Schuster T, Mehilli J, et al. Stent thrombosis after drug-eluting stent implantation: incidence, timing, and relation to discontinuation of clopidogrel therapy over a 4-year period. Eur Heart J. 2009;30:2714– 2721. 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. Hallas J, Dall M, Andries A, et al. Use of single and combined antithrombotic therapy and risk of serious upper gastrointestinal bleeding: population based case-control study. BMJ. 2006;333:726.
Ó 2014 Lippincott Williams & Wilkins
Optimal Duration of Dual Antiplatelet Therapy After Drug-eluting Stent Implantation: A Meta-analysis of 3 Randomized Controlled Trials Mao Liu, MD,* Jian Chen, MD,* Dan Huang, MB,* Jianting Ke, MD,† Wenyi Tang, MB,* and Wei Wu, MD, PhD*
Purpose: The optimal duration of dual antiplatelet therapy (DAPT) after drug-eluting stent (DES) implantation is still unclear. We conducted a meta-analysis of randomized trials to assess the optimal duration of DAPT after DES implantation.
Methods: Articles were identified through a literature search of EMBASE, Pubmed, Europubmed, and the Cochrane Library until November 2013. Data were independently extracted by 2 reviewers. A random effect model was used to calculate the pooled odds ratios (ORs) with 95% confidence intervals (CIs) of the clinical outcomes concerned.
Results: Three randomized controlled trials with zotarolimus- or everolimus-eluting stents and 6679 patients were included. There were no significant differences between short-term DAPT and standard-term DAPT in the comparison of incidences of cardiac death (OR, 0.84; 95% CI, 0.53–1.35; P = 0.48), myocardial infarction (OR, 1.21; 95% CI, 0.83–1.75; P = 0.32), stent thrombosis (OR, 1.30; 95% CI, 0.50–3.39; P = 0.59), and target vessel revascularization (OR, 1.16; 95% CI, 0.89–1.52; P = 0.26). Short-term DAPT did not increase the risk of all-cause death (OR, 0.86; 95% CI, 0.59– 1.26; P = 0.44), cerebrovascular accidents (OR, 0.88; 95% CI, 0.421.81; P = 0.72), and major bleeding events (OR, 0.59; 95% CI, 0.30–1.15; P = 0.12). Conclusions: The results indicate that short-term DAPT do not increase the risk of cardiac death, myocardial infarction, stent thrombosis, target vessel revascularization, major bleeding, cerebrovascular accidents, and all-cause death at 12 months after implantation of DES compared with current standard-term DAPT. However, only 3 studies with second generation of DES are included in this meta-analysis. Further well-designed studies are still needed. Key Words: drug-eluting stent, dual antiplatelet therapy, myocardial infarction, meta-analysis (J Cardiovasc Pharmacol Ô 2014;64:41–46)
Received for publication December 25, 2013; accepted February 12, 2014. From the Departments of *Cardiology; and †Nephrology, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, China. M. Liu and J. Chen have contributed equally. The authors report no conflicts of interest. Reprints: Wei Wu, MD, PhD, Department of Cardiology, The Fifth Affiliated Hospital of Sun Yat-Sen University, No. 52 Meihua East Rd, Zhuhai 519000, China (e-mail: [email protected]). Copyright © 2014 by Lippincott Williams & Wilkins
J Cardiovasc Pharmacol ä Volume 64, Number 1, July 2014
INTRODUCTION Previous studies have demonstrated that implantation of a drug-eluting stent (DES) reduces the rates of restenosis and associated clinical events compared with the bare-metal stent.1–3 However, the risk of death or myocardial infarction (MI) was reported to be higher after DES than after baremetal stents, which may be because of the different incidences of late or very late stent thrombosis.4–6 Therefore, to reduce the major adverse cardiac events, dual antiplatelet therapy (DAPT, mostly aspirin plus clopidogrel) is widely used after the implantation of stents.7,8 And the current recommendation of the DAPT duration after DES implantation is at least 12 months.7 However, it remains unclear whether short-term (,12 months) DAPT is as safe and effective as the standard-term therapy. Recently, several reports have shown that short-term DAPT is noninferior to the standard DAPT with respect to the occurrence of cardiovascular death, MI, stent thrombosis, and target vessel revascularization (TVR).9–12 In this study, to assess the optimal duration of DAPT after DES implantation systematically, we pooled relevant randomized trials and conducted a meta-analysis.
METHODS We performed an electronic search of Pubmed, Europubmed, EMBASE, and the Cochrane Library from their inception to November 28, 2013. To find the potential studies, we used the following search terms: DAPT, clopidogrel, aspirin, short-term, and randomized trial. The language was restricted to English. Additional articles were identified through searching the reference lists of primary articles and review articles. Titles and abstracts were screened by 2 investigators (W.T. and D.H.) independently. Two investigators (J.C. and M.L.) identified appropriate articles and conducted data extraction independently. Standard-term DAPT in our study was defined as aspirin 100–200 mg/d plus clopidogrel 75 mg/d for 12 months. Short-term DAPT meant that the duration of DAPT was less than 12 months. The selection criteria for eligible studies were as follow: (1) study design: randomized controlled trials; (2) study population: patients received DAPT after DES implantation; (3) grouping: short-term DAPT versus standard-term DAPT; (4) endpoints: all-cause death, cardiac death, MI, stent thrombosis (definite or probable), cerebrovascular accidents, TVR, any bleeding, and major bleeding; and (5) follow-up: at www.jcvp.org |
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were extracted. We assessed the quality of the randomized controlled studies using the Jadad’s scale,13 which evaluated the studies with respect to the method of randomization, adequacy of blinding, and appropriate description of withdrawals. A randomized controlled study can be awarded a highest score of 5. Funnel plot was used to evaluate the publication bias. All quality assessments of articles were performed by 2 reviewers. Inter-rater agreement was assessed using the k statistic. Discrepancies were resolved by contacting a third author.
Statistical Analysis
FIGURE 1. Flow diagram of the systematic review process.
least 12 months. Meeting abstracts, case reports, editorials, and reviews were excluded. All studies included in the analysis were approved by the respective ethics committees. Data extraction was completed independently by 2 investigators (J.K. and J.C.). Study design, country, study population characteristics, inclusion and exclusion criteria of each study, endpoints, number of patients, mean age, stent types, durations of DAPT, and incidences of adverse events were extracted. In case of suspicion of double reporting of the same patient populations, data from the main publication
Cochrane’s Q test and I2 were used to investigate the heterogeneity. The P value for significance of heterogeneity tests was set at 0.10. The I2 values of 0%–25%, 26%–50%, and .50% were considered as low, moderate, and severe statistical heterogeneity, respectively. To reduce the bias, we chose random effect model to calculate pooled odds ratio (OR) in all the analyses progress in this article. ORs with 95% confidence interval (CI) were used as summary statistics. The P value for significance was set at 0.05. All the P values were 2-tailed. All statistical tests were performed with Review Manager 5.1 software (Cochrane Collaboration, Copenhagen, Denmark).
RESULTS A total of 476 relevant publications were evaluated at the beginning. Finally, 3 randomized trials4,9,11 met the inclusion criteria. Flow diagram was shown in Figure 1. In the assessment of inter-rater agreement, the k was 0.88. Two studies4,9 were from Asia and 111 from South America. The loading dose of clopidogrel was 300–600 mg in these studies. The durations of short-term DAPT group were set as 3
FIGURE 2. Funnel plots of the included studies.
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Ó 2014 Lippincott Williams & Wilkins
J Cardiovasc Pharmacol ä Volume 64, Number 1, July 2014
Meta-analysis of DAPT Duration
TABLE 1. Main Characteristics of the Included Studies OPTIMIZE Study DAPT duration, mo No. patients Age, yr Males, n (%) BMI, kg/m2 Hypertension, n (%) Diabetes, n (%) Heart failure, n (%) Dyslipidemia, n (%) Current smoker, n (%) ACS, n (%) Stable CAD, n (%) Multi-vessel disease, n (%) Types of DES
Stents per patient, n Publication year Main inclusion criteria
Primary endpoint
Length of follow-up, mo Jadad’s score
RESET
EXCELLENT
Short
Standard
Short
Standard
Short
Standard
3 1563 61.3 6 10.4 992 (63.5) — 1350 (86.4)
12 1556 61.9 6 10.6 982 (63.1) — 1371 (88.2)
3 1059 62.4 6 9.4 682 (64.4) 25.0 (3.2) 660 (62.3)
12 1058 62.4 6 9.8 665 (62.9) 24.9 (3.1) 650 (61.4)
6 722 63.0 6 9.6 470 (65.1) 24.9 (3.1) 525 (72.7)
12 721 62.4 6 10.4 461 (63.9) 25.1 (3.0) 532 (73.8)
554 (35.4) 64 (4.3) 953 (63.2)
549 (35.3) 64 (4.2) 952 (63.7)
316 (29.8) 120 (11.3) 611 (57.7)
305 (28.8) 125 (11.8) 634 (59.9)
272 (37.7) 4 (0.6) 543 (75.2)
278 (38.6) 5 (0.7) 550 (76.3)
290 (18.6)
269 (17.3)
267 (25.2)
241 (22.8)
198 (27.4)
186 (25.8)
494 (31.6) 1069 (68.4) 396 (25.34)
502 (32.3) 1054 (67.7) 413 (26.54)
588 (55.5) 471 (44.5) 456 (43.1)
568 (53.7) 490 (46.3) 454 (42.9)
369 (51.1) 353 (48.9) 375 (51.9)
375 (52.0) 346 (48.0) 375 (52.0)
Zotarolimus
Sirolimus, everolimus, zotarolimus —
Zotarolimus 1.6 6 0.8
Zotarolimus 1.6 6 0.8
—
2013 Stable angina, silent ischemia, low-risk ACS, at least 1 lesion with stenosis .50% located in a native vessel at least 2.5-mm in diameter
2012 Angina, acute MI, stenosis .50% diameter in a coronary artery
A composite of death from any cause, MI, stroke, or major bleeding 12
Cardiovascular death, MI, stent thrombosis, TVR, or bleeding 12
5
4
Everolimus, sirolimus 1.6 6 1.0
Everolimus, sirolimus 1.6 6 0.9
2012 Angina, silent ischemia, recent MI, reversible changes on ECG consistent with ischemia, at least 1 lesion in a native coronary vessel, stenosis .50%, reference diameter is 2.25–4.25 mm A composite of cardiac death, MI, or TVR 12 3
BMI, body mass index; CAD, coronary artery disease; ECG, electrocardiogram; EXCELLENT, Efficacy of Xience/Promus versus Cypher to Reduce Late Loss After Stenting; OPTIMIZE, Optimized Duration of Clopidogrel Therapy Following Treatment With the Zotarolimus-Eluting Stentin Real-World Clinical Practice; RESET, Real Safety and Efficacy of 3-month dual antiplatelet Therapy following Endeavor zotarolimus-eluting stent implantation.
months in 2 studies9,11 and 6 months in the other trial.4 According to the funnel plot shown in Figure 2, the publication bias was acceptable. The types of DESs used in these studies included zotarolimus-eluting stents, everolimus-eluting stents, and sirolimus-eluting stents. Totally, 6679 patients were included in this meta-analysis. Among these patients, about 63.7% of them were men. There were 2896 (43.4%) patients with acute coronary syndrome (ACS), 3344 cases were in short-term DAPT group, and the other 3335 patients received standard-term DAPT. Loss at follow-up was minimal in each study. The main characteristics of included studies are reported in Table 1. In this meta-analysis, adverse cardiac events consisted of the composite of fatal or nonfatal MI, Ó 2014 Lippincott Williams & Wilkins
cardiovascular death, definite or probable stent thrombosis, and TVR. No statistical heterogeneity was found in the heterogeneity test. The pooled results indicated that there was no significant difference between short-term DAPT and standard-term DAPT in the comparison of incidences of cardiac death (0.99% vs. 1.17%; OR, 0.84; 95% CI, 0.53–1.35; P = 0.48), MI (1.91% vs. 1.59%; OR, 1.21; 95% CI, 0.83–1.75; P = 0.32), stent thrombosis (0.63% vs. 0.48%; OR, 1.30; 95% CI, 0.50–3.39; P = 0.59), and TVR (3.68% vs. 3.18%, OR, 1.16; 95% CI, 0.89–1.52; P = 0.26). The pooled composite rates of cardiac death or MI were 2.66% and 2.37%, respectively (OR, 1.13; 95% CI, 0.83–1.54; P = 0.44). Information in detail is shown in Figure 3. www.jcvp.org |
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J Cardiovasc Pharmacol ä Volume 64, Number 1, July 2014
FIGURE 3. Forest plot illustrating the comparison of adverse cardiac events between short-term and standard-term DAPT.
All-cause death, cerebrovascular accident, any bleeding, and major bleeding were analyzed together to evaluate the safety of short-term and standard-term DAPT. No statistical heterogeneity was found in this analysis (P values for heterogeneity test were 0.62, 0.83, 0.49, and 0.69, respectively). As shown in Figure 4, compared with standard-term DAPT, short-term DAPT did not increase the risk of all-cause death (1.56% vs. 1.80%; OR, 0.86; 95% CI, 0.59–1.26; P = 0.44), cerebrovascular accidents (0.42% vs. 0.48%; OR, 0.88; 95% CI, 0.42–1.81; P = 0.72), any bleeding events (1.32% vs. 1.95%; OR, 0.67; 95% CI, 0.46–1.00; P = 0.05), and major bleeding events (0.42% vs. 0.72%; OR, 0.59; 95% CI, 0.30–1.15; P = 0.12).
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DISCUSSION The DAPT with aspirin and clopidogrel for at least 12 months after implantation of a DES is the mainstay antiplatelet strategy to prevent ischemic events.14,15 However, the optimal or minimal necessary duration of DAPT remains undetermined.4,16,17 The current recommendation is the lack of randomized trial data. It is mainly based on limited trial data and retrospective analyses from registered studies.11,18–20 And the findings of observational studies have been inconsistent.18,21–23 Moreover, DAPT increases bleeding risk and costs compared with aspirin alone.4,24,25 In consequence, the optimal duration of DAPT becomes an interesting and meaningful topic. Ó 2014 Lippincott Williams & Wilkins
J Cardiovasc Pharmacol ä Volume 64, Number 1, July 2014
Meta-analysis of DAPT Duration
FIGURE 4. Forest plot illustrating the comparison of safety endpoints between short-term and standard-term DAPT.
Recently, Feres et al11 randomly assigned 3119 patients, with stable coronary artery disease or low-risk ACS treated with zotarolimus-eluting stents, into 2 groups according to DAPT duration: 3-month DAPT (short-term group, n = 1563) versus 12-month DAPT (long-term group, n = 1556). The primary endpoints were net adverse clinical and cerebral events (a composite of all-cause death, MI, stroke, or major bleeding), and the secondary endpoints were major adverse cardiac events (a composite of all-cause death, MI, emergent coronary artery bypass graft surgery, or target lesion revascularization). Between 91 and 360 days, no statistical significance was observed in the comparison of the 2 groups for net adverse clinical and cerebral events, and major adverse cardiac events and stent thrombosis. The results indicated that 3month DAPT was noninferior to standard 12-month DAPT after the implantation of DESs. To assess the benefits and risks of short-term and longterm DAPT after a DES implantation systematically, we Ó 2014 Lippincott Williams & Wilkins
conducted this systematic review and meta-analysis. The results indicate that clinical outcomes of cardiac death, MI, stent thrombosis, and TVR do not differ significantly between patients taking short-term DAPT of 3–6 months compared with the standard 12-month DAPT. Also, short-term DAPT does not increase the risk of major bleeding, cerebrovascular accidents, and all-cause death. In this study, all included studies were randomized controlled trials, and the Jadad’s scores ranged from 3 to 5. According to the funnel plot, the publication bias of this meta-analysis was acceptable. Sensitivity analysis also indicated that no single study significantly altered the summary ORs for each endpoint. Furthermore, we selected random effect model in all the analyses progress to reduce potential bias, although there was no statistical heterogeneity among these studies. Consequently, it suggested a high quality of the evidence in this study. The results of this meta-analysis presented supporting evidence for shortening the duration of DAPT after DES implantation. www.jcvp.org |
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Liu et al
However, several potential limitations should be considered. First, only publications in English were considered in our search process. Studies in other languages were lost inevitably. Second, the number of eligible studies for metaanalysis was relatively few. There were only 3 studies and 6679 subjects included. Besides, 2 of these trials were conducted in Asia. Data from other countries and races are still lacking. Moreover, the number of patients with ACS only accounts for 43.4% of all the included patients, which may lead to a relatively lower risk of adverse cardiac events. In addition, the types of DES in these studies were varied. All 3 studies included second generation of DES (zotarolimus- or everolimus-eluting stents), which may be associated with a reduction in adverse outcomes compared with first generation of DES. But 2 of them4,9 also included first generation of DES. Furthermore, the incidence of adverse events was overall very low, and therefore the analysis is limited in power. All these contributed to the risk of bias in a certain degree. Finally, the comparisons in this study were limited to the duration of 12 months versus 3–6 months. The clinical outcomes in longer durations were not explored. In conclusion, the results of this meta-analysis indicate that short-term DAPT do not increase the risk of cardiac death, MI, stent thrombosis, TVR, major bleeding, cerebrovascular accidents, and all-cause death at 12 months after implantation of DES compared with current standard-term DAPT. However, only 3 studies with zotarolimus- or everolimus-eluting stents are included in this meta-analysis. To confirm the efficiency and safety of short-term DAPT, further well-designed studies are still needed.
8.
9.
10.
11. 12. 13. 14. 15.
16.
17.
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Ó 2014 Lippincott Williams & Wilkins
