The duration of dual-antiplatelet therapy (DAPT) after coronary stenting has garnered tremendous attention during the last decade. After concerns were raised of increased mortality and myocardial infarction (MI) due to stent thrombosis (ST) in patients treated with drug-eluting stents (DES) compared to patients treated with bare-metal stents (BMS), the US Food and Drug Administration (FDA) convened a Circulatory System Devices Advisory Panel discussing DES in 2006, which concluded that DAPT should be maintained for at least 12 months after DES implantation. In the United States, we have been practicing by this mantra ever since1; however, citing concerns of bleeding risk and improved safety of second-generation DES, the 2014 European Society of Cardiology recommended DAPT for only 6 months after DES implantation without acute coronary syndrome and for a maximum of 12 months with acute coronary syndrome.2 However, even with newer stent types, late stent-related and -unrelated events occur after percutaneous coronary intervention, suggesting potential benefit to continued DAPT.3 In this article, we review data from recent randomized clinical trials evaluating the application of short and extended P2Y12 inhibitor use on a background of aspirin therapy after DES implantation.

EVIDENCE FOR SHORTER-TERM P2Y12 INHIBITOR USE

In 2012, the EXCELLENT study was the first to evaluate the use of short-duration P2Y12 inhibitor use after DES implantation. In 1,443 patients, Gwon et al found that 6 months of P2Y12 inhibitor use was noninferior to 12 months of therapy in reducing rates of target vessel failure (hazard ratio [HR], 1.14; 95% confidence interval [CI], 0.7–1.86; P = .6; P = .001 for noninferiority), defined as the composite of cardiac death, MI, or target vessel revascularization. However, the authors observed a trend for increased ST with shorter-duration P2Y12 inhibitor use (0.9% vs 0.1% [HR, 6.02; 95% CI, 0.72–49.96; P = .1]).4 The PRODIGY trial demonstrated that extended-duration (24 months) P2Y12 inhibitor use was not superior to short-duration P2Y12 inhibitor use (6 months) using a composite endpoint of death, MI, or cerebrovascular accidents (HR, 0.98; 95% CI, 0.74–1.29; P = .91); however, the study also demonstrated an increased risk of all prespecified bleeding endpoints with continued P2Y12 inhibitor use.5 Notably, both studies included a large proportion of patients presenting with acute coronary syndrome.4,5

The five additional studies of short- versus long-duration P2Y12 inhibitor therapy adopted primary endpoints that included both ischemic and bleeding parameters in an effort to determine net clinical benefit. The RESET and OPTIMIZE trials specifically investigated the noninferiority of 3 months of P2Y12 inhibitor use relative to 12 months of therapy,6,7 whereas the SECURITY, ITALIC, and ISAR-SAFE studies compared 6 and 12 months of P2Y12 inhibitor use after DES implantation.8-10 Each study reported noninferiority of shorter-duration P2Y12 inhibitor therapy relative to 12 months of P2Y12 inhibitor use.

It is notable that none of the aforementioned trials comparing short- to standard- or long-duration P2Y12 inhibitor use after percutaneous coronary intervention possessed sufficient statistical power to assess individual components of their composite primary endpoints and, in some cases, even to assess the composite endpoint.11 Specifically, comparisons of the rates of ST, MI, major bleeding, and death between treatment arms were underpowered. Several meta-analyses and pooled analyses have consequently attempted to clarify the impact of short-duration P2Y12 inhibitor use on these endpoints. These studies have largely concluded that short-duration (3–6 months) P2Y12 inhibitor use results in similar rates of ST, MI, and death and reduced bleeding risk when compared to long-duration (12–24 months) P2Y12 inhibitor therapy after DES implantation.11-13

EVIDENCE FOR LONGER-TERM P2Y12 INHIBITOR USE

Three randomized clinical studies have been conducted to evaluate the safety and efficacy of continued P2Y12 inhibitor use beyond 1 year on a background of aspirin therapy. Both the DES-LATE and the ARCTIC-Interruption trials were extensions of earlier studies.14,15 The DES-LATE trial, an extension of the merged REAL-LATE and ZEST-LATE trials, was a multicenter, open-label, randomized trial. At 12-month follow-up, 2,071 patients who were free of major adverse cardiac and cerebrovascular events (MACCE) and major bleeding were randomly assigned to clopidogrel and aspirin for an additional 12 months or aspirin alone. Rates of the primary endpoint, a composite of cardiac death and MI, were comparable between treatment arms after a median follow-up of 19.2 months (HR, 1.65; 95% CI, 0.8–3.36; P = .17).14

The ARCTIC-Interruption trial was a planned extension of the ARCTIC-Monitoring trial, in which 2,440 patients had been randomly assigned either to conventional therapy or antiplatelet therapy guided by platelet function testing. After 12 months of follow-up, patients without a contraindication to P2Y12 inhibitor interruption underwent a second randomization within the open-label ARCTIC-Interruption trial. A total of 1,259 patients were randomized to continuation of P2Y12 inhibitor and aspirin for an additional 6 to 18 months or interruption of P2Y12 inhibitor therapy (aspirin alone).15 The primary endpoint, the composite of death, MI, ST, stroke, or urgent revascularization, occurred with equal frequency within the two treatment arms (HR, 1.17; 95% CI, 0.68–2.03; P = .58). As opposed to the DES-LATE trial, ARCTIC-Interruption reported a nonsignificant reduction in major bleeding with interruption of P2Y12 inhibitor therapy (HR, 0.15; 95% CI, 0.68–2.03; P = .58).14,15

In 2008, the FDA Critical Path Initiative announced the need for a large, pragmatic public health trial exploring the benefit of extending P2Y12 inhibitor therapy beyond 12 months in patients treated with DES. The FDA request resulted in a unique public-private partnership in which four stent companies (Abbott Vascular, Boston Scientific Corporation, Cordis Corporation, and Medtronic plc), four pharmaceutical companies (Bristol-Myers Squibb/Sanofi Aventis Pharmaceuticals Partnership, Eli Lilly and Company, and Daiichi Sankyo Company Limited), the Department of Health and Human Services, and the National Institutes of Health sponsored the academically led (Harvard Clinical Research Institute) DAPT study. The DAPT study is the largest randomized trial involving coronary stenting and the only study of extended-duration P2Y12 inhibitor use to employ a double-blind design and that was adequately powered to evaluate ST.16 The DAPT study enrolled 22,866 patients after DES implantation and 2,816 patients after BMS implantation. After 12 months of follow-up, 9,961 DES patients and 1,687 BMS patients who remained event-free (from death, MI, stroke, repeat coronary revascularization, ST, and the Global Use of Strategies to Open Occluded Arteries [GUSTO] moderate or severe bleeding) and remained compliant were randomized to either P2Y12 inhibitor therapy for an additional 18 months (30-month P2Y12 inhibitor arm) or placebo (12-month P2Y12 inhibitor arm). After completion of the randomized treatment period, all patients were observed for an additional 3-month, aspirin-alone period (months 30–33 after enrollment) to assess the effect of P2Y12 inhibitor discontinuation on ischemic events. The coprimary efficacy endpoints were the cumulative incidence of definite or probable ST and MACCE (composite of death, MI, or stroke) during the randomized treatment period. The safety endpoint was the incidence of moderate or severe GUSTO bleeding.16,17

Within the DES cohort, the continued P2Y12 inhibitor treatment arm had significantly lower cumulative incidence of ST (HR, 0.29; 95% CI, 0.17–0.48; P < .001) and MACCE (HR, 0.71; 95% CI, 0.59–0.85; P < .001) compared to placebo. In addition, continued use of P2Y12 inhibitors was associated with lower rates of MI (HR, 0.47; 95% CI, 0.37 – 0.61; P < .001) and non–ST-related MI (1.8 vs 2.9%; HR, 0.59; P < .001). Rates of death from cardiac and vascular causes were comparable between treatment arms; however, the rate of death from any cause was increased in patients receiving continued P2Y12 inhibitor therapy (HR, 1.36; 95% CI, 1–1.85; P = .05). In addition, the rate of moderate or severe bleeding during the primary analysis period was higher in the P2Y12 inhibitor arm than in the placebo arm (HR, 1.61; 95% CI, 1.21–2.16; P = .001). There was no significant difference in the rates of GUSTO severe or fatal bleeding.

Several prespecified secondary analyses conducted within the DAPT study have demonstrated relatively consistent reductions in ischemic endpoints with continued P2Y12 inhibitor use. Among the 1,687 patients treated with BMS, there were nonsignificant reductions in the rates of ST (0.5% vs 1.11% [HR, 0.49; 95% CI, 0.15–1.64; P = .24]) and MACCE (4.04% vs 4.79% [HR, 0.92; 95% CI, 0.57–1.47; P = .72]) and a borderline increase in the rate of moderate or severe GUSTO bleeding (2.03% vs 0.9% [HR, 1.12; 95% CI, –0.06–2.31; P = .07]). The authors conclude that the BMS analyses may be underpowered, but results of pooled analyses of the BMS and DES cohorts were comparable to the primary DES analyses.18

Because patients presenting with acute MI may derive particular benefit from continued P2Y12 inhibitor use, Yeh and colleagues assessed the benefits and risks of 30 months versus 12 months of P2Y12 inhibitor therapy among patients undergoing percutaneous coronary intervention with and without MI within the DAPT study.19 Continued P2Y12 inhibitor use reduced ST in patients presenting with (HR, 0.27; 95% CI, 0.13–0.57; P < .001) and without MI (HR, 0.33; 95% CI, 0.18–0.6; P < .001; interaction P = .69). Rates of MACCE were similarly reduced with continued P2Y12 inhibitor use as compared to placebo in patients with and without MI, but the magnitude of reduction was greater in those with MI (MI: HR, 0.56; 95% CI, 0.42–0.76; P < .001; without MI: HR, 0.83; 95% CI, 0.68–1.02; P = .08; interaction P = .03).

Finally, because cobalt-chromium everolimus-eluting stents (EES) have been associated with low rates of ST,20,21 Hermiller and colleagues performed a subgroup analysis of DAPT study participants receiving an EES.22 Within the DES cohort (N = 9,961), 4,703 received an EES. Among EES patients, continued P2Y12 inhibitor compared to placebo was associated with reduced ST (HR, 0.38; 95% CI, 0.15–0.97; P = .04) but not MACCE (HR, 0.89; 95% CI, 0.67–1.18; P = .42). The lack of effect on MACCE was due to discrepant effects of continued P2Y12 inhibitor use on MI (HR, 0.63; 95% CI, 0.44–0.91; P = .02) and all-cause mortality (HR, 1.80; 95% CI, 1.11–2.92; P = .02).

EXTENDED P2Y12 INHIBITOR USE AND MORTALITY

Despite significant and robust reductions in ST and MI, continued P2Y12 inhibitor use was associated with higher rates of all-cause mortality than placebo within the DAPT study, both during the primary (12–30 months) and secondary (12–33 months; HR, 1.36; 95% CI, 1.02–1.82; P = .04) analysis periods.17 The imbalance in rates of death was largely due to an increased rate of noncardiovascular death with continued P2Y12 inhibitor use (HR, 1.8; 95% CI, 1.12–2.88; P = .01). Although bleeding-related deaths tended to occur more frequently with continued P2Y12 inhibitors than with placebo (11 vs 3 deaths; P = .06), a greater imbalance was observed in the number of cancer-related deaths, which was significantly greater with continued P2Y12 inhibitor use (31 vs 14; P = .02).

Upon recognition of a mortality signal with extended-duration P2Y12 inhibitor use,17 a second blinded clinical events committee composed of two cardiologists and four oncologists was established to readjudicate mechanisms of death within the trial and specifically to determine the contribution of bleeding, cancer, and trauma to mortality.17,23 Within the subsequent analysis of mortality with the DAPT study, we found that fatal bleeding was rare and accounted for only 6.8% (15 of 222) of all deaths. A more inclusive evaluation of deaths that were possibly, probably, or definitely related to bleeding found that bleeding contributed to 13.5% (30 of 222) of all deaths, and there was no difference in bleeding-related deaths between treatment arms (risk difference, 0.1%; P = .36). Similarly, there was no difference in the rate of deaths preceded by any bleeding within 30 days (risk difference, 0%; P > .99) or since randomization (risk difference, 0.1%; P = .68; Figure 1). Therefore, although continued P2Y12 inhibitor therapy was associated with an increased bleeding risk, particularly in the setting of unexpected major trauma, bleeding accounted for a small fraction of the observed difference in mortality between randomly assigned treatment arms in the DAPT study.23

The largest contributor to the excess mortality seen with continued P2Y12 inhibitor use within the DAPT study was cancer-related mortality.17,23 There was an excess of 17 cancer-related deaths in the continued P2Y12 inhibitor arm of the trial compared to the control arm (risk difference, 0.3%; P = .02), a minority of which (n = 3) were also related to bleeding. Cancer-related deaths were most commonly due to solid tumors without predilection for specific cell type or location. Cancer was diagnosed prior to enrollment in nine patients who subsequently died, eight of whom were randomized to a continued P2Y12 inhibitor. Exclusion of these nine patients in a sensitivity analysis resulted in 26 (0.4%) versus 16 (0.3%) cancer-related deaths with continued P2Y12 inhibitor use and placebo, respectively (P = .16). Despite the imbalance in cancer-related mortality, the rates of new cancers in those receiving a continued P2Y12 inhibitor and placebo between enrollment and randomization and after randomization were similar.

Analyses of mechanisms of mortality within the DAPT study revealed that bleeding did not drive the increased mortality seen with a continued P2Y12 inhibitor, but instead implicated cancer. Experimental data suggest involvement of platelets in promoting tumor metastases,24-27 but data are conflicting with regard to the effect of platelet inhibition on tumor metastasis.28-33 In previous clinical trials of antiplatelet therapy, a greater degree of platelet inhibition has been associated with earlier detection of colorectal cancers32; however, in a more recent study comparing prasugrel with clopidogrel, the frequency of new neoplasms was similar between treatment arms.33

If a true association exists between P2Y12 inhibitor therapy and mortality and/or cancer, it should not be confined to only those patients undergoing coronary procedures with a particular stent type. We, therefore, conducted a large meta-analysis of 14 randomized trials of patients with cardiac, vascular, or cerebrovascular disease (N = 69,644).34 We found no significant association between clopidogrel use and mortality (Figure 2), regardless of whether the data from the DAPT study were included and regardless of restricting the analysis to 42,616 subjects with coronary artery disease. Meta-regression also found no relationship between the duration of P2Y12 inhibitor exposure to mortality. Recently, the FDA similarly reviewed data on extended-duration P2Y12 inhibitor use within a meta-analysis including 56,799 patients. In a safety communication, they concluded that they “found no evidence of either a harmful or beneficial effect of clopidogrel on overall mortality in a population with, or at risk for, coronary artery disease, and no effect on cancer.”35

CLINICAL IMPLICATIONS

Although data regarding the optimal duration of DAPT after DES implantation appear somewhat contradictory and perhaps confusing, several key points are clear and easily translatable to clinical practice (Figure 3). First and foremost, decisions regarding the duration of P2Y12 inhibitor therapy do not need to be finalized at the time of the index procedure and may instead be adjusted in response to a patient’s evolving risk profile and condition. Short-duration DAPT (3–6 months) appears to be acceptably safe after second-generation DES use and therefore is reasonable in the event of a major hemorrhagic complication or need for an urgent invasive procedure, or in patients at very high risk of bleeding, on long-term oral anticoagulation, or with limited life expectancy due to cancer, assuming they are not concurrently at high risk for ischemic complications (ie, presentation with acute coronary syndrome). For all other patients, the default duration of P2Y12 inhibitor therapy should be 12 months. After 12 months of follow-up, the approach can be reconsidered and the bleeding/ischemia balance and patient preferences reassessed. Continued-duration P2Y12 inhibitor therapy beyond 12 months should be the preferred strategy for patients in whom the risk of bleeding is not high, given its efficacy in reducing the risk of ST and non–stent-related MI. In patients with recurrent events, the decision is relatively straightforward—therapy should be discontinued in those with bleeding events, whereas those with ischemic events on DAPT should continue P2Y12 inhibitor therapy. For the remainder of patients in whom the bleeding/ischemia balance is less clear, the recently developed DAPT score may provide needed guidance. The score includes five clinical factors and three index procedural characteristics (score range, -2 to 10) and provides an estimate of the balance between ischemic and bleeding risks in patients who have remained free of ischemic or bleeding events 1 year after DES. In patients with DAPT scores < 2, bleeding risk outweighs ischemic risk; whereas, with scores ≥ 2, ischemic risk outweighs bleeding risk.36 The DAPT score may therefore help clinicians determine who should be treated with continued P2Y12 inhibitors beyond 1 year after stent implantation. It is therefore prudent that decisions regarding the duration of P2Y12 inhibitor use be personalized to fit each individual patient.

Sammy Elmariah, MD, MPH, FACC, FAHA, is with the Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School; and the Harvard Clinical Research Institute in Boston, Massachusetts. He has stated that he has no financial interests related to this article. Dr. Elmariah may be reached at (617) 726-6120; selmariah@mgh.harvard.edu.

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22. Hermiller JB, Krucoff MW, Kereiakes DJ, et al. Benefits and risks of extended dual antiplatelet therapy after everolimus-eluting stents. JACC Cardiovasc Interv. In press.

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27. Bakewell SJ, Nestor P, Prasad S, et al. Platelet and osteoclast beta3 integrins are critical for bone metastasis. Proceed Nat Acad Sci USA. 2003;100:14205-14210.

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35. US Food and Drug Administration (FDA). FDA drug safety communication: FDA review finds long-term treatment with blood-thinning medicine Plavix (clopidogrel) does not change risk of death. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm471286.htm. Accessed November 8, 2015.

36. Yeh RW, Secemsky EA, Kereiakes DJ, et al. Antiplatelet therapy after percutaneous coronary intervention: an analysis from the DAPT study. Presented at the American Heart Association Scientific Sessions; November 10, 2015; Orlando, FL.