During the last several years, a significant paradigm shift has occurred in the field of percutaneous coronary intervention (PCI) regarding the optimal duration of dual-antiplatelet therapy (DAPT) after PCI with drug-eluting stents (DES). Although early concerns for late thrombosis motivated recommendations for prolonging DAPT up to 1 year or longer, the pendulum has now shifted toward shorter DAPT durations after PCI. In large part, these changing trends are attributable to the introduction of safer stent platforms that may mitigate the adverse effects of stopping DAPT while simultaneously increasing the DAPT-related bleeding risk.1

The lack of evidence and relative uncertainty surrounding the optimal DAPT duration after PCI is reflected in differences between European and American guidelines. Whereas the European Society of Cardiology recommends DAPT for 6 to 12 months after DES implantation,2 current American College of Cardiology/American Heart Association recommendations mandate a minimum DAPT duration of at least 12 months after DES implantation.3 Both societies recommend a year of DAPT after acute coronary syndrome, regardless of stent type. This article provides a contemporary overview of both observational and randomized evidence to date surrounding this issue, highlight clinical and temporal factors that influence DAPT-related risk, and provide an algorithm for DAPT duration within the context of contemporary PCI.

HISTORICAL PERSPECTIVE

Vascular injury and platelet activation after intracoronary stent implantation require systemic DAPT to lessen the risk for near-term thrombotic events.4 This course is extended in the setting of DES because antiproliferative agents inhibit vascular healing and stent endothelialization. Randomized trials leading to regulatory approval of the first-generation paclitaxel-eluting and sirolimus-eluting stents, which tended to enroll low-risk patients and/or lesions, suggested that DAPT durations of 3 to 6 months may be sufficient after implantation of paclitaxel-eluting and sirolimus-eluting stents, respectively.5 Subsequent analyses involving real-world patients, however, challenged this notion by demonstrating a higher thrombotic risk with the use of first-generation DES versus bare-metal stents (BMS), particularly when implanted in an off-label fashion.6,7 Moreover, other reports suggested that sustained or prolonged DAPT may yield a protective benefit after DES implantation.9,10

Among patients treated with DES who were event-free at either 6 or 12 months, Eisenstein et al found that clopidogrel use was associated with significant reductions in death and death or myocardial infarction at up to 24 months after PCI.11 In contrast, no apparent advantage was observed for prolonged clopidogrel use among patients treated with BMS. Analogously, Iakovou et al found that the premature discontinuation of DAPT was the strongest predictor of stent thrombosis among patients receiving first-generation DES.7 Among diabetic patients, Brar et al also found a protective effect of prolonged DAPT (> 6 months) after PCI with DES or BMS.9

In aggregate, findings of excess risk with first-generation DES, coupled with observations suggesting a protective effect with prolonging DAPT, led to consensus statements and guidelines mandating at least 12 months of DAPT after intracoronary DES implantation.12 It is important to note, however, that such recommendations were based on consensus opinion and observational data rather than randomized studies. Statistical associations between discontinuation of DAPT and thrombosis do not necessarily imply a cause-and-effect relationship between these two parameters. Overcoming such limitations requires randomized comparisons specifically examining the impact of different DAPT durations on risk after PCI.

RANDOMIZED STUDIES

To date, four randomized trials comparing different durations of DAPT after PCI have been reported.13-16 Despite differences in design, as well as patient and lesion case mix, these studies have not found any consistent advantages for prolonging DAPT in the prevention of ischemic events, but demonstrated a higher bleeding risk with long durations of DAPT.

The largest and initial comparison of different DAPT durations after PCI was reported by Park et al.15 In this study, patients (n = 2,701) who received first- or second-generation DES and were event-free at 1 year were subsequently randomized to DAPT or aspirin monotherapy for an additional year. At 24 months, there was no significant difference in the primary endpoint of myocardial infarction or cardiac death between the two regimens (1.8% vs 1.2%; P = .17).

Two subsequent studies compared a 6-month versus longer DAPT duration after PCI.13,16 In the PRODIGY trial, Valgimigli et al compared a 6-month versus 24-month DAPT duration after PCI with either first- or second-generation DES or BMS. The cohort was relatively high risk, as approximately 75% of patients presented with an acute coronary syndrome. The study was well powered, as overall event rates were higher than anticipated, and with no differences between the groups at 2 years for the primary endpoint of all-cause death, myocardial infarction, or cerebrovascular accident (10.1% vs 10%; P = .91). Bleeding rates, however, were significantly higher among those receiving prolonged DAPT. Similarly, Gwon et al examined the affect of 6 months versus 12 months of DAPT in a non-inferiority trial primarily enrolling patients receiving Xience everolimus-eluting stents (Abbott Vascular, Santa Clara, CA).13 Concordant with the findings of the PRODIGY trial, a 6-month DAPT regimen was no worse than a 12-month course in preventing target vessel failure (hazard ratio, 1.14; 95% confidence interval, 0.7–1.86). However, results were not consistent across all subgroups, as a longer DAPT regimen was associated with significant benefit among diabetic patients (9.1% vs 2.96%; P = .005). Whether this reflects a chance finding or a true treatment effect favoring longer durations of DAPT in diabetic patients remains unknown.

Finally, in the RESET trial, Kim et al compared a regimen of 3-month DAPT among patients receiving the Endeavor zotarolimus-eluting stent (Medtronic, Inc., Minneapolis, MN) to a 12-month duration among those receiving a comparator first- or second-generation DES.14 At 1 year, no significant differences were found between the groups for the primary ischemic endpoint (4.7% vs 4.7%; P = .84). Pooling the aggregate data of these four trials, Cassese et al found no significant benefit in terms of reducing ischemic events with standard DAPT duration (median, 6.2 months) versus extended therapy (median, 16.8 months), as shown in (Figure 1).8 In contrast, extended DAPT was associated with a significant increase in major bleeding (hazard ratio, 2.64; 95% confidence interval, 1.31–5.3).

Although these studies suggest that shorter DAPT durations may be safe after PCI with predominantly second-generation DES, it is important to note that these studies only included durable polymer DES and that DAPT consisted of clopidogrel plus aspirin. Therefore, whether these results are generalizable to newer stent platforms, such as biodegradable or polymer-free devices or among patients treated with novel antiplatelet agents, is unknown.

FACTORS INFLUENCING DAPT CESSATION RISK

Despite concerns for excess thrombus with early or premature discontinuation of antiplatelet therapy, emerging evidence has clearly shown that both the direction and magnitude of this association is influenced by a host of contextual, clinical, and temporal parameters and have important implications for patients and physicians. With respect to context, novel findings from the recently reported PARIS trial demonstrate that the affect of DAPT cessation is highly dependent on the underlying mode in which therapy is discontinued.17 In this real-world registry of more than 5,000 patients undergoing PCI with predominantly second-generation DES, Mehran et al found that DAPT cessation occurring under physician guidance was associated with a significantly lower major adverse cardiac events risk compared to patients staying on DAPT. Although brief interruptions in DAPT lasting up to 2 weeks appeared safe, disruption due to bleeding or noncompliance was associated with a significantly higher risk for major adverse cardiac events, particularly in the first month after disruption.

Clinical presentation and underlying risk factors may also play an important role in modulating the effect of DAPT cessation and as a corollary DAPT duration. Patients presenting with acute coronary syndromes, for example, benefit from potent platelet inhibition, regardless of a conservative or invasive treatment approach, based on the results of several randomized trials.18,19 This benefit is concordant with recent registry data demonstrating a significant reduction in ischemic events among patients with acute coronary syndromes who were treated with DAPT beyond 3 months versus shorter time periods.20 The necessity for prolonged DAPT among patients with diabetes mellitus also remains controversial. The findings of Brar et al suggest a benefit for prolonging DAPT after PCI among diabetics irrespective of stent type (BMS or DES).9 The uniform benefits across stent platforms suggest that DAPT may prevent both stent-related and systemic events after PCI in high-risk patients with diabetes mellitus. Analogously, results of the randomized EXCELLENT trial suggest that a 12-month DAPT duration may be superior to a 6-month duration among those with diabetes mellitus.13 Clearly, larger studies enrolling higher-risk patients are needed to further define the optimal DAPT duration after PCI in such patients.

The temporal relationships between DAPT cessation and risk after PCI are influenced by both time after PCI and time after antiplatelet therapy discontinuation. With respect to the former, consistent findings from several observational studies suggest the possibility of a temporal inflection point of approximately 6 months after PCI, beyond which, risk with DAPT cessation appears minimal.21 These results are consistent with randomized studies demonstrating an excess bleeding risk without further reduction in ischemic events with DAPT regimens extending beyond 6 months.8 As a result, a 6-month DAPT duration may be optimal in select low-risk patients receiving second-generation DES. Similarly, results from the PARIS registry show that risk after DAPT cessation is not uniform but rather varies over time.17 More specifically, the highest-risk time period after DAPT disruption is in the first 4 weeks after stopping antiplatelet therapy, with much less risk thereafter.

CONCLUSION

Addressing the question of the optimal DAPT duration after PCI with DES remains an active and evolving area of clinical investigation. Although unresolved, it does not appear that the answer will come in the form of a “one-size-fits-all” approach but will rather take into account patient risk factors, stent platforms, and time interval from PCI. A proposed algorithm that considers such factors is presented in (Figure 2).

Patients with acute coronary syndromes will most likely continue to remain on DAPT for at least 1 year regardless of stent type, as articulated in current guidelines. For stable patients with certain high-risk clinical and/or anatomic criteria, a 12-month course remains reasonable based on exist existing evidence. A 6-month course appears to be sufficient for less-complex patients receiving DES, whereas those receiving a first-generation platform may require a 6- to 12-month course. It is important to note that this algorithm and existing comparisons of different DAPT regimens after PCI have only been performed using clopidogrel. Whether more potent antiplatelet therapy will obviate the need for aspirin after PCI, for example, remains unknown. Ongoing trials and registry-based studies will continue to further refine and ultimately answer the question of the optimal DAPT duration after PCI with DES.

Usman Baber, MD, MS, is with the Icahn School of Medicine at Mount Sinai in New York, New York. He stated that he has no financial interests related to this article..

Roxana Mehran, MD, is with the Icahn School of Medicine at Mount Sinai in New York, New York. She has disclosed that she has received institutional research grant support from The Medicines Co., Bristol-Myers Squibb/Sanofi-Aventis, and Lilly/Daiichi Sankyo, and consulting fees from Abbott Vascular, AstraZeneca, Boston Scientific, Covidien, CSL Behring, Janssen Pharmaceuticals, Maya Medical, Merck, and Regado Biosciences. Dr. Mehran may be reached at (212) 659-9691; roxana.mehran@mountsinai.org.

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