Dual antiplatelet therapy following drug-eluting stent implantation: how long is long enough?

Abstract

A period of dual antiplatelet therapy (DAPT) is mandatory after drug-eluting stent (DES) implantation to reduce the risk of stent thrombosis as a consequence of inflammation during the healing process. DAPT is also claimed to be associated with other benefits beyond this, including a reduction in ischemic events and improvements in clinical outcomes. A number of studies have investigated the feasibility of shortened DAPT in a bid to maximize benefits, while reducing adverse events; however, there are recent data to suggest that prolongation of DAPT may be associated with additional benefits at the risk of increased bleeding complications. On the basis of currently available evidence, we believe that all patients should be treated with DAPT for a minimum of 6 months after drug-eluting stent (DES) implantation. However, the decision to prolong therapy beyond this should be made on an individual basis, taking into account the potential benefits against specific risk factors for subsequent adverse events.

Keywords:

• bleeding
• DAPT
• drug eluting stents
• dual antiplatelet therapy
• duration
• thrombosis

While the use of contemporary drug-eluting stents (DES) for the treatment of coronary artery disease has significantly improved on some of the limitations of previous stent designs [1], a period of dual antiplatelet therapy (DAPT) (consisting of aspirin and a P2Y12-receptor inhibitor) after implantation is mandatory to prevent thrombotic complications of the stented segment due to inflammation during healing [2,3]. Furthermore, in addition to affording protection to the treated segment, DAPT is also associated with benefits beyond this including a reduction in ischemic events and improvements in clinical outcomes [4]. However, these benefits are countered by a significant increased risk of bleeding complications, with specific patient factors including age, prothrombotic comorbid factors, and tendency for bleeding all increasing the risk for potential bleeding. Therefore, the optimal duration of DAPT to maximize the benefit of this treatment regimen while limiting adverse events remains to be determined.

Current evidence

Current guidelines recommend the administration of DAPT for a minimum of 6–12 months after DES implantation [5,6] with prolongation of therapy at the discretion of the physician and patient if the bleeding risk is low in the presence of high ischemic burden. Currently available P2Y12-receptor inhibitor drug options that are administered in conjunction with aspirin include:

• Clopidogrel (irreversible inhibitor of P2Y12): 300 mg loading dose, 75 mg once daily thereafter.

• Prasugrel (prodrug, irreversible inhibitor antagonist of ADP): 60 mg loading dose, 10 mg once daily thereafter.

• Ticagrelor (reversible inhibitor of P2Y12): 180 mg loading dose, 90 mg twice daily thereafter.

Shorter DAPT duration

With recent advances in coronary stent technology, which have been designed to reduce complications, including the risk of stent thrombosis [1], the majority of recent studies have sought to challenge these guideline and have investigated the efficacy of further reducing the duration of DAPT to reduce the incidence of adverse bleeding complications. The Bleeding Academic Research Consortium (BARC) criteria are commonly used to define significant events if Type 3 (life-threatening, requiring transfusion) or Type 5 bleeding (fatal) occur, whereas minor bleeding events are not usually regarded as clinical events.

The Optimized Duration of Clopidogrel Therapy Following Treatment With the Zotarilmus-Eluting Stent in Real-World Clinical Practice (OPTIMIZE) trial randomized patients to 3 or 12 months of DAPT and demonstrated no increase in adverse outcomes in the group with shorter DAPT duration [7]. These findings were supported by the Efficacy of Xience/Promus Versus Cypher to Reduce Late Loss After Stenting (EXCELLENT) trial that demonstrated non-inferiority in 6 month DAPT compared with 12 months [8]. The more recent Second Generation Drug-Eluting Stent Implantation Followed by Six- Versus Twelve-Month DAPT (SECURITY) similarly demonstrated non-inferiority of 6 months DAPT in comparison to 12 months with regards to cardiac death, myocardial infarction (MI), stroke, stent thrombosis, and Bleeding Academic Research Consortium (BARC) type 3 or 5 bleeding at 12 months after second-generation DES implantation [9]. It should be noted, however, that these studies had one or more limitations, including small sample sizes or low frequency of events [10,11].

Longer DAPT duration

Due to the potential benefit of prolonged DAPT therapy in patients with cardiovascular disease, the prolongation of DAPT beyond 12 months has also been investigated. Park et al. [12] investigated the effects of prolonging DAPT to 24 months in patients who had completed 12 months therapy which did not show any benefit over aspirin monotherapy, although patients in this study were almost exclusively treated with first-generation DES and the study was underpowered for this endpoint. The PROlonging Dual antiplatelet treatment after Grading stent-induced Intimal hyperplasia study (PRODIGY) demonstrated non-inferiority of 6 month DAPT versus 24 month DAPT on the composite endpoint of MI, stroke or death after the implantation of DES or bare-metal stents [13]. Importantly, this study, in addition to the The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance [14] (CHARISMA) trial both demonstrated a significantly higher incidence of bleeding with prolonged DAPT highlighting the importance of acknowledging the risks of this treatment strategy. These findings have been broadly supported by recent meta-analyses [15,16].

The DAPT study

Mauri et al. [17] have recently published the results of the DAPT Study that investigated the effect of prolonging DAPT beyond the currently recommended 12–30 months. After DES implantation and completion of 12 months DAPT, 9961 patients were randomized to continued, (for another 18 months,) thienopyridine (clopidogrel or prasugrel; n = 5020) or placebo (n = 4941), in addition to low-dose aspirin. The primary endpoints of ST and major adverse cardiac and cerebrovascular events (MACCE; composite of death, MI, or stroke) at 12–30 months were significantly reduced with continued DAPT (stent thrombosis 0.4 vs 1.4%, hazard ratio: 0.29, 95% CI: 0.17–0.48; p < 0.001, and MACCE 4.3 vs 5.9%, hazard ratio: 0.71, 95% CI: 0.59–0.85; p < 0.001). However, this benefit was at the expense of an increase in the occurrence of moderate or severe bleeding that increased with the administration of continued thienopyridine (2.5 vs 1.6%; p = 0.001), and was most pronounced in patients greater than 75 years old. However, there were no differences between groups with regards to Global Utilization Of Streptokinase and Tpa For Occluded Arteries severe bleeding or Bleeding Academic Research Consortium (BARC) defined fatal bleeding [18].

To determine the applicability of these findings to routine clinical practice, it is important to highlight some important aspects of this study. Patients were only recruited having completed 12 months of DAPT, who had suffered no MACCE events during this period and were compliant with therapy. This resulted in the exclusion of a significant minority of the patients that had initially been treated with a DES (23%) and initially considered eligible. Thus, these results cannot be generalized to an unselected population with the highest risk patients (those that suffered early events) excluded from the final analysis.

On closer examination of the results, the benefit of prolonged DAPT was predominantly driven by a reduction in non-stent thrombosis-related MI (55% of the treatment benefit). It is interesting to note that in both groups there was an acute rise in ischemic events (not ST) on cessation of DAPT and was independent of the thienopyridine administered. While the study was not powered to identify a difference between the type of DES implanted, in the 2666 (26.8%) patients treated with paclitaxel eluting stents (PES), there were 10 ST (0.8%) in the continued thienopyridine group vs. 38 ST (3%), in the placebo group and this stent was the only one associated with a significant difference in MACCE with continued thienopyridine treatment. It may therefore be interesting to investigate the effect of prolonged DAPT with current generation DES and with the exclusion of paclitaxel eluting stents (PES).

Conclusion

The DAPT study, in support of previous studies exploring the use of prolonged DAPT and recent meta-analyses, convincingly show that this treatment strategy is associated with a higher risk of serious bleeding complications. On the other hand, it is also apparent that some patients would benefit from a prolonged duration of DAPT.

On the basis of currently available evidence, we therefore believe that all patients should be treated for a minimum mandatory period of 6 months after implantation of contemporary DES. The decision to prolong therapy beyond this should be made on an individual basis taking into account the potential benefits against specific patient risk factors including age, prothrombotic comorbid factors, and tendency to bleeding in support of the current European Society of Cardiology guideline. The results of currently ongoing trials that are investigating the role of prolonged DAPT including the OPTImal DUAL antiplatelet trial [19] and EDUCATE trials [20] are awaited to add clarity to this issue in particular in the context of new generation DES. Finally, the emergence of bioresorbable scaffolds and more potent anti-platelet agents may also impact upon optimal DAPT duration in the future.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.