Dual antiplatelet pharmacotherapy reduces ischemic events at the cost of excess bleeding in patients who underwent coronary stenting. The currently recommended treatment period is based on trials held some 20 years ago and not relevant to current clinical practice. In recent years, numerous clinical trials have tried to answer the question of what is the optimal duration of therapy to maximize clinical benefit. These trials showed 2 seemingly conflicting answers—on one hand, shorter treatment duration seems to be safer in reducing bleeding while not increasing ischemic events, and on the other hand, longer duration is superior in terms of preventing ischemic events albeit at the cost of increased bleeding rates. In this review, we summarize the evidence favoring each approach, highlight the limitations of the various pivotal clinical trials in this field, review future directions of research and changes in practice that may influence the duration of antiplatelet therapy, and attempt to propose a personalized approach to achieve maximal benefit for the individual patient.
Coronary artery disease (CAD) remains a major cause of mortality and morbidity in the western world. The clinical manifestations of CAD range from stable angina through acute coronary syndromes (ACS) and myocardial infarction (MI). Platelets play a key role in the pathophysiology of ACS because thrombosis of coronary plaques is the primary cause for these events. Platelet aggregation inhibition using aspirin has been the foundation of treatment for ACS for decades, regardless of additional treatment strategy. Since the early 2000s, dual antiplatelet pharmacotherapy (DAPT) with thienopyridine medications added to aspirin has become the standard of care for ACS. This drug combination also emerged as the treatment of choice after coronary stent implantation. One of the major unsettled issues regarding DAPT is the optimal duration of treatment in stable patients and patients with ACS who underwent coronary stenting. Recent years have seen new data in support of seemingly 2 conflicting practices: for example, prolonging versus shortening the duration of DAPT intake after coronary stenting. The purpose of this review was to present the most contemporary knowledge on this issue and to propose an algorithm for guiding clinicians as to the optimal time point for cessation of DAPT.
Establishing the Benefits of DAPT After Coronary Stenting
The benefits of DAPT were first shown in the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial by reducing the composite end point of cardiovascular events by 20% compared to aspirin treatment alone. The CURE trial included patients with ACS sustaining non–ST-segment elevation myocardial infarction events and <25% underwent percutaneous coronary intervention (PCI). A separate analysis of the trial, the PCI-CURE substudy showed even greater benefit with 30% risk reduction (RR) for cardiovascular events at mean treatment duration of 8 months. A post hoc analysis of the CURE trial also showed that the benefits of DAPT continued to accrue up to 9 months after non–ST-segment elevation myocardial infarction and/or PCI, laying the foundation for recommending prolonged DAPT period. The findings of the PCI-CURE were duplicated a year later by the Clopidogrel for the Reduction of Events During Observation (CREDO) trial that included the same patient population but was restricted to patients planned for invasive treatment. This trial showed a 27% reduction in mortality/MI/stroke with 12 months of DAPT compared to aspirin treatment alone. In both the PCI-CURE and CREDO trials, major bleeding was not increased in a statistically significant level with DAPT compared to aspirin alone.
The importance of DAPT became more evident with the increasing use of drug-eluting stents (DES) in the mid-to-late 2000s. Such a shift in practice raised the issue of stent thrombosis (ST), in particular, late (30 days to 1 year) and/or very late (>1 year) ST to the forefront of interventional cardiology. Premature interruption of DAPT was established by large observational trials to be the most powerful predictor of late ST. These findings led to a statement by the American College of Cardiology/American Heart Association which was adopted worldwide, stressing the importance of completing 12 months of DAPT after coronary stent implantation. By this time, the duration of DAPT was dictated by the perceived risk of late ST and also by that the first-generation DESs were used in clinical practice (e.g., Cypher and Taxus DES).
Changes in Practice Challenging the Standard Duration of DAPT
In recent years, 3 factors have challenged the recommended duration of DAPT.
- i.
The replacement of the first-generation DESs with second-generation platforms, designed with a better safety and biocompatibility profile especially with regards to endothelial healing and the continued risk of ST. Such an evolution raised the possibility of shortening DAPT duration to reduce bleeding risk without putting patients at increased risk for ST.
- ii.
Findings from large prospective observational trials which have shown that the risk of ST is not significantly reduced after 1 year and remains roughly the same through 2 years and even up to 4 to 5 years of follow-up. The cumulative data raised the question whether DAPT should be continued beyond 1 year to reduce late cardiovascular ischemic events including late ST beyond 1 year.
- iii.
The availability of second-generation P2Y 12 inhibitors such as prasugrel and ticagrelor, that proved to be superior to clopidogrel in prevention of ischemic cardiovascular events but at a cost of increased bleeding risk. The question was raised again whether prolongation of DAPT is indicated using these novel antithrombotic medications to improve overall cardiovascular outcomes.
Changes in Practice Challenging the Standard Duration of DAPT
In recent years, 3 factors have challenged the recommended duration of DAPT.
- i.
The replacement of the first-generation DESs with second-generation platforms, designed with a better safety and biocompatibility profile especially with regards to endothelial healing and the continued risk of ST. Such an evolution raised the possibility of shortening DAPT duration to reduce bleeding risk without putting patients at increased risk for ST.
- ii.
Findings from large prospective observational trials which have shown that the risk of ST is not significantly reduced after 1 year and remains roughly the same through 2 years and even up to 4 to 5 years of follow-up. The cumulative data raised the question whether DAPT should be continued beyond 1 year to reduce late cardiovascular ischemic events including late ST beyond 1 year.
- iii.
The availability of second-generation P2Y 12 inhibitors such as prasugrel and ticagrelor, that proved to be superior to clopidogrel in prevention of ischemic cardiovascular events but at a cost of increased bleeding risk. The question was raised again whether prolongation of DAPT is indicated using these novel antithrombotic medications to improve overall cardiovascular outcomes.
Evidence Supporting Shorter DAPT Duration
The safety of shortened DAPT duration has been studied in several randomized controlled trials published in recent years ( Table 1 ). These trials mostly included patients with stable CAD who were treated using second-generation DESs; thus, the issue of DAPT intake specifically after ACS has not been fully addressed. Nonetheless, these trials clearly showed that shorter duration of DAPT (3 to 6 months) might be equivalent to 1 year of treatment in terms of ST and overall ischemic events and significantly reduced bleeding episodes, including life-threatening bleeding events. The latest meta-analysis of these trials found no increased mortality and showed a significant reduction in major bleeding events with earlier interruption of DAPT. A common finding in all the trials was a very low rate of ischemic coronary events in total, and late ST in particular, compared to previous observational trials. This is believed to be related to the improved PCI techniques and/or medical treatment aimed at secondary prevention. The clinical data mentioned previously were the basis for the European Society of Cardiology 2014 revascularization guidelines recommendation to shorten DAPT duration to 6 months for patients with stable CAD treated with second-generation DES. The DAPT recommendations after ACS with or without PCI remain the same, for example, 1 year after stenting.
| A <12 months vs. 12 months+ DAPT Duration | ||||
|---|---|---|---|---|
| Trial | Sample size | Protocol | Primary endpoint | Results of primary endpoint |
| EXCELLENT | 1,443 | 6 vs. 12 months DAPT | CVD/MI/TVR at 12 months | 4.8% vs 4.3% |
| OPTIMIZE | 3,119 | 3 vs. 12 months DAPT | Death/MI/CVA/Major Bleeding at 12 months | 6% vs 5.8% |
| PRODIGY | 2,013 | 6 vs. 24 months DAPT | Death/MI/CVA at 24 months | 10% vs. 10.1% |
| RESET | 2,117 | 3 vs. 12 months DAPT | CVD/MI/ST/TVR/Bleeding at 12 months | 4.7% vs. 4.7% |
| ITALIC | 1,894 | 6 vs. 24 months DAPT | Death/MI/CVA/TVR/Major Bleeding at 12 months | 1.6% vs. 1.5% |
| ISAR-SAFE | 4,000 | 6 vs. 12 months DAPT | Death/MI/CVA/ST/Major Bleeding at 9 months | 1.5% vs. 1.6% |
| B 12 months vs. 12 months+ DAPT Duration | ||||
|---|---|---|---|---|
| Trial | Sample size | Protocol | Primary endpoint | Results of primary endpoint |
| ARCTIC INTERUPTION | 1,259 | 12 vs.18-30 months DAPT | Death/MI/CVA/ST/TVR at median 17 months follow up | 4% vs. 4% |
| DES-LATE | 5,045 | 12 vs. 36 months DAPT | CVD/MI/CVA from 12 to 36 months | 2.4% vs. 2.6% |
| DAPT | 9,961 | 12 vs. 30 months DAPT | Coprimary endpoints: 1)ST 2) Death/MI/CVA from 12 to 30 months | 1)1.4% vs. 0.4% 2)5.9% vs. 4.3% |
| PEGASUS TIMI-54 | 21,162 | 12 vs. additional 33 months (mean) of Ticagrelor(90/60 mg BID) | Efficacy: CVD/MI/CVA Safety: TIMI major bleeding | Efficacy: 9.04% vs. 7.85% vs. 7.77% Safety: 1.06% vs. 2.60% vs. 2.30% |
It is important however to remember several limitations of the trials supporting shorter DAPT duration:
- •
Most of these trials included patients with stable CAD with a low percentage of ACS (apart from the PRODIGY [Prolonging Dual Antiplatelet Treatment After Grading Stent-Induced Intimal Hyperplasia Study] trial. )
- •
A relatively small sample size that did not allow for evaluation of ST as a primary end point.
- •
The exclusion of patients with complex coronary anatomy, or in stent restenosis, limiting the external validity of the results.
- •
A heterogenous definition of the bleeding component in the composite primary end point.
- •
The early termination of several of the trials due to slow recruitment and lower than expected rate of clinical outcomes.
- •
The treatment arm allocation was not blinded from the attending physicians.
- •
All but one of the trials did not report patient adherence to the prescribed DAPT regimen.
Evidence in Favor of Prolonged DAPT Duration
Three randomised clinical trials (RCTs) tested the benefits of prolonged DAPT ( Table 1 ):
The Duration of Clopidogrel Therapy After Drug-Eluting Stent (DES-LATE) trial randomized 5,045 patients who underwent DES implantation, completed 12 months of DAPT with clopidogrel with no experience of any ischemic/bleeding event, continued DAPT versus aspirin treatment alone for additional 24 months. At the end of follow-up, there was no difference in terms of the primary composite end point (cardiovascular death/MI/stroke) or any of the secondary end points including ST. Major bleeding was numerically but not statistically increased with prolonged DAPT. When considering net clinical benefit (ischemic events plus major bleeding), there was again no statistically significant difference between the 2 groups. Because the main driver for prolonging DAPT duration was reducing the occurrence of very late ST, the major limitation of the DES-LATE trial was the sample size which was not large enough to show reductions in ST.
The most significant attempt to show benefits from DAPT prolongation was conducted in the DAPT trial. The DAPT trial was initiated in response to a call by the Food and Drug Administration to design a large-scale randomized control trial to test the benefits of prolonged DAPT period with a primary end point of ST. The DAPT trial randomized 9,961 patients, free of clinical events after 12 months of DAPT intake after DES implantation to prolonged DAPT intake (additional 18 months, overall 30 months) or continued aspirin alone. Patients were followed for an additional 3 months after discontinuation of DAPT versus placebo (i.e., 30 to 33 months after stenting). Importantly, 42% of patients underwent PCI because of ACS and 33% of the patients received the more potent P2Y 12 inhibitor prasugrel.
The DAPT trial showed significant reduction in both co-primary efficacy end points in favor of prolonged DAPT: (1) ST was 0.4% versus 1.4% (hazard ratio [HR] 0.29, p <0.001) and (2) major adverse cardiovascular and cerebrovascular events were 4.3% versus 5.9% (HR, p <0.001). Analysis of secondary end points showed a significant reduction in MI (2.1% vs 4.1%; HR 0.47, p <0.001). However, the main safety end point of major bleeding was increased with prolonged DAPT (2.5% vs 1.6%, p = 0.001). The results were not related to the type of theinopyridine used during the trial.
We think that the important findings of the DAPT trial should be viewed in context of several important considerations:
- •
The overall effect on mortality: there was a strong trend toward increased overall mortality rates in the prolonged DAPT arm compared to placebo (RR 1.32, p = 0.052). The increment was solely due to a more than double rate of noncardiovascular mortality (RR 2.23, p = 0.002), mainly cancer related. The investigators later conducted a meta-analysis of all the RCTs that compared longer versus shorter duration of DAPT and found no association between overall mortality and longer DAPT duration with or without the DAPT trial results.
- •
The external validity of the trial: of 22,866 patients screened, only 43% were eventually randomized, 58% of screened but not randomized patients were eligible to participate but were not included mainly because of withdrawal of consent. This raised a theoretical possibility for a selection bias and thus weakened the generalizability of the trial results to an all-comers PCI population.
- •
The magnitude of the overall benefit from prolonged DAPT: because there is no beneficial effect of prolonged DAPT on overall mortality, the decision whether to recommend longer DAPT duration depends on the balance between the improved ischemic outcomes and the increased risk of bleeding. The DES-LATE trial investigators approached this issue by presenting a primary end point of net clinical benefit that included both ischemic and bleeding events. However, this approach is somewhat problematic because of the heterogenous nature and different prognostic effect of both MI versus bleeding. The DAPT trial investigators considered this issue differently and separated the primary end points into efficacy (prevention of ischemic events) and safety (bleeding). This decision was based on the Markov model that predicts the RR in ST and major adverse cardiovascular events required to justify the added risk of bleeding. The model is applied to support prolonging the duration of DAPT in terms of quality-adjusted life years (QALY). This approach is probably more appropriate, and the referenced Markov model represents the most advanced attempt to find a solution to the issue of balancing the benefits and hazards of prolonged DAPT. However, when exploring the eventual benefits in terms of QALY predicted by the referred model, the gains for prolonged DAPT are relatively small (approximately 0.5 QALY at most). Hence, when considering cost-effectiveness factors, using the previously cited benefits in QALY and at the current price of clopidogrel and prasugrel in the United States, the cost of prolonging DAPT will range from $58,000 to $97,000 per QALY which is higher than the accepted $50,000 per QALY benchmark.
Extended DAPT duration with second-generation P2Y 12 inhibitors
The recently published PEGASUS TIMI-54 (Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagre- lor Compared to Placebo on a Background of Aspirin–Thrombolysis in Myocardial Infarction 54) trial randomized 22,162 patients who were 1 to 3 (median 1.7) years after MI (53% had STEMI) to receive either placebo or 1 of 2 doses of ticagrelor for a median duration of 33 months. The trial showed that extended DAPT with both doses of ticagrelor significantly reduced the primary end point of cardiovascular mortality/MI/stroke compared to placebo (RR 0.15, p = 0.008 and RR 0.16, p = 0.004 for the 90 and 60 mg twice daily doses, respectively). This was driven by a reduction in MI (RR 0.19, p = 0.01 and RR 0.16, p = 0.03) and stroke (RR 0.18, p = 0.14 and RR 0.25, p = 0.03). There was no significant reduction in overall and/or cardiovascular mortality. Major bleeding rates were again higher with extended DAPT and did not seem to differ between the 2 ticagrelor doses (HR 2.69, p <0.001 and HR 2.32, p <0.001 for the 90 and 60 mg twice daily doses, respectively). These results are in accordance with the DAPT trial and strengthen the evidence of improved efficacy associated with extended duration of DAPT.
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
