There is no doubt that the results of the Dual Antiplatelet Therapy (DAPT) Study , the largest randomized clinical trial to examine longer duration of DAPT, added knowledge to the optimal duration of DAPT following percutaneous coronary intervention (PCI). The study, however, has also ignited controversy and discussion with respect to the role of short-duration DAPT, which was not part of the study mission. The DAPT Study randomized a total of 9961 event-free patients after 12 months from the index PCI with first- and second-generation drug-eluting stent implantation to continue DAPT or receive placebo for another 18 months. The patient population in DAPT included stable patients and patients presenting with acute coronary syndrome (ACS). The DAPT Study showed a reduced risk of both co-primary endpoints, including stent thrombosis and major adverse cardiac and cerebrovascular events (MACCE), in patients randomized to 30- vs. 12-month DAPT. These patients, however, had a higher risk of moderate to severe bleeding and an alarming signal for higher all-cause mortality for the prolonged duration of DAPT.

Investigators and academicians immediately differentiated between the need of DAPT to address the stent-related issues, such as stent thrombosis, and the patient-related issues using DAPT as a secondary prevention for subsequent cardiovascular events. The goal of introducing DAPT following DES implantation was to prevent thrombotic events while preserving safety to avoid bleeding, but the ideal duration of DAPT in patients undergoing PCI remains a matter of debate. Although, in patients with ACS, 12 months of DAPT was acceptable globally based on the results of the CREDO (Clopidogrel for the Reduction of Events During Observation) trial , in stable patients, there is an ongoing discrepancy in the guidelines between the United States and Europe for the optimal duration of DAPT.

Current European Society Cardiology (ESC) guidelines on stable coronary artery disease recommend a duration of 6 to 12 months of DAPT in patients undergoing PCI with DES. Recent ESC guidelines on myocardial revascularization recommended a DAPT duration of 6 months after DES implantation in patients with stable coronary artery disease (Class I, Level B) and call for individualized treatment according to bleeding and thrombotic risk. The American College of Cardiology Foundation/American Heart Association guidelines recommend a 12-month duration of DAPT in patients undergoing PCI with DES for stable coronary artery disease at low bleeding risk.

Over time, with improved DES technology, thinner struts, and improved biocompatible polymers, many investigators challenged the recommended duration of DAPT in both ACS and stable patients. In the past years, thousands of patients were enrolled in randomized clinical trials to examine short DAPT (3–6 months) for patients undergoing PCI with DES. At large, these studies pointed out that shorter duration is feasible, safe, and associated with a reduction of bleeding when compared to a longer duration of DAPT. Some of these studies are still ongoing. However, these studies were underpowered, and the majority included net ischemic and bleeding events, which can skew the results by the lack of the proportion of the event rate for the components of combined safety and efficacy endpoints (higher bleeding rate versus low stent thrombotic events).

Nevertheless, the ongoing bleeding events with longer duration of DAPT continued to motivate investigators to explore a well-powered study design to address the question of whether shorter duration DAPT of 1 to 3 months would be safe and which population should be targeted for such short duration of DAPT. The rationale of short DAPT trials is based on prior evidence from studies that apply shorter duration DAPT protocols and on interruption DAPT data that demonstrated a very low risk of stent thrombosis and no evidence for an increased risk of cardiac death or myocardial infarction. So far, short DAPT study protocols were not accepted by the regulators following the results of the DAPT study. Most recently, the PEGASUS (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin) trial supported longer duration of DAPT in patients postmyocardial infarction and demonstrated that long-term dual antiplatelet therapy with low-dose aspirin and ticagrelor reduced the risk of cardiovascular death, myocardial infarction, or stroke with an increase in the risk of thrombolysis in myocardial infarction, major bleeding but not fatal bleeding or intracranial haemorrhage.

So with two studies that demonstrate advantages of longer duration of DAPT, a shorter duration recommendation is being challenged. One of the arguments for a short DAPT trial was the fact that in the DAPT Study, new-generation everolimus-eluting stents represented less than 50% of implanted DES, and there was a significant interaction in the risk of MACCE according to the DES type. The risk of MACCE in patients who underwent everolimus-eluting stent implantation was not reduced with 30-month DAPT (HR [95% CI] 0.89 [0.67–1.18]), while the protective effect of long DAPT was evident for early generation DES, such as sirolimus- (HR [95% CI] 0.54 [0.31–0.93]) and paclitaxel-eluting stents (HR [95% CI] 0.52 [0.37–0.71]) . Further, the population that was enrolled into the DAPT Study excluded patients who had cardiac events, including bleeding events in the first 12 months prior to the randomization. Furthermore, nearly half of the screened population was not eligible to participate in the study. Perhaps this group should be eligible for a short DAPT study.

It is apparent that we need to separate the stent and the disease state. Although long duration of DAPT is beneficial to the reduction of events, it should be related to the requirement for prevention of stent-related events, such as stent thrombosis. Statins are recommended for life irrespective of the type of stent that is used. Yet, we do need to know the minimum duration of DAPT that is required to prevent stent thrombosis primarily in patients who are at high risk for bleed and patients who could not meet the inclusion criteria of the DAPT Study. Once the characteristics of these patients are disclosed, the DAPT Study could be considered as a study population for a short DAPT trial. Another option would be to perform a short DAPT trial in patients at high risk for bleed similar to the study design of the Leaders Free trial, utilizing only one month of DAPT and comparing polymer-free DES versus bare metal stents. The problem with such a study design is the definition of high risk for bleeding and that it applies to only a narrow population that would be difficult to enroll in an adequately powered study.

Another proposal is the “DAPT holiday” study design, which will apply to a broad population, including stable and unstable patients with planned interruption of DAPT in one arm of the study after a short duration of 1–3 months for a period of up to 6 months. These patients will resume the DAPT thereafter, while the control group will continue with DAPT uninterrupted. These groups can be stratified by risk for bleeding based on existing large registries and available data from the DAPT Study.

Investigators should consider the futility and the economics of such adequately powered mega studies required to answer the question: What is the optimal short DAPT regimen for second-generation DES. It is possible that meanwhile most physicians will adopt personalized medicine strategies regardless of the results of these studies by prescribing a longer duration of DAPT based on the DAPT and PEGASUS trials to their patients who are at low risk for bleed and interrupting DAPT upon bleeding. So for those who still have an appetite for a short DAPT trial, maybe it is time to move on and to focus on identifying who will benefit from a long duration of DAPT, who is at high risk for bleed, and what can be done to reduce bleeding risk while on DAPT.