By Jeffrey Zimmet, MD, PhD

Associate Professor of Medicine, University of California, San Francisco; Director, Cardiac Catheterization Laboratory, San Francisco VA Medical Center

Dr. Zimmet reports no financial relationships relevant to this field of study.

SYNOPSIS: Among patients with high-risk percutaneous coronary intervention who had completed three months of dual antiplatelet therapy with ticagrelor, patients who were randomized to ticagrelor alone experienced similar ischemic outcomes and a lower risk of bleeding at one year compared with those maintained on ticagrelor and aspirin.

SOURCE: Mehran R, et al. Ticagrelor with or without aspirin in high-risk patients after PCI. N Engl J Med 2019; Sep 26. doi: 10.1056/NEJMoa1908419. [Epub ahead of print].

The optimal duration of dual antiplatelet therapy (DAPT) following percutaneous coronary intervention (PCI) has been the subject of intense study and debate for years now. Longer DAPT duration has been demonstrated to reduce the chances for ischemic outcomes at the expense of an increase in clinically relevant bleeding. In most cases, the completion of DAPT has meant paring down to single antiplatelet therapy with aspirin alone. Most clinical trials studying shortened DAPT duration have followed this paradigm. However, more recently, trials have taken the opposite approach, shortening the duration of DAPT by withdrawing aspirin, leaving the P2Y12 inhibitor for a longer course.

The authors of TWILIGHT, the most recent entry in this space, sought to enroll patients after PCI who had clinical and angiographic features associated with elevated risk for ischemic and bleeding events. In this multinational trial involving 187 sites in 11 countries, Mehran et el enrolled 9,006 patients in the direct post-PCI period. Of these, 7,119 were randomized after completing three months of DAPT with aspirin and ticagrelor, with the remainder excluded due to issues including nonadherence to DAPT (the majority), adverse clinical events during the three months post-PCI, and withdrawal of consent or failure to follow up. Ultimately, 3,564 patients were randomized to continue ticagrelor plus aspirin to complete 12 months of therapy, while the remaining 3,555 received ticagrelor and placebo. Randomized patients were a mean age of 65 years, 36.8% were diabetic, 23.8% were female, and 64.8% had undergone PCI for acute coronary syndrome (a combination of NSTEMI and unstable angina; STEMI patients were excluded specifically).

At one year, patients who continued on ticagrelor monotherapy had a lower incidence of the primary endpoint of Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding (4.0% vs. 7.1%; hazard ratio [HR], 0.56; 95% confidence interval [CI], 0.45-0.68; P < 0.001). Incidence of more serious BARC types 3 and 5 bleeding also was significantly lower in the ticagrelor monotherapy group compared with the DAPT group (1% vs. 2%; HR, 0.49; 95% CI, 0.33-0.74). The composite of all-cause death, nonfatal myocardial infarction (MI), and nonfatal stroke was 3.9% in both groups. Similarly, the incidences of MI and definite or probable stent thrombosis were not different between groups.

The authors concluded that for post-PCI patients who had completed three months of DAPT with aspirin and ticagrelor, subsequent ticagrelor monotherapy was associated with a lower risk of bleeding compared with continued DAPT, without an increased hazard of ischemic outcomes (including death, MI, and stroke).

COMMENTARY

In this large, extremely well-conducted study, the trialists demonstrated a significant bleeding reduction by dropping aspirin after an initial three months of DAPT and continuing monotherapy with the potent antiplatelet agent ticagrelor.

Until recently, the major focus of short DAPT trials has been on ischemic endpoints, primarily MI, stent thrombosis, and mortality. More recently, we have seen increasing recognition that bleeding carries significant hazards, too, and rivals MI for contribution to all-cause death. TWILIGHT is the third major trial this year concerning shortened duration of DAPT post-PCI using P2Y12 inhibitor monotherapy after initial DAPT. SMART-CHOICE and STOPDAPT2 transitioned from DAPT to clopidogrel monotherapy (at three months for SMART and one month for STOPDAPT), with parallel findings of decreased bleeding with similar ischemic event rates in the arms without aspirin. It is entirely possible that the efficacy of prolonged DAPT, as seen in the 2014 DAPT (primarily clopidogrel) and 2015 PEGASUS (ticagrelor) trials, may see benefits primarily from prolonged P2Y12 inhibition.

These recent trials suggest that we may be able to achieve that benefit with less bleeding by dropping aspirin and retaining the P2Y12 inhibitor. Although TWILIGHT patients were required to present with some higher-risk features for ischemic events, the trialists did not focus on acute coronary syndrome (ACS). Fully one-third of the study population was composed of stable elective patients, who in the United States generally would be treated with six months of DAPT. It also is notable that of the ACS patients who were included, more than half were troponin-negative unstable angina patients, and STEMI patients were not included by design. It is unlikely that this trial will be enough to change current thinking regarding use of 12 months of DAPT post-ACS.

One obvious question is why last year’s GLOBAL LEADERS trial (Lancet 2018;392:940-949), which on the surface featured a similar design, failed to show a similar result. The authors of GLOBAL LEADERS recruited nearly 16,000 patients post-PCI and randomized them (after an initial one-month period of DAPT with aspirin and ticagrelor) to either ticagrelor monotherapy for 23 months or DAPT for 12 months followed by aspirin alone for 12 months. In that trial, there was no apparent benefit of ticagrelor monotherapy in terms of either bleeding or rates of ischemic events.

The TWILIGHT authors noted the double-blind (vs. open label) design of their trial, the enrollment of higher-risk patients, the different duration of therapy studied, and the use of central adjudication of bleeding events (vs. site-reported) as central points contributing to distinct results. In addition, by randomizing only patients who had successfully completed three months of DAPT, TWILIGHT featured a cleaner design that decreased noise and reduced issues from protocol nonadherence. TWILIGHT suggests that shortening duration of DAPT to three months after PCI with continuation of P2Y12 inhibitor monotherapy is a safe approach that may be considered to decrease bleeding risk. Time will tell whether these data are sufficient to move the needle for revising national guidelines.