Large Study Lends Support to Clopidogrel Monotherapy After DAPT Cessation

MONTREAL, Canada—In PCI patients who have had 12 months of dual antiplatelet therapy (DAPT), switching over to P2Y12 inhibitor monotherapy is associated with better outcomes than guideline-recommended aspirin alone, according to a large observational study of high-risk patients.

At 36 months, the rate of net adverse clinical events (NACE), consisting of death from any cause, MI, stroke, or BARC type 2, 3, or 5 major or clinically relevant nonmajor bleeding was 4.7% in the aspirin group and 2.5% in those on clopidogrel (log-rank P < 0.001).

Presenting the results in a late-breaking trials session last week at the Society for Cardiovascular Angiography and Interventions 2026 meeting, Hao-Yu Wang, MD, PhD (Fuwai Hospital, Beijing, China), said they add to other evidence from trials like HOST-EXAM and SMART-CHOICE 3 that support clopidogrel monotherapy after standard DAPT.

“However, we found maybe a new clue [of] more pronounced [effect] of clopidogrel therapy in high-risk patients,” Wang noted.

In an analysis that stratified patients by bleeding risk, the absolute magnitude of the net clinical benefit of clopidogrel versus aspirin monotherapy trended higher in those with both high bleeding risk and a complex PCI (P = 0.012), an advantage driven by fewer ischemic events.

Wang noted that despite accumulating data supporting clopidogrel monotherapy, both the United States and European guidelines have a high-grade recommendation for low-dose aspirin for patients with CAD and prior myocardial revascularization.

“Is it time for a guideline change?” asked session co-moderator Dean J. Kereiakes, MD (The Christ Hospital Heart and Vascular Institute, Cincinnati, OH).

Wang responded that while he thinks so, it’s true that much of the evidence in support of clopidogrel monotherapy comes from cohorts of Asian patients, making it important to gather more data on Western populations. The cohort did not have CYP2C19 phenotyping for clopidogrel response.

“The population certainly makes a difference,” said panelist Andrew M. Goldsweig, MD (University of Massachusetts Baystate Medical Center, Springfield), adding that about 25% of white patients are nonresponders to clopidogrel.

“Do I need to test people before going for clopidogrel monotherapy?” he wondered. “For your lower-risk patients, there may be a different answer than for your higher-risk patients, . . . and what you’re really getting at here is the importance of personalized medicine. The guidelines need to say which patients would benefit from aspirin, which patients would benefit from clopidogrel monotherapy, which patients should have sustained dual antiplatelet therapy, and how that decision can be made.”

The Panel Weighs In

The study was comprised of 5,664 patients (24.2% women) who completed 12 months of  DAPT following their PCI and did not experience any clinical events. Of these, 20% had a high risk of bleeding and 34.5% had undergone complex PCI, defined as three or more stents implanted, three or more lesions treated, bifurcation with two stents implanted, total stent length more than 60 mm, or treatment of chronic total occlusion. Aspirin monotherapy was prescribed in 3,690 patients and clopidogrel monotherapy in 1,974 patients.

Regardless of the risk of bleeding and/or PCI complexity, patients in the clopidogrel group had lower rates of all-cause death, MI, and stroke over 36 months of follow-up compared with those in the aspirin group (1.3% vs 3.0%; log-rank P < 0.001). The individual endpoint of BARC type 2, 3, or 5 bleeding, however, was similar in the clopidogrel and aspirin groups over the same time period (1.2% and 1.9%; log-rank P = 0.077).

“I think this is one more nail in the coffin, and I mean that, of aspirin monotherapy following DAPT after PCI,” Kereiakes said. “Monotherapy wins versus DAPT, P2Y12 wins versus aspirin. I just can’t imagine why our guidelines don’t move at a more rapid pace.”

In his 60-physician group, they have put this into practice because “the data are there.” Kereiakes then asked the panel members to weigh in on how they deal with this at their centers.

Monotherapy wins versus DAPT, P2Y12 wins versus aspirin. Dean J. Kereiakes

Sandeep Nathan, MD (University of Chicago, IL), said that while he routinely uses clopidogrel or ticagrelor monotherapy in recently stented, high-bleeding-risk ACS patients, he has some concerns.

“The one thing that I worry about is CYP2C19 is just one of six enzymes that are responsible for breaking down clopidogrel bisulfate into the biometabolite,” he said. While he does advocate for phenotype testing, the data have shown that 42% of ethnic minorities, diabetics, and renal failure patients may not have a dichotomous response to clopidogrel at 24 hours.

“What we don’t know is whether some of those people actually convert and their platelet reactivity goes down, because [we know] 42% of these folks aren’t having ACS events afterwards,” Nathan added.

Jun Li, MD (University Hospitals Harrington Heart & Vascular Institute, Cleveland, OH), said she routinely converts patients with PAD to clopidogrel monotherapy if they also have CAD. “I find that it is much more helpful to prevent secondary events compared to monotherapy  with aspirin,” Li explained.

Frederick G.P. Welt, MD (University of Utah Hospital, Salt Lake City), said he agrees that taken together, the data in support of clopidogrel are “fairly convincing,” in spite of the strategy not being guideline recommended. While his institution hasn’t moved away from routine aspirin monotherapy, “ I think maybe it’s time that we had the discussion,” he said.

Lastly, co-moderator Suzanne J. Baron, MD (Massachusetts General Hospital and BAIM Institute for Clinical Research, Boston), said she is open to using clopidogrel monotherapy frequently. “It’s very variable in my institution, but I’ve really been buying into a lot of the data as well, particularly in the high-bleeding-risk patients,” she said.