Five Years Post-PCI, Clopidogrel Monotherapy Holds Up in STOPDAPT-2

The long-term use of clopidogrel monotherapy after stopping dual antiplatelets following PCI appears to be more effective at reducing clinical events when compared with standalone aspirin, a benefit that was seen without any differences in the risk of bleeding, according to late follow-up from the STOPDAPT-2 randomized trial.

Treatment with clopidogrel was associated with a significant 23% lower risk of major cardiovascular outcomes at 5 years, including a reduction in MI. These results were similar when investigators performed an on-treatment analysis and a landmark analysis focusing on maintenance therapy between 1 and 5 years.

“The risk reduction in cardiovascular events was mainly driven by the statistically significant 39% risk reduction in myocardial infarction,” write lead investigator Hirotoshi Watanabe, MD (Hyogo Medical University, Nishinomiya, Japan), and colleagues online January 1, 2024, in the Journal of the American College of Cardiology. “Moreover, stent thrombosis and ischemic stroke were numerically reduced in the clopidogrel group versus the aspirin group, consistent with previous studies.”

The current European and US guidelines recommend default dual antiplatelet therapy (DAPT) durations of 6 months following PCI for patients with stable CAD and 12 months for those with ACS. However, several clinical trials in recent years have shown that shortened DAPT—ranging from 1 to 3 months—could be an option in select patients. One question, though, is what’s the best antiplatelet option once DAPT is discontinued. The guidelines recommend aspirin as monotherapy following DAPT stoppage (class IA recommendation), with a P2Y12 antagonist considered an alternative in those who are unable to take aspirin (class IIa recommendation).

“I think it's one of the questions that really remain,” Davide Capodanno, MD, PhD (University of Catania, Italy), who wasn’t involved in the study, told TCTMD. “The question on the long-term chronic maintenance therapy remains because essentially there are few trials.”

The scant data available suggest a possible advantage to continuing with clopidogrel over aspirin. In long-term follow-up of the HOST-EXAM study, for example, treatment with clopidogrel after stopping DAPT was associated with a reduction in net adverse cardiovascular events (NACE), a composite endpoint that factors in bleeding. A network meta-analysis suggested that aspirin after post-PCI DAPT was associated with a higher risk of MI compared with clopidogrel and that there was no difference in major bleeding. A landmark analysis from LEADERS also found a benefit to going with P2Y12 monotherapy with ticagrelor.

Ajay Kirtane, MD (NewYork-Presbyterian/Columbia University Irving Medical Center, New York, NY), said that clopidogrel was traditionally the drug pulled when DAPT was stopped.

“For many physicians now, myself included, we're often thinking that instead of dropping the P2Y12 inhibitor, because clopidogrel is generic, potentially just dropping the aspirin instead,” he told TCTMD. “It does seem like that's a reasonable strategy. I thought it was interesting—and again, this is not a randomized comparison—that in this analysis there was really no difference in bleeding. A lot of times we make the move because we think aspirin is going to cause more bleeding than clopidogrel but that was not really seen in this study.”

Both Strategies Work Well

In STOPDAPT-2, investigators randomized 3,005 patients (mean age 68.6 years; 22.3% women) undergoing PCI, including 38.3% with ACS, with a cobalt-chromium everolimus-eluting stent (Xience; Abbott Vascular) to one of two strategies: DAPT with aspirin plus clopidogrel 75 mg or prasugrel 3.75 mg for 1 month, followed by clopidogrel monotherapy for 11 months, or DAPT for 12 months.

At 1 year, as previously reported by TCTMD, the shortened DAPT strategy was superior to 12 months of DAPT with respect to the primary NACE endpoint, a composite of CV death, MI, definite stent thrombosis, stroke, or TIMI major/minor bleeding, and the secondary endpoint of TIMI major/minor bleeding.

The story building up here is that aspirin is not necessarily the only drug that you may consider. Davide Capodanno

After 12 months, patients in the shortened-DAPT arm continued with clopidogrel while those treated with standard-duration DAPT continued with aspirin alone.

At 5 years, the primary NACE endpoint occurred in 11.75% of those treated with clopidogrel versus 13.57% of those treated with aspirin (P < 0.001 for noninferiority; P = 0.13 for superiority). Major cardiovascular events occurred in 8.61% of those treated with clopidogrel and 11.05% of those treated with aspirin (P = 0.03 for superiority). There was no difference in major bleeding (4.44% vs 4.92%; P = 0.51).

These results were similar when investigators performed an analysis looking only at those who were adherent to treatment at 1 year. 

In a landmark analysis focused on 1 to 5 years, clopidogrel monotherapy was noninferior to aspirin for the primary NACE endpoint (9.57% vs 10.05%; P < 0.001) and there was a trend toward fewer cardiovascular events with clopidogrel than with aspirin (6.79% vs 8.68%; P = 0.06). Again, there was no difference in major bleeding between the two monotherapy strategies between years 1 and 5 (3.99% vs 3.32%; P = 0.31).

Clopidogrel an Alternative as Monotherapy

Both Capodanno and Kirtane emphasized that the STOPDAPT-2 findings should be considered hypothesis-generating, noting that the extended follow-up was not the study’s primary endpoint. Kirtane pointed out that it’s also not a clean comparison of one monotherapy strategy versus the other because there were some patients maintained on DAPT during follow-up. Capodanno added that landmark analyses can create selection bias given that events in the first year are not counted.

Additionally, Capodanno emphasized that STOPDAPT-2 included relatively low-risk patients and that the vast majority underwent PCI with adjunctive intravascular imaging, something that is not yet common practice elsewhere. Also, the Japanese population has a different bleeding-risk profile than North American or European patients. For these reasons, the study will require confirmation, but these and other data suggest, at a minimum, that clopidogrel is no worse than aspirin over the long term.

“The story building up here is that aspirin is not necessarily the only drug that you may consider,” said Capodanno. “The question is whether clopidogrel can be more than just an alternative. I think it could be, but that would call for a randomized study.”

Kirtane agreed, noting that the data suggest “whatever strategy you choose, people did pretty well,” but he urged against any conclusions implying a clopidogrel advantage. “There has to be a little hesitancy there,” he said. “It does make intuitive sense, though, that the P2Y12 inhibitor might actually be better at [preventing] those types of events than aspirin alone, but I don't think we can use this trial to prove that.”

In an editorial, Anne Bellemain-Appaix, MD (Antibes Hospital/GHT Sofia-Antipolis, France), and Gilles Montalescot, MD, PhD (Sorbonne University/Pitié-Salpêtrière Hospital, Paris, France), write that there’s been a concern about P2Y12 inhibition for long-term treatment after discontinuing DAPT because of variable responses in poor metabolizers of clopidogrel, its higher cost compared with aspirin, its lack of effect on cancer prevention compared with aspirin, and other practical issues, such as future procedures (noncardiac surgeries or biopsies) that can be performed on aspirin but not clopidogrel.

De-escalation of DAPT after PCI “needs to be carefully thought out,” write Bellemain-Appaix and Montalescot, noting it can be harmful in some patients, particularly those with ACS.  

“DAPT should remain the standard of care for 1 month after coronary stent implantation,” they add. “Beyond 1 month, possibly 3 months in ACS or high ischemic risk patients, de-escalation strategies to a P2Y12 inhibitor alone may become the new standard of care among select, if not most, patients. Whether practical limitations to adoption of P2Y12 lifelong treatment outweigh the results of this current analysis remains to be determined.”     

To TCTMD, Kirtane said that if a patient is advised to stopped clopidogrel monotherapy because they are undergoing a procedure, such as dental work or a biopsy, he advises them to start aspirin, at least during the procedure so they have some protection from ischemic events.