P2Y12 Inhibitors Top Aspirin for Long-term Secondary Prevention: PANTHER

BARCELONA, Spain—(UPDATED) Aspirin has long been the antiplatelet of choice for long-term secondary prevention in patients with coronary disease, but a meta-analysis of several trials suggests P2Y12 inhibitor monotherapy has some advantages.

Over a median follow-up of about one-and-a-half years, the risk of CV death, MI, or stroke was lower in patients who were taking a P2Y12 inhibitor alone versus aspirin alone (5.5% vs 6.3%; HR 0.88; 95% CI 0.79-0.97), mostly driven by fewer MIs, Marco Valgimigli, MD, PhD (Cardiocentro Ticino Institute, Lugano, Switzerland), reported here at the European Society of Cardiology Congress 2022.

Though major bleeding overall occurred at similar rates with either approach, risks of GI bleeding and hemorrhagic stroke were lower with P2Y12 inhibitor therapy. No outcomes favored aspirin.

“Based on all available randomized evidence, long-term P2Y12 inhibitor [therapy] may be warranted instead of long-term aspirin monotherapy for secondary prevention in patients with coronary artery disease,” Valgimigli concluded at a press conference.

PANTHER Meta-analysis

Aspirin has been the mainstay of secondary prevention in patients with established coronary disease for decades, with P2Y12 inhibitors being added as part of dual antiplatelet therapy (DAPT) among patients with ACS and/or after coronary revascularization. However, the relative efficacy and safety of monotherapy with a P2Y12 inhibitor versus aspirin is not completely understood for patients with established CAD, said Valgimigli, who noted that guidelines currently recommend lifelong aspirin after DAPT is stopped.

Based on all available randomized evidence, long-term P2Y12 inhibitor [therapy] may be warranted instead of long-term aspirin monotherapy for secondary prevention in patients with coronary artery disease. Marco Valgimigli

To explore the issue, he and his colleagues performed a meta-analysis dubbed PANTHER. It included patient-level data from several randomized trials that at least partly included a comparison of P2Y12 inhibitor or aspirin monotherapy in patients with established coronary disease and no indication for oral anticoagulation. Trials with an initial DAPT phase were included, but data from those studies were limited to the monotherapy phase.

The investigators included seven trials—ASCET, CADET, CAPRIE, DACAB, GLASSY, HOST-EXAM, and TiCAB—with an overall patient population of 35,752 from 492 sites in Asia, Europe, and North America. After excluding patients who did not have established CAD, who left the studies early, who had an event during an initial DAPT phase, or who received DAPT exclusively, there were 24,325 participants (mean age 64 years; 22% women) left for the analysis.

Most patients (60.6%) had presented with ACS, and the remaining had chronic coronary syndromes. More than half (54.9%) had a history of PCI, 10.6% a history of CABG, and 4.4% a history of both; 30.2% had never undergone revascularization.

P2Y12 inhibitor therapy included clopidogrel in 62% and ticagrelor in 38%; there are no trials comparing aspirin and prasugrel monotherapy, Valgimigli said. Median treatment duration was 557 days.

The advantage for P2Y12 inhibitors over aspirin on the primary composite efficacy outcome of CV death, MI, or stroke worked out to a number needed to treat of 123. The better outcomes were mostly related to a lower risk of MI (HR 0.77; 95% CI 0.66-0.90), as there were no significant differences between groups for overall stroke (HR 0.85; 95% CI 0.70-1.02) or CV death (HR 1.02; 95% CI 0.86-1.20).

Major bleeding occurred in 1.2% and 1.4% of patients treated with P2Y12 inhibitors and aspirin, respectively, a nonsignificant difference (HR 0.87; 95% CI 0.70-1.09).

Combining the efficacy outcome and major bleeding, the rate of net adverse clinical events was significantly lower with P2Y12 inhibitors (6.4% vs 7.2%; HR 0.89; 95% CI 0.81-0.98).

Some of the secondary outcomes favored P2Y12 inhibitor therapy as well, including:

• Hemorrhagic stroke (HR 0.32; 95% CI 0.14-0.75)
• Definite stent thrombosis (HR 0.42; 95% CI 0.19-0.97)
• Definite/probable stent thrombosis (HR 0.46; 95% CI 0.23-0.92)
• GI bleeding (HR 0.75; 95% CI 0.57-0.97)

The results were similar across 16 subgroups, with no significant interactions. There was a suggestion of greater benefits associated with P2Y12 inhibitors among patients who had undergone PCI, but Valgimigli cautioned against reading too much into that finding.

End of Aspirin?

Asked during the press conference whether this marks the beginning of the end for aspirin for secondary prevention in CAD, Valgimigli said he doesn’t think so: “I think it’s the rise of [an] available alternative to aspirin.”

Guidelines state that aspirin is the first-line option for long-term antiplatelet therapy, with P2Y12 inhibitors as an option when aspirin is contraindicated, Valgimigli said, indicating that it’s unclear how these new data will influence future guidance.

“I think now we have two at least equally effective alternatives. To take aspirin completely out of the picture, probably that would require additional studies because aspirin has been there for 125 years,” he said.

Serving as a discussant following the presentation, Steffen Massberg, MD (Ludwig-Maximilians-Universität München, Germany), also indicated that it’s not time to get rid of aspirin, and went through a number of potential issues to consider when interpreting the PANTHER results, including the heavy weight of the CAPRIE trial in the analysis, the relatively young age of the patient cohort, and the small effect size, which plays into discussions of cost-effectiveness.

“The results are definitely very important, and they will have impact on the clinical practice,” he said. Nevertheless, he added, “I think that still aspirin is a valid standard because it’s associated with less noncompliance, has less variation in treatment response, particularly compared to clopidogrel, and most likely is also more cost-effective, although this has not been formally demonstrated. But this is reasonable considering the low effect size with the P2Y12 inhibitors.”

Even so, Massberg said, “I think PANTHER and also HOST-EXAM are giving us good arguments to use P2Y12 inhibitors instead of aspirin monotherapy, particularly in younger patients with a history of revascularization.”

This is bread-and-butter cardiology that you would see in the office every day managing patients long term. Edward Fry

Commenting for TCTMD, American College of Cardiology President Edward Fry, MD (St. Vincent Medical Group, Indianapolis, IN), said the PANTHER meta-analysis could have a significant impact on the day-to-day management of patients with coronary disease. “This is bread-and-butter cardiology that you would see in the office every day managing patients long term,” he said.

And, with a large data set, “it helps support what a lot of people are doing in practice already” at the end of a period of DAPT due to concerns about the long-term risks of aspirin, particularly bleeding, Fry said. When a P2Y12 inhibitor is chosen for this purpose, it’s mostly clopidogrel due to considerations around the higher cost and twice-daily dosing of ticagrelor and the longer experience clinicians have with using clopidogrel, he added. Moreover, when patients have an indication for adjunctive oral anticoagulation in addition to P2Y12 therapy, most of the existing data addresses use of clopidogrel.

When it comes to use of P2Y12 inhibitor versus aspirin monotherapy, Fry said, “it’s sort of the best of both worlds: better efficacy and certainly no increased risk. . . . And in these subsets of GI bleeding and hemorrhagic stroke, there’s a definite advantage towards a P2Y12 inhibitor.”

Fry said the US guidelines don’t specify which antiplatelet agent should be used for long-term secondary prevention in patients with coronary disease. “I suspect in future guidelines this will be a consideration, or at least there will be some suggestion that practitioners consider what antiplatelet therapy they’re using long term, looking at both efficacy and risk,” he predicted.