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Should Clopidogrel Become the ‘New Aspirin’ in CAD?


A P2Y12 inhibitor, such as clopidogrel or ticagrelor, might be a better choice than aspirin for antiplatelet monotherapy in patients with coronary artery disease, results of a new meta-analysis suggest.

The PANTHER meta-analysis showed that P2Y12 inhibitor treatment lowered the risk for subsequent ischemic events, particularly myocardial infarction (MI), compared with aspirin, without increasing bleeding risk.

The relative risk for the primary composite endpoint — cardiovascular death, MI, and stroke — was reduced by 12% in patients who received a P2Y12 inhibitor, compared with aspirin, primarily driven by a 23% relative reduction of MI. Stroke was also numerically but not significantly lower with P2Y12 inhibitor therapy.

The overall risk of major bleeding did not significantly differ, whereas gastrointestinal bleeding and hemorrhagic stroke occurred less frequently in patients who received a P2Y12 inhibitor rather than aspirin monotherapy.

“Based on this evidence, long-term P2Y12 inhibitor monotherapy may be warranted instead of long-term aspirin monotherapy for secondary prevention in patients with coronary artery disease,” lead investigator of the analysis, Marco Valgimigli, MD, Cardiocentro Ticino Foundation, Lugano, Switzerland, concluded.

Valgimigli presented the data at the recent European Society of Cardiology (ESC) Congress 2022 held in Barcelona, Spain.

The “Rise of Alternatives” to Aspirin

Commenting on the study for theheart.org | Medscape Cardiology, Heinz Drexel, MD, Vorarlberg Institute for Vascular Investigation and Treatment, Feldkirch, Austria, said; “Aspirin is the bedrock of cardiovascular medicine, but recent data have started to suggest that P2Y12 inhibitors may be better in terms of reducing both ischemic events and bleeding compared to aspirin. In general, I would say this is the beginning of the future. The difference is not so large as to completely abandon aspirin, but the advantages seem clearly better for P2Y12 inhibitors.”

Clopidogrel was the P2Y12 inhibitor used in most patients in this analysis, and is available generically, Drexel added, “so does not cost much. So I think clopidogrel should now become the first choice for antiplatelet monotherapy. Clopidogrel should now become the new aspirin.”

Responding to a question of whether this is the beginning of the end for aspirin, Valgimigli said: “I don’t think it’s the end of aspirin. I think it’s more the rise of alternatives to aspirin. Many guidelines currently recommend aspirin as the first-line antiplatelet. If aspirin is contraindicated or not tolerated, then the second option is a P2Y12 inhibitor. I think now we can say that a P2Y12 could also be considered first line. To take aspirin completely out of the picture may require additional studies.”

Valgimigli explained that aspirin is the cornerstone of secondary prevention in patients with established coronary heart disease, and the addition of a P2Y12 inhibitor on top of aspirin has become the new standard of care for higher-risk patients — such as those with acute coronary syndromes (ACS) and those undergoing percutaneous coronary intervention (PCI) — owing to greater protection against ischemic events, although this is associated with an increased risk of major bleeding.

The comparative efficacy of monotherapy with an oral P2Y12 inhibitor, compared with aspirin alone, remains incompletely understood in patients with established coronary artery disease, and current guidelines recommend aspirin as first-line therapy after the cessation of dual antiplatelet therapy.

The current meta-analysis involved randomized trials that compared monotherapy with an oral P2Y12 inhibitor or aspirin for the secondary prevention of ischemic events in patients with established heart disease but without an indication for oral anticoagulation.

Trials with an initial dual antiplatelet phase were eligible, but their contribution was limited to the prespecified monotherapy comparison after the exclusion of patients who prematurely stopped the trial during the initial dual antiplatelet phase.

The seven trials involved were CAPRIE, HOST-EXAM, GLASSY, TICAB, DACAB, ASCET, and CADET. The study population consisted of 24,325 patients from these seven trials, of which 12,178 were assigned to P2Y12 inhibitor monotherapy (clopidogrel 62.0%, ticagrelor 38.0%) and 12,147 were assigned to aspirin monotherapy. The median treatment duration was 557 days.

Risk for the primary efficacy outcome — a composite of cardiovascular death, MI, and stroke — was lower with P2Y12 inhibitor monotherapy than with aspirin monotherapy (5.5% vs 6.3%; hazard ratio [HR], 0.88; 95% CI, 0.79 – 0.97; = .014).

The number needed to treat to prevent one adverse outcome was 123 patients.

The risk of major bleeding was numerically but not significantly lower with P2Y12 inhibition than with aspirin (1.2% vs 1.4%; HR, 0.87; 95% CI, 0.70 – 1.09; P = .23), but there was a clear and significant reduction in hemorrhagic stroke (HR, 0.32) and gastrointestinal bleeding (HR, 0.75).

The risk for net adverse clinical events — defined as the composite of the primary efficacy endpoint and major bleeding — was lower with P2Y12 inhibitor monotherapy than with aspirin monotherapy (6.4% vs 7.2%; HR, 0.89; 95% CI, 0.81 – 0.98; P = .020), giving a number needed to treat of 121 patients.

The benefit of the P2Y12 inhibitor monotherapy over aspirin was driven by a reduction in MI (2.3% vs 3.0%; HR, 0.77; 95% CI, 0.66 – 0.90; < .001). The number needed to treat to prevent one MI with a P2Y12 inhibitor was 136 patients. The risk for definite or probable stent thrombosis in patients undergoing PCI was also significantly reduced, by more than 50%.

There was no evidence of different effects in any subgroup examined, including age, sex, smoking status, diabetes, peripheral arterial disease (PAD), previous stroke or MI, history of kidney disease, clinical presentation, and type of P2Y12 inhibitor used.

But Valgimigli drew attention to one particular group of patients. “PCI patients showed an impressive 30% reduction in the composite endpoint with a P2Y12 inhibitor, whereas patients undergoing surgical revascularization, or no revascularization, were less impressive,” he reported.

“This may be overinterpretation of the data, but this observation fits quite well with the finding of a remarkably large reduction in stent thrombosis with P2Y12 inhibitors versus aspirin,” he commented.

Important Clinical Implications

Discussant of the study at the ESC Hotline session, Steffen Massberg, MD, University Hospital Munich, called this “a very important, well-performed, contemporary analysis,” and said that “the findings have important clinical implications.”

He noted that the analysis revisited a dogma in many guidelines, which recommend aspirin monotherapy as first line for secondary prevention in patients with stable coronary artery disease, with a P2Y12 inhibitor only considered in patients with PAD or cerebrovascular disease.

He explained that the reason for this is mostly based on historic evidence from the large CAPRIE study, which suggested some benefit of clopidogrel over aspirin, but this mainly occurred in patients with PAD or with a history of stroke, and no benefit was seen in the subgroup of patients with previous MI.

In the past few years, several other studies have looked at this question — including the larger GLASSY, TICAB, and HOST-EXAM trials — and when the data from all these trials were combined in the PANTHER meta-analysis, a “moderate” benefit was seen on the composite ischemic endpoint with a P2Y12 inhibitor, he said. Results also suggest a particular benefit of P2Y12 inhibitors in patients who have undergone PCI.

In contrast to previous meta-analyses, PANTHER used individual participant data, only enrolled patients with documented coronary artery disease, and excluded studies with outdated P2Y12 inhibitors (ticlopidine), he noted.

On potential limitations of the analysis, Massberg pointed out that the mean age in the PANTHER analysis was 64 years, raising the question of whether the data are applicable to older patients. Also, the previous bleeding history was low (0.4%), so there could have been bias toward enrolment of patients with a low risk of bleeding, and prasugrel was not used in any of the trials involved so the results cannot be generalized to all P2Y12 inhibitors.

“My personal take is that these results are very important and will affect clinical practice, but I believe aspirin is still a valid standard, as it is associated with better compliance and fewer off-target side effects (compared with ticagrelor), less variation in treatment response (compared with clopidogrel), and most likely is more cost-effective,” he commented.

“Yet PANTHER, and particularly the HOST-EXAM study, gives us good arguments to use P2Y12 inhibitors instead of aspirin monotherapy, particularly in younger patients with a history of revascularization,” he added.

Benefit Seen Despite Lack of Genotyping

Cochair of the ESC HOTLINE session, Gabriel Steg, MD, Hôpital Bichat, Paris, noted that “when discussing P2Y12 inhibitors, we are discussing largely clopidogrel.”

There is a large variation in the metabolism of clopidogrel, which could have important clinical consequences, he pointed out, although benefit was seen in this analysis even though no genotyping was performed to identify poor clopidogrel metabolizers.

“I was impressed that Asian patients, who tend to have a higher prevalence of genotypes that predispose to poor clopidogrel metabolism, appeared to do at least as well as other groups with P2Y12 inhibitors,” he said.

“I honestly think that only a relatively low number of patients do not respond to clopidogrel, roughly about 5% who have the homozygous mutation,” Valgimigli explained. “If you look at acute studies in ACS patients, you do see a signal early on that if you drop aspirin and leave the patient on clopidogrel, there may be an increased risk of MI, but in this meta-analysis, we were more focusing on long-term therapy, where the ischemic risk is lower and patients have more time to metabolize the drug. Perhaps that is the reason why, in the long-term, you don’t see a difference between clopidogrel and ticagrelor.”

The PANTHER analysis was funded by two academic institutions, the Cardiocentro Ticino Foundation, Lugano, and Inselspital, Bern, Switzerland. 

European Society of Cardiology (ESC) Congress 2022. Presented August 29, 2022.

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