Fewer MACCE With P2Y12 Inhibitor vs Aspirin Monotherapy Over 5 Years

Long-term maintenance with P2Y12 inhibitor monotherapy after discontinuing dual antiplatelet therapy (DAPT) in patients who’ve undergone PCI seems to reduce MACCE compared with aspirin monotherapy without increasing major bleeding, according to a new meta-analysis.

Over 5.5 years’ follow-up, there was a 33% lower risk of MACCE with the P2Y12 inhibitor versus aspirin in more than 16,000 patients who had previously taken DAPT for about 1 year after PCI.

While aspirin has long been the gold standard drug for these patients, researchers say the new data should encourage physicians to try P2Y12 inhibitors to lower the rate of lifetime adverse events.

“Guidelines should start recommending either of the two,” senior author Marco Valgimigli, MD, PhD (Cardiocentro Ticino Institute, Ente Ospedaliero Cantonale, Lugano, Switzerland), told TCTMD. “A preference towards aspirin monotherapy as the only option for a class 1a is probably now not entirely supported by the data. . . . I don't want to go against aspirin monotherapy, but I would say that we have at least an as effective and as safe treatment option, which is a P2Y12 inhibitor, which should be considered at least as important as aspirin.”

What the authors propose is truly a paradigm shift, as “everyone always thinks of aspirin for the long term,” said Davide Capodanno, MD (University of Catania, Italy), who added that concerns over clopidogrel resistance beginning decades ago hindered the use of that drug long-term in this population. While it’s a “pharmacodynamic reality” that some patients have partial or complete loss of response to clopidogrel, this hasn’t translated into a difference in population-level clinical outcomes, he said.

Because of these new findings, along with prior research, “at the very least, [aspirin and clopidogrel] should have equal recommendations,” Capodanno told TCTMD.

Usman Baber, MD (University of Oklahoma Health Sciences Center, Oklahoma City), feels similarly.

“What this meta-analysis does and what other similar studies have done is extend the paradigm of monotherapy from early PCI periods now to long-term secondary prevention,” he told TCTMD. “With this study and the trials that comprised it, I really do think we're at a point now where monotherapy with P2Y12 inhibitors is a safe and effective therapeutic option.”

Meta-analysis Findings

For the study, published online last week in the BMJ, Daniele Giacoppo, MD, PhD (University of Catania), Valgimigli, and colleagues analyzed data from 16,117 patients (mean age 65 years; 23.8% women; 55.5% ACS) who underwent PCI and received DAPT for a median duration of 12 months before being randomly assigned to P2Y12 inhibitor or aspirin monotherapy in one of five randomized trials: ASCET, CAPRIE, GLASSY, HOST-EXAM, and STOPDAPT-2. In patients who took a P2Y12 inhibitor, 58.7% received clopidogrel and 41.3% received ticagrelor.

Over a median follow-up period of 1,351 days, MACCE—comprised of cardiovascular death, MI, or stroke—was reported in 341 patients receiving P2Y12 inhibitor monotherapy (1.49 per 100 person-years) and in 441 patients randomized to aspirin monotherapy (1.93 per 100 person-years). This translated to a lower overall risk of MACCE with a P2Y12 inhibitor compared with aspirin (HR 0.77; 95% CI 0.67-0.89), with a number needed to treat of 45.5 to benefit one patient. The findings held up in multiple multivariate analyses.

Major bleeding, a co-primary endpoint, did not differ between the study groups: 0.70 per 100 person-years for both P2Y12 inhibitor and aspirin monotherapy.

The risk of net adverse cardiovascular and cerebrovascular events, which included all cause death, CV death, MI, stroke, ischemic stroke, hemorrhagic stroke, definite or probable stent thrombosis, definite stent thrombosis, probable stent thrombosis, major gastrointestinal bleeding, any bleeding, and any gastrointestinal bleeding, was reduced with P2Y12 vs aspirin monotherapy (HR 0.86; 95% CI 0.75-0.98).

Regarding individual endpoints, there were no differences between treatment arms in terms of all-cause death, CV death, MI, or stroke. There were, however, a significantly lower risk of ischemic stroke and a numerically lower risk of definite or probable stent thrombosis in those receiving P2Y12 inhibitor monotherapy compared with aspirin. The risk of any bleeding was higher in the P2Y12 monotherapy group, although there was significant heterogeneity detected across trials, and the risks of major gastrointestinal bleeding and any gastrointestinal bleeding were also higher with the P2Y12 inhibitor.

In a landmark analysis beginning at 1,000 days, researchers found no difference in the early and late treatment effects of the study drugs.

Subgroup analyses showed no differences in the main findings with regard to age, sex, body mass index, trial geography, index clinical presentation, proton pump inhibitor use, aspirin dose, and P2Y12 inhibitor type. Results were also comparable when the less contemporary ASCET and CAPRIE data were removed, as well as when GLASSY—the only included trial to look at ticagrelor—was excluded.

‘Medium-term’ Data

In an accompanying editorial, Rohin Reddy, MBBS (Imperial College London, England), and colleagues argue that the meta-analysis “supports preferential prescription of P2Y12 inhibitor monotherapy over aspirin owing to reductions in MACCE without increasing major bleeding in the medium term, further validated by results from the recent SMART-CHOICE-3 trial.”

But the data are still “medium term” and might not be representative of what happens over the course of a lifetime, they add. “Whether the beneficial ischemic and bleeding trade-off with antiplatelets remains durable over time is contentious, particularly in older adults, and randomized data are lacking beyond ~4 years. In the current body of evidence, the appropriateness of existing recommendations for lifelong antiplatelet monotherapy remains an unanswered question.”

For this to be clear, a large, global RCT comparing multiple monotherapy strategies, including discontinuation, with extended follow-up would be needed, the editorialists say.

For Valgimigli, though, the data are “solid” enough to change practice now. In fact, the only reason he says he’ll use aspirin monotherapy is for patients with plans to undergo surgery. “We do not have very clear-cut comparative data with respect to the surgical bleeding,” he said. “I can tell you because I’ve tried to convince surgeons for years and nobody would be willing to operate on a patient taking clopidogrel monotherapy or ticagrelor monotherapy not because there is bad data, but there is simply no data.”

As far as which P2Y12 inhibitor to choose, Valgimigli said the evidence would support either clopidogrel or ticagrelor, but that cost might weigh in, as even generic clopidogrel is generally more expensive than aspirin. It’s possible though, he suggested, that the worldwide cost of clopidogrel might go down if practice shifted to using it more often.

Cost is of critical importance, as are side effects and tolerability, but the choice of which drug to use should be looked at holistically, Baber added.

“Aspirin, I'm sure, is still much cheaper than generic clopidogrel,” he said. “But if generic clopidogrel is yielding a 23% reduction in MACE without bleeding, I think from a population standpoint you would still be saving money to the healthcare system, because you're reducing MIs and strokes and very costly events. I think in addition to comparing these strategies to one another, doing cost analysis to figure out which one of these would be most cost-effective is also important.”

Does Clopidogrel Responsiveness Still Matter?

The question of how to factor in potential clopidogrel responsiveness remains unanswered. Valgimigli said he is looking into this with another meta-analysis that will incorporate two additional trials—STOPDAPT-3 and SMART CHOICE-3—and include outcomes related to clinical predictors of poor responsiveness.

Looking at clinical factors will be most important, he said, because they affect a larger proportion of patients who don’t respond to clopidogrel, whereas genetics account for a maximum of 15% of variability in clopidogrel responsiveness.

“If you really want to screen the patients who are most likely to be good responders to the drug versus those who are less-good responders to the drug, first you should look into patient characteristics more than genes,” Valgimigli said. “We are obsessed about thinking about the genes, but actually we should simply phenotype the patients, not necessarily genotype.”

Baber added that he is less concerned about clopidogrel responsiveness in the long-term. “My suspicion is that the clopidogrel resistance is a more important consideration in the early period after PCI or ACS when thrombotic risk is much higher,” he said. “But as we all know, over time, thrombotic risk actually goes down, whereas the potential for bleeding harm is a more constant concern.”

Overcoming ‘Clinical Inertia’

As far as moving beyond aspirin, Valgimigli said it will be an uphill battle to get many physicians to change their practice. “Most likely the evidence that we have now will be deemed to be insufficient, it'll be criticized. They will say: ‘We do not have enough evidence.’ And that's clear. It'll be always like this. Evidence will never be sufficient.” But the studies that originally supported long-term use of aspirin have not been “digested in a contemporary way,” Valgimigli added. “If you critically look into those studies, I think people will be shocked about how limited those studies are.”

He stressed that he is not trying to “discredit” aspirin monotherapy but rather encourage clinicians to “start opening their mind when they prescribe a single antiplatelet agent. Long-term aspirin is one option, but there is another one, which is at least as good and as effective as aspirin, which is a P2Y12 inhibitor.”

Even the question of whether any of the antiplatelet agents should be given lifelong remains elusive. “These drugs have been established in an era where they were the only drugs,” Capodanno said. “But now we have lipid-lowering therapies. Maybe one day we'll have anti-inflammatory [drugs]. It's very exciting because we are learning that over the long-term, maybe one of the pathways will prevail over another.”

He’d like to see a study look at aspirin-free strategies over the long-term to overcome the “clinical inertia” physicians have with such a cornerstone drug. “I think it has to be reassessed whether there is a real value [with aspirin] over the existing other therapies,” said Capodanno.

The meta-analysis and the discussion it has stirred are essentially “history repeating itself,” Baber commented.

“From a big-picture standpoint, I see these studies as sort of recapitulating what we've done in the early period after PCI,” he said. “In other words, we established DAPT as the standard and we have now developed monotherapy as a clear alternative with the net benefit compared to DAPT. Now with long-term secondary prevention, we have DAPT as an option. We have the dual pathway inhibition as an option, all compared to a background of aspirin. And now finally, monotherapy is showing extreme promise for long-term secondary prevention.”