No Benefit to P2Y12 Inhibitor Pretreatment in STEMI, Bern-PCI Data Confirm

Treating patients thought to have STEMI with P2Y12 inhibitors before they get to the hospital does not reduce their risk of major adverse cardiovascular or cerebrovascular events, data from the BERN-PCI registry confirm anew.

The practice of pretreatment, once thought to help reduce ischemic events in ACS patients destined to undergo PCI, fell out of favor in STEMI patients after ATLANTIC and a SWEDEHEART study showed no benefit. Studies in NSTEMI, including an analysis from the SCAAR registry and a substudy of the ACCOAST trial, raised concerns that the practice would harm more than help, by increasing the risk of bleeding. As a result, the most recently updated ESC guidelines for the management of ACS downgraded the recommendation of routine pretreatment with a P2Y12 inhibitor for STEMI patients from class 1 to a class 2B, and continued to advise that their use in NSTEMI should be restricted to patients in whom delays to treatment might surpass 24 hours.

The new BERN-PCI data “corroborate the finding that there is probably no excess in ischemic events if you do not preload with a P2Y12 inhibitor,” senior author Lorenz Räber, MD, PhD (Bern University Hospital, Switzerland), told TCTMD. “And also, of course, in that sense, supports the recently issued ESC recommendation.”

At this point, the answer is clear for Elmir Omerovic MD, PhD (Sahlgrenska University Hospital, Gothenburg University, Sweden), who was involved in the Swedish analyses but not the current report: pretreatment should not be done for anyone. The authors “have been rather restrained in their conclusions,” he commented to TCTMD. “They could make some more definite conclusions given the totality of evidence.”

With “do no harm” as a guiding principle of medicine, Omerovic added that “you should do nothing, unless you have clear cut evidence that [pretreatment] really makes a difference in terms of saving lives.”

No MACCE Difference

For the study, published online this week in JACC: Cardiovascular Interventions, Miklos Rohla, MD, PhD (Bern University Hospital), Räber, and colleagues looked at all STEMI patients undergoing primary PCI (mean age 65 years; 24% female) in the Bern-PCI registry between 2016 and 2020. There were 1,116 patients treated between October 2016 and September 2018—when P2Y12 pretreatment was recommended—and 847 from the time period between October 2018 through September 2020, when pretreatment was only recommended if coronary anatomy could be confirmed.

The majority (63.4%) of the early cohort received pretreatment, with a median time from loading dose to angiography of 52 minutes, while only a handful did in the later cohort (5.8%), with a longer median dose-to-angiography time of 100 minutes. Ticagrelor was used most often overall (77%), but prasugrel was used more frequently in the later compared to the earlier cohort (16% vs 11%; P < 0.01).

There were no differences in the MACCE rates (primary endpoint) between the early and late cohorts (10.1% vs 8.1%; adjusted HR 0.91; 95% CI 0.65-1.28) as well as none between patients receiving pretreatment or not (7.1% vs 8.4%; adjusted HR 1.17; 95% CI 0.78-1.74). There were also no differences noted in bleeding.

Räber highlighted the length of time from loading dose to angiography seen in their study, particularly among the latter cohort, which was about three times as long as was observed in ATLANTIC. “You could argue that in the ATLANTIC trial, the absence of difference in ischemic outcomes was due to the very short time difference between the two groups when they received their loading,” he said. “It was considerably longer in our registry, . . . and I think it is pathophysiologically a very important finding.”

A Tool for Precision Medicine?

In an accompanying editorial, George A. Stouffer, MD (University of North Carolina, Chapel Hill), and colleagues write that while the study does not support the practice of pretreatment with P2Y12 inhibitors in STEMI patients, “there is no safety signal suggesting that pretreatment is harmful, and thus either strategy can be used on the basis of the available data.”

Altogether, however, the study “obscures the fact that each individual patient presenting with STEMI has specific characteristics—age, comorbidities, ability to take oral medications, localization of ST-segment elevations on electrocardiography suggesting single or multivessel disease, and others—that could influence the decision regarding pretreatment,” they continue. Potentially, pretreatment can become another component of personalized medicine, the editorialists argue.

Omerovic disagreed with the notion of there being no safety signal associated with pretreatment, citing an editorial he co-wrote in 2015. As for whether pretreatment might be used preferentially in certain patients, he said that remains to be seen.

“Precision medicine is the future of medicine for all of us, but how can you arrive at the decision to pretreat?” he said. “We are very susceptible to cognitive dissonance, and we think we are doing good by prescribing X milligrams of ticagrelor or prasugrel up front, but actually we are harming the patients, many of them with dissections, bleedings, other things. Thrombocyte inhibition with P2Y12 receptor blockers can be catastrophic in some patients.”

There’s still potential for certain subgroups of patients, such as those with long travel distances to PCI centers, to benefit from pretreatment, but data have yet to clarify this, Räber said. “In the ideal word, we would still see a large-scale trial powered for clinical outcomes, but whether this will happen is highly questionable.”

Because of the nature of STEMI and how quickly emergency medical services need to act, there’s often not time nor expertise to confirm anatomy and calculate ischemic and bleeding risk, he continued. “It was proposed that the tailored approach might be the way, but I would gently disagree with that because there is no doctor in contact with a STEMI patient, and there's no time to really go for an in-depth assessment when a patient has to be brought to the hospital as soon as possible,” Räber said, adding that this is why his institution made the decision to simplify the process by enacting a blanket “no pretreatment” strategy back in 2018. “We just lack time, and we lack the staff with specific knowledge to make this decision. That's the reason why we are trying to simplify.”