P2Y12 Inhibitor Pretreatment Worth Considering in STEMI When PCI Is Delayed

Guidelines have downgraded the practice, but new registry data show no increase in bleeding, making a case for pretreatment.

P2Y12 Inhibitor Pretreatment Worth Considering in STEMI When PCI Is Delayed

Pretreatment with P2Y12 inhibitors is associated with a lower risk of MACE compared with giving these medications at the time of primary PCI, at least in those STEMI patients facing delays of greater than 80 minutes, Spanish registry data suggest.

Despite progress made in enhancing STEMI care networks and reducing ischemic time, delays to care remain a reality for many. The concept of early administration of P2Y12 inhibitors is not new, but data from the ATLANTIC trial, as well as newer Bern-PCI registry results, have not shown a benefit of this practice in the current era. The 2023 European Society of Cardiology guidelines for the management of ACS downgraded the indication for pretreatment in STEMI from class 1 to class IIb.

This latest registry analysis, however, suggests early administration of these drugs still has a role to play.

“We found that the benefits are time dependent, and we found that the benefit in a reduction of a MACE consists of all-cause mortality, myocardial infection, stroke, and definite stent thrombosis with treatment,” lead author Manuel Almendro-Delia, MD, PhD (Hospital Universitario Virgen Macarena, Seville, Spain), told TCTMD. However, he said, the study is too small to warrant a change in practice at this time: “This is the first time we have demonstrated a response relationship in this setting.”

Dominick Angiolillo, MD, PhD (University of Florida College of Medicine – Jacksonville), who was not involved in the study, told TCTMD the findings support “some potential benefit from pretreatment” in patients who have long waits before reaching the cath lab. “You need to know your own geographic reality,” he added. “If there's going to be a time delay to get to the cath lab, you should be getting the antiplatelet drug on board as soon as possible.” This strategy is valid for patients with NSTEMI as well, Angiolillo said.

But mostly, he continued, the study “does emphasize that certain networks may have some work to do in terms of improving their time to get to the cath lab.”

Fewer MACE With Pretreatment

For the study, published in the June 23, 2024, issue of the Journal of the American College of Cardiology, Almendro-Delia and colleagues included 1,624 STEMI patients (mean age 63 years; 24 % female) undergoing primary PCI between 2015 and 2019 within the CREA-ARIAM registry in Spain (six academic hospitals). In all, 1,033 received pretreatment with a P2Y12 inhibitor and the rest were treated in the cath lab. The median time difference between the two loading strategies was 88 minutes.

The 30-day rate of MACE was 8.8%, with 55% events occurring within the first 72 hours of admission and approximately 40% happening within the first 24 hours. Those who received pretreatment had a lower rate of MACE at 30 days (7.5% vs 11.0%; adjusted HR 0.53; 95% CI 0.37-0.76). This was primarily driven by lower rates of all-cause mortality (adjusted HR 0.66; 95% CI 0.47-0.94), urgent TLR (adjusted HR 0.73; 95% CI 0.61-0.87), and definite stent thrombosis (adjusted HR 0.67; 95% CI 0.47-0.95).

The risk of bleeding did not seem to differ between the treatment strategies (adjusted HR 0.47; 95% CI 0.26-0.86).

Subgroup analyses largely reflected the main findings. However, one analysis showed a treatment-by-time interaction demonstrating no benefit in MACE when the time between the loading dose and PCI was less than 80 minutes but an increase in risk with longer delays (P for trend = 0.009).

Notably, clopidogrel was the most frequently used loading agent, in 75% and 51.8% of the pretreatment and no-pretreatment groups, respectively. Ticagrelor was used in 19.5% and 40.6%, and prasugrel was used in only 5.5% and 7.6% of the groups, respectively.

Personally, Almendro-Delia he “recommend[s] pretreatment in all patients with STEMI, irrespective of the timing in which they are [receiving] the primary PCI.” There is no sign of harm with respect to increased bleeding with this strategy, he added.

‘Rapid Progress’ Ongoing

Nevertheless, Angiolillo warned about the reality of false activations and the potential for harm that pretreatment might inflict on those patients. “In those cases, if this is a patient having another type of medical emergency, such as an aortic dissection, [pretreatment] may increase the risk of bleeding in this patient requiring urgent surgery,” he said.

Angiolillo also pointed out that the frequent use of clopidogrel in this study is not “standard of care in patients with STEMI,” especially given how long it can take to exert its effects. “We'll see how more modern strategies with some of these newer drugs will ultimately play out,” he said, adding that ongoing work with the injectable selatogrel as well as zalunfiban look promising.

If there's going to be a time delay to get to the cath lab, you should be getting the antiplatelet drug on board as soon as possible. Dominick Angiolillo

In an accompanying editorial, Johanne Silvain, MD, PhD, Gilles Montalescot, MD, PhD, and Paul Guedeney, MD, PhD (All Hôpital Pitié-Salpêtrière, Paris, France), write that the small size of the study is its biggest limitation, but acknowledge that its strength lies in the granularity of the data.

It confirms that “upstream platelet inhibition is crucial in STEMI patients, especially when system delays increase ischemic times,” they write. “In this case, observational data provides us with a glimpse of what we should expect from early platelet inhibition in STEMI management beyond the limitations of rapid treatment and shorter ischemic times that may occur in selected randomized trial patients.”

Further, this field is experiencing “rapid progress” with regard to potential new therapies that might change protocol, the editorialists write, also noting the ongoing DAPT-SHOCK-MI trial with cangrelor in shock patients. “We remain hopeful that early, potent pharmacologic reperfusion with antiplatelet agents will not be forgotten by the new generation of cardiologists,” they say. “While we wait for the results of new trials reevaluating upstream antiplatelet therapy in STEMI, physicians should remember that every minute counts for antiplatelet drugs, coronary stents, and the patient.”

  • Data collection for this subanalysis was partially supported by an unrestricted research grant from AstraZeneca Pharmaceuticals.
  • Almendro-Delia reports receiving honoraria for lectures from Eli Lilly Co, Daiichi-Sankyo, and AstraZeneca; and has received consulting fees from AstraZeneca and Daiichi-Sankyo.
  • Silvain reports receiving research grants/consultant fees/lectures fees from AstraZeneca, Bayer HealthCare SAS, Abbott Medical France SAS, Biotronik, Boehringer Ingelheim France, CSL Behring SA, Gilead Science, Sanofi France, Terumo France SAS, and Zoll; and is a stockholder of 4P-Pharma.
  • Montalescot reports receiving research grants/consultant fees/lectures fees from Abbott, Amgen, AstraZeneca, Axis, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Boston Scientific, Cell Prothera, CSL Behring, Idorsia, Leo-Pharma, Lilly, Medtronic, Novartis, Pfizer, Quantum Genomics, Sanofi, and Terumo.
  • Guedeney reports no relevant conflicts of interest.
  • Angiolillo reports having received consulting fees or honoraria from Abbott, Amgen, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Bristol Myers Squibb, Chiesi, CSL Behring, Daiichi Sankyo, Eli Lilly, Haemonetics, Janssen, Merck, Novartis, PhaseBio, PLx Pharma, Pfizer, Sanofi, and Vectura, as well as research grants to his institution from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi Sankyo, Eisai, Eli Lilly, Gilead, Idorsia, Janssen, Matsutani Chemical Industry Co., Merck, Novartis, and the Scott R. MacKenzie Foundation.