High Prasugrel Loading Dose Limits Platelet Reactivity after Primary PCI for STEMI

A high loading dose of prasugrel achieves better platelet inhibition than the standard dose in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). The findings, from a nonrandomized pharmacodynamic study, were published online March 25, 2014, ahead of print in Circulation: Cardiovascular Interventions.

Researchers led by Dimitrios Alexopoulos, MD, of Patras University Hospital (Patras, Greece), enrolled 82 STEMI patients receiving primary PCI within 12 hours of symptom onset at 3 centers. The patients, all P2Y12 inhibitor-naive, were given either a high prasugrel loading dose of 100 mg (n = 47) or a standard dose of 60 mg (n = 35). Platelet reactivity was assessed using the VerifyNow point-of-care assay (Accumetrics, San Diego, CA).

More Effective with No Impact on Safety

At 2 hours, high-dose prasugrel decreased platelet reactivity as expressed in P2Y12 reaction units (PRUs; primary endpoint) and increased platelet reactivity percentage inhibition. Compared with the standard dose, the 100-mg dose also resulted in a smaller proportion of patients with high on-treatment reactivity, whether the cutoff was 230 or 208 PRUs. In addition, the rate of patients with 20% or lower platelet inhibition was reduced by the higher dose (table 1).

Table 1. Effect of Prasugrel Dose at 2 Hours

 
At 4 hours, the 100-mg dose continued to lower platelet reactivity compared with the 60-mg dose at 29.6 vs 60.8 PRUs (P = 0.02).

In-hospital bleeding rates were numerically higher for patients given the higher loading dose, though the differences were not significant (table 2). However, no MACE occurred in-hospital or within 30 days in either group.

Table 2. Bleeding Academic Research Consortium Events

According to the researchers, the study tested the highest prasugrel dose ever given to humans.

“It is unknown whether a higher than 100-mg [loading dose] might achieve an earlier platelet inhibition or at which point a saturation effect might occur,” they write. “Even more importantly, the safety of the 100-mg [loading dose] or a higher dose is questionable. In the relatively small cohort of our STEMI population, with the known prothrombotic diathesis and the documented delayed onset of antiplatelet action exhibited by the standard prasugrel [loading dose], the high [loading dose] was well tolerated without any obvious excess of clinically significant bleeding.”

Pharmacodynamic Data May Not Extend to Practice

In an email, John Petersen, MD, MHS, of Swedish Medical Center (Seattle, WA), told TCTMD that it is common to give prasugrel after angiography but before PCI during STEMI. “The best data,” he said, “come from TRITON-TIMI 38, in which the drug was given after angiography but no later than 1 hour after completing PCI.”

Dr. Alexopoulos reported that his center administers a 60-mg loading dose of prasugrel to almost half of its patients with a door-to-angiography time typically within 10 minutes. Patients who have a history of stroke/TIA, age greater than 75 years, body weight of less than 60 kg, or high risk of bleeding are excluded. The other half of patients are given ticagrelor, he said.

Dr. Petersen stressed that the differences in platelet reactivity observed in the current study, however, may not be clinically relevant. “The field of point-of-care platelet testing has taken a major hit after GRAVITAS and ARCTIC, so it’s not clear that adjusting dosing of antiplatelet meds based on markers of inhibition means anything clinically,” he said.

The pharmacodynamic findings, specifically “earlier and more constant platelet inhibition 2 hours post-loading as assessed by VerifyNow,” may not translate into clinical differences, Dr. Alexopoulos agreed. “However, a high loading dose represents a way to overcome—at least partially—the well-described delay in the onset of antiplatelet action seen in STEMI patients even when loaded with novel oral P2Y12 inhibitors,” he said, adding that the delay after a clopidogrel loading dose of 600 mg is “more pronounced and variable, with up to 50% of patients retaining high platelet reactivity even 24 hours later.

“Of note, although in theory pathophysiologically correct, a direct link between earlier and stronger platelet inhibition by oral P2Y12 inhibitors in STEMI and surrogate endpoints (ie, troponin rise and infarct size) is missing,” he continued, adding that a direct link to clinical endpoints is even more elusive.

Few Downsides to Prasugrel

Like the researchers, Dr. Petersen also was unconcerned that the dose would carry a higher risk of bleeding in the ‘conventional US population,’ so long as clinicians follow the US Food and Drug Administration’s ‘black box’ warning to tailor prasugrel dose according to age, weight, and stroke history.

If there was an increase in bleeding, though, it would indeed be an issue, he commented, adding, “[It is also] unclear [the 100-mg dose] would translate into a more prolonged washout effect in the event bypass surgery is needed.”

Dr. Alexopoulos pointed out that “a high thrombotic state exists” in acute STEMI. “In our small series we did not encounter any worrisome signs of more bleeding by giving 40 mg prasugrel [above] the standard loading doses,” he commented. “Needless to say, more work is definitely required with careful assessment of the bleeding potential of the proposed higher dose.”

At the moment, the only downside to high-dose prasugrel appears to be a “slightly higher chance of vomiting,” due to patients having to swallow 10 tablets of the drug rather than the usual 6, Dr. Alexopoulos noted.

 

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Source:
Alexopoulos D, Makris G, Xanthopoulou I, et al. Onset of antiplatelet action with high (100 mg) versus standard (60 mg) loading dose of prasugrel in patients with ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention: pharmacodynamic study. Circ Cardiovasc Interv. 2014;Epub ahead of print.

 

 

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