Crushed Prasugrel Pills Beat Whole Tablets for Controlling Platelets During Primary PCI
Crushing prasugrel tablets before primary PCI instead of asking STEMI patients to swallow them leads to faster and more potent antiplatelet effects, according to data from the randomized CRUSH study.
Prior research on P2Y12 inhibitors administered the standard way—as whole tablets—has shown that “it’s very scary how long it takes for antiplatelets to have an effect,” said Cindy Grines, MD (Detroit Medical Center, MI), commenting on CRUSH for TCTMD. Importantly, those studies were done in normal volunteers, she stressed.
“Our patients . . . are older,” she noted. “Once they’re lying supine and treated with sedatives, then of course it slows down the absorption even further.” Maximum absorption may not occur until as long as 12 hours later, she said.
That begs the question of what to do about the gap, especially since many physicians who don’t follow the literature may not even be aware about the “big delay” in action, Grines said.
Faster, Better Inhibition Seen
For the CRUSH trial, published online recently in the Journal of the American College of Cardiology, lead author Fabiana Rollini, MD, along with senior author Dominick J. Angiolillo, MD, PhD, and colleagues (University of Florida College of Medicine-Jacksonville), prospectively randomized 52 STEMI patients undergoing primary PCI to receive their prasugrel (Effient; Eli Lilly) 60-mg loading dose as either whole or crushed tablets.
The level of P2Y12 reaction units (PRUs) was lower in patients who received crushed rather than whole prasugrel tablets by 30 minutes, and the difference was maintained at 2 hours (mean 95 vs 164; P = 0.022), the primary endpoint of the study. Crushed prasugrel resulted in reduced platelet reactivity for up to 4 hours. However, a significant difference was no longer evident by 6 hours. Similar patterns were observed when measured as platelet reactivity index.
High on-treatment platelet reactivity, defined as PRU > 208, was significantly less common in patients given crushed compared with whole tablets. At 2 hours after loading, approximately half of patients given whole tablets had high on-treatment reactivity, nearly double the rate seen with crushed tablets (P = 0.044).
The researchers also reported pharmacokinetic data showing that absorption was more than three times faster with crushed versus whole tablets.
There were no cases of major bleeding or other serious in-hospital adverse events during the trial. One minor bleeding event (hematuria) occurred in the crushed prasugrel arm but did not require drug discontinuation.
‘Something People Are Already Doing’
Angiolillo told TCTMD that after initial pharmacodynamic studies raised concerns, “people have more and more embraced the crushing of their oral P2Y12 inhibitor tablets in practice, something which is very simple to do and that nurses have been used to doing for many years.”
CRUSH helps build the case that “crushing accelerates the pharmacodynamic effect,” and supports the idea that the mechanism is due to faster drug absorption and metabolism, he said. “We cannot infer, necessarily, clinical implications based on pharmacodynamic studies. We would need dedicated clinical trials. What we do know is that having high on-treatment platelet reactivity is a marker of thrombotic risk. And therefore, shy of a clinical study, these data are very informative.”
Both he and Grines predicted a clinical trial would be unlikely, as it would require a very large number of patients to detect a difference in outcomes.
In 2015, the US Food and Drug Administration updated ticagrelor’s labeling to allow crushing. Angiolillo would not speculate as to whether prasugrel’s manufacturers would seek the same. “That’s something that we [as researchers] don’t do. We provide the science,” he said. “But I believe that irrespective of whether this [winds up] on the label, it’s something that people are already doing. And we have data to support that crushing in STEMI is clearly associated with a more prompt and potent antiplatelet effect, which is what you want in [this] clinical setting.”
But Is Crushing Easy to Do?
Crushing is the only option in intubated patients, Angiolillo observed. “However, for patients who can swallow, it has always been a question in the past, ‘Well, why would you need to crush?’”
To answer this, the study was intentionally done in patients who could swallow, Angiolillo noted. The data here are so strong, he said, that the question should instead be: “Why shouldn’t you crush always in all your patients with STEMI? . . . Based on this information, there’s not a reason not to.” Crushing is simple, he said, “and it goes a long way.”
In her own experience, Grines related, crushing is not easy to do. “First of all, it’s hard to crush it. It’s not like we have a mortar and pestle handy in our cath lab, and you try to crush it up with syringes or whatever and put it in a plastic cup. Then the particles stick to the side of the cup,” she said. “So we completely abandoned that.”
Angiolillo said that for CRUSH, the technique involved a pill crusher syringe. “It’s very easy to crush. You can aspirate fluid in it, you shake it, and you put it in a cup,” he explained. “And then yes, there is some residual, which you rinse with further water and put it [back in the cup]. And patients drink it. So it really isn’t that difficult at all.”
Grines suggested another solution: chewing.
“What we’re doing is we’re having the patients chew their antiplatelets,” she said, whether the drug is clopidogrel, ticagrelor, or prasugrel. Though patients say the taste is slightly bitter, they only mention it when asked later. “Now if the patient was intubated and they were on a ventilator and they had to have a [nasogastric (NG)] tube placed, that’s a different story,” Grines noted. “Then I’d crush and put it in an NG.” But under ordinary circumstances, she would choose chewing over crushing.
In editorial accompanying the paper, Gennaro Sardella, MD (Sapienza University of Rome, Italy), and colleagues describe CRUSH’s exclusion of patients requiring an NG tube as a “methodological problem,” one shared by the earlier MOJITO trial of crushed ticagrelor. “In daily practice, this subset of patients could have a greater benefit from the crushed drug, but as [Rollini et al state], we do not yet know what may interfere with a correct [pharmacokinetic/pharmacodynamic assessment],” they write.
Yet they too come down in support of crushing, noting that the rate of stent thrombosis within 24 hours is 2.1% even with the newer antiplatelet agents ticagrelor and prasugrel. “[H]ence, every adjunctive strategy or technique must be used to move faster and safer in STEMI patients with no fear to crush,” the editorialists conclude.
Rollini F, Franchi F, Hu J, et al. Crushed prasugrel tablets in patients with STEMI undergoing primary percutaneous coronary intervention: the CRUSH study. J Am Coll Cardiol. 2016;Epub ahead of print.
Sardella G, Calcagno S, Mancone M. Different prasugrel administration in STEMI patients: go faster and no fear to crush! J Am Coll Cardiol. 2016;Epub ahead of print.
- The study was funded by an investigator-initiated grant from Daiichi Sankyo and Eli Lilly.
- Angiolillo reports receiving consulting fees or honoraria from Sanofi, Eli Lilly, Daiichi Sankyo, The Medicines Company, AstraZeneca, Merck, Abbott Vascular, and PLx Pharma; participating in review activities for CeloNova, Johnson & Johnson, and St. Jude Medical; and receiving institutional payments for grants from GlaxoSmithKline, Eli Lilly, Daiichi Sankyo, The Medicines Company, AstraZeneca, Janssen Pharmaceuticals, Osprey Medical, Novartis, CSL Behring, and Gilead.
- Rollini, Grines, and Sardella report no relevant conflicts of interest.