Crushed prasugrel offers no reperfusion benefit prior to PCI

Giving crushed prasugrel to patients with ST-segment elevation myocardial infarction (STEMI) en route to the hospital for planned PCI* does not improve reperfusion rates compared with giving the tablets whole in the COMPARE CRUSH trial.

The finding was a stark contrast to observations that early dosing with crushed pills improved platelet inhibition over integral tablet ingestion. [J Am Coll Cardiol 2016; 3;67:1994-2004; https://clinicaltrials.gov/ct2/show/NCT01992523]

While COMPARE CRUSH did show an enhanced degree of platelet inhibition in the group receiving crushed prasugrel, the benefits did not translate to reperfusion effects.

At pre-PCI angiography, patients treated with crushed prasugrel or whole prasugrel had similar rates of the coprimary endpoints of  TIMI 3** flow in the infarct-related artery (31 percent vs 32.7 percent; p=0.64) and complete ST-segment resolution at 1 hour post-PCI (59.9 percent vs 57.3 percent; p=0.55). There were also no differences between groups in partial (30–70 percent), minimal (<30 percent), or >50 percent resolution. [Circulation 2020;doi:10.1161/CIRCULATIONAHA.120.051532]

“These findings hold in spite of the fact that crushed tablets of prasugrel led to more potent platelet inhibition vs integral tablets,” said study author Dr Georgios Vlachojannis from the University Medical Center Utrecht, the Netherlands during his presentation at TCT 2020. “Whether faster and more potent antiplatelet therapy can improve coronary reperfusion in contemporary STEMI treatment regimen warrants further investigation.”

To crush or not: It doesn’t matter

The study enrolled 727 patients (mean age 62 years, 23 percent female) with suspected STEMI and symptom onset within 6 hours. They were randomized to a 60 mg loading dose of crushed  prasugrel or whole prasugrel  in addition to 500 mg of intravenous aspirin and 5,000 units of intravenous heparin in the ambulance.

In terms of the primary safety endpoint of TIMI major and BARC type 3 or higher bleeding within 48 hours post treatment, there was no difference observed between the crushed and integral groups (0.4 percent vs 0.7 percent).

Death, MI, stroke, and urgent revascularization rates were also comparable between groups during index hospitalization and at 30 days. Definite stent thrombosis occurred in one patient in the crushed group and two patients in the integral group.

In exploratory analysis, the coprimary endpoint results were consistent across multiple subgroups, although there was a trend toward greater benefit on TIMI 3 flow in the crushed tablet group in patients older than 75 years (p_{for interaction}=0 .04), and those presenting with anterior infarction (p_{for interaction} = 0.03), or with a history of prior PCI (p_{for interaction} <0.01).

“Nevertheless, these results should be regarded as hypothesis-generating,” the authors said. “Opioid use in the ambulance was remarkably low in our study vs that in the ATLANTIC trial, which might explain why we did not observe any significant interaction.”

“What we know with COMPARE CRUSH, and this is important, is that we tried to give the medication as soon as possible and tried to give this in a formulation which has the most favourable pharmacodynamics profile, and we still see it’s not doing the job,” Vlachojannis said.

On questions whether treatment time may have played a role in teasing out the relatively modest differences that platelet reactivity may have on clinical outcomes, Vlachojannis said the short time intervals to medical contact have certainly influenced the outcomes.