No Reperfusion Benefit From Crushed Prasugrel Prior to PCI: COMPARE CRUSH
The findings contrast with observations that early dosing with crushed pills improves platelet inhibition over integral tablets.
(UPDATED) Giving crushed prasugrel tablets in the ambulance to STEMI patients with planned primary PCI does not improve reperfusion rates compared with giving the tablets whole, according to results of the COMPARE CRUSH trial.
Georgios J. Vlachojannis, MD (University Medical Center Utrecht, the Netherlands), said no differences were seen either in TIMI 3 flow in the infarct-related artery before PCI or in rates of complete ST-segment resolution at 1 hour after PCI. Several prior studies, including CRUSH and MOJITO, have provided support for the idea that crushing prasugrel or ticagrelor accelerates pharmacodynamic effects of the P2Y12 inhibitors, resulting in more potent antiplatelet effects. While COMPARE CRUSH did show an enhanced degree of platelet inhibition in the group receiving crushed pills prior to primary PCI, the benefits did not translate to reperfusion effects.
“Whether faster and more-potent antiplatelet therapy can improve coronary reperfusion in contemporary STEMI treatment regimen warrants further investigation,” Vlachojannis said in a press conference prior to TCT Connect 2020, where he presented the trial as part of the meeting’s first late-breaking clinical science session. In a paper simultaneously published online ahead of print in Circulation, he and his colleagues speculate that early oral administration of crushed tablets should perhaps be compared against parenteral antiplatelet agents like cangrelor (Kengreal; Chiesi) or glycoprotein IIb/IIIa receptor inhibitors to assess reperfusion effects.
But panelist Adnan Kastrati, MD (Deutsches Herzzentrum München, Munich, Germany), noted that multiple studies of STEMI pretreatment with either prasugrel or ticagrelor have similarly shown no benefit on clinical outcomes, raising the question of where platelet inhibition falls on the scale of importance.
Vlachojannis said while that opinion is “absolutely valid,” many clinicians do believe there is an important role for early and potent platelet inhibition obtained from pretreatment en route to the hospital.
No Differences in Clinical Endpoints
For the COMPARE CRUSH trial, 727 patients with suspected STEMI and symptom onset within 6 hours were randomly assigned by EMS to 60 mg crushed or whole prasugrel in addition to 500 mg IV aspirin and 5,000 IU IV heparin.
At pre-PCI angiography, TIMI 3 flow in the infarct-related artery (primary endpoint) was 31.0% in the crushed group and 32.7% in the integral group (P = 0.64). Similarly, complete ST-segment resolution at 1 hour after PCI occurred in 59.9% in the crushed group and 57.3% in the integral group (P = 0.55). There also were no differences between the groups in partial (30-70%), minimal (< 30%), or > 50% resolution.
In exploratory analysis, the findings were consistent across multiple subgroups, although there was a trend toward greater benefit on TIMI 3 flow among patients in the crushed group who were older than age 75 (P for interaction = 0.04) as well as those presenting with anterior infarction (P for interaction = 0.03) or prior PCI (P for interaction < 0.01).
Compared with the integral group, platelet reactivity was significantly lower at a median of 45 minutes after administration of prasugrel in the crushed group (P2Y12 reactivity units, 192 vs 227; P < 0.01). As a result, fewer patients in the crushed group had high platelet reactivity prior to the start of PCI (43.3% vs 62.6%; P < 0.01).
Clinical outcomes also were not significantly different between the two treatment groups during index hospitalization or at 30 days. All-cause death at 30 days was 1.8% in the crushed group and 1.4% in the integral group (P = 0.76). Similarly, CV death occurred in 1.5% of the crushed group and 1.4% of the integral group (P = 1.00). The same was true for other hard endpoints, including MI, stent thrombosis, stroke, and the composite of death, MI, and urgent revascularization. There also were no differences in TIMI major or BARC ≥ type 3 bleeding.
To TCTMD, Vlachojannis said a unique aspect of the study was that the pretreatment regimen from randomization to pill crushing took place in the ambulance. As in the CRUSH trial, COMPARE CRUSH utilized a pill-crusher dosing syringe.
“It has little dents in it and you can rotate it, and this is how we crushed the prasugrel tablets,” he said. “But prasugrel is bitter. A lot of patients told us that this was very bitter to swallow the crushed tablets, and they are very hard; it's difficult to chew them.”
In their paper, Vlachojannis and colleagues say the findings “underscore the need for alternative strategies to achieve faster and more potent platelet inhibition in patients undergoing primary PCI,” adding that IV antiplatelet therapies currently represent the best option for bridging the gap in platelet inhibition in STEMI.
“Crushing does work, but it does not work fast enough,” Dominick J. Angiolillo, MD, PhD (University of Florida College of Medicine-Jacksonville), a co-author of both COMPARE CRUSH and CRUSH, told TCTMD. In that regard, he agreed with Vlachojannis that IV therapies, as well as the investigational P2Y12 inhibitor selatogrel, which is given subcutaneously, may be “the only avenues that we have left at this point.”
Given that patients were pretreated within an hour of symptom onset, panelist P. Gabriel Steg, MD (Hôpital Bichat, Paris, France), wondered whether the timing of the intervention may have played a role in masking modest differences.
“Certainly, the time metrics in . . . a study hypothesis like this are very important and . . . the short time intervals have certainly influenced the outcomes,” Vlachojannis agreed, adding that the ATLANTIC trial, which also showed no effect on reperfusion, used a similarly short time to initiation of therapy.
Angilillo added that while the short time delays in both COMPARE CRUSH and ATLANTIC may have played a role in the neutral findings, crushing “definitely accelerates absorption and allows you to achieve more adequate platelet inhibition in a shorter timeframe.” Based on the CRUSH findings, he said he has adopted the use of crushing prasugrel and ticagrelor routinely in STEMI patients undergoing primary PCI.
“There aren't any downsides, and if you can get the drug kicking in quicker, that's better, which is something we believe, although this has not translated to clinical differences for the patient,” Angiolillo said.
Vlachojannis GJ. COMPARE CRUSH: a randomized trial of prehospital crushed vs uncrushed prasugrel in STEMI. Circulation. 2020;Epub ahead of print.
- The trial was sponsored by Maasstad Cardiovascular Research B.V. with unrestricted grants from Shanghai MicroPort Medical and Daiichi Sankyo.
- Vlachojannis reports consulting fees from AstraZeneca; and research grants from Daiichi Sankyo and Shanghai MicroPort.
- Angiolillo reports consulting fee/honoraria/speaker's bureau from Amgen, Arena, Aralez, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, Deerfield, Daiichi-Sankyo, Eli Lilly, Haemonetics, Idorsia, Janssen, Merck, PhaseBio, PLx Pharma, Pfizer, Sanofi, and The Medicines Company; and grant support/research contracts from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead, Idorsia, Janssen, Matsutani Chemical Industry Co., Merck, Novartis, Osprey Medical, and Renal Guard Solutions.