With No RCTs, Propensity-Score Matched Analysis Informs Choice Between Cangrelor and GPIs in the Cath Lab

New research combining patient outcomes from the CHAMPION trials shows similar ischemic risk and less risk-adjusted bleeding with cangrelor compared with clopidogrel plus glycoprotein IIb/IIIa inhibitors (GPIs) in patients undergoing PCI. While the researchers are confident these findings cement the safety and efficacy of cangrelor in the cath lab, others question the trustworthiness of the safety analysis and say GPIs still have a place in practice.

Cangrelor (Kengreal, Chiesi) is the potent P2Y12 antagonist that was approved by the US Food and Drug Administration last summer for the reduction of periprocedural thrombotic events in patients who have not been preloaded with an oral P2Y12 inhibitor and will not receive a GPI. The drug’s distinguishing characteristic is its rapid onset and offset—clearing the system within an hour. GPIs, on the other hand, have been successfully and cost-effectively used in the cath lab for as long as many of today’s interventionalists have been in practice.

According to senior study author Deepak Bhatt, MD, MPH (Brigham and Women’s Hospital, Boston, MA), the current analysis answers a question that has persisted since cangrelor’s approval: should cath lab physicians reach for GPIs or cangrelor? “The key differentiating feature though is that cangrelor has a very, very short biological half-life, whereas the IIb/IIIa inhibitors have longer biological half-lives. For that reason the efficacy is very similar for the duration of the procedure but then the bleeding risk appears to be much lower,” he said. “That's what the pharmacodynamics and pharmacokinetics would predict, but that's what our study actually found.”

Published online last week ahead of print in JAMA Cardiology, the results of this propensity-score matched analysis of 1,021 pairs of patients treated with either strategy in CHAMPION PCI, CHAMPION PLATFORM, or CHAMPION PHOENIX demonstrated similar efficacy outcomes with cangrelor alone compared with clopidogrel plus GPIs. Patients treated with cangrelor alone experienced lower rates of TIMI-defined major or minor bleeding, ACUITY-defined major bleeding, and “any blood transfusion”—all safety endpoints used in the CHAMPION PCI or CHAMPION PLATFORM trials. However, rates of GUSTO-defined moderate/severe bleeding as well as severe/life-threatening bleeding—the primary safety endpoint used in CHAMPION PHOENIX—were numerically but not statistically lower in these patients compared with those treated with clopidogrel and GPIs.

Propensity-Matched Efficacy and Safety Outcomes at 48 Hours

^aAll-cause mortality, MI, ischemia-driven revascularization, or stent thrombosis.

“The analysis shows that cangrelor is a very user-friendly and patient-friendly drug,” Bhatt said. “It's extremely potent when the interventionalist needs it in the cath lab during the procedure, but then once it’s shut off the effect goes away rapidly and the oral ADP receptor antagonist can kick in. In a patient where there’s a desire to reduce ischemic risk because they are believed to be at high ischemic risk, this seems like a good solution, with the benefits that IIb/IIIa inhibitors used to bring in an older era when we used to use them very commonly but without the same bleeding price.”

While praising the researchers for conducting an analysis in a field with no randomized trial data, Sunil Rao, MD (Duke University Medical Center, Durham, NC), who was not involved in the study, told TCTMD that GPIs likely still have a role to play. “The reality is they serve a very, very useful purpose. People have a tremendous amount of comfort with them. The prices are decreasing,” he said. “But the crux of the question, which this article goes partway toward addressing, is: at what point do you decide to choose cangrelor versus IIb/IIIa? I don't think we have a solid answer for that question yet. This article is important because it at least tells us that if you’re someone who prefers to use cangrelor, there certainly doesn't seem to be any penalty.”

The crux of the question, which this article goes partway toward addressing, is: at what point do you decide to choose cangrelor versus IIb/IIIa? I don't think we have a solid answer for that question yet. Sunil Rao

Rao took some issue with the bleeding results in this analysis, notably the fact that while TIMI and ACUITY bleeding were significantly in favor of cangrelor, GUSTO bleeding was not. “In a way, what they have done was selected two different bleeding endpoints that were statistically significantly different to make the conclusion that cangrelor is safer. And while it may be, I'm not sure that the paper as it stands really shows that,” he said.

The difference in choosing one strategy over another then comes down to other issues, Rao continued. “What do you already have on formulary? Are you going to get more pushback from your [Pharmacy and Therapeutics] Committee to add yet another parenteral antiplatelet agent? And then fundamentally cost. When you don’t have significant differences between the two strategies, the thing that's going to drive [the decision] are convenience and cost, and those obviously just weren't collected in these studies,” he said.

Rao noted that his institution does have cangrelor on formulary, but general practice is to preload patients with oral P2Y12 inhibitors, with the exception of intubated STEMI patients who cannot swallow, where “cangrelor is very useful.”

Bhatt argued that “cangrelor is beneficial in even those situations where doctors perhaps aren't using IIb/IIIa inhibitors. At least my sense is that in the US, IIb/IIIa inhibitor use has really fallen off, so I don't know that I would necessarily restrict cangrelor use to just those few situations where IIb/IIIa inhibitors are commonly used. But certainly for hospitals and doctors that are using lots of IIb/IIIa inhibitors in the context of PCI now, it seems like cangrelor would be a sensible type of substitution.”

Lots of Choices

One limitation of the study, the authors acknowledge, was the exclusion of patients at high bleeding risk, although this is the case for a majority of studies in general. Bhatt guessed “that if we had included patients who are at higher bleeding risk than the ones in this analysis, that separation in terms of bleeding risk between IIb/IIIa inhibitors and cangrelor would be even greater.” While it is unlikely that a clinician would use either agent in a patient at very high bleeding risk, he continued, if necessary he would choose cangrelor due to its shorter half-life.

Another factor that might affect the relative performance of cangrelor versus GPIs is radial access, Rao suggested. “Our institution is a radial first institution. We don't really worry too much about access-site bleeding because radial access will basically eliminate that,” he explained. “It would have been interesting to see if radial access mitigated even more the differences between the two [antiplatelet agents].

“As the radial approach increases in the US,” Rao predicted, “I think people are going to feel potentially more comfortable with these more potent antithrombotic therapies.”

The study ultimately shows that “interventionalists’ hands aren’t tied,” with regard to their PCI preferences and what antiplatelet agent they would like to use, Bhatt said. This is not only in regard to a radial versus femoral approach, but also the decision between bivalirudin and unfractionated heparin—a still-contentious debate in the cardiology field. “Cangrelor works well in all those situations, so it's not necessary to use heparin, it's not necessary to use bivalirudin. It's whatever the interventionalist prefers,” he explained.

Interventionalists’ hands aren’t tied. . . . It's whatever the interventionalist prefers. Deepak Bhatt

Both Bhatt and Rao said a randomized trial comparing GPIs and cangrelor alone would be unlikely. “IIb/IIIa inhibitors are sort of in their senescence now, and . . . cangrelor has already done three large randomized trials,” Rao noted. “So I don’t see a lot of appetite for another randomized study, although I think for clinicians, it's incredibly important to know.”

For now, “you’ve got a lot of choices,” Rao said, and “that’s a good thing.”

Note: Study co-author Gregg Stone, MD (Columbia University Medical Center, New York), is a faculty member of the Cardiovascular Research Foundation, the publisher of TCTMD.