November 15th, 2009
Cangrelor Not Beneficial in ACS Patients Receiving Clopidogrel and PCI
Richard A. Lange, MD, MBA
In ACS patients undergoing PCI, giving cangrelor with clopidogrel did not reduce cardiac ischemic events (a composite end-point of death, MI, and ischemia-driven revascularization) compared with clopidogrel alone.
Since they both have the same antiplatelet mechanism of action (P2Y12 inhibitor), what’s the rationale for using cangrelor with clopidogrel?
Clopidogrel has two major limitations: its platelet inhibition has a delayed onset of action (hours after it is administered) and is irreversible, which is problematic if CABG is imminent. Conversely, cangrelor has a rapid onset of action (within minutes of its intravenous administration) and is short lasting; its antiplatelet effects resolve within an hour of its discontinuation.
So, although it seems rational to use a rapidly effective, short-acting antiplatelet agent in combination with clopidogrel, it wasn’t beneficial in CHAMPION: 2 large, randomized studies (see here and here).
In our Discussion Forum, the investigators and the author of an invited editorial provide their perspectives on the studies.
We invite you to join the discussion below.
10 Responses to “Cangrelor Not Beneficial in ACS Patients Receiving Clopidogrel and PCI”
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Not A Champion, Yet?
Just attended the late breaking session here at AHA where CHAMPION-PCI and CHAMPION-PLATFORM were presented. The primary endpoint was not significantly different with the use of cangrelor in addition to clopidogrel in either trial. Dr. David Faxon, who discussed the trials, highlighted the difficulty of accurately adjudicating peri-procedural myocardial infarctions in the two trials which may have obscured a significant finding in favor of the new intravenous, reversible platelet inhibitor. I think that he raised some interested points which were, of course, also discussed during the course of the formal presentations by Drs. Robert Harrington and Deepak Bhatt. Of note, several members of the panel seemed to conclude that there may still be a role of cangrelor and commented that this compound deserves further investigation.
Thoughts on CHAMPION
While the top line results of CHAMPION PCI were certainly disappointing to me and the investigators involved in the trial, additional analyses raise the possibility that the drug may have some value that warrants further testing in settings where rapid, predictable and reversible ADP blockade may be desired. A large platelet substudy (large by standards of these mechanistic substudies) demonstrates a biological effect of cangrelor. But lots of questions remain in the review of the clinical data, including for example how best to define MI in this peri-PCI setting and how long to provide a drug like this. We’ll be doing additional analyses and thinking a lot about where to go from here. Would be interested in people’s thoughts and comments.
Competing Interests: Research funding for CHAMPION PCI to DCRI
Bob: In CHAMPION-PLATFORM, patients received cangrelor or placebo during PCI and all patients received clopidogrel (600 mg) following the procedure. At 48 hrs, stent thrombosis and mortality was lower in the cangrelor-treated patients, compared to the placebo-treated patients. In the CHAMPION PCI study, patients received cangrelor or clopidogrel prior to PCI, and all were treated with clopidogrel (600 mg) following the procedure. At 48 hrs, stent thrombosis and mortality were similar in the cangrelor and clopidogrel treated patients. Does this suggest to you that timing (i.e., loading with an ADP receptor blocker prior to PCI) is more important than the specific agent?
Cangrelor is doing all what is expected from it to do in patients with acute coronary syndromes (ACS) undergoing an invasive strategy: it has a potent, fast and reversible antiplatelet effect. Yet, is was not superior to a 600 mg loading dose of clopidogrel in the 2 CHAMPION trials. The first thing that comes to mind is that the results might have been different under different study conditions: different starting time of cangrelor and control drug (we should pay more attention to upstream treatment of ACS patients), longer cangrelor infusion and different mode of transition to oral antiplatelet agents. The discussion on definition of periprocedural myocardial infarction (MI) is important, but does not help much the interpretation of CHAMPION trials results. Effectiveness of other antiplatelet agents has been proven and led to their approval based on periprocedural MIs diagnosed on the basis of similarly problematic definitions. As interventional cardiologists, we know that not all periprocedural MIs are events that can be prevented by antiplatelet therapy. It is the same as for death, integral part of primary endpoints of antiplatelet therapy trials. I do not believe that considering only Q-wave MIs will solve the challenging issue of definition of postprocedural MI. A Q-wave MI might also be a late expression of what began as a non-ST-Elevation ACS.
Competing Interests: Have been declared in the Edtorial on CHAMPION trials
The “Perfect” Cangrelor Study
Rob and Adnan:
Contrary to the prevailing hypotheses/opinions, cangrelor was not better than clopidogrel in PCI-treated ACS patients. The study design and definition of post-procedure MI in the CHAMPION studies have been called into question. In Deepak Bhatt’s study, the investigators state, “Further study of potent intravenous ADP blockade with cangrelor may be warranted.”
My question to y’all is this. In order to definitively prove — or disprove — that cangrelor is better than clopidogrel, what should the study look like and what endpoints should be assessed?
What studies to consider?
We have a number of challenges in cosniedring what to do next (if anything) with cangrelor. The drug seems to be biologically active according to the platelet substudy compared with clopidogrel. There are signals in the data but, as many have pointed out, nothing definitive. 600 mg of clopidogrel is certainly a formidable comparator. As Rick points out, maybe this is one of the trial’s key lessons: treat early and intensely prior to PCI with ADP blockade. How do we prove that there is clinical benefit to a very rapidly acting and reversible ADP blocker? Did we study the wrong setting? Would a bridging study be better for this (one is underway)? Should we push for an STE MI study and try to further improve on the early effects of prasugrel and ticagrelor? Do these need to be the comparators in such a study? What about in stable patients (normal biomarkers) undergoing ad hoc PCI? Would this be a good setting for a trial? There are no easily definable pathways here for the next steps. Thoughts and comments appreciated.
Ideas about future studies with cangrelor
I fully agree with Bob Harrington about his great ideas on potential studies on cangrelor in the future. I would like to highlight 2 areas that seem more interesting to me. First, it is very common to pretreat patients with STEMI with 600 mg of clopidogrel. However, pretreatment interval (time to PCI) is short in these patients. It would be interesting to evaluate whether upstream cangrelor, with the speed and intensity of platelet inhibition that it achieves, is a superior strategy. Second, for patients with stable or unstable angina planned for diagnostic angiography, it is interesting to see whether cangrelor given after the indication for PCI is established obviates the need to pretreat with 600 mg of clopidogrel before angiography a number of patients much larger than that eventually requiring PCI.
Competing Interests: See above
More on Study Designs
Adnan- Thanks for the comments. In a STE MI trial, what should be the endpoints? Death? Stent thrombsis? Infarct size by some imaging modality? What would provide compelling evidence that rapid ADP blockade is better than treatment with oral therapy?
Competing Interests: PI of CHAMPION trials with research funding from sponsor
Cangrelor in STEMI
Bob, I am for a clinical primary endpoint: death, stent thrombosis (definite or probable), stroke. A substudy may also include infarct size measurements.
More on Trials
The challenge is with the sample size. The absolute risk of the “hard” endpoints at 48 hrs in CHAMPION is quite low. Composites of death/QMI/Stent thrombosis for example yield sample sizes in the 20,000 range. This is obviously not practical for a therapy like this, although I like the definitivess of these endpoints. We need to keep brainstorming about designs and would appreciate Adnan’s (and others) thoughts here.
Competing Interests: As stated above