Cangrelor's success rose from prior failure


Designing a trial to establish the efficacy and safety of a drug may seem like science, but there is a lot of art as well. And sometimes achieving a positive trial result also requires confidence in and commitment to a concept, and the persistence to try a second time when it doesn’t work at first.

All of that happened in the unusual path that the intravenous antiplatelet drug cangrelor has navigated since researchers first devised trials in 2005 to test its efficacy in acute coronary syndrome patients who undergo coronary stenting. Arguably the most clinically important finding reported at the American College of Cardiology annual meeting earlier this month was from the CHAMPION PHOENIX trial, which showed safety and added efficacy from treatment with cangrelor, compared with clopidogrel, in this setting.

Courtesy Wikimedia Commons/Public Domain

While the CHAMPION PHOENIX trial was a clear success, it was impossible to forget the failure from which it rose.

But while CHAMPION PHOENIX was a clear success, it was impossible to forget the failure from which it rose, a background that had everything to do with the trial’s myth-based name.

In 2009, results from a pair of cangrelor phase III trials, CHAMPION PCI and CHAMPION PLATFORM showed no added benefit from cangrelor in studies roughly similar in design to the PHOENIX study. The biggest difference between the success of PHOENIX and the failure of the earlier PCI and PLATFORM studies was that the researchers used a different approach to define and track the myocardial infarctions that patients developed during the studies and that served as primary end points.

Close analysis of the 2009 results from PCI and PLATFORM showed that, because many patients with acute coronary syndrome underwent coronary artery stenting so soon after becoming hospitalized, it was hard to discern new MI compared with prior events, said Dr. Robert Harrington, a Stanford (Calif.) University cardiologist and a coleader of all three studies. He, Dr. Deepak Bhatt (the other coleader), and their associates tweaked their original design three ways to address this problem, Dr. Harrington told me.

They obtained baseline measurements on the level of creatinine kinase MB in all patients, they took more frequent measures of CKMB from patients following baseline to track the development of new MIs, and they required, in addition to a further elevation in CKMB, some other indication of a new myocardial infarction: ischemic symptoms, ECG changes, or angiographic evidence. Along with their revised approach to detecting new-onset MIs, they also used a more refined definition of stent thrombosis within the first 48 hours of the study and set up the study presuming that the comparator drug, clopidogrel, would be more effective than they had anticipated the first time around.

These changes made the PHOENIX trial positive where the first two had failed.

Why did they do all this and keep at it so doggedly? Because they saw clear signals of efficacy in the two negative trials, and because they believed strongly in what a boon to cardiology practice would come from having a new drug available that interventionalists could quickly start in patients undergoing coronary catheterization and stenting but also quickly stop and clear from patients who were headed to coronary surgery following their diagnostic catheterization. That’s possible because the clinical effects from cangrelor persist for about an hour after an infusion stops, as opposed to days following a dose of an oral antiplatelet drug like clopidogrel, prasugrel, or ticagrelor.

"This drug will give us the flexibility to use a short-acting, intravenous agent," Dr. Bhatt said at the meeting. "We now give clopidogrel in the emergency department [to acute coronary syndrome patients] prior to knowing a patient’s coronary anatomy. If the patient has anatomy that needs urgent surgery, the patient has to wait a few days until the medicine clears out. By using cangrelor instead that uncomfortable situation disappears."

"The investigators thought that something was there [in CHAMPION PCI and PLATFORM], something useful for patients," added Dr. Bhatt of the Veterans Administration Boston Healthcare System.

Many interventionalists at the meeting agreed that cangrelor will bring an important new dimension of thrombotic protection and treatment flexibility to acute coronary syndrome patients undergoing coronary angiography.

"This is a blockbuster randomized controlled trial that will alter practice on numerous levels," said Dr. Gregg Stone, an interventional cardiologist at Columbia University in New York.

And it is "incredibly important for the treatment of patients undergoing catheterization who may need to have surgery," said Dr. Roxana Mehran, an interventionalist at Mount Sinai Hospital in New York.


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