Cangrelor became the first intravenous antiplatelet agent acting on ADP receptors for adult patients undergoing percutaneous coronary intervention to receive marketing approval from the Food and Drug Administration, The Medicines Company announced on June 22.
While cangrelor’s unique delivery route and rapid onset and off-set of action set it apart and may give it certain clinical advantages over the three approved oral drugs that target the same platelet receptor – clopidogrel, prasugrel (Effient), and ticagrelor (Brilinta) – cangrelor will also be distinguished by its much higher price. The standard dosage to treat one patient undergoing percutaneous coronary intervention (PCI) with cangrelor (Kengreal) will have a wholesale acquisition cost of $749, Raymond Russo, senior vice president of The Medicines Company, said at a June 23 press briefing. That prices cangrelor substantially above its brand-name competition, which costs roughly $10 for similar treatment, as well as generic clopidogrel, which costs about $3 for the same indication.
“I believe in the strength of the data that showed that cangrelor was superior to the comparator drug [clopidogrel], and if cost were not an issue I’d use cangrelor routinely, but I am not naive; cost is an issue,” said Dr. Deepak L. Bhatt , professor of medicine at Harvard University and executive director of interventional cardiology programs at Brigham and Women’s Hospital in Boston, and co–lead investigator for the CHAMPION PHOENIX pivotal trial that led to cangrelor’s approval ( N. Engl. J. Med. 2013;368:1303-13 ).
Whether or not interventional cardiologists and the centers where they work decide to use cangrelor or one of the oral antiplatelet drugs for coronary artery disease (CAD) patients undergoing PCI will likely depend on a series of considerations that will need to take into account not just drug cost but also practice strategies, a patient’s clinical state, and the potential for ancillary costs from following an entirely different management approach.
The first issue is whether the interventionalist decides to pretreat a patient scheduled for angioplasty and possible immediate PCI following angiography with an ADP-receptor antagonist (also known as a P2Y12-receptor inhibitor) prior to the start of angiography or opts to defer that treatment until the angiography results are available and a decision is made to proceed with PCI. Recent nationwide registry data suggest that roughly half of U.S. interventionalists treat their patients upfront with an ADP-receptor antagonist, usually clopidogrel for patients with stable angina or prasugrel or ticagrelor if they have either a non-ST-elevation MI or a ST-elevation MI, while the other 50% of interventionalists will wait to administer the ADP-receptor antagonist until angiography is complete, Dr. Bhatt explained in an interview.
The advantage to upfront treatment is that by the time the patient is ready for PCI an oral ADP-receptor antagonist is fully absorbed and on board. The disadvantage is that if the coronary anatomy demands a surgical approach to revascularization many surgeons would elect not to operate on a patient freshly dosed with an antiplatelet agent, and these patients often remain hospitalized for several days until the ADP-receptor antagonist clears and the patient’s platelet function returns to normal. Angiography generally identifies 10%-15% of these patients with a CAD distribution that necessitates surgical coronary bypass, and the potential hospitalization expense of waiting for their ADP-receptor antagonist to clear could be a major cost to counterbalance the price of cangrelor, which would obviate this expense if the quick-to-start-and-to-clear cangrelor were used instead of a more lumbering oral drug, he noted.
The other 50% of U.S. interventionalists, Dr. Bhatt included, take a different approach. Recognizing the potential downside of upfront oral antiplatelet therapy if the patient is pegged for bypass surgery following angiography, they elect to wait until the angiography results are in hand. If the angiography results show the patient is destined for surgery or for medical management, then the patient receives no ADP-receptor antagonist. The cardiologist administers an ADP-receptor antagonist only if the patient’s CAD is appropriate for PCI, the fate for most of these CAD patients following angiography. It’s under these circumstances that the advantages of cangrelor kick in, as shown in the results from CHAMPION PHOENIX.
This trial randomized patients to two different types of ADP-receptor antagonist treatment while they were in the coronary catheterization laboratory. The study results showed a statistically significant, 22% relative-risk reduction in the primary endpoint in favor of intravenous cangrelor compared with oral clopidogrel delivered while patients were “on the table” in the interval between angiography and PCI. That 22% relative improvement in outcomes, driven primarily by reductions in periprocedural MIs and stent thrombosis, improved to a 31% relative-risk reduction when The Medicines Company performed a new analysis of the study results at the FDA’s request using a more stringent and conventional definition of periprocedural MIs and stent thrombosis. The time needed to perform this and other FDA-requested analyses largely caused the greater than 2-year gap between the 2013 publication of the CHAMPION PHOENIX results and the FDA’s approval.
But the editorial that accompanied the 2013 publication highlighted what the editorialists perceived as flaws in the study’s design, such as an inadequate loading dose of clopidogrel delivered to a quarter of the patients randomized to that arm, inadequate time allowed for the clopidogrel to fully kick in before PCI began in a third of patients, and the use of clopidogrel as the comparator drug and not a more potent alternative drug, either prasugrel or ticagrelor ( N. Engl. J. Med. 2013;368:1356-7 ).
“Cangrelor was never tested against prasugrel or ticagrelor, and it was compared with inadequate clopidogrel treatment. That was a problem,” reiterated Dr. Richard A. Lange , one of the 2013 editorialists, when interviewed following news of cangrelor’s FDA approval. CHAMPION PHOENIX “wasn’t really a comparison [of two drugs], it was a study of an intravenous strategy, and it’s not a strategy that is needed very often,” said Dr. Lange, an interventional cardiologist and president of the Texas Tech University Health Sciences Center in El Paso. In Dr. Lange’s opinion, the only real need for an intravenous ADP-receptor antagonist is for CAD patients undergoing PCI who are unable to take an oral agent, for example because they are on a ventilator, unable to hold down an oral pill, or unconscious, which collectively are “rare” situations, he said.
Dr. Bhatt noted that another clear indication for an intravenous agent is when MI patients receive morphine for their pain, a situation recently documented to interfere with absorption of oral ADP-receptor antagonists.
From Dr. Bhatt’s perspective, the major issue is practice patterns: “Do the interventionalists treat [with an ADP-receptor antagonist] upstream or not. If they do, then they should do the math,” and determine if the expense of holding a significant minority of patients in the hospital just to allow them to clear the ADP-receptor antagonist prior to coronary bypass surgery outweighs the cost for delaying this treatment and administering cangrelor later only to patients scheduled for PCI. At the center where he practices, Brigham and Women’s Hospital in Boston, he sees a roughly equal mix of interventionalists who prefer to treat patients with clopidogrel upfront, those who treat with ticagrelor upfront, and those who practice as he does and wait until the PCI is a go.
“For my personal practice, cangrelor will fit in quite nicely,” Dr. Bhatt said.
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