Crushing It: Cangrelor and Ticagrelor Can Be Used Together Safely in STEMI, Small Study Hints
A 50-patient pharmacodynamic study seems to rule out an IV-oral drug interaction.
A strategy of combining IV cangrelor (Kengreal; Chiesi) and crushed ticagrelor in STEMI patients undergoing primary PCI—to cover the delay in absorption of the oral drug—enhances platelet inhibition without creating a drug-drug interaction, results of a randomized, pharmacodynamic study show.
Compared with patients who received crushed ticagrelor alone, those who also received cangrelor had lower platelet reactivity as early as 5 minutes after the initial bolus, a difference that was sustained for the entire 2-hour duration of the infusion, lead author Francesco Franchi, MD (University of Florida College of Medicine – Jacksonville), and colleagues reported online January 11, 2019, ahead of print in Circulation.
“This study clearly demonstrates a few things. First, it confirms the very fast-acting as well as sustained antiplatelet effects of cangrelor,” senior author Dominick Angiolillo, MD, PhD (University of Florida College of Medicine – Jacksonville), told TCTMD. “Second, it confirms that [with] the oral therapies, even when crushed, although you’re able to accelerate absorption, you still cannot compete with the speed of onset of an intravenous agent.”
And finally, he said, the study “was able to rule out any drug-drug interactions, which provides a lot of reassurance to the clinicians.”
Ultimately, these findings might make physicians “feel more comfortable with using two very important drugs for the treatment of patients with acute presentations such as STEMI,” Angiolillo said.
High On-Treatment Platelet Reactivity Lower With Cangrelor
Though the newer oral P2Y12 inhibitors ticagrelor and prasugrel represent the current standard of care for STEMI patients undergoing primary PCI, Angiolillo said, these were not tested in the CHAMPION PHOENIX trial, which pitted cangrelor against clopidogrel and led to cangrelor’s approval by the US Food and Drug Administration. Thus, he said, there has been a paucity of data regarding the performance of cangrelor in patients treated with ticagrelor or prasugrel.
Chances of having another large-scale trial powered for clinical outcomes to compare cangrelor with the newer agents are “extremely slim,” Angiolillo said, and even though this pharmacodynamic study cannot replace such an effort, it “is perhaps the best data that we have looking at cangrelor together with ticagrelor in patients with STEMI.”
For the study, called CANTIC, the investigators enrolled 50 patients who were undergoing primary PCI for STEMI at their center. All patients received a 180-mg loading dose of crushed ticagrelor at the same time an infusion of either cangrelor (30 µg bolus followed by 4 µg/kg/min infusion) or placebo was started.
Antiplatelet effects were measured in two ways—as P2Y12 reaction units (PRU) with the VerifyNow assay (Accriva) and as platelet reactivity index (PRI) with vasodilator-stimulated phosphoprotein (VASP; Biocytex).
Platelet reactivity did not differ between the two arms at baseline. PRU was reduced in the cangrelor arm shortly after the start of the infusion and remained so for the duration of the infusion. At 30 minutes, the primary endpoint, PRU was 63 in the cangrelor arm and 214 in the placebo arm (P < 0.001). Platelet reactivity at 1 and 2 hours after the end of the infusion did not differ between groups. Findings were similar using PRI assessments.
Rates of high on-treatment platelet reactivity (HPR; defined as PRU > 208 or PRI > 50%), a surrogate for thrombotic complications, were lower in the cangrelor arm during the infusion. In fact, no patients receiving cangrelor had HPR, compared with half of patients in the placebo arm at the end of PCI and one-third at the end of the infusion. After the infusions ended, HPR rates were low and similar in the two groups.
“The latter observations are in line with the lack of a drug-drug interaction between cangrelor and ticagrelor,” the authors say.
Do You Really Need Both?
The authors note that in the United States, ticagrelor is allowed by the FDA to be given at any point during cangrelor infusion, whereas European regulators recommend administering the oral drug at the end of the infusion or up to 30 minutes before the end of the infusion.
Angiolillo said he routinely gives crushed ticagrelor at the beginning of the cangrelor infusion. “Using a crushed formulation of the oral drug for when you stop the cangrelor infusion allows the oral drug to be available once you interrupt the cangrelor infusion,” he said. “I think you get the best of both worlds.”
But Gennaro Sardella, MD (“Sapienza” University of Rome, Italy), questioned whether there is a need to use both drugs concomitantly, pointing to the very low rate of acute stent thrombosis with modern stents. It might make sense to use both drugs in certain subsets of patients, such as those with a particularly high risk for thrombotic complications, those treated with morphine, and those with cardiogenic shock, he told TCTMD, “but in the overall [STEMI] population I think that it’s a little bit of an overtreatment of the patients.”
If physicians went with ticagrelor alone, there would be some delay until the full antiplatelet effects were seen, even with a crushed formulation, but considering the low rate of thrombotic complications, that delay might not have a “very high clinical impact,” Sardella said.
Sardella said his preferred approach in areas where cangrelor is readily available (it’s not at his hospital) would be to use cangrelor for primary PCI followed by ticagrelor in the chronic phase, acknowledging however that the higher cost of cangrelor might limit its use to high-risk groups of patients.
Also, he said, there remains a need for an adequately powered clinical trial to compare cangrelor and ticagrelor to help define the best strategy.
Nevertheless, this pharmacodynamic study provides important information by showing that there is no drug-drug interaction between cangrelor and ticagrelor, Sardella said. “We know that if we need . . . to reinforce the action of ticagrelor or avoid the delay of ticagrelor action, we can use cangrelor without any safety problem.”
Franchi F, Rollini F, Rivas A, et al. Platelet inhibition with cangrelor and crushed ticagrelor in patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention: results of the CANTIC study. Circulation. 2019;Epub ahead of print.
- The study was funded by an investigator-initiated grant from Chiesi.
- Franchi reports receiving consulting fees or honoraria from AstraZeneca and Sanofi.
- Angiolillo reports receiving consulting fees or honoraria from Amgen, Aralez, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, Daiichi Sankyo, Eli Lilly, Haemonetics, Janssen, Merck, PLx Pharma, Pfizer, Sanofi, and The Medicines Company; participating in review activities from CeloNova and St. Jude Medical; and receiving institutional payments for grants from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi Sankyo, Eisai, Eli Lilly, Gilead, Janssen, Matsutani Chemical Industry Co, Merck, Novartis, Osprey Medical, and Renal Guard Solutions.