Fentanyl, Ubiquitous in US Cath Labs, Blunts Antiplatelet Drugs in PCI

BARCELONA, Spain—Fentanyl has made headlines for its role in the opiate epidemic sweeping North America, but a new study is casting a spotlight on its use during acute MI care and warning that the powerful analgesic may also interfere with antiplatelet inhibition.

“We’re giving fentanyl fairly routinely in US cath labs and I come from Ireland where I knew, in the European setting, we weren’t giving fentanyl to anybody,” John W. McEvoy, MD (Johns Hopkins University School of Medicine, Baltimore, MD), lead investigator for the PACIFY trial, told TCTMD. “Given what we know about morphine, we thought it would be important to see if we could demonstrate a similar effect for fentanyl for P2Y12 inhibitor absorption.”

Recent years have seen a growing appreciation of morphine’s ability to blunt the effects of the newer, more potent antiplatelet drugs used as loading doses in PCI. McEvoy, who said he was surprised to learn how entrenched fentanyl use is in the US during acute MI care, decided to look at whether fentanyl also had similar drug-drug interaction.

PACIFY was a small, single-center, double-blind randomized trial that enrolled 212 patients undergoing clinically indicated coronary angiography who were randomized to receive fentanyl (105 patients) or no fentanyl (107 patients). Thirty-five patients in each arm were also given ticagrelor 180 mg after being deemed candidates for PCI. Patients given ticagrelor consented to blood draws at baseline, 30 minutes, and 1, 2, 4, and 24 hours. These were then tested for ticagrelor concentration and platelet reactivity.

All patients (n = 212) completed a survey gauging their pain experience during their hospital admission. Of note, all patients received midazolam as deemed necessary by the operator, and bailout fentanyl was permitted as needed in the no-fentanyl group. Two patients ultimately required bailout fentanyl for pain management.

Pain and Platelets

The primary outcome, ticagrelor blood levels as measured by plasma concentration time area under the curve (AUC) over 24 hours, was significantly higher in patients in the no fentanyl group, with the curves diverging within the first 30 minutes and not converging again until after the 4-hour mark.

“We saw that the AUC is about 70% higher in the no-fentanyl group than in the fentanyl group, so more concentration, more drug onboard, in the patients’ blood stream in the first 24 hours if they haven’t received fentanyl,” McEvoy said.

For the trial’s secondary endpoint, platelet function as measured by the VerifyNow test (Accriva Diagnostics), investigators showed that more than 20% of patients in the fentanyl group had high reactivity at 2 hours, a number that rose to more than 35% when platelet aggregometry was used.

Importantly, while pain measures and procedural anxiety were slightly higher, numerically, in the no-fentanyl group than in the fentanyl group, none of these reached statistical significance. And of note, total midazolam dose was similar in both groups.

Similar Effects to Morphine

“The first take-home is that fentanyl does have similar properties to morphine,” McEvoy said, “so it does delay the absorption of P2Y12 inhibitors and therefore does delay their inhibition of platelets. That’s important for cardiologists to know about, specifically because we are giving fentanyl routinely in the cath lab.”

Second, McEvoy continued, ACS patients or other high-risk patients may be particularly vulnerable to stent thrombosis, “and in that setting it might be reasonable to try and mitigate the amount of fentanyl given for the procedure. The main point that I would make—that makes sense to me based on our study outcomes, based on the pain results, and based on the known geographic variation in fentanyl use—is that we may not need to give fentanyl prophylactically at the beginning of the case and nonselectively in the absence of any pain.”

That said, he continued, “it’s still reasonable to give fentanyl for patients who are complaining of pain.”

Commenting on the study for TCTMD, Laura Mauri, MD (Brigham and Women’s Hospital, Boston, MA), pointed out that the first rationale for using fentanyl remains “to make our patients feel as comfortable as possible. I think it’s good advice for any medication to use the minimal amount necessary and that’s true for fentanyl for many reasons. We also don’t want to oversedate patients, because we do these procedures with the patient’s cooperation.”

But fentanyl “has a long track record for safety” in the cath lab, she continued, “so I don’t think I would change my practice based on these results.”

It’s still reasonable to give fentanyl for patients who are complaining of pain. John W. McEvoy

Also weighing in, Ajay Kirtane, MD (NewYork-Presbyterian Hospital/Columbia University Medical Center, New York, NY), agreed that US operators use more sedation than is used in Europe, but he doesn’t envision that changing. “It would be safe to say, in my estimation, that US patients would prefer analgesics during their procedures, rather than undergoing a procedure without an analgesic onboard,” he commented.

The real issue, said Kirtane, is whether cath labs are preloading with antiplatelet drugs or not. It’s guideline-recommended, but many physicians are reluctant to preload out of fears that patients may be sent to surgery, he said.

“That’s the bottom line: the best way of assuring you have antiplatelet onboard at the time of the PCI is you preload with oral antiplatelets 1 to 2 hours before [or] you give an agent like cangrelor or you give a GP IIb/IIIa inhibitor, both of which are IV medications,” Kirtane explained. “For other patients that are being loaded on the table, it takes time for antiplatelets to take effect, and what this study shows is that that’s even more exacerbated if you administer opiates at the same time.”

The solution for Kirtane, however, is not to back off on the fentanyl but rather to “be cognizant of the effect” of opiates.

“To me, it’s backward to say we shouldn’t use fentanyl because fentanyl does this. We should solve the problem another way. And that’s why we preload patients 2 hours before with an oral agent; then this issue is likely not going to manifest,” he said.

McEvoy, for his part, said he believes most operators may not be aware that fentanyl is posing a potential risk, albeit one that should be looked at in larger trials with hard outcomes. For now, the question of whether fentanyl use may be linked to stent thrombosis cannot even be easily addressed, since it is not typically recorded in databases such as the NCDR ACTION Registry that track for these kinds of events, he noted. “It’s something that’s been completely off the radar.”

Patients themselves, he added, are typically unaware that fentanyl will be used for their procedures.

When they were enrolling patients into PACIFY, it was around the time that the fentanyl overdose by the pop star Prince was much in the news, McEvoy said. “We found that a lot of people were actually surprised they were getting fentanyl and were open to not receiving it. This was a complete surprise for us, because we expected it would be a challenge to get them to participate in the study because we were telling them, look, you may not get opiates unless you need them. Instead, more patients were willing to participate in the study because they weren’t going to get opiates—they were actually quite eager that they not be randomized to fentanyl.”

On this point, Mauri observed that given the kinds of fentanyl stories currently making headlines, “it might be more feasible now to do a larger study, because there may be more patient buy in to the tradeoffs” of not using routine fentanyl.