Patrice Wendling

September 12, 2017

BARCELONA, SPAIN — A provocative new study shows that fentanyl delays and reduces the antiplatelet effects of the P2Y12-receptor inhibitor ticagrelor (Brilinta/Brilique, AstraZeneca) in patients undergoing PCI[1].

"We did the study because we knew that morphine has an effect, so we thought if fentanyl does too, that may have big implications for our generic use of fentanyl in the cath lab," first author Dr John W McEvoy (Johns Hopkins University School of Medicine, Baltimore, MD) told | Medscape Cardiology.

Last year, European researchers reported that morphine significantly lowers ticagrelor absorption in patients with acute MI, indicating reduced thrombolytic potential. But the two drugs have different pharmacokinetics, with fentanyl being much shorter-acting, so the drug-drug interaction was not a foregone conclusion, he observed.

"I hope this study generates a conversation around routine and often nonselective fentanyl use, particularly in the context of this wide difference between the US and Europe."

Most data are anecdotal, but in a recent international survey of cath-lab practices and analgesia[2], routine sedation was used by 92% of North American cardiologists performing PCI vs 38% of respondents outside North America, with fentanyl the most frequent opioid used for sedation.

Indeed, the new study, presented at the recent European Society of Cardiology 2017 Congress, was met with skepticism by European cardiologists, because "they didn't think it was relevant for their care" and "were surprised that any fentanyl was being given for angiography at all," McEvoy said.

Commenting for | Medscape Cardiology, Dr Cindy Grines (Hofstra Northwell School of Medicine, Manhasset, NY) said in an email that fentanyl "is in use in all the cath labs where I have worked" to reduce pain including sheath insertion pain, back pain from lying on the table, or chest pain during PCI.

That both morphine and fentanyl have been shown to reduce the rate of absorption and delay the antiplatelet effects of dual antiplatelet therapy (DAPT), however, "is a real problem" since it may be responsible for an increased risk of acute stent thrombosis, she noted.

"As you know, the greatest risk of stent thrombosis is in the first 24 hours, and these studies make me wonder whether it may be due to the fact that we have inadequate antiplatelet coverage," Grines said.

Platelet Inhibition

The PACIFY study allocated 212 patients undergoing clinically indicated coronary angiography to receive fentanyl (n=105) or no fentanyl (n=107). All patients received local anesthetic and IV midazolam, with 35 patients in each arm requiring PCI loaded with 180-mg ticagrelor intraprocedurally.

Platelet function and ticagrelor plasma concentrations were measured by blinded assessors at baseline; 30 minutes; and 1, 2, 4, and 24 hours. Bailout fentanyl was permitted in the control arm—an option used for pain management by two patients. The mean total fentanyl dose was 9.3 µg in the no-fentanyl arm vs 96.3 µg in the fentanyl arm (P<0.0001).

Compared with the patients who received the powerful IV opiate, the primary end point of plasma concentration time area under the curve (AUC) was significantly higher in the first 24 hours among patients not receiving fentanyl (P=0.03).

High platelet reactivity at 2 hours was 0% without fentanyl compared with more than 20% with fentanyl when assessed by the VerifyNow test (Accriva Diagnostics) and reached 37% when assessed by platelet aggregometry. The between-group differences were statistically significant (P=0.02 and 0.03, respectively), but by 4 hours both groups were reasonably well inhibited.

"We replicated what was found for morphine with fentanyl, which has wider potential implications, given the widespread use of the latter in our cath labs," McEvoy said, but he added, "It's hard to know what the clinical implications of a 2-hour difference would be, although it's likely there may be some patients exposed to excess risk. We need more study."

Of special note, previously unreported data from a secondary post hoc analysis show high-sensitivity cardiac troponin levels were twice as high in patients given fentanyl during PCI than those who went without (mean 12 ng/L vs 6 ng/L; P=0.02), suggesting the impact on platelet resistance may have implications for the myocardium.

"I'm not saying we shouldn't give fentanyl when it's needed for pain, it is important, but we need to ration our administration of opiates, particularly when given routinely and for nonpain symptoms," he said. "We have a big issue with opiates in the US, and it's reasonable to consider being thoughtful about how we administer them."

McEvoy noted the study was started around the time of Prince's fentanyl overdose and that some patients were actually hoping they would not be randomized to fentanyl.

Notably, there were no differences between the two groups in procedural anxiety or four different measures of pain.

Based on the results, Grines said "Perhaps we should just use Versed for sedation, and not routinely give preventive pain medications. These could be reserved only for patients who develop severe pain. In addition, we need to give the DAPT ASAP."

In her practice, patients are asked to chew and swallow DAPT with sips of water while lying on the table, as soon as a decision is made to perform PCI. She noted that many doctors allow it to be given in the holding room after the PCI and don't order it to be crushed or chewed but pointed out that whole pills further delay absorption.

"If the patients are already on DAPT, then fentanyl should be fine," she said. "We have gone away from IV antiplatelets, but perhaps the physician needs to be reminded that even the newer agents can take several hours to become effective and consideration should be given to coverage with IV agents for several hours if the patient has ACS or if there are angiographic predictors of stent thrombosis, such as long or overlapping stents, bifurcations, small vessels, etc."

Dr Robert F Storey (University of Sheffield, UK), who was not involved in the study, said he was unaware of how common fentanyl use is in the US but that "the results suggest there should be a change in practice if clinicians are administering fentanyl and loading with oral P2Y12 inhibitors at the same time or after the procedure."

He also noted that the absorption and onset of action of clopidogrel, ticagrelor, and prasugrel (Effient, Lilly/Daiichi-Sankyo) may be delayed for up to 8 hours after opiate administration, predisposing patients to acute stent-thrombosis risk. For elective PCI, this risk can be avoided by loading with oral P2Y12 inhibitor at least 2 hours before the procedure and before any opiate is administered.

"Where opiate is administered before or shortly after a loading dose of oral P2Y12 inhibitor, strong consideration should be given to parenteral antithrombotic therapy to cover the 8-hour window, such as high-dose bolus tirofiban followed by a 6-hour infusion," he suggested. "This is a particular issue in STEMI patients who are at higher risk of acute stent thrombosis than elective PCI patients, who have an extremely low risk of acute stent thrombosis with contemporary PCI techniques and stents, assuming a good technical result from stenting."

McEvoy and Grines reported no relevant financial relationships.  Storey reported institutional research grants/support from AstraZeneca and PlaqueTec; consultancy fees from Actelion, AstraZeneca, Avacta, Bayer, Bristol Myers Squibb/Pfizer, Novartis, PlaqueTec, and the Medicines Company; and honoraria from AstraZeneca.

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