More Concern Over Morphine, Clopidogrel Interaction in ACS 

Sue Hughes  

January 22, 2020

New data have added more concerns about using morphine and clopidogrel together in patients presenting with non-ST-segment elevation ACS (NSTEACS).

Previous studies have shown that morphine can reduce the absorption of clopidogrel, and now a new study among patients presenting with a high-risk, invasively managed NSTEACS has shown concomitant morphine use with clopidogrel pretreatment to be associated with higher risk for short-term cardiac ischemic events compared with patients receiving clopidogrel without morphine.

"Our study adds to what was already known from platelet reactivity studies and some limited clinical data. And our study, although observational, provides the strongest evidence yet that this interaction has clinical implications," senior author, Robert P. Giugliano, MD, Brigham and Women's Hospital, Boston, told Medscape Medical News

They had a large patient population and conducted several statistical adjustments to account for potential confounders, he noted.

"The increased clinical outcomes we saw in this study when patients received both morphine and clopidogrel are the ones we worry about most — an early increase in [myocardial infarction (MI)]," Giugliano added. "I think it is time to take action and not to give these two agents together.”  

The new findings are published online in the January 28 issue of the Journal of the American College of Cardiology.

The researchers note that morphine has long been recommended for management of acute chest pain in patients with ACS, and is currently endorsed by all guidelines for such use, although no randomized trial has been conducted so far to assess its clinical safety.

It is known from pharmacological studies that morphine and other opioids can delay absorption and blunt the antiplatelet effect of clopidogrel. The interaction has also been shown with the other oral adenosine diphosphate (ADP) receptor blockers — prasugrel and ticagrelor — and all three antiplatelets now carry a warning about drug interaction with morphine and other opioids, they note.  

However, the clinical relevance of these pharmacological findings has not been clear, with previous studies showing conflicting results.

The current study aimed to look into this issue further with an analysis of data from 5438 patents pretreated with clopidogrel before percutaneous coronary intervention (PCI) in the EARLY ACS trial, of whom 11.3% patients were administered morphine early on.

Results showed that, in patients pretreated with clopidogrel, morphine use was associated with higher rates of ischemic events at 96 hours (adjusted odds ratio [OR], 1.40; P = .026), and there was also a trend for higher rates of death or MI at 30 days (adjusted OR, 1.29; P = .072).

The trial also included 3462 patients who were not pretreated with clopidogrel, and in this group the use of morphine was not associated with increased ischemic events at 96 hours or any increase in death or MI at 30 days.

"These patients who were not pre-treated with clopidogrel are acting as negative controls and the results in this group show that it is not morphine itself that is harmful," Giugliano said.

"Our results provide important new information for both society NSTEACS guidelines and regulatory agencies," the researchers add.

"Given the paucity of effective non-narcotic options for pain management in NSTEACS, our results are intended to encourage new investigation on alternative treatments," the authors say. Replacing morphine with other opioids may be a reasonable approach, they suggest.  

However, the randomized, placebo-controlled PACIFY trial showed that fentanyl blunted ticagrelor effect and led to more myocardial damage during elective PCI, thus raising concerns that this interaction could be a class effect from all opioids.

Another study, PERSEUS, is now planned, in which 56 ST-segment elevation myocardial infarction (STEMI) patients undergoing primary PCI and treated with ticagrelor will be randomized to receive morphine versus fentanyl and platelet reactivity as the primary endpoint will be assessed.

Giugliano says hospitals should think carefully about their policy on morphine use for ACS patients. "If it is their practice to give morphine routinely, then I think this needs to be re-evaluated. Obviously strong analgesia cannot be eliminated as some patients can be in extreme pain, but maybe there could be a higher threshold of when to give morphine.

"Then we also need to be looking at alternatives to clopidogrel for up-front antiplatelet therapy," he added.

Giugliano says that in his hospital they use the intravenous P2Y12 inhibitor cangrelor in high-risk patients for the first few hours. "This gives a full antiplatelet effect almost immediately." 

An alternative could be to use the more potent oral agents, ticagrelor or prasugrel, and to crush the tablets to improve absorption, he suggested.

The researchers acknowledge that their data is observational so cannot establish a definitive causal relationship because the results may be related to unmeasured confounders. However, they point out that they found consistent results in two different models used to adjust for imbalances between the two groups regarding baseline characteristics and concomitant treatments.

They also note that all events were centrally adjudicated by a clinical events committee, which has not been the case in prior similar reports on the same topic, and this thus "provides more consistency and reliability to our findings."

They say they cannot extrapolate their results to other oral ADP receptor blockers, adding, "it might be possible that, due to their faster onset of action and higher levels of platelet inhibition, our findings may not apply to prasugrel and ticagrelor," even though mechanistic studies have shown the same interaction with these drugs.

Interaction May Be 'Catastrophic'

In an accompanying editorial, Robert F. Storey, MD, University of Sheffield, and William A. E. Parker, MD, South Yorkshire Cardiothoracic Centre, Sheffield, United Kingdom, say the current study presents new evidence for a clinically important adverse interaction between morphine and clopidogrel in patients with ACS.

They note that the P2Y12 inhibitors clopidogrel, prasugrel, and ticagrelor are entirely dependent on intestinal absorption, and that opiates, such as morphine, delay gastric emptying into the small intestine, and may thus trap oral drugs within the stomach for many hours, sometimes until the opiate effect has worn off and gastrointestinal motility recovers.

"The results of this may be catastrophic when the effect of the P2Y12 inhibitors is required to prevent acute stent thrombosis," they add. 

The editorialists suggest using parenteral therapy with a GP IIb/IIa antagonist, or cangrelor, to cover the window between administration of an oral P2Y12 inhibitor and up to an 8-hour delay in its onset of action when an opiate is given concurrently.

The subcutaneous P2Y12 inhibitor selatogrel offers some promise for the future, having a longer half-life than cangrelor and potential for easier administration in the emergency setting, they add. Also, a 6-hour regimen of enoxaparin, which inhibits thrombin-induced platelet activation, also looks attractive and warrants further study, they say.

"Clinicians should take note of these findings when using clopidogrel in the management of ACS as part of a dual oral antiplatelet strategy," Storey and Parker state.   

Noting that clinical guidelines recommend the use of ticagrelor or prasugrel in preference to clopidogrel in patients without an indication for oral anticoagulation, they say that "these are clearly more reliable options in morphine-treated ACS patients, accepting the need to still consider the potential delay in their onset of action."

"When clopidogrel is used concurrently with morphine or another opiate, the results of the present analysis and prior pharmacodynamic studies suggest that a further loading dose of clopidogrel should be considered at 6 to 8 h after the last dose of opiate to optimize the chances of achieving therapeutic levels of platelet P2Y12 inhibition," they add.

Giugliano has received research grants and honoraria from Amgen, Daiichi Sankyo, and Merck; has provided CME lectures for Amgen, Daiichi Sankyo, Merck, and Servier; and has served as a consultant/on the advisory board for Akcea, Amarin, American College of Cardiology, Amgen, Angel Med, Beckman Coulter, Boehringer Ingelheim, Bristol-Myers Squibb, CVS Caremark, Daiichi Sankyo, GlaxoSmithKline, Janssen, Lexicon, Merck, Portola, Pfizer, St. Jude, and Stealth Peptides. Storey has received institutional research grants/support from AstraZeneca and GlyCardial Diagnostics; has received consultancy fees from Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb/Pfizer, GlyCardial Diagnostics, Haemonetics, Actelion/Idorsia, Novartis, Portola, and Thromboserin; and has received honoraria from AstraZeneca, Bayer, Bristol-Myers Squibb/Pfizer, and Medscape. Parker reports no relevant relationships.

J Am Coll Cardiol. 2020; January 28 issue. Abstract. Editorial.

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