Morphine May Impede Platelet Inhibition in STEMI Patients

Administration of morphine to ease STEMI pain appears to dampen the antiplatelet effects of newer P2Y12 inhibitors in the hours after primary PCI, according to a study in the January 2015, issue of Circulation: Cardiovascular Interventions. The effect was similar for both prasugrel and ticagrelor loading doses. 

Considering the importance of platelet inhibition and the lack of data supporting morphine use in this setting, “more caution should be used regarding morphine administration in STEMI patients, and a restricted morphine use seems to be reasonably recommended,” Guido Parodi, MD, PhD, of Careggi University Hospital (Florence, Italy), and colleagues write.

The researchers looked at data from 300 patients undergoing primary PCI at 3 institutions who received a loading dose of either 60 mg of prasugrel (Effient; Eli Lilly/Daiichi Sankyo; n = 95) or 180 or 360 mg of ticagrelor (Brilinta; AstraZeneca; n = 205). Platelet reactivity was measured by the VerifyNow assay (Accumetrics) at 1, 2, and 4 hours after the loading dose. Patients also received aspirin and either bivalirudin (Angiomax; The Medicines Company) or unfractionated heparin. No glycoprotein IIb/IIIa inhibitors were allowed.

In all, 31.62% of patients received morphine at a median dose of 4 mg (ranging from 2 to 12 mg). Baseline characteristics mostly were similar between those who did and those who did not receive morphine except for a lower BMI and a higher rate of bivalirudin use in morphine-treated patients. Morphine use was also associated with a higher rate of vomiting within 2 hours of the loading dose (15% vs 2%; P = .001).

Average P2Y12 reactivity unit (PRU) value was higher among morphine-treated patients across measurements from 1 to 4 hours, at 2 hours after the loading dose (primary endpoint), and at the 2-hour time point among patients who did not vomit (table 1). The difference persisted at 4 hours (P = .04).

High residual platelet activity (PRU ≥ 208) was found in 53% of morphine-treated patients and 29% of other patients at 2 hours (P < .001), with no difference based on the specific P2Y12 inhibitor used.

On multivariate analysis, morphine use was an independent predictor of high residual platelet activity at 2 hours (OR 2.91; 95% CI 1.71-4.97) as was age (OR 1.03; 95% CI 1.01-1.05). Morphine remained associated with high residual activity even after propensity score adjustment (OR 1.89; 95% CI 1.40-2.56).

The researchers also examined the relationships between morphine use and in-hospital clinical events and found none, “possibly reflecting the small sample size and the limited time of observation,” they explain.

Plausible Biological Explanation

Morphine is recommended to treat pain in the setting of STEMI but there are few data to support the practice, according to Dr. Parodi and colleagues. Moreover, a small randomized trial led by Dr. Parodi showed that morphine use was associated with a 5-fold increase in the likelihood of having high platelet reactivity after loading doses of either prasugrel or ticagrelor—a finding that they say spurred the current analysis.

Although not proven, a causal explanation is possible, the researchers write. “The morphine-antiplatelet agent interaction is likely a non–drug-specific phenomenon and related to the inhibition of the normal muscular activity of the stomach and the intestines, which may lead to vomit or delayed gastric emptying, which in turn delays absorption and decreases peak plasma levels of orally administered drugs.”

Clopidogrel was not used in any of the study patients, but, the authors note, “given the well-known delayed onset of action and effect variability of clopidogrel as compared with prasugrel and ticagrelor, it is easy to anticipate a similar and even more clinically evident interaction between morphine and clopidogrel.”

They acknowledge, however, that it is possible the findings could be explained by the use of morphine in higher-risk patients, even though the propensity score–adjusted analysis yielded similar results.

“[It] is not possible to rule out that in sicker patients, hemodynamic disarrangement, adrenergic activation, [and] systemic vasoconstriction with the reduction of blood volume to the abdomen may contribute to the delayed drug [absorption] and to the reduced platelet inhibition,” they write.

Other potential limitations, Dr. Parodi and colleagues note, are the nonrandomized study design, the small sample size precluding an assessment of clinical effects, and the lack of a pharmacokinetic analysis to confirm impaired drug absorption in the morphine group.

Source:
Parodi G, Bellandi B, Xanthopoulou I, et al. Morphine is associated with a delayed activity of oral antiplatelet agents in patients with ST-elevation acute myocardial infarction undergoing primary percutaneous coronary intervention. Circ Cardiovasc Interv. 2014;Epub ahead of print.

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• Platelet Reactivity in Response to Prasugrel Depends on the Test