Outcomes with early opioid administration in acute coronary syndromes: Does sex matter?

Cardiovascular disease kills more women than men every year, and the annual mortality rate for women exceeds that for men as well, despite improvement in women's mortality rate over the past 20 years. Each year 262,000 American women are hospitalized with acute coronary syndromes (ACS), and although women more frequently present with atypical symptoms compared to men, chest pain remains the predominant symptom for both women and men. Opioid therapy has served as the cornerstone for pain relief in ACS for several decades. The 2013 ACCF/AHA Guidelines for ST‐ Elevation Myocardial Infarction (STEMI) designated morphine sulfate as the drug of choice to relieve pain in patients with STEMI, especially when complicated by pulmonary edema due to its favorable mitigation of ventricular load, work of breathing, and anxiety. The 2014 ACCF/AHA Guidelines for Non‐STEMI (NSTEMI) have deemed the use of morphine to be reasonable (Class IIb) for continued ischemic chest pain despite maximally tolerated anti‐ischemic medications. Moreover, in the contemporary era of heightened use of transradial access for percutaneous coronary intervention (PCI) in patients with ACS, administration of preprocedural sedation with fentanyl has been associated with lower rates of radial artery spasm, access site crossover, and intraprocedural discomfort. While randomized controlled trials (RCTs) have suggested impaired P2Y12 inhibition in patients receiving fentanyl and morphine, data regarding sex‐specific differences in opioid dispense and outcomes in adults with ACS have remained sparse until recently. In the current issue of CCI, Nan Tie and colleagues utilize the Victorian Cardiac Outcomes Registry to study the sex‐related disparities in pain scores, opioid administration, and outcomes in men and women with ACS. In this registry of over 10,000 patients, 26% were women. Approximately 57% of women received opioids compared to 65% of men (p < 0.001) despite similar median pain scores in both sexes upon presentation. While both men and women receiving opioids were more likely to present with STEMI and receive ticagrelor and a glycoprotein IIb/IIIa inhibitor, no significant difference in any major adverse cardiac events or its components were noted in the presence or absence of opioid use in either men or women. A subanalysis of the patients presenting with STEMI revealed that opioid administration significantly correlated with higher risk‐adjusted rates of TIMI 0–1 flow before PCI in both men and women. While the current study adds important insights regarding the disparities in the early treatment of ACS‐related pain in men and women, several questions regarding the impact of opioid use in patients with ACS remain. First, given that patients receiving opioids were likely to haveTIMI 0–1 flow in the STEMI subgroup, it is unclear whether these patients with impaired flow had higher levels of pain requiring opioid administration or if the prehospital administration of opioids further impaired blood flow in the culprit artery. Second, whether opioid use affected antiplatelet drug concentrations or antiplatelet effects in this study is uncertain. In the Platelet Aggregation after Ticagrelor Inhibition and Fentanyl randomized trial (NCT02683707), administration of fentanyl was associated with lower plasma concentrations of ticagrelor with corresponding delays in its antiplatelet effect, likely due to slowed gastric emptying and impaired absorption. Similarly, the Influence of Morphine on Pharmacokinetics and Pharmacodynamics of Ticagrelor in Patients with Acute Myocardial Infarction (IMPRESSION) randomized trial (NCT02217878) demonstrated that morphine was associated with a lowered total exposure to ticagrelor and its active metabolite as well as a delay in maximal plasma concentrations of ticagrelor. Finally, the ultimate question becomes whether patients with ACS would be more optimally treated with a nonopioid analgesic (e.g., acetaminophen, ketamine, dexmedetomidine). While Nan Tie et al. confirm no change in short‐term clinical outcomes with the use of opioids for pain reduction in adults with ACS, adequately powered RCTs examining the impact of nonopioid versus opioid analgesia on pain reduction, antiplatelet pharmacokinetics, and intraprocedural (i.e., radial artery spasm, procedure‐ related discomfort) and postprocedural outcomes in patients with ACS undergoing PCI appear warranted.