We performed the first retrospective cohort study to evaluate the safety of morphine use in patients with STEMI and AHF undergoing PPCI. The main findings of the study confirmed that morphine use significantly increased the composite frequency of primary outcomes (cardiovascular death and cardiogenic shock) as well as the requirement for invasive mechanical ventilation in-hospital. In contrast, no such association with adverse outcomes was observed after 1 year of follow-up.
The guidelines for the management of AMI in patients with STEMI continue to recommend intravenous morphine as a drug of choice for the alleviation of chest pain, with a class IIA indication[10]. Morphine administration is expected to reduce sympathetic tone and decrease venous return, which leads to increased cardiac workload[11] and results in smaller infarcts and significantly less microvascular obstruction determined by cardiac magnetic resonance[12]. Nevertheless, studies have revealed a correlation between morphine use and worse mortality. In 2005, the observational CRUSADE registry study was the first to demonstrate that intravenous morphine administration in patients presenting with NSTE-ACS was statistically associated with a higher rate of adverse outcomes (3.80% vs 3.00% for MI, 3.80% vs 2.30% for cardiogenic shock, 5.50% vs 4.70% for in-hospital death, and 8.50% vs 7.10% for composite of death and MI)[13]. Zaza et al. found that intravenous morphine was associated with in-hospital MACEs and 30-day mortality and most strongly associated with admission Killip class III–IV (OR=2.3, 1.5–3.5)[9]. According to the studies described above, morphine was not associated with significant adverse outcomes in AMI without HF, but the opposite result was observed in AMI patients with HF.
In our study, we included STEMI patients with advanced Killip class II–IV at admission, which was different from previous studies. Administration of intravenous morphine was associated with elevated risks of cardiac death (OR=2.509), cardiogenic shock (OR=2.636), and a need for mechanical ventilation (OR=2.308) during in-hospital treatment for STEMI with AHF. Similar results were unequivocally confirmed by the observational ADHERE (acute decompensated heart failure national registry) analysis, which revealed that intravenous morphine was independently related with an increased rate of adverse events, including a greater frequency of mechanical ventilation (15.40% vs 2.80%, p<0.001), prolonged hospitalization (5.60 vs 4.20 days, p<0.001), more ICU admissions (38.70% vs 14.40%, p<0.001), and higher mortality (13.00% vs 2.40%, p<0.001) in acute decompensated heart failure[5]. Caspi et al. demonstrated a strong relationship between morphine dosage and in-hospital mortality (17.4% vs 13.4%, OR=1.43). Additionally, intravenous morphine use significantly contributed to a marked risk for the need for additional mechanical ventilation (7.4% vs 3.6%, OR=2.13)[14]. The following factors may explain these results. First, intravenous morphine use might induce respiratory depression and increase the rate of intubation[5]. Second, morphine inhibits gastrointestinal absorption and decreases peak plasma levels of oral antiplatelet drug, potentially leading to decreased treatment efficacy[15-17]. From IMPRESSION trial, co-administration of morphine and ticagrelor resulted in a weaker and retarded antiplatelet effect in patients with AMI[15]. However, an administration of GP IIb/IIIa would diminish the negative impact of morphine on oral P2Y12 receptor, which just 71.2% of patients received GP IIb/IIIa treatment in the iv morphine group v.s 83.3% of patients received GP IIb/IIIa treatment in the without morphine group (p=0.096) in our study. Accordingly, recurrent MI and unstable angina in-hospital in the iv morphine group was higher but did not reach statistical significantly in this study. Furthermore, intravenous morphine use has been linked to multiple gastrointestinal dysfunction, including inhibition of gut motility and vomiting, which significantly affects antiplatelet drug absorption and the occurrence of aspiration pneumonia[18].
Our data also showed that morphine use was not associated with long-time adverse outcomes over 1-year follow-up. Our result was similar to that reported by Zaza[8]. The perhaps reason was that the short-time use of iv morphine was significantly associated with high requirement of in-hospital invasive mechanical ventilation, but not increase recurrent MI and unstable angina in-hospital or during follow-up in STEMI with AHF.
We should acknowledge the limitations of the present study. First, the most obvious limitation of the cohort trial is the non-randomized, retrospective nature. Accordingly, there was a non-significant trend toward older age and a higher percentage of Killip IV cases among patients receiving morphine at baseline. Other unmeasured confounding factors including that decisions with respect to morphine use differed between operators. Secondly, a subgroup study considering different Killip classes should be completed to confirm the different clinical results with morphine use. Additionally, we did not record the dosage of intravenous morphine administered to the morphine group. A previous study demonstrated a dose-dependent risk of morphine in terms of the risk of needing invasive ventilation and the risk of mortality[8]. Finally, larger multicenter, randomized controlled trials are needed to provide more convincing data.