Correlations between Morphine Use and Adverse Outcomes in Acute ST-Segment Elevation Myocardial Infarction with Acute Heart Failure: a retrospective study

Background: Studies examining the safety of intravenous morphine use for acute heart failure (AHF) have reported inconsistent results. Objective: The comprehensive meta-analysis assessed and compared the clinical outcomes of intravenous morphine use in AHF. Methods: We formally searched electronic databases before June 2020 to identify potential studies. All clinical trials were eligible for inclusion if they compared intravenous morphine or not in patients with AHF. Results: 3 propensity-matched cohorts and 2 retrospective analysis with a total of 151867 patients met the inclusion criteria were included in our meta-analysis (intravenous morphine group=22072, without morphine group=127895). The use of intravenous morphine was associated with increased risk of in-hospital mortality [over all odds ratio (OR)=5.49, 95% con�dence interval (CI) 5.20 to 5.79, p<0.001, I 2 =96.7%; subgroup analysis: OR=1.60, 95%CI


Background
Morphine has been recommended for treatment of chest pain during acute myocardial infarction (AMI) [1][2] and the amelioration of pulmonary edema in acute heart failure (AHF) for several decades [3].However, intravenous morphine has been shown to cause slower absorption, delayed onset of action, and reduced bioavailability of oral anti-platelet agents, which may lead to failure of early anti-platelet treatment in susceptible individual patients [3][4].Moreover, intravenous morphine can cause brainstem respiratory center suppression, heart rate depression, and hypotension in patients with heart failure [5].Despite its longstanding use in AMI and AHF patients, a consensus on the safety of intravenous morphine in these patients has yet to be reached, with different published studies reporting con icting results.
The French Registry of Acute STEMI (FAST-MI) study included 2438 ST-elevation MI (STEMI) patients, of whom 453 patients received morphine and 1985 patients did not, and found that mortality and complications among STEMI patients while receiving in-hospital treatment or during 1 year of follow-up were not associated with morphine use [6].An important limitation of that study was that only 6% of the cases treated with morphine were Killip class ≥2 in the FAST-MI study.In another study with a higher proportion of patients with Killip class ≥2 of 14.8% (88/617), morphine use correlated with higher death or recurrent MI with 30 days of follow-up in patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS) [7].Moreover, in the multivariate analysis of Zaza et al., morphine use was associated with a high in-hospital and 30-day mortality rate [odds ratio (OR)=2.0,1.1-3.5, p=0.02] and was most strongly associated with admission Killip class III-IV in patients with or without ACS (OR=2.3, At present, the available data regarding the safety of morphine use in cases of STEMI with AHF (Killip ≥2) remain insu cient.

Study Design
From January 2017 to December 2019, 275 STEMI with AHF patients undergoing primary percutaneous coronary intervention (PPCI) were consecutively enrolled and separated into two groups: patients who received morphine (n=125) and patients who did not receive morphine (n=150).The combined endpoints were the incidences of major adverse cardiovascular events (MACEs) and the requirement of invasive mechanical ventilation while receiving in-hospital treatment and during hospitalization and 1 year of follow-up.All participants provided written informed consent.The study protocol was approved by the institutional review board of the Hospital.

Inclusion Criteria
Eligible patients with STEMI and a Killip class II-IV at admission were included.All the included patients had been sent to the hospital within 12 hours from the onset of acute chest pain and were immediately scheduled to receive PPCI.The diagnosis of STEMI was made according to the 2017 Guidelines for STEMI, including ST-segment elevation ≥0.2-0.3 mV in two contiguous leads [1].Intravenous morphine was administrated at dosage from 3 mg to 6 mg with the rst 24 h after hospital admission.

Exclusion Criteria
Patients who received treatment with morphine before hospital admission or beyond 24 h after admission were excluded from participation in the preset study.In addition, patients with Killip class I at admission, age >90 years, a coexisting major hemorrhage, or a large cerebral infarction at admission also were excluded.

Study Endpoints
The primary endpoint was in-hospital complications including a composite of MACEs (Cardiac death +recurrent MI + unstable angina + cardiogenic shock), cardiac death, recurrent MI, unstable angina, and cardiogenic shock [9].The secondary endpoint was the requirement of in-hospital invasive mechanical ventilation.Finally, the incidence rates of cardiac death, all-cause death, and MACEs over 1 year of followup were evaluated.Follow-up data were collected by telephone interview.

Statistical Analysis
Statistical analysis was performed using SPSS 22.0 (SPSS, Inc., Chicago, IL, USA).Data are reported as mean ± standard deviation or count (percentage).Group comparisons of continuous data were conducted using Student's test or Kruskal-Wallis test, whereas group comparisons of categorical data were performed using the Chi-squared or Fisher Exact test.Univariable (binary logistic regression) and multivariable analysis was applied to evaluate the adjusted odds ratios (ORs) for the association of morphine with different outcomes.MACE-free survival, all-cause death, and cardiac death were analyzed by the Kaplan-Meier method (log rank test).Statistically signi cance was de ned by a p value <0.05.

Results
Baseline Characteristics of STEMI Patients with AHF Morphine was given in 125 (45.45%) patients in this study.The baseline demographic features, angiographic characteristics, and treatment details are presented in Table 1.The mean ages of the patients in the with morphine and without morphine groups were 61.70±13.67 years and 58.71±13.03years, respectively (p=0.066).Additionally, no statistically signi cant differences were found between the two groups for the percentage of males, body mass index (BMI), systolic blood pressure (SBP), heart rate (HR), coronary risk factors, chronic obstructive pulmonary disease (COPD), clinical manifestations, Killip class at admission, symptom onset to rst medical contact, angiographic characteristics, nal ow of thrombolysis in myocardial infarction (TIMI), or medical treatment.However, non-signi cant trends were observed for increasing age and a higher percentage of Killip IV patients among those who received morphine treatment at baseline.

Survival of STEMI Patients with AHF During 1 Year of Follow-up after PPCI
The Kaplan-Meier survival-free curves for MACEs in patients in the with morphine and without morphine groups showed no differences (Log-rank test, p=0.436; Figure 3).Additionally, no signi cant difference in survival free of cardiac death or all-cause death was observed between the groups throughout the followup period (log-rank test, p=0.392 and p=0.265, respectively; Figure 2).

Discussion
We performed the rst retrospective cohort study to evaluate the safety of morphine use in patients with STEMI and AHF undergoing PPCI.The main ndings of the study con rmed that morphine use signi cantly 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 signi cantly 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 rst 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 inhospital 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 signi cant 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 con rmed 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 signi cantly 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 e cacy [15][16][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 signi cantly in this study.Furthermore, intravenous morphine use has been linked to multiple gastrointestinal dysfunction, including inhibition of gut motility and vomiting, which signi cantly 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 1year follow-up.Our result was similar to that reported by Zaza[8].The perhaps reason was that the shorttime use of iv morphine was signi cantly 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-signi cant 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 con rm 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.

Conclusion
In conclusion, the results of this study indicate that increased awareness of the potential adverse clinical effects, including cardiac mortality and invasive mechanical ventilation, of in-hospital intravenous morphine use is warranted in STEMI patients with AHF.Kaplan-Meier curves for survival free of MACEs over 1 year of follow-up in the groups of STEMI and AHF patients treated with morphine and without morphine in-hospital.

Table 1 .
Baseline characteristics of the included STEMI with AHF according to TIMI = thrombolysis in myocardial infarction; ACEI/ARB = angiotensin-converting enzyme inhibitor/angiotensin receptor blocker; eGFR = estimated glomerular filtration rate; LVEF = left ventricular ejection fraction.Table2.Primary secondary outcomes in-hospital for patients in two groups.