What is the primary reason for administering morphine to a client with an mi?

Journal Article

Etienne Puymirat,

1

Department of Cardiology

,

European Hospital of Georges Pompidou, Assistance Publique des Hôpitaux de Paris (AP-HP)

,

15-20 rue Leblanc

,

Paris 75015

,

France

2

University Paris Descartes

,

Paris

,

France

3

INSERM U-970

,

Paris

,

France

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Revision received:

10 August 2015

Accepted:

04 October 2015

Published:

17 November 2015

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  Etienne Puymirat, Lionel Lamhaut, Nicolas Bonnet, Nadia Aissaoui, Patrick Henry, Guillaume Cayla, Simon Cattan, Gabriel Steg, Laurent Mock, Gregory Ducrocq, Patrick Goldstein, François Schiele, Eric Bonnefoy-Cudraz, Tabassome Simon, Nicolas Danchin, Correlates of pre-hospital morphine use in ST-elevation myocardial infarction patients and its association with in-hospital outcomes and long-term mortality: the FAST-MI (French Registry of Acute ST-elevation and non-ST-elevation Myocardial Infarction) programme, European Heart Journal, Volume 37, Issue 13, 1 April 2016, Pages 1063–1071, https://doi.org/10.1093/eurheartj/ehv567

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Abstract

Introduction

The use of opioids is recommended for pain relief, breathlessness, and anxiety in patients with acute myocardial infarction (AMI), although data from randomized controlled trials documenting its benefit or safety on hard outcomes are completely lacking.1,2 Beyond its analgesic benefit per se, the use of opioids appears justified because pain is associated with sympathetic activation that causes vasoconstriction and increased cardiac workload.2

In heathy volunteers, however, recent data have demonstrated a drug–drug interaction between morphine and clopidogrel: concomitant injection of morphine slows clopidogrel absorption, decreases plasma levels of its active metabolite, retards, and diminishes its pharmacologic effects, a mechanism which could lead to treatment failure at the acute stage of MI.3 Likewise, in ST-elevation myocardial infarction (STEMI) patients, inhibition of platelet reactivity by prasugrel and ticagrelor is delayed when morphine is co-administered.4 Recently, the Administration of Ticagrelor in the cathLab or in the Ambulance for New ST elevation myocardial Infarction to open the Coronary artery (ATLANTIC) trial showed more frequent ST-segment resolution before percutaneous coronary intervention (PCI) in patients treated with ticagrelor in the ambulance when they did not receive pre-hospital morphine, whereas no such effect was observed in morphine-treated patients; there was no interaction between morphine use and infarct-related artery patency, however.5

The aim of this study was to assess the correlates of pre-hospital morphine use, and its relationship with clinical outcomes, in STEMI patients from the French Registry of Acute ST-elevation and non-ST-elevation Myocardial Infarction (FAST-MI) 2010. Consistency of the results was assessed by replicating the analyses in STEMI patients from the FAST-MI 2005 registry. In this latter cohort, special consideration was given to the patients who had been pre-treated with clopidogrel, according to genetic polymorphisms of ABCB1 and CYP2C19 enzymes, which are involved in clopidogrel absorption and metabolism.6,7

Methods

Primary analysis

For the main analysis, we selected patients with STEMI or left bundle branch block (LBBB) from FAST-MI 2010, the methodology of which has been previously described in detail.8,9 Briefly, the primary objective was to evaluate practices for MI management in ‘real life’ and to measure their association with medium- and long-term outcomes in patients admitted to intensive care units (ICUs) with AMI. This registry results from a prospective multicentre (213 centres) study, including 4169 patients, recruited consecutively from ICUs over a period of 1 month, with a possible extension of recruitment up to one additional month. Participation in the study was offered to all French institutions, university teaching hospitals, general and regional hospitals, and private clinics with ICUs in the capacity to receive acute coronary syndrome (ACS) emergencies, and 76% participated.

We included men or women aged over 18 years, admitted within 48 h after symptom onset for an AMI characterized by the elevation of troponin or creatine phosphokinase myocardial band associated with at least one of the following elements—symptoms compatible with myocardial ischaemia, new pathological Q waves, ST-T changes compatible with myocardial ischaemia—and who agreed to take part in the study. For the present study, only patients presenting with persistent ST-elevation, presumed new Q waves, or presumed new LBBB were included.

The main exclusion criteria were (i) iatrogenic MI, defined as MI occurring within 48 h of a therapeutic procedure (bypass surgery, coronary angioplasty, or any other medical or surgical intervention); (ii) ACS diagnosis invalidated in favour of another diagnosis; and (iii) patients with unstable angina and no increase in cardiac biomarkers.

The registry was conducted in compliance with Good Clinical Practice guidelines, French law, and the French data protection law. The protocol was reviewed and approved by the Committee for the Protection of Human Subjects of Saint-Louis University Hospital, and the data file of FAST-MI was declared to the Commission Nationale Informatique et Liberté. All patients gave informed consent for their participation in the study. Clinicaltrials.gov identifier: NCT01237418.

Baseline characteristics (demographics, risk factors, and medical history) were collected prospectively. All data were recorded on computerized case record forms by dedicated research technicians sent in each of the centres at least once a week. In-hospital complications (recurrent MI, stent thrombosis, bleeding, or transfusion) were collected. Recurrent MI was defined as recurrence of clinical symptoms or occurrence of ECG changes accompanied by a recurrent increase of cardiac markers. Stent thrombosis was defined as definite or probable according to the Academic Research Consortium definition.10 Bleeding was classified as major or minor according to the Thrombolysis in Myocardial Infarction (TIMI) criteria.11 Follow-up data were collected through contacts with the attending physicians, the patients, or their family. If missing, vital status was assessed from the civil registries of the patients' birthplaces. One-year follow-up was 99% complete.

Replication analysis

For assessing the robustness of the results, we repeated the analysis in patients (n = 1726) with STEMI or LBBB in the FAST-MI 2005 registry, which had been carried out 5 years before, using a similar methodology, and in which polymorphisms of CYP2C19 and ABCB1 had been assessed in 66% of the patients.6,12,13 Clinicaltrials.gov identifier: NCT00673036. In the 2005 registry, the only thienopyridine used was clopidogrel, and fewer patients had undergone primary PCI. The set of variables collected in 2005 was essentially similar to that collected in 2010, but some variables of interest, in particular stent thrombosis, had not been recorded in 2005.

Genetic testing in the FAST-MI 2005 cohort

Genomic DNA was extracted from whole-blood specimens with the use of a purifier (the MagNA Pure Compact Instrument, Roche) according to the manufacturer's recommendations. Genotyping for CYP2C19 and ABCB1 was performed with the use of an oligonucleotide ligation assay (SNPlex, Applied Biosystems) after initial amplification by means of a polymerase chain-reaction assay involving two primers for the major variant alleles CYP2C19*2 (rs4244285), CYP2C19*3 (rs4986893), and ABCB1 (rs1045642). Genotyping for known variants of CYP2C19 with functional importance—CYP2C19*4 (rs28399504), CYP2C19*5, CYP2C19*17 (rs12248560)—was performed with the use of an allelic discrimination assay (Custom TaqMan) and a detection system (ABI prism 7900HT Sequence Detection System, Applied Biosystems). Base numbering and allele definitions follow the nomenclature of the Human Cytochrome P450 (CYP) Allele Nomenclature Committee (www.cypalleles.ki.se).

Statistical analysis

Continuous variables are reported as means and standard deviations (SDs) or medians and interquartile ranges (IQRs), when appropriate. Discrete variables are described as counts and percentages. Comparisons were made with χ2 or Fisher's exact tests for discrete variables, and by unpaired t tests, Wilcoxon sign-rank tests, Mann–Whitney tests, or one-way analyses of variance for continuous variables. Backward binary logistic regression analysis, using pre-hospital morphine use, baseline characteristics, and therapeutic management as covariates, was used to determine independent correlates of in-hospital complications. In addition, a propensity score for getting morphine was calculated using multiple logistic regression (using baseline characteristics of the patients and concomitant pre-hospital medications received) and used to build two cohorts of patients (388 patients each) matched on the propensity score, using a greedy matching procedure; the C-statistic for the propensity score was 0.87, and the Hosmer–Lemeshow test was not significant (P = 0.32). The differences between the two matched cohorts were assessed by calculating the absolute value of standardized differences, and were always ≤10%. The matched population would give an 80% power to detect an absolute 6% increase in 1-year mortality in the morphine group, based upon an expected 7% mortality in the control group. Survival curves were estimated using the Kaplan–Meier estimation and compared using log-rank tests. Multivariate analyses of predictors of in-hospital endpoints were made by using backward, stepwise multiple logistic regressions. Correlates of survival were determined using a multivariate backward stepwise Cox analysis, using baseline characteristics and early management data as covariates. Statistical analyses were performed using IBM SPSS 20.0 (IBM SPSS Inc.) and NCSS 9 (NCSS, LLC. Kaysville, UT, USA). For all analyses, a two-sided P value of <0.05 was considered to be statistically significant.

Results

Main analysis in FAST-MI 2010

Baseline characteristics and clinical presentation

Of the 4169 patients included, 2438 had STEMI or LBBB, of whom 453 (19%) received morphine in the pre-hospital setting. Patients receiving morphine were younger, more often male, with a lower cardiovascular risk profile, and a lower early GRACE score (136 ± 31 vs. 145 ± 35, P < 0.001). Their past medical history, however, was not significantly different (Table 1).

Table 1

Baseline characteristics: demographics, risk factors according to pre-hospital use of morphine

ACE, angiotensin-converting enzyme; ARB, angiotensin-receptor blocker; GRACE, Global Registry of Acute Coronary Events.

aIncluded patients with previously documented diagnosis of hypercholesterolaemia be treated with diet or medication or new diagnosis made during this hospitalization with elevated total cholesterol >160 mg/dL; did not include elevated triglycerides.

Table 1

Baseline characteristics: demographics, risk factors according to pre-hospital use of morphine

ACE, angiotensin-converting enzyme; ARB, angiotensin-receptor blocker; GRACE, Global Registry of Acute Coronary Events.

aIncluded patients with previously documented diagnosis of hypercholesterolaemia be treated with diet or medication or new diagnosis made during this hospitalization with elevated total cholesterol >160 mg/dL; did not include elevated triglycerides.

Morphine was used in similar proportions of patients during the day (7:00 to 22:59) compared with night (23:00 to 6:59): 19 vs. 17%, P = 0.44, but more frequently during weekends compared with the rest of the week (22 vs. 18%, P = 0.02).

Finally, morphine was more often used in patients calling earlier, with typical chest pain, more severe chest pain, anterior MI, and in patients with lower heart rate and lower Killip class at presentation (Table 2). There was an inverse relationship between chest pain intensity and age: the proportion of patients with a pain score ≥7 decreased from 53% under 60 years of age to 47% for age 60–74 and 38% in patients 75 years of age or older (P = 0.008).

Table 2

Clinical presentation and management according to pre-hospital use of morphine

ICU, intensive care unit; IQR, interquartile ranges; MI, myocardial infarction; PCI, percutaneous coronary intervention; TIMI, Thrombolysis In Myocardial Infarction.

Table 2

Clinical presentation and management according to pre-hospital use of morphine

ICU, intensive care unit; IQR, interquartile ranges; MI, myocardial infarction; PCI, percutaneous coronary intervention; TIMI, Thrombolysis In Myocardial Infarction.

Pre- and in-hospital management

Pre-hospital morphine use was linked to initial pathways (Table 2). All patients who received morphine pre-hospital were managed by mobile ICU, with morphine prescribed by the physicians on board the ambulances. In these patients, time from ECG to primary PCI was shorter, and the use of antiplatelet and anticoagulant therapy was higher compared with patients without morphine. Metoclopramide, an antiemetic agent, was used more often in patients given morphine.

The percentage of patients admitted to centres with catheterization laboratories was higher when morphine was used (93 vs. 68%, P < 0.001), as was the use of primary PCI (90 vs. 77%, P < 0.001).

In-hospital evolution and 1-year clinical outcomes

Pre-hospital use of morphine was associated with a decrease in heart rate (−3.4 ± 18.8 vs. +1.5 ± 18.9 b.p.m., P < 0.001) but no change in systolic blood pressure (+13 ± 28 vs. +14 ± 28 mmHg, P = 0.69), while change in Killip class was similar in patients with or without morphine (Tables 2 and 3). In patients who underwent coronary angiography, the rate of TIMI 2 or 3 flow prior to PCI was similar in patients with (41%) or without (41%) pre-hospital use of morphine. In those given morphine, TIMI 2 or 3 flow as found as frequently in those receiving metoclopramide (43%) or not (41%).

Table 3

Evolution of haemodynamic parameters and in-hospital complications according to pre-hospital use of morphine

MI, myocardial infarction; TIMI, Thrombolysis In Myocardial Infarction.

Table 3

Evolution of haemodynamic parameters and in-hospital complications according to pre-hospital use of morphine

MI, myocardial infarction; TIMI, Thrombolysis In Myocardial Infarction.

After adjustment, in-hospital mortality and most in-hospital complications did not differ according to pre-hospital morphine use; the rate of non-fatal recurrent MI, however, was higher in patients pre-treated with morphine (1.8 vs. 0.7%, P = 0.03; Table 3).

At 1 year, crude mortality rates were lower in patients with morphine (3.3%) vs. without morphine (8.7%). However, pre-hospital use of morphine was not an independent correlate of lower mortality (adjusted hazard ratio (HR) = 0.69; 95% confidence interval (CI): 0.35–1.37, P = 0.29) (Figure 1).

Figure 1

One-year survival according to pre-hospital morphine use. Kaplan–Meier curve for overall survival up to 1-year follow-up.

Analyses restricted to only those patients having been transported by emergency medical services yielded similar results (data not shown).

Propensity score-matched cohorts

Two propensity score-matched cohorts of 388 patients with similar baseline characteristics were built (see Supplementary material online, Table S1). Patients who received morphine had a greater decrease in heart rate and systolic blood pressure than those who did not. In-hospital death and 1-year mortality were similar in the patients who received compared with those who did not receive pre-hospital morphine (1.0 vs. 1.5% and 3.4 vs. 5.4%, respectively; Supplementary material online, File S1). Other in-hospital complications were not significantly different in both groups (including stent thrombosis 1.0 vs. 1.0% and non-fatal recurrent MI: 1.8 vs. 1.0%). Rate of TIMI 2 or 3 flow before PCI was lower in patients having received morphine (40 vs. 46%).

Subgroup having received thienopyridines in the pre-hospital setting

Among the 1108 patients in whom thienopyridines were administered pre-hospital (18% treated with prasugrel), 415 (37%) had also received morphine before hospital admission. As in the whole cohort, morphine-treated patients were younger and had a lower GRACE risk score (see Supplementary material online, Table S2). In-hospital complications were numerically less frequent in patients receiving morphine, and in-hospital death was significantly lower. After adjustment on baseline characteristics and reperfusion therapy, however, there was no difference in hospital complication rates according to pre-hospital use of morphine (see Supplementary material online, Table S3). One-year mortality, however, was lower in patients receiving pre-hospital morphine (2.4 vs. 5.9%; adjusted HR = 0.45; 95% CI: 0.21–0.93, P = 0.03).

Replication cohort

Among the 3059 patients included in the FAST-MI 2005 registry, 1726 had STEMI of LBBB, of whom 279 (16%) had received morphine in the pre-hospital setting. Baseline characteristics differed between patients with or without pre-hospital morphine, with a pattern consistent with what was found in the 2010 cohort (see Supplementary material online, Table S4). Likewise, there was no evidence of increased complications in patients treated with morphine: in-hospital mortality was significantly lower in the morphine-treated population, but only a non-significant trend persisted after multivariate adjustment. Similar results were also observed in the population who had also received thienopyridines before hospital admission (see Supplementary material online, Table S5). One-year survival was also not significantly different in patients with vs. without pre-hospital morphine (whole cohort: adjusted HR 0.79, 0.46–1.36, P = 0.39; patients having received pre-hospital clopidogrel: adjusted HR 0.75, 0.18–3.10, P = 0.70).

Pre-hospital morphine use and outcomes according to genetic determinants of clopidogrel response in pre-hospital clopidogrel users

Genetic testing was available in 160 patients having received pre-hospital clopidogrel (Table 4). Variants of ABCB1, a genetic determinant of clopidogrel absorption, were correlated with initial infarct-related artery patency: TIMI 3 flow before PCI was observed in 37% of the patients with the wild-type allele (CC genotype), 23% of those with one variant allele (CT genotype) and 11% of those with two variant alleles (TT genotype) (P for trend = 0.01). The impact on 30-day (2.3, 2.3, and 3.6%) and 1-year death (4.7, 5.7, and 10.7%) rates, however, was not statistically significant. Neither TIMI 2 or 3 flow nor death rates differed in patients having or not received pre-hospital morphine, whatever the ABCB1 genotype. Likewise, although infarct-related artery patency was correlated with CYP2C19 loss-of-function variant alleles (P for trend = 0.049), no interaction was observed with pre-hospital morphine use; in particular, in patients without CYP2C19 loss of function variant alleles, TIMI 3 flow was found in 31% of those receiving morphine, compared with 27% in those without morphine (P = 0.66), and mortality was also not significantly different.

Table 4

Thrombolysis in Myocardial Infarction 3 flow before percutaneous coronary intervention and mortality with respect to pre-hospital morphine use in patients with pre-hospital clopidogrel, according to genetic variants of CYP2C19 (clopidogrel metabolism) and ABCB1 (clopidogrel absorption)

Table 4

Thrombolysis in Myocardial Infarction 3 flow before percutaneous coronary intervention and mortality with respect to pre-hospital morphine use in patients with pre-hospital clopidogrel, according to genetic variants of CYP2C19 (clopidogrel metabolism) and ABCB1 (clopidogrel absorption)

Discussion

The present data from a nationwide registry indicate that, in STEMI patients, pre-hospital morphine use was more frequent in younger patients with typical chest pain, calling earlier, and with more intense chest pain. Morphine use was associated with a decrease in heart rate, a potentially beneficial haemodynamic effect, and was not associated with higher rates of in-hospital complications or worse long-term survival. These results were observed both in the whole population of STEMI patients and in the population having received thienopyridines in the pre-hospital setting. The results were consistent after multivariate adjustments and propensity score matching and were confirmed by the replication analysis in a second cohort. Exploratory genetic analyses also suggest that there was no deleterious impact of pre-hospital morphine use in patients treated with pre-hospital clopidogrel, whatever their genetic profile in terms of CYP2C19 (clopidogrel metabolism) and ABCB1 (clopidogrel absorption).

Pre-hospital morphine use is a class I recommendation for pain relief, breathlessness, and anxiety in patients presenting with AMI.1,2 Despite these recommendations, and likely because of the absence of specific studies designed to assess its efficacy, morphine was used in a minority of patients in the pre-hospital setting (19%), even among those managed by emergency medical services (23%). Data on the use of opioids in the pre-hospital management of ACS patients are scarce. In the ATLANTIC trial,5 ST resolution before primary PCI, an endpoint which was not collected in our study was observed more often after pre-hospital administration of ticagrelor when morphine had not been administered. However, it is noteworthy that in ATLANTIC, TIMI 3 flow of the infarct-related artery before PCI according to pre-hospital administration of ticagrelor did not markedly differ in patients having received morphine or not (14 vs. 21% in patients with ticagrelor and 15 vs. 20% in those without pre-hospital ticagrelor). The reasons for the discrepancy between the impact of pre-hospital administration of ticagrelor on infarct-related artery patency and ST-resolution observed in ATLANTIC remain speculative. In contrast, de Waha et al.14 found that intravenous morphine at the acute stage of STEMI reduced reperfusion success after primary PCI as assessed by magnetic resonance imaging, irrespective of pre-PCI TIMI flow. In the CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the ACC/AHA Guidelines) registry, 29.8% of patients with non-ST-elevation ACS received morphine within 24 h of presentation,15 and patients treated with morphine either alone, or in combination with nitroglycerin, had a higher mortality even after risk adjustment (OR 1.41; 95% CI 1.26–1.57).

These results have generated interrogations on the role of morphine in STEMI patients. Indeed, opioids inhibit gastric emptying, which delays absorption and might decrease peak plasma levels of oral drugs.16 Recently, Hobl et al.3 showed that, in healthy volunteers, administration of morphine retards the absorption of clopidogrel, consequently leading to low initial concentrations of its active metabolite, and thereby delaying the pharmacodynamics (PDs) response by an average of 2 h. At the acute stage of MI, morphine has also been shown to delay absorption of other cardiovascular medications such as isosorbide mononitrate.17,18

Our results, both in the whole cohort and in the population having received thienopyridines in the pre-hospital setting, show that the above-mentioned pharmacokinetic (PK) and PD findings do not appear to translate into relevant early or long-term clinical consequences. This lack of correlation between PK/PD data and clinical events has also been observed in other instances such as the proton pump inhibitor and clopidogrel interaction.19 In the FAST-MI 2005 cohort, including both STEMI and non-ST-elevation myocardial infarction patients, genetic polymorphisms of ABCB1 and CYP2C19 were correlated with occurrence of ischaemic events in patients treated with clopidogrel.6 In the current analysis restricted to STEMI patients treated with pre-hospital clopidogrel, infarct-related artery patency before primary PCI was correlated with ABCB1 and CYP2C19 polymorphisms, but no interaction with morphine administration was found regardless of CYP2C19 and ABCB1 genetic polymorphisms.

Although the association between pre-hospital morphine administration and 1-year mortality was not statistically significant, the HR indicating a 31% lower risk of death in the 2010 cohort, and a 21% reduction in the 2005 replication cohort, might correspond to a clinically relevant impact and warrants further studies on the clinical role of morphine in this setting. In fact, a plausible explanation of the absence of deleterious clinical impact of morphine is that its favourable haemodynamic effects at the acute stage of MI, namely, a decrease in heart rate without significant change in systolic blood pressure, consistent with previous data,20 may have counterbalanced any potential deleterious impact in terms of thienopyridine absorption delay.

Study limitations

Our study provides a detailed description of patients pre-treated with morphine in the pre-hospital setting, rarely available from real-world data. It suffers the same limitations as all observational studies, however. Comparisons between patients pre-treated with morphine and those not pre-treated were not randomized and, despite careful adjustments on a large number of potentially confounding variables, the results can only be considered indicative, even if the use of propensity score matching may limit some of the biases inherent to observational data, by giving the opportunity to compare outcomes in cohorts of patients with very similar baseline characteristics. Of note, however, the results in the replication cohort were remarkably consistent with the main analysis. The precise timing of morphine and thienopyridine administration in the ambulance was not available. Finally, because of the relatively small number of patients who had received thienopyridines in the pre-hospital setting and had a genetic evaluation, the results of the analyses according to the genetic profile of CYP2C19 and ABCB1 can only be considered exploratory.

Conclusions

In a routine practice setting, pre-hospital morphine use in STEMI patients was not associated with increased rates of in-hospital complications, including stent thrombosis and 1-year death. At this stage, considerations on the PK/PD interaction between morphine and P2Y12 inhibitors do not seem sufficient to reconsider international guidelines on morphine use in STEMI patients. Pending a specific trial on the use of morphine at the acute stage of myocardial infarction, it still seems advisable to continue using morphine as appropriate in patients with severe chest pain.

Supplementary material

Supplementary material is available at European Heart Journal online.

Authors’ contributions

E.P. and N.D.: performed statistical analysis. T.S. and N.D.: handled funding and supervision, and acquired the data. E.P., T.S., and N.D.: conceived and designed the research, and drafted the manuscript. L.L., N.B., N.A., P.H., G.C., S.C., G.S., L.M., G.D., P.G., F.S., and E.B.-C.: made critical revision of the manuscript for key intellectual content.

Funding

FAST-MI 2010 is a registry of the French Society of Cardiology, supported by unrestricted grants from: Merck, the Eli-Lilly-Daiichi-Sankyo alliance, AstraZeneca, Sanofi-aventis, GSK, and Novartis. FAST-MI 2005 is a registry of the French Society of Cardiology, supported by unrestricted grants from Pfizer and Servier. Additional support was obtained from a research grant from the French Caisse Nationale d’Assurance Maladie.

Conflict of interest: None declared.

Acknowledgements

The authors are deeply indebted to the patients who accepted to participate and to all physicians who took care of them. Special thanks to all involved in the collection and analysis of the data: ICTA contract research organization (Fontaine-lès-Dijon, France), and the devoted personnel of the URCEST (Assistance Publique des Hôpitaux de Paris and University Paris 6) and INSERM U 1027 (Toulouse). Special thanks to Vincent Bataille, PhD, for his careful data management, to Benoît Pace (Société Française de Cardiologie) for his invaluable assistance in designing the electronic CRF, and to Geneviève Mulak, Pharm D. (Société Française de Cardiologie) and Elodie Drouet, MSc, who supervised patient follow-up.

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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: .

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: .

Topic:

• non-st elevated myocardial infarction
• st segment elevation myocardial infarction
• morphine
• st segment elevation
• process of absorption
• mortality
• p-glycoprotein
• thienopyridine
• cyp2c19 protein, human
• fast-mi registry

Supplementary data

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Re:"Correlates of pre-hospital morphine use in ST-elevation myocardial infarction patients and its association with in-hospital outcomes and long-term mortality: the FAST-MI (French Registry of Acute ST-elevation and non-ST-elevation Myocardial Infarction) p…"Puymirat, et al., 37 (13): 1063-1071 doi:10.1093/eurheartj/ehv567

13 April 2016

Etienne Puymirat, MD

European Hospital of Georges Pompidou

Dear Editor,

We do thank Dr McEvoy for giving his view on our paper about pre-hospital morphine use in STEMI patients. As rightly pointed out, observational data are always subject to confounding.

However, multivariate analyses and propensity score analyses offer means to (at least partly) limit the impact of confounders. Contrary to what Dr McEvoy thinks, we did adjust for many potential confounders, including type of centre and type of reperfusion therapy used (i.e. primary PCI or intravenous fibrinolysis), as stated in the methods section. As shown in Supplemental Table 1, most patient characteristics in the propensity score-matched cohorts were balanced; specifically, to answer Dr McEvoy's concern, 42% of the patients in each group were admitted to academic institutions, 20% in the pre-hospital morphine group and 19% in the matched group without morphine received pre-hospital fibrinolytic treatment, and 75% and 74%, respectively, had primary PCI. Thus, although the possibility of bias still remains, most of the main prognostic factors were well balanced between the 2 matched cohorts, and adjusted for in the Cox multivariate analysis of the whole cohort. Since the preparation of the published manuscript, we have had the opportunity to obtain 3-year follow-up data; the adjusted hazard ratio for 3-year mortality with pre-hospital morphine was 1.01, 95% confidence interval 0.65-1.57, P=0.96.

Finally, as suggested by Dr McEvoy, we looked at the relationship between morphine administration in the first 24 hours and one-year death; adjusted hazard ratio for one-year mortality in patients receiving morphine either pre-hospital or within 24 hours of admission was 0.98, 95% confidence interval 0.60-1.60, P=0.92.

Regards,

Etienne Puymirat 1, MD, PhD, Tabassome Simon 2,3,4, MD, PhD and Nicolas Danchin 1, MD, PhD

1 European Hospital of Georges Pompidou, Department of Cardiology, Assistance Publique des Hôpitaux de Paris (AP-HP), Paris, France; University Paris Descartes, Paris, France; INSERM U-970, Paris, France

2 AP-HP - Hospital Saint Antoine, Clinical Research Unit (URC) - Est, Paris, France

3 INSERM, U-698 Paris, France

4 UPMC-Paris 06, Paris, France

Submitted on 13/04/2016 12:00 AM GMT

Re:"Correlates of pre-hospital morphine use in ST-elevation myocardial infarction patients and its association with in-hospital outcomes and long-term mortality: the FAST-MI (French Registry of Acute ST-elevation and non-ST-elevation Myocardial Infarction) p…"Puymirat, et al., 37 (13): 1063-1071 doi:10.1093/eurheartj/ehv567

28 January 2016

John William McEvoy, Assistant Professor of Medicine and Cardiology

Johns Hopkins University School of Medicine

A large retrospective analysis, conducted by Puymirat et al. and published in the European Heart Journal, assessed in-hospital cardiac complications and 1-year survival according to pre-hospital morphine use in 4,164 STEMI patients from a contemporary French acute coronary syndrome registry. The authors found that, after multivariable adjustment and propensity matching, in-hospital complications and 1-year survival were not increased with pre-hospital morphine use (e.g. HR=0.69; 95% CI: 0.35-1.37). However, it is very possible that the results of this analysis are biased by residual confounding. Patients in this registry who received pre-hospital morphine were more like to undergo fibrinolysis, be admitted to hospitals with catheterization laboratories (93 vs. 68%, P <0.001), and to receive primary PCI (90 vs. 77%, P<0.001), none of which were appropriately and fully accounted for in either the multivariable adjustment or in the propensity score. This creates the possibility of significant bias as these three variables are all associated with the exposure (pre-hospital morphine) and are also clearly associated with (improved) outcomes (thereby fulfilling the classic definition of confounding). I respectfully suggest that the authors consider repeating the propensity score by including these important variables in the model. In particular, these results are at odds with multiple prior reports (Am Heart J. 2005:1043-1049, Clinical research in cardiology. 2015;104:727-734, and The New England journal of medicine. 2014;371:1016-1027). It is also worth noting that, despite their main findings, Puymirat et al report a higher rate of non-fatal recurrent MI in patients pretreated with morphine (1.8 vs. 0.7%, P=0.03). Furthermore, this study only evaluated pre-hospital morphine (not in-hospital use which is when most P2Y12 inhibitors are administered). Respectfully,

Submitted on 28/01/2016 12:00 AM GMT

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