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Three Part Question

In [patients presenting with acute decompensated heart failure], does [use of opiates] is [associated with an increased mortality] ?

Clinical Scenario

During a night shift, you receive in your resuscitation room your classical 6am pulmonary oedema patient. You start nitrates, furosemide and you initiate positive pressure ventilation, but you are asking yourself if you should still use the M of your LMNOP treatment mnemonic.

Search Strategy

1.No BestBets answering the clinical question was found

2.The website clinicaltrials.gov was searched for an ongoing trial on the topic: 1 completed observational cohort study was found, with completion of data collection in 2009 which was also found in MEDLINE

3.MEDLINE (PUBMED)

4. EMBASE

5.Cochrane : There were no Cochrane review on the subject



.MEDLINE (PUBMED) :
-1: opioid [all fields] OR opiates [all fields] OR morphine [all fields] OR hydromorphone [all fields] OR fentanyl [all fields] : 152 337
-2: (((heart failure) OR left ventricular) OR acute decompensated) OR pulmonary edema OR pulmonary oedema: 356 122
-3: 1+2: 1791
-4: 1+2 filter human and clinical trial and observational study and comparative study (in order to exclude reviews): 386 papers
-After abstract/title review = 6 relevant papers
-1 small study was excluded because written in other language than English and was a chart review (4)
-1 small study was excluded because was comparing combination therapy (furosemide + opiates vs nitrates) (5)
-1 review article was excluded because contained mainly small retrospective studies not concerning mortality (6)
-3 relevant papers included

4.Embase
a.'opiate'/exp OR opiate OR morphine OR opioids: 196 489
b.'congestive cardiac failure' OR 'pulmonary oedema' OR acute AND decompensated AND cardiac AND failure: 1796
c.A+b combined: 25 articles
i.After abstract review, 4 relevent papers, only one new paper not previously found but was excluded because it was an abstract
d.'opiate'/exp OR opiate AND ('heart'/exp OR heart) AND failure: 1586
e.Clinical trial AND retrospective filter: 370
f.After abstract review: no new paper

Search Outcome

Relevant papers included = 3

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Peackock and al. 2008 United States	Patients with discharge diagnosis of ADHF from ADHERE registry N=147 362	Retrospective study (registry analysis) with multivariate analysis and logistic regression. Patients who received morphine (14.1%) vs not (5.9%)	Mechanical ventilation	15.4% vs 2.8% (p<0.001)	Retrospective study without randomization Morphine could have been given more often in patients with more severe disease for palliative/symptomatic purposes No precision on amount of morphine received
			Length of hospitalisation	5.6 vs 4.2days (p<0.001)
			ICU admissions	38.7% vs 14.4% (p<0.001)
			Mortality	13.0% vs 2.4% (p<0.001)
			Adjusted OR Mortality	4.84 95% CI 4.52 to 5.18
Gray and al. 2010 United Kingdom	Patients with severe acidotic pulmonary oedema N=1062	Retrospective analysis of a RCT cohort (3CPO)Patients with opiates (51.4%) vs not (48.6%)	7 days mortality	10.4% vs 8.8% (p 0.395)	Might be underpowered to detect small differences Severe symptoms limiting external validity to non acidotic patients or patients with ADHF without ACPO
			Change in pH	0.093 vs 0.105 (p <0.05)
Iakobishvili and al. 2011 Israel	Patients with ADHF hospitalised in any public hospital during a two months period N= 2336	Prospective cohort of a national survey Patients who received i.v. morphine (9.3%) vs not (90.7)	Unadjusted mortality	11.5% vs 5%	Observational study not randomized No information on dose received Relatively small cohort No information on mechanical ventilation (more severe patients with increased mortality and more chance of receiving morphine for sedation)
			Adjusted OR of in-hospital mortality	2.0 ( 95% CI 1.1-3.5 p= 0.02)
			multivariate regression of 218 matched pairs of patients in-hospital morality OR	1.2 (95% CI 0.6-2.4)

Comment(s)

Abbreviations : ADHF acute decompensated heart failure, ACPO acute cardiogenic pulmonary oedema, ICU intensive care unit, RCT randomized controlled trial, OR odd ratio, VAS visual analogue scale All three relevant studies showed an association between morphine and mortality in patients with ADHF. However, the only study who made a propensity analysis did not find a statistically significant increase in mortality among patients who received intravenous morphine. Therefore, no causality between use of morphine and the increased mortality rate can be identified. Furthermore, patients who received morphine were at higher risk of needing an intubation, an ICU admission or having an increased length of stay in hospital, although there is still no causality that can be identified. The only study looking at breathlessness level did not report a benefit on a VAS among patients receiving opiates. Since all studies were retrospective analysis, we lack a prospective randomized trial to correctly answer our clinical question.

Clinical Bottom Line

Although use of opiates in ADHF is associated with an increased mortality, there is no evidence that this association is in fact a causality effect. Since the clinical benefit seems to be limited or even absent and it might be associated with an increased risk of mechanical ventilation, ICU admission and length of stay, it should be used with caution.

References

1. Peacock WF, Hollander JE, Diercks DB, Lopatin M, Fonarow G, Emerman CL. Morphine and outcomes in acute decompensated heart failure: an ADHERE analysis. Emerg Med J. 2008 Apr;25(4):205-9.
2. Gray A1, Goodacre S, Seah M, Tilley S. Diuretic, opiate and nitrate use in severe acidotic acute cardiogenic pulmonary oedema: analysis from the 3CPO trial. Q J Med 2010; 103:573–581
3. Iakobishvili Z, Cohen E, Garty M, Behar S, Shotan A, and al. & for the Heart Failure Survey in Isarel (HFSIS) Investigators. Use of intravenous morphine for acute decompensated heart failure in patients with and without acute coronary syndromes Acute Cardiac Care 2011, 13:2, 76-80