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Three Part Question

In [adults with moderate to severe acute left ventricular failure] are [nitrates better than opiates and diuretics] at [reducing mortality]?

Clinical Scenario

A 69 year old male with a history of heart failure presents to the A & E department with acute onset of shortness of breath. The clinician wonders whether it would be better to treat him with nitroglycerin or a combination of furosemide and morphine.

Search Strategy

Medline 1966 to June 2005 week 4
EMBASE search 1980 to Week 31 2005
Medline search (exp Heart Failure, Congestive/ OR exp Adult/ OR exp Cardiac Output, Low/ OR cardiac failure.mp/ OR ccf.mp/ OR exp Pulmonary Edema/ OR exp Cardiotonic Agents/ OR exp Acute Disease/ OR exp Natriuretic Peptide, Brain/ OR pulmonary edema.mp/ OR pulmonary oedema.mp/ OR exp Ventricular Dysfunction, Left/ OR acute systolic failure.mp/ OR shortness of breath.mp/ OR exp Dyspnea/ OR dyspnoea.mp/ OR exp Morphine/ OR left ventricular failure.mp/ OR lv failure.mp/ OR left ventricular heart failure.mp/ OR lvf.mp.) AND (opiates.mp. OR exp Narcotics/ OR morphine.mp. OR MORPHINE/ OR exp MORPHINE DERIVATIVES/) AND (nitrates.mp. OR exp NITRATES/ OR exp Coronary Vessels/ OR exp Vasodilator Agents/ OR exp Nitroglycerin/ OR gtn.mp. OR exp Heart/ OR glyceryl trinitrate.mp.) AND (diuretics.mp. OR exp DIURETICS, OSMOTIC/ OR exp DIURETICS, THIAZIDE/ OR exp DIURETICS/ OR exp DIURETICS, SULFAMYL/ OR furosemide.mp. OR exp FUROSEMIDE/ OR frusemide.mp.)
Embase search - Heart failure.mp OR exp heart failure OR exp heart left ventricle failure OR exp heart left ventricle performance OR lvf.mp OR ccf.mp congestive cardiac failure.mp. OR exp congestive heart failure OR ventricular dysfunction.mp. OR exp heart ventricle function OR exp paroxysmal dyspnea OR exp dyspnea OR dyspnea.mp OR dyspnoea.mp OR pulmonary edema.mp OR exp lung edema OR pulmonary oedema.mp OR cardiac insufficiency.mp OR failing heart.mp AND diuretic$.mp. OR exp diuretic agent OR exp furosemide OR furosemide.mp OR frusemide.mp OR loop diuretic.mp. OR exp loop diuretic agent AND exp glycerol nitrate OR nitrate$.mp OR exp isosorbide 5 nitrate or exp glycerol 1 nitrate OR exp glycerol 2 nitrate OR exp nitrate OR exp isosorbide 2 nitrate OR glyceryl trinitrate.mp. OR exp glyceryl trinitrate OR vasodilator.mp. OR exp vasodilator agent exp morphine OR morphine.mp OR opiate$.mp OR exp opiate LIMIT to human and English language

Search Outcome

1471 papers were found on the medline search and 268 on the EMBASE search.
2 papers were deemed relevant.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Beltrame et al 1998 Australia	87 patients presenting with acute pulmonary oedema over a 16 month period were initially selected. 18 patients not enrolled due to exclusion criteria (MI, ARF, need for intubation, unable to consent). Of 69 patients left 4 subsequently not shown to have pulmonary oedema but included in the intention to treat analysis. 32 patients were given furosemide and morphine (FM). 37 patients were given nitroglycerine and N-acetylcysteine (NN).	Randomised Controlled Trial	Clinical parameters at 1hr (dyspnoea & crepitations score, resp rate, pulse and systolic BP)	No significant difference found.	Method of randomisation not clear. Clinical outcomes for patients following treatment period difficult to ascertain. Text mentions 3 in-hospital deaths but states not attributed to pulmonary oedema and does not specify treatment group. Estimated a priori that 62 patients would provide 90% power at ?=0.05 to detect 10mmHg difference in PaO2 but post hoc analysis gave only an 80% power to detect 18.5mmHg PaO2 difference.
			Gas exchange parameters at 1hr (pH, Pa02/FiO2 ratio, PaCO2)	No significant difference found.
Cotter G et al Feb 1998 Israel	110 patients who presented with signs of heart failure to mobile emergency units were treated with oxygen, 40mg furosemide iv and 3mg morphine. Inclusion criteria included pulmonary oedema on CXR and oxygen saturations of <90% on air when sitting up. They were then randomised to either group A who received high-dose nitrates(3mg isosorbide dinitrate every 5min) and low-dose diuretic(only the initial 40mg furosemide) or group B who received low-dose nitrates (isosorbide dinitrate 1mg/h increasing every 10min by 1mg/h) and high-dose diuretics(80mg furosemide every 15min).	Randomised, controlled trial.	Death in hospital	Group A - 1 (2%), Group B - 3 (6%) P=0.61	Each patient in study had both treatments,although in different proportions, as it was felt to be unethical to withhold standard treatment from these patients. The amounts of drug received by each patient group is markedly different and the outcomes do appear to have been influenced by this.
			Required mechanical ventilation	Group A - 7 (13%), Group B - 21 (40%) P=0.0041
			Myocardial Infarction (new Q waves on ECG or increase in Creatinine Phosphokinase over 150IU/L with MB fraction greater than 6%)	Group A - 9 (17%), Group B - 19 (37%) P=0.047

Comment(s)

Acute pulmonary oedema due to cardiac failure is an increasingly common presentation in patients due to an ageing population and improved survival in patients with cardiac disease. Although treatment with oxygen, opiates, diuretics and now nitrates is well established there is little evidence demonstrating the benefits of the individual components of this treatment.

Clinical Bottom Line

Nitrate therapy is likely to be as effective in treating acute heart failure as a combination of diuretic and opiate therapy. High dose nitrate with low dose diuretic is likely to improve outcome compared with low-dose nitrate and high dose diuretic.

Level of Evidence

Level 3 - Small numbers of small studies or great heterogeneity or very different population.

References

1. Beltrame J F, Zeitz C J, Unger S A et al Nitrate Therapy Is an Alternative to Furosemide/Morphine Therapy in the Management of Acute Cardiogenic Pulmonary Edema Journal of Cardiac Failure 1998;4(4):271-279
2. Cotter G, Metzkor E, Kaluski E, Faigenberg Z, Miller R, Simovitz A, Shaham O, Marghitay D, Koren M, Blatt A, Moshkovitz Y, Zaidenstein R, Golik A Randomised trial of high-dose isosorbide dinitrate plus low-dose furosemide versus high-dose furosemide plus low-dose isosorbide dinitrate in severe pulmonary oedema The Lancet 7 Feb 1998; 389-393