Heart failure: pulmonary oedema: high dose nitrates and low dose diuretics were effective.

Clinical bottom line (level 1b)

  1. Patients with severe pulmonary oedema who received high dose isosorbide dinitrate and low dose furosemide compared with high dose furosemide and low dose isosorbide dinitrate were less likely to require mechanical ventilation (NNT = 4 at 12 hours) or have a myocardial infarct (NNT = 5 at 24 hours) .
  2. The effect on mortality and adverse events was unclear.
  3. Patients on high dose isosorbide dinitrate had a greater rise in oxygen saturation (mean of 5%) and a greater fall in respiratory rate (mean of six breaths a minute).
Cotter et al: Lancet 1998; 351: 389-393
Expires July 2003

The study

Unblinded concealed randomised trial with intention-to-treat
Setting: mobile emergency room of four acute hospitals, Israel

104 patients (aged mean 74 years, 52% male) pulmonary oedema (clinical signs confirmed on chest x-ray and oxygen saturation <90% with the patient sitting)

Excluded if
  • current treatment with oral nitrates >40 mg daily
  • isosorbide mononitrate >2 times a day; isosorbide trinitrate >3 times a day
  • current furosemide therapy >80 mg daily
  • blood pressure <110/70 mmHg
  • previous adverse reaction to study drugs


    • Control Group: (n = 52, 52 analysed): furosemide 80 mg iv bolus, and isosorbide dinitrate 1 mg/hour (16 µ g/min) increased by 1 mg/hour every 10 minutes
    Experimental Group: (n = 52, 52 analysed): isosorbide dinitrate 3 mg bolus iv every 3 minutes
    All patient were sat up, had oxygen at 10 l/min, morphine 3 mg iv, and furosemide 40 mg iv. Treatment was continued until oxygen saturation was 96% or mean arterial blood pressure decreased by = 30% or <90 mmHg.
    100% followed for ?
    Outcome notes:
    • need for mechanical ventilation : within 12 hours of admission (oxygen saturation <80% for >20 minutes, or progressive dyspnoea, apnoea or severe arrhythmias despite treatment)
    • myocardial infarction : new Q waves on ECG or an increase in CK>150 with CK-MB>6%
    • adverse effects : severe bradyarrhythmia or tachyarrhythmias, excessive reduction in mean blood pressure

    The evidence

    Outcome Time to outcome CEREERRRR
    (95% CI)    		ARR
    (95% CI)    		NNT
    (95% CI)
    death unknown 3
    (5.77%)    		 1
    (1.92%)    		 67%
    (-210% to 96%)    		 3.85%
    (-3.51% to 11.2%)    		 26
    (NNT = 9 to infinity;
    NNH = 28 to infinity)
    need for mechanical ventilation 12 hours 21
    (40.4%)    		 7
    (13.5%)    		 67%
    (28% to 84%)    		 26.9%
    (10.7% to 43.2%)    		 4
    (2 to 9)
    myocardial infarction 24 hours 19
    (36.5%)    		 9
    (17.3%)    		 53%
    (5% to 76%)    		 19.2%
    (2.59% to 35.9%)    		 5
    (3 to 39)
    adverse effects unknown 7
    (13.5%)    		 5
    (9.62%)    		 46%
    (-111% to 76%)    		 3.85%
    (-8.41% to 16.1%)    		 26
    (NNT = 6 to infinity;
    NNH = 12 to infinity)

    Outcome Control Group
    (SD)    		 Experimental Group
    (SD)    		 Mean Difference
    (95% CI)
    fall in respiratory rate 5
    (6)     		11
    (7)     		6
    (3 to 9)
    rise in oxygen saturation (%) 13
    (9)     		18
    (9)     		5
    (1 to 9)

  • No patient developed a severe arrhythmia.

    • Comments

    1. The study is too small to show any clear effect on mortality or adverse effects when using high dose isosorbide dinitrate.
    2. The does of furosemide used with nitrate is very small in comparison to that usually used.

    Citation

    1. Cotter G, Metzhor E, Kaluski E, et al: Randomised trial of high-dose isosorbide dinitrate plus low-dose furosemide versus high-dose furosemide plus low-dose isosorbide dinitrate in severe pulmonary oedema. Lancet 1998; 351: 389-393
    Search Terms: hand search: found in Evidence-Based Medicine (1999) issue 1
    Contributor: Chris Ball and Clare Wotton, July 2000
    Reviewer: Christian Torp-Pedersen

    Clinical Question.
    Patient heart failure
    Intervention or Exposure high dose isosorbide dinitrate and low dose furosemide
    Comparison low dose isosorbide dinitrate and high dose furosemide
    Outcome mortality, mechanical ventilation, MI