Table 3.
Randomized controlled trials of inotropes in heart failure
| Source, design | N | Follow-up | Inotrope | Cardiac index at baseline | Mortality | Other outcomes in the inotrope group vs placebo |
|---|---|---|---|---|---|---|
| Poor outcomes | ||||||
| Cohn et al, 199867 Vesnarinone Trial, randomized to vesnarinone in two different doses and placebo |
3,833 | 286 days | Vesnarinone, oral | NR | Mortality: Vesnarinone lower dose: 21% Vesnarinone higher dose: 22.9% Placebo: 18.9%, P<0.02 (vs placebo), the difference is presumably due to sudden (arrhythmic) death |
Improved quality of life |
| Cowley et al, 199466 The Enoximone Trial, a randomized, double-blind, placebo-controlled trial: enoximone vs placebo |
151 | One year | Enoximone, oral | NR | Number of deaths: Enoximone: 27 Placebo: 18, P<0.05 Sudden deaths: Enoximone: 11 Placebo: 5 Progressive HF death: Enoximone: 12 Placebo: 11 The trial was ended early because of an excess mortality in the patients treated with enoximone |
Improved quality of life |
| Uretsky et al, 199065 Enoximone trial Double-blind, randomized, placebo-controlled enoximone vs placebo |
102 | 4 months | Enoximone, oral | NR | Mortality: Enoximone: 5 patients Placebo: 0 patients, P<0.05 Two deaths were sudden, two were from progressive HF, and one was from acute myocardial infarction |
No differences in symptoms or exercise duration at the end of 4 months |
| Hampton et al, 199768 Randomized, placebo-controlled ibopamine vs placebo |
1,906 | About 1 year | Ibopamine, oral | NR | Mortality: Ibopamine: 232 (25%) Placebo: 193 (20%) RR: 1.26 (95% CI: 1.04–1.53), P=0.017. The trial was stopped early, because of an excess of deaths in the ibopamine group |
|
| Packer et al, 199169 Prospective Randomized Milrinone Survival Evaluation (PROMISE) trial Double-blind, randomized oral milrinone vs placebo |
1,088 | 6 months | Oral milrinone | NR | Mortality from all causes: Milrinone: 30% Placebo: 24% (A 28% increase in all cause mortality, P=0.038, and a 34% increase in cardiovascular mortality, P=0.016). The trial stopped prematurely because of survival compromise on milrinone |
Hospitalizations: Milrinone 44% Placebo 39%, P=0.041 |
| The Xamoterol in Severe Heart Failure Study, 199085 Randomized, double-blind, placebo-controlled Randomization: xamoterol vs placebo |
516 | 13 weeks | Xamoterol, oral (beta receptor agonist) | NR | Mortality: Xamoterol: 9.1% Placebo: 3.7%, P=0.02 |
|
| Metra et al, 200975 The Studies of Oral Enoximone Therapy in Advanced HF (ESSENTIAL), two identical, randomized, double-blind, placebo-controlled trials that differed only by geographic location |
1,854 | 17 months | Enoximone, oral | NR | All-cause mortality: no difference | The 6-minute walk distance increased with enoximone, compared with placebo, in ESSENTIAL-I (P=0.025, not reaching, however, the pre-specified criterion for statistical significance of P<0.020) |
| Elis et al, 199847 Randomized, double-blind, placebo-controlled dobutamine vs placebo over a 24-hour period every 2 to 3 weeks |
19 | 6 months | Dobutamine IV, intermittent | NR | The median survival: Dobutamine: 4.6 months Placebo: 8 months No difference |
No difference between the number of admissions for HF |
| Erlemeier et al, 199248 Dobutamine vs placebo |
20 | 4 weeks | Dobutamine, IV intermittent | NR | No mortality difference | Dobutamine: exercise duration increase, body weight decreased Placebo: no change |
| Oliva et al, 199949 DICE (Dobutaminanell’Insufficienza Cardiaca) trial: dobutamine vs standard treatment |
38 | 6 months | IV dobutamine, intermittent | 1.89±0.1 L/minute/m2 | Dobutamine: 5 deaths, 2 heart transplants Standard treatment: 3 deaths No difference |
Hospitalizations for all causes: no difference Dobutamine: 11 (7 for HF) Standard treatment: 17 (11 for HF) No difference in NYHA class and in 6-minute walking test |
| Massie et al, 198578 Double-blind, placebo-controlled amrinone vs placebo |
99 | 12 weeks | Amrinone, oral | NR | No mortality difference | Exercise tolerance: no difference |
| Narahara, 199179 The Western Enoximone Study Randomized, placebo-controlled enoximone vs placebo |
164 | 12 weeks | Enoximone, oral | NR | No mortality difference | Enoximone: greater increases in exercise time than placebo treatment at weeks 4 and 8 but not after 12 weeks |
| Van Veldhuisen et al, 199380 The Dutch Ibopamine Multicenter Trial Double-blind placebo-controlled, randomized ibopamine vs digoxin vs placebo |
161 | 6 months | Ibopamine, oral | NR | No mortality difference | |
| Good outcomes | ||||||
| Dubourg et al, 199081 A double-blind, randomized trial Enoximone vs placebo |
30 | 31 days | Enoximone, oral | 2.17±0.7 L/minute/m2 | Mortality: Enoximone: 1 Placebo: 3 |
Symptoms improvement on enoximone |
| Feldman et al, 200776 EMOTE trial (Enoximone in Intravenous Inotrope-Dependent Subjects Study) Enoximone vs placebo Enoximone was used to wean patients from IV inotropes |
201 | 6 months | Oral enoximone | NR | Alive and free of IV inotropes at 30 days: Enoximone: 62 (61.4%) Placebo: 51 (51%) At 60 days Enoximone: 46.5% Placebo: 30%, P=0.016 Time to death or re-initiation of IV inotropes: At 6 months: HR: 0.76 (95% CI: 0.55–1.04) At 60 days: HR: 0.62 (95% CI: 0.43–0.89), P=0.009 At 90 days: HR: 0.69 (95% CI: 0.49–0.97), P=0.031, favoring enoximone |
|
| Feldman et al, 199382 Vesnarinone Study Randomized, double-blind, placebo-controlled vesnarinone vs placebo |
477 | 6 months | Vesnarinone, oral | NR | Mortality plus worsening HF: Vesnarinone: 26 Placebo: 50, P=0.003 A 62% reduction (95% CI: 28%–80%) in the risk of dying from any cause among the patients receiving vesnarinone |
Vesnarinone: quality of life improved to a greater extent than in the placebo group over 12 weeks (P=0.008) |
| Nanas et al, 200471 Randomized, double-blind, placebo-controlled clinical trial Dobutamine vs placebo |
30 | 6 months | Dobutamine, IV intermittent, plus amiodarone | 2.3±0.7 L/minute/m2 | Survival: Dobutamine plus amiodarone vs placebo plus amiodarone HR: 0.403 (95% CI: 0.164–0.992; P=0.048) 1-year survival estimate: Dobutamine plus amiodarone: 69% Placebo plus amiodarone: 28%, P<0.05 2-year survival estimate: Dobutamine plus amiodarone: 44% Placebo plus amiodarone: 21%, P<0.05 |
|
| Likoff et al, 198483 Randomized, double-blind, placebo-controlled After being stabilized on amrinone, patients were randomized into continuation on amrinone or withdrawal of amrinone |
9 | Two 13-week stages | Amrinone, IV | 1.9±0.2 L/minute/m2 | Placebo: 7 patients had a significant deterioration of symptoms or exercise tolerance, or both. After 4 weeks of readministration of amrinone, clinical status improved | |
| Khalife et al, 198787 Double-blind, randomized, placebo-controlled Randomization: after the first phase when IV enoximone was given to all patients, they were randomized into oral enoximone or placebo |
17 | 12 weeks | Enoximone, IV and oral, in a 2-part study | 3.42±0.72 L/minute/m2 (after enoximone IV) | Enoximone: LVEF improved from 30.1%±6.8% to 33.9%±9.9% Placebo: unchanged |
|
Abbreviations: CI, confidence interval; HR, hazard ratio; IV, intravenous; NR, not reported; NYHA, New York Heart Association; RR, relative risk; LVEF, left ventricular ejector fraction; HF, heart failure; vs, versus.