Continuous IV Dobutamine Is Associated With Increased Risk of Death in Patients With Advanced Heart Failure We studied outcomes of CHF patients getting continuous IV dobutamine in the FIRST Trial (Flolan International Randomized Survival Trial). Methods: 471 patients with class 3-4 heart failure who were enrolled in the FIRST trial were studied. Eighty patients treated with dobutamine were compared to 391 patients not treated with dobutamine. Worsening heart failure, need for vasodilators, heart attack, and total mortality were compared between the 2 groups. Results: The dobutamine group had a higher rate of first event (85% vs 65%) and a higher mortality rate (71% vs 37%) compared with the no dobutamine group. Conclusions: Dobutamine use was associated with a higher 6-month mortality rate. Long version Introduction: Advanced heart failure has high mortality and death rates, frequent and long hospital stays, and expensive medical cost for the individual and the health care system. Continuous or intermittent IV dobutamine is often used for symptom improvement and for preventing hospitalizations in advanced CHF patients. Small clinical studies have shown that IV dobutamine use may improve heart failure symptoms. However, some data suggest that continuous IV dobutamine increases mortality in CHF patients. We studied data from FIRST (Flolan International Randomized Survival Trial), a trial of continuous IV epoprostenol plus ACE inhibitors, diuretics and digoxin vs drug therapy alone in CHF patients. We studied the effects of dobutamine (at time of randomization) on clinical events and death. The outcomes of interest in FIRST were survival, heart failure symptoms, quality of life, and exercise capacity. The results showed a trend toward increased mortality in patients in the epoprostenol group. The purpose of this analysis was to measure the outcomes of CHF patients getting continuous IV dobutamine at baseline vs patients not getting dobutamine. 471 patients with class 3-4 heart failure and EF of less than 25% participated. Data Collecting: Patients had follow-up visits at 2 weeks and at one month after randomization and at monthly intervals afterward. A functional status test and physical exam were done at each follow-up visit. A 6-minute walk test and quality of life tests were done at baseline, 2 weeks, one and 3 months, and every 3 months afterward. Continuous IV Dobutamine Analysis: 2 patient groups were studied. Patients getting continuous IV dobutamine at randomization for the FIRST trial were compared to patients who were not. Dobutamine was given as a continuous IV infusion with a standard dose range of 2.5-20µg/kg/min. The following end points were modeled: worsening heart failure, need for IV vasoactive drugs, need for mechanical assist device, intubation, sudden cardiac death, heart attack, death, first event, and first morbid event (any end point except death). Results: 80 of the 471 patients (17%) in the FIRST trial were receiving continuous IV dobutamine at randomization and 391 patients (83%) were not. The average age was 65 years. Ischemic heart disease was the most common cause of heart failure. More patients in the dobutamine group were taking other IV vasoactive drugs, including nitroprusside, nitroglycerin, or milrinone (31% vs 4%). More patients received IV dobutamine in North America than in Europe, 21% vs 6%. The average dobutamine dose was 9µg/kg/min, and patients had been treated with dobutamine for an average of 14 days. On exam, patients treated with dobutamine were more likely to have a systolic murmur, S3 gallop, and class 4 CHF symptoms. In contrast, no major differences were seen in right-sided pressure, pulmonary capillary wedge pressure, or left and right EF. Heart rate and cardiac output were slightly higher in the dobutamine group. Six-month mortality rates were twice as high in the dobutamine group. The total number of deaths in the dobutamine group was 51 (64%) compared to 137 (35%) deaths in the no-dobutamine group. After adjusting for baseline factors like - age, sex, EF, other IV drugs, cause, heart class, and 6-minute walk distance - dobutamine remained one of the most important independent risk factors for death. Patients treated with dobutamine had lower survival rates regardless of heart class. Five of the nine class 3 patients given dobutamine died, while 41 of the 183 class 3 patients not treated with dobutamine died. Forty-six of the 71 class 4 patients treated with dobutamine died, and 95 of the 207 class 4 patients not receiving dobutamine died. There were no significant differences between the groups in quality of life measures. Although a trend to greater walk distance for the dobutamine group was seen, no significant differences were measured. Discussion: Our analysis of FIRST data indicate that continuous IV dobutamine may be detrimental to CHF patients. Dobutamine was associated with worse survival and clinical outcomes, and did not improve quality of life. Previous data have shown symptom and function improvement in CHF patients treated with short-term dobutamine. Dobutamine might adversely affect mortality in several different ways. It increases the risk of arrhythmias and sudden cardiac death. Dr. Dies concluded that death in patients taking dobutamine happened more often in patients with pre-existing ventricular arrhythmia. It is hard to know if the increase in sudden cardiac death is caused by dobutamine or by the underlying disease itself, since CHF is associated with a high rate of ventricular arrhythmias and sudden cardiac death. In addition to the risk of ventricular arrhythmia, dobutamine increases the heart's oxygen demand. Patients receiving dobutamine showed a heart rate 10 beats per minute higher. This may potentially result in worsening pump failure or heart attack. Neurohormones are elevated in CHF patients. There is a link between neurohormonal activity and increased mortality. Dobutamine increases neurohormones, which might explain the worse outcomes associated with its use. Although a trend to longer walk distance was seen in the dobutamine group, the lack of a significant difference in quality of life scores was surprising. Previous reports have shown consistent improvement in quality of life regardless of outcome. Several factors may contribute to this. In advanced CHF patients, rapid deterioration is common. Second, prolonged dobutamine infusion has not been well studied. In this study, IV dobutamine was given continuously for 2 weeks. Tolerance to dobutamine could have developed during this period, limiting benefit to quality of life. This study was not designed with the primary endpoint of death. A definitive trial of dobutamine in CHF would require 600-4000 patients with advanced heart failure and is unlikely to be financially supported at this time. Differences in baseline factors could have affected the results of this study. More patients in the dobutamine group were receiving other IV vasoactive drugs and had class 4 heart failure than those in the no- dobutamine group. Clearly, doctors select patients for dobutamine treatment because they have more severe heart failure and a poorer prognosis than patients not treated with dobutamine. However, the differences in survival were large between the 2 groups. In fact, even when the baseline differences were considered, continuous IV dobutamine was still associated with a 2-fold increase in mortality. This study addresses one method of dobutamine administration: continuous IV therapy, from 7 to 52 days, with an average length of 14 days. Short-term "bailout" use for decompensated heart failure or long-term intermittent use are used in CHF and are not addressed here. So these results should be viewed with caution. Despite these limits, this study supports the notion that dobutamine may increase mortality in patients with advanced heart failure. Conclusion: This analysis suggests that patients with advanced heart failure treated with continuous IV dobutamine may have a higher death rate at 6 months compared to patients not receiving dobutamine. Inotropic drugs that improve survival or quality of life remain in need of development. The FIRST trial was funded by Glaxo Wellcome, Inc. This analysis was funded independently of the FIRST trial by the Duke Clinical Research Institute Am Heart J 138(1):78-86, 1999