Intermittent 6-Month Low-Dose Dobutamine Infusion in Severe Heart Failure:
DICE Multicenter Trial

	Patients with end-stage heart failure often do not respond to
maximum oral drug therapy, and they have high mortality rates, poor quality
of life, and frequent hospitalizations. Intermittent dobutamine use has been
suggested as an option.
	Thirty-eight class 3-4 patients with a cardiac index greater than
2.2L/min/m2, and EF higher than 30% were randomly assigned to get either
intermittent dobutamine or best standard treatment. Dobutamine was given by
IV at 2.5µg/kg/min with a portable pump for 48 hours per week for 6 months.
	The primary endpoint was reduction of hospitalizations for worsening
CHF. Changes in heart class, 6-minute walk test, and mortality rates were
secondary endpoints.
	During the 6-month follow-up, all patients had weekly visits, with
blood sodium and potassium measurement. Patients were an average age of 65,
heart class 3-4, average EF 22%, and cardiac index 1.89L/min/m2.
Hospitalizations for all causes over a 6-month period were 17 in the control
group and 11 in the dobutamine groups. Four control patients but none in the
dobutamine group had 2 or more hospitalizations for worsening of CHF. There
were no significant differences in heart class or 6-minute walk test. Three
patients in the control group died and 5 in the dobutamine group died. Two
patients in the dobutamine group had a heart transplant.
	Conclusion: 6 month intermittent low-dose dobutamine was well
tolerated by patients with severe CHF. It did not improve functional status
and did not significantly increase mortality rate. However,
hospitalizations for all causes and for worsening of CHF tended to be fewer
in the dobutamine group.

Long version

	Introduction: A combination of diuretics, vasodilators, digoxin,
ACE inhibitors, and beta-blockers is often not enough to prevent worsening
heart failure. Patients with end-stage CHF require frequent hospitalizations,
which are expensive. Heart failure that does not respond to drugs or surgery
leaves only heart transplant as an option. Even though recently there have
been some unfavorable data on long-term use of inotropes, in certain
situations they are the most acceptable solution. Dobutamine, a sympathetic
adrenergic receptor agonist, might improve heart function in severe CHF
patients and might have an effect lasting longer than expected. Intermittent
treatment is used to prevent drug tolerance.
	Considering the very high, potentially toxic doses of dobutamine
used in previous studies, many lacking a proper control group, the randomized,
controlled DICE trial was designed to test intermittent low-dose dobutamine
infusion on complications and mortality rates of patients with severe CHF.

	Methods: The primary purpose of this study was to reduce
hospitalizations for worsening of CHF. The following data were reported for
each hospitalization: dates of entry and discharge, signs and symptoms, and
interventions during the hospital stay with special reference to IV
inotropes. Hospitalization for CHF was defined as an episode of worsening of
pre-existing CHF requiring more than a 24-hour hospital stay and IV inotropes
or Lasix.
	The secondary objectives were to improve functional ability, heart
class and 6-minute walk test, and to decrease mortality.
	Patients all had chronic heart failure, class 3-4. Patients all had
been hospitalized for CHF and had received IV inotropes despite 6 months or
more of maximum oral drug therapy for their CHF. They all had cardiac index
greater than 2.2L/min/m2 and an EF higher than 30%. All had a physical exam,
blood chemistry, echo, 24-hour Holter monitoring and 6-minute walk test.
	The next day they were admitted to the intensive care unit and had a
balloon-tipped catheter inserted into the pulmonary artery for monitoring,
and a dose titration curve was obtained with dobutamine starting at
2.5µg/kg/min and increasing to doses of 5 and 7.5µg/kg/min if tolerated.
Dobutamine was stopped and the patient was not enrolled in the trial if:
their heart rate went higher than 110 beats per minute, they developed a-fib,
ventricular ectopic beats more than 6 per minute, or sustained ventricular
tachycardia.
	Patients were then assigned to maximum oral therapy or both maximum
oral therapy plus intermittent low-dose dobutamine. Dobutamine was given at
2.5µg/kg/min for 48 hours per week, which could be increased to no more than
5µg/kg/min infused for 72 hours per week, if needed. In the dobutamine
group, a long-term venous access catheter was implanted. The patients were
instructed on use of an external battery-powered infusion pump with a
disposable container holding a solution of dobutamine hydrochloride.
	After hospital discharge, for the next 6 months, all patients in
both groups had a weekly follow-up with electrolytes and kidney function
measured. Holter recording was done after 2 weeks, 6-minute walk test and
right heart cath after 8 weeks, and 6-minute walk test again after 6 months.
	When 38 patients were randomly assigned and no evidence of excess
risk was seen, the steering committee stopped enrollment. The decision was
because an open trial could not be continued while many investigators had
started using dobutamine intermittent infusion in their routine practice.

	Results: Between July 1994 and December 1995, 38 patients (31 men
and 7 women) were enrolled at 14 sites. The average age was 65 (range 36 to
79 years). The cause of heart failure was coronary artery disease in 18
patients, idiopathic dilated cardiomyopathy in 16, and valve disease in 4
patients. Twenty-one patients were class 4 and 17 patients were class 3.
Distance covered in 6 minutes was very low. The left ventricle was dilated
and its function very depressed. Most patients were receiving maximum drug
therapy of ACE inhibitors, Lasix, and digoxin.
	During the acute test with dobutamine, the lowest dose - 
2.5µg/kg/min - produced a significant increase in cardiac index without
changing the heart rate and pulmonary wedge pressure. We did not see
significant differences in right atrial pressure, average pulmonary arterial
pressure or average systemic arterial pressure compared with baseline.
At the eighth week, hemodynamic measurements for right heart cath (13
patients in the dobutamine group and 10 in the control group) did not change
significantly.

	Hospitalizations: The total number of hospitalizations for any cause
was 17 in the control group and 11 in the dobutamine groups. During the
6-month follow-up, 7 patients receiving dobutamine and 5 patients in the
control group had one CHF episode requiring hospitalization. None of the
patients in the dobutamine group had more than one hospitalization, whereas
4 patients in the control group needed 2 or more hospitalizations for
worsening CHF.

	Heart Class: At baseline, average functional class was class 4 in
both groups. At the 8-week follow-up, it became class 3 in the control group
and class 2 in the dobutamine group. At 6 months, heart class was class 3 in
the control group and 2.5 in the dobutamine group.

	6-Minute Walk Test: There was a trend toward improvement in the
distance covered by patients receiving dobutamine at 8 weeks and 6 months,
compared with baseline.

	Events: Overall there were 8 deaths: 3 in the control group and 5 in
the dobutamine group. Average time to death was 114 days in the control group
and 93 days in the dobutamine groups. One patient stopped dobutamine therapy
because Holter monitoring showed a significant increase of nonsustained
ventricular tachycardia episodes. In the dobutamine group, 2 patients had
heart transplant and one patient withdrew consent one month into the study.

	Discussion: Despite the growing treatment choices for CHF, a sizable
number of patients do not respond to drug treatment, and only a few can
have a heart transplant. The cost of hospitalization and the observation
that some patients remain stable or even improve with low doses of dobutamine
without significant side effects, has led to outpatient strategies.
Previously gathered data led us to prefer intermittent dosing to prevent drug
tolerance.
	The largest randomized, placebo-controlled trial on outpatient
dobutamine therapy showed symptom improvement and increased exercise time
but was stopped after 20 patients died, 7 of 29 taking placebo, and 13 of 31
taking dobutamine. The average rate of infusion of dobutamine was high
(average 8µg/kg per minute; range 5 to 16µg/kg/min). Because some recent
non-controlled studies with low-dose dobutamine showed a low risk of
sudden death, DICE was designed to test safety and effectiveness of a low
dobutamine dose in outpatients with severe heart failure.
	In the 6 months before the study the patients of both groups had
about the same number of hospital readmissions for worsening of CHF. During
the follow-up, we saw a decrease in the average number of hospitalizations
in both groups, from an average of 1.7 per patient in 6 months to 0.5 per
patient in 6 months. The combination of maximum oral drug therapy plus
intermittent low-dose dobutamine seemed to prevent repeated failures.
	We found that this low dose of dobutamine does not increase the risk
of cardiovascular death and of worsening heart failure. However, it does not
prolong the time free of hospitalization in these patients. Only repeat
hospitalizations were prevented by dobutamine.
	Intermittent dobutamine could be an alternative for carefully
selected patients with severely symptomatic and advanced heart failure,
conventional therapies having failed.

This study was independently designed and conducted. Eli Lilly supported
meetings and secretarial expenses. Pharmacia of Milan kindly donated a
portable infusion system to each participating clinical center.

Am Heart J 138(2):247-253, 1999