Can any physician consider using intermittent inotropic therapy in patients with congestive heart failure?
Can any physician consider using intermittent inotropic therapy in patients with congestive heart failure? The consensus is that this form of therapy is harmful. The conclusions are in, the issue is dead in the water, and it is a fait accompli that the “evidence” against intermittent inotropic therapy is overwhelming. Peers in the field of congestive heart failure may ridicule my speaking out about this therapy, but perhaps the issue is not dead and requires closer scrutiny.
Since 1988, my colleagues and I have been using intermittent inotropic therapy in patients with congestive heart failure who are resistant to optimal forms of medical and mechanical therapy.1 These patients are approximately 75 years of age, are receiving optimal medical therapy, and are not candidates for heart transplantation. They enter our program with a New York Heart Association functional class V diagnosis (resistant class IV congestive heart failure). If they had an initial hospitalization for congestive heart failure and were receiving maximal medical therapy, they undergo a course of milrinone or dobutamine therapy for 48 to 72 hours. If they are readmitted within 2 weeks for congestive heart failure, they are reintroduced to the inotrope regimen and are scheduled for outpatient weekly 6-hour monitored inotropic therapy. The results among a small set of patients,1 as well as a review of the entire world literature on this form of therapy, were previously published.2 Although the data were limited and it was not a double-blind, placebo-controlled trial, the study1 demonstrated decreased hospital admissions and documented the safety and efficacy of inotropic therapy for resistant congestive heart failure.
There is significant opposition to and controversy surrounding the use of intermittent inotropic therapy. The main concern is its association with increased sudden death and other mortality. The evidence comes from the following published studies.
Diès3 described 60 patients (31 received dobutamine and 29 received placebo) with class III or IV chronic cardiac failure who underwent weekly 48-hour unmonitored inotropic therapy. The dobutamine group received a mean dose of 8.1 µg per kilogram of body weight per minute. There were 10 sudden deaths in the dobutamine group and 4 sudden deaths in the placebo group. Five patients (4 receiving dobutamine and 1 receiving placebo) died of congestive heart failure, and 1 patient (receiving dobutamine) died of septic shock. The results of this multicenter, randomized, double-blind clinical trial are often cited to argue against this form of therapy. Diès did not report on the patients’ potassium, magnesium, or digoxin levels. Monitoring was not done; at that time, the association of increased ventricular arrhythmias and sudden death with intermittent inotropic therapy was unreported. My opinion of the regimen described by Diès is that the dose of dobutamine was too high (predisposing the patient to arrhythmias) and that weekly 48-hour therapy was too long.
The PROMISE study4 reported an increased incidence of mortality and sudden death among patients with severe chronic heart failure receiving oral milrinone. The study evaluated results of the administration of milrinone at maximal hemodynamic doses. There was a 28% increase in all-cause mortality ( = .038) and a 34% increase in cardiovascular mortality ( = .016) associated with its use. The adverse effects were greatest in patients with class IV heart failure. Milrinone therapy was also associated with an increase in hospitalizations. Electrolyte monitoring, but not arrhythmia monitoring, was performed, and β-blocker therapy was not used to protect the left ventricle. This study is notable for its use of large doses of oral milrinone (40 mg/d) and its long durations of therapy.
The OPTIME-CHF study5 evaluated the results of intermittent inotropic therapy administered in the form of intravenous milrinone among 951 patients with congestive heart failure who were admitted with an exacerbation of systolic heart failure not absolutely requiring intravenous inotropic therapy. The mean dose of milrinone was 0.5 µg per kilogram of body weight per minute for 48 hours, without a loading dose. Potassium and digoxin levels were monitored, but magnesium levels were not reported. The median cumulative number of days of hospitalization for cardiovascular reasons within 60 days following randomization was not significantly different between patients administered milrinone (6 days) vs placebo (7 days) ( = .71), nor was there a significant difference in in-hospital mortality (3.8% in the milrinone group vs 2.3% in the placebo group) ( = .19). Hypotension requiring intervention and new supraventricular arrhythmias were more prevalent in the milrinone group. My concerns about the results of this and other such “negative” trials are that the doses of the drugs were excessive, the therapy was too long, monitoring was not routinely performed, and the potassium, magnesium, and digoxin levels (if measured) were not reported.
The American College of Cardiology/American Heart Association 2005 guidelines for the management of patients with chronic heart failure state that long-term oral therapy with inotropic drugs has not improved patients’ symptoms or clinical status.6 The guidelines suggest that the close observation of these patients and the adjustment of their medications are what makes them improve. Nevertheless, the guidelines acknowledge that the clinical trials investigating this therapy have been small, of short duration, and without serious cardiac events.
In the double-blind, placebo-controlled trial by Elis et al,7 who evaluated 19 patients with class III or IV ischemic congestive heart failure, dobutamine was administered during a 24-hour period every 2 to 3 weeks for 6 months. The dose was titrated from 1 to 7.5 µg of dobutamine per kilogram of body weight per minute, and monitoring was performed. There was no significant difference between the dobutamine group and the placebo group in the subsequent number of hospital admissions for congestive heart failure ( = .11). The median survival was 4.6 months in the dobutamine group and 7.97 months in the placebo group. There were no deaths related to the dobutamine therapy, and no ventricular arrhythmias were recorded. Most deaths occurred outside of the hospital. The causes of death were resistant congestive heart failure or malignant ventricular arrhythmia, with no notable differences between the dobutamine and placebo groups among patients for whom the information was available. In this study by Elis et al, the duration of therapy was long (24 hours), the dose was in the high range, and the patients’ potassium, magnesium, and digoxin levels were not reported.
In our practice, the mean dose of intermittent inotropic therapy is 2.5 µg of dobutamine or 0.25 µg of milrinone per kilogram of body weight per minute, without a loading dose. The duration of therapy is 6 hours once or twice a week depending on the patient’s severity of heart failure. The therapy is always monitored; potassium levels must be at least 4.0 mEq/L, magnesium levels must exceed 1.7 mg/dL (>0.70 mmol/L), and digoxin levels must be less than 1.0 ng/dL (<1.28 nmol/L). During therapy, the patient’s blood pressures must not exceed 140 mm Hg, and the heart rate must be 100 beats/min or less. The dose is halved in the event of frequent premature ventricular contractions, couplets, or ventricular tachycardia, or therapy is discontinued.
It is important that patients undergoing intermittent inotropic therapy are not actively ischemic. Systolic blood pressures are maintained in the range of 90 to 100 mm Hg (or higher if the patient is symptomatic). Medications are adjusted so that patients are kept azotemic, with blood urea nitrogen levels of 80 to 100 mg/dL (28.6-35.7 mmol/L) and creatinine levels of 2 to 3 mg/dL (177-265 µmol/L). Prerenal azotemia does not cause uremic symptoms or complications.
As intermittent inotropic therapy has evolved, all of our patients are prescribed beta blockers, have automatic implantable cardiodefibrillators, and (when indicated) receive biventricular pacing. In the last 20 years, our patient population has not experienced sudden death, had automatic implantable cardiodefibrillator firing, or needed cardiopulmonary resuscitation during intermittent inotropic therapy. One patient with ventricular tachycardia required cardioversion. Some may scoff at the low dose of dobutamine used, but this has been effective in our patient population. The lower doses of inotropes and the 6-hour infusions decrease the risk of ventricular arrhythmias.
A recent evaluation of 7 of our patients (5 men and 2 women) showed a notable decrease in B-type natriuretic peptide levels after intermittent inotropic therapy (AWF, unpublished data, 2006). Five of these patients who had troponin levels measured before and after completion of intermittent inotropic therapy did not show any significant abnormalities. This is also significant, as another criticism has been that patients become ischemic during the infusions.
To my knowledge, there has not been a fair study evaluating intermittent inotropic therapy. We all see patients with congestive heart failure who experience recurrent hospitalizations and whose quality of life is limited. Biventricular pacing is an option in some but is ineffective in 30% of the patients who are candidates for this.8 The left ventricular assist device was shown to be effective in the REMATCH study,9 but its use was associated with an increased incidence of bleeding, infection, and stroke. The device provides a maximum life span of approximately 2 years in patients younger than 65 years.9 Most of our patients offered this form of therapy have refused. In our present group of patients receiving intermittent inotropic therapy, the mean duration of therapy and survival are approximately 5 years.
I do not accept the premise that the improvement in quality of life with intermittent inotropic therapy is gained at the sacrifice of duration of life. Our experience (as well as a 1999 review of the world literature2) demonstrates no association of intermittent inotropic therapy with sudden death. In contrast, inotropic therapy for resistant congestive heart failure improves patients’ quality of life and decreases recurrent hospitalizations.1
A large double-blind, placebo-controlled trial of intermittent inotropic therapy is needed among resistant class IV patients, with careful evaluation of their monitored laboratory data (potassium, magnesium, and digoxin levels). The doses should be in the range of 1.25 to 2.5 µg of dobutamine or 0.25 µg of milrinone per kilogram of body weight per minute, without loading doses. Critics will argue that bringing in these patients once or twice a week for this type of care will make them more compliant and result in the “adherence” effect phenomenon.10 Indeed, this could explain the observed improvement, as it would be necessary to evaluate medication use and diet among patients with recurrent congestive heart failure as frequently as 2 times a week to avoid hospitalization. Visiting nurse investigations have had mixed outcomes in decreasing recurrent hospitalizations by increasing frequencies of visits.11
The use of intermittent infusions of nesiritide among patients with heart failure is under evaluation in the outpatient setting.12 Results of larger studies are pending. Early data suggest a rise in creatinine levels and possible increased death associated with intermittent nesiritide therapy.13 From the PRECEDENT study,14 we know that nesiritide is not arrhythmogenic. Its association with increased death is troublesome. Such therapy may interfere too much with the neuroendocrine system, as demonstrated by the negative trial results of the use of the endothelin receptor antagonist bosentan among patients with congestive heart failure.15
Costanzo et al16 recently reported the use of ultrafiltration before intravenous administration of diuretics in patients with congestive heart failure. The experience with ultrafiltration has been positive but requires an invasive approach with a peripherally inserted 16-gauge 35-cm withdrawal catheter and a regular 18-gauge 3.5-cm infusion catheter inserted into the brachial cephalic vein. Approximately 100 to 500 mL of fluid were removed per hour. This represents a mild invasive approach but remains a new and untested therapy for resistant congestive heart failure.
In conclusion, there is no effective therapy available for patients with resistant severe class IV congestive heart failure, to my knowledge. I would like a fair trial to be given to intermittent inotropic therapy.
The author acknowledges the technical assistance of Jennifer Brown, Kristin Mrdjenovich, and Leanne Neibar.