Robert DiBianco

Effect of Oral Milrinone on Mortality in Severe Chronic Heart Failure

BACKGROUND Milrinone, a phosphodiesterase inhibitor, enhances cardiac contractility by increasing intracellular levels of cyclic AMP, but the long-term effect of this type of positive inotropic agent on the survival of patients with chronic heart failure has not been determined. METHODS We randomly assigned 1,088 patients with severe chronic heart failure (New York Heart Association class III or IV) and advanced left ventricular dysfunction to double-blind treatment with (40 mg of oral milrinone daily (561 patients) or placebo (527 patients). In addition, all patients received conventional therapy with digoxin, diuretics, and a converting-enzyme inhibitor throughout the trial. The median period of follow-up was 6.1 months (range, 1 day to 20 months). RESULTS As compared with placebo, milrinone therapy was associated with a 28 percent increase in mortality from all causes (95 percent confidence interval, 1 to 61 percent; P = 0.038) and a 34 percent increase in cardiovascular mortality (95 percent confidence interval, 6 to 69 percent; P = 0.016). The adverse effect of milrinone was greatest in patients with the most severe symptoms (New York Heart Association class IV), who had a 53 percent increase in mortality (95 percent confidence interval, 13 to 107 percent; P = 0.006). Milrinone did not have a beneficial effect on the survival of any subgroup. Patients treated with milrinone had more hospitalizations (44 vs. 39 percent, P = 0.041), were withdrawn from double-blind therapy more frequently (12.7 vs. 8.7 percent, P = 0.041), and had serious adverse cardiovascular reactions, including hypotension (P = 0.006) and syncope (P = 0.002), more often than the patients given placebo. CONCLUSIONS Our findings indicate that despite its beneficial hemodynamic actions, long-term therapy with oral milrinone increases the morbidity and mortality of patients with severe chronic heart failure. The mechanism by which the drug exerts its deleterious effects is unknown.

A comparison of oral milrinone, digoxin, and their combination in the treatment of patients with chronic heart failure.

We randomly assigned 230 patients in sinus rhythm with moderately severe heart failure to treatment with digoxin, milrinone, both, or placebo. The effects of each were compared during a 12-week, double-blind trial. Treatment with milrinone or digoxin significantly increased treadmill exercise time as compared with placebo (by 82 and 64 seconds respectively; 95 percent confidence limits, 44 and 123, and 30 and 100). Both treatments reduced the frequency of decompensation from heart failure, from 47 percent with placebo to 34 percent with milrinone (P less than 0.05; 95 percent confidence limits, 22 and 46) and 15 percent with digoxin (P less than 0.01; 95 percent confidence limits, 7 and 26). However, the clinical condition of 20 percent of the patients taking milrinone deteriorated within two weeks after treatment was begun, as compared with only 3 percent of those taking digoxin (P less than 0.05). The left ventricular ejection fraction at rest was not significantly changed by milrinone (+0.2 percent; 95 percent confidence limits, -1.5 and 1.9), but it was increased by digoxin (+1.7 percent; P less than 0.01; 95 percent confidence limits, -0.03 and 3.4) and decreased by placebo (-2.0 percent; 95 percent confidence limits, -3.8 and -0.1). Three-month survival was related inversely to the base-line ejection fraction. Analysis of mortality from all causes according to the intention to treat suggested an adverse effect of milrinone (P = 0.064). After adjustment for an excess of patients with lower ejection fractions randomly assigned to receive milrinone, this trend was not significant (P = 0.26). Increased ventricular arrhythmias occurred more frequently in patients who received milrinone than in those who did not (18 vs. 4 percent; P less than 0.03). We conclude that milrinone significantly increased exercise tolerance and reduced the frequency of worsened heart failure. However, in the population of patients studied, milrinone or the combination of milrinone and digoxin offered no advantage over digoxin alone. Furthermore, our data suggest that milrinone may aggravate ventricular arrhythmias.

Effects of nadolol on the spontaneous and exercise-provoked heart rate of patients with chronic atrial fibrillation receiving stable dosages of digoxin

Nadolol, a long-acting beta-adrenergic-blocking agent, was evaluated in 20 patients with chronic atrial fibrillation by means of a randomized, double-blind, crossover study. Patients were required either to demonstrate resting heart rates in excess of 80 bpm or to show a rate of 120 bpm or an increment of greater than 50 bpm during mild treadmill exercise provocation (3 minutes, 1.75 mph, 10% grade). With placebo the group averaged a heart rate of 92 +/- 19 bpm, determined by 24 hours of ambulatory ECG recordings; this rate was significantly reduced to 73 +/- 16 bpm (p less than 0.001) with nadolol (mean dosage, 87 +/- 43 mg/day). During standardized exercise testing, heart rates increased to 153 +/- 26 bpm with placebo and to 111 +/- 24 bpm with nadolol (p less than 0.001), representing 65% and 52% increments, respectively. Digoxin blood levels averaged 0.8 +/- 0.5 ng/ml with placebo and were similar with nadolol (0.9 +/- 0.4; p = NS). Total exercise time on a modified Bruce treadmill protocol was 466 +/- 143 seconds with placebo and was significantly decreased by nadolol (380 +/- 143; p less than 0.01). During initial dose titration with nadolol, one patient was dropped from study for intolerable fatigue and one for worsened claudication. No patients were dropped from the double-blind treatment periods, although two patients receiving nadolol and one patient receiving placebo complained of moderate fatigue. We conclude that nadolol is a safe and effective agent for the control of spontaneous and exercise-provoked heart rates in patients with chronic atrial fibrillation who were already receiving digoxin treatment.

Efficacy and safety of esmolol vs propranolol in the treatment of supraventricular tachyarrhythmias: A multicenter double-blind clinical trial

The efficacy and safety of intravenous esmolol infusion was compared to that of intravenous propranolol injection in patients with supraventricular tachyarrhythmias (SVT) in a multicenter double-blind parallel study. A total of 127 patients were randomized to either the esmolol (n = 64) or propranolol (n = 63) group. Therapeutic response was achieved in 72% of esmolol and 69% of propranolol patients (p = NS). The average dose of esmolol in responders was 115 +/- 11 micrograms/kg/min. Therapeutic response was sustained in the 4-hour maintenance period in 67% of esmolol and 58% of propranolol patients (p = NS). Rate of conversion to normal sinus rhythm was similar in the two treatment groups. After discontinuation, rapid recovery from beta blockade (decrease in heart rate reduction) was observed in esmolol patients (within 10 minutes) compared to propranolol patients (no change in heart rate up to 4.3 hours). The principal adverse effect was hypotension, reported in 23 esmolol (asymptomatic in 19) and four propranolol (asymptomatic in three) patients. In the majority of esmolol patients, hypotension resolved quickly (within 30 minutes) after esmolol was discontinued. It was concluded that esmolol was comparable in efficacy and safety to propranolol in the treatment of patients with SVT. Unlike propranolol, because of the short half-life of esmolol, rapid control of beta blockade is possible with esmolol in clinical conditions when required.

Clinical and prognostic significance of serum magnesium concentration in patients with severe chronic congestive heart failure: The Promise Study

OBJECTIVES The aim of this study was to determine the prognostic significance of alterations in serum magnesium in patients with moderate to severe congestive heart failure. BACKGROUND Reductions in serum magnesium have been postulated to play a role in promoting arrhythmias and to have an adverse impact on survival in congestive heart failure, although support for this postulate is lacking. METHODS Serum magnesium levels were measured in 1,068 patients enrolled in a survival study of class III or IV heart failure at the time of double-blind randomization to milrinone, a phosphodiesterase inhibitor, or placebo. All patients received conventional therapy with digoxin, diuretic drugs and a converting enzyme inhibitor throughout the trial. The median follow-up period was 6.1 months (range 1 day to 20 months). RESULTS Patients with high serum magnesium (defined as > or = 1.9 mEq/liter, n = 242) were less likely to survive than were patients with a normal magnesium level (n = 627) (p < 0.05, risk ratio = 1.41). Patients with a low magnesium level (defined as < or = 1.5 mEq/liter, n = 199) had no difference in survival compared with the group with a normal magnesium level (p = NS, risk ratio = 0.89). At baseline, the patients in the high magnesium group were older and had more severe functional and renal impairment. An analysis after adjustment for these variables demonstrated no difference in survival comparing the low, normal and high magnesium groups. Although the three groups had no difference in frequency of ventricular tachycardia, length of longest run or frequency of ventricular premature beats on baseline Holter monitoring, the group with hypomagnesemia had more frequent ventricular couplets. CONCLUSIONS Serum magnesium does not appear to be an independent risk factor for either sudden death or death due to all causes in patients with moderate to severe heart failure. Hypomagnesemia is associated with an increase in the frequency of certain forms of ventricular ectopic activity, but this is not associated with an increase in clinical events. The higher mortality rate among the patients with hypermagnesemia is attributable to older age, more advanced heart failure and renal insufficiency.

Clinical consequences of angiotensin-converting enzyme inhibitor withdrawl in chronic heart failure: A double-blind, placebo-controlled study of quinapril☆

Objectives. This study was performed to the efficacy, safety and clinical consequences of abrupt cessation of quinapril therapy in a placebo-controlled,, randomized, double-blind withdrawal trial. Background. Angiotensin-converting enzyme inhibitor therapy has assumed a pivotal role in the treatment of chronic heart failure. Quinnpril hydrochloride, a nonsulfydryl angiotensinconverting enzyme inhibitor, has shown beneficial clinical effects in previous studies. Methods. After ≥ 10 weeks of single-blind quinapril therapy, 224 patients with New York Heart Association class II or III heart failure were randomized in double-blind fashion to continue quinapril (n = 114) or to receive placebo (n = 110) for 16 weeks. Changes in treadmill exercise time, New York Heart Association functional class, quality of life and symptoms of heart failure were assessed. Results. Patients withdrawn to placebo had a significant deterioration in exercise tolerance (median change -16 s with placebo vs. +3 s with quinapril, p = 0.015). New York Heart Association fractional class (p = 0.004) and quality of life were improved and and symptoms of congestive heart failure were lessened in those remaining on quinapril therapy compared with those receiving placebo. During double-blind treatment, 18 patients were withdrawn from the placebo group because of worsening heart failure compared with 5 patients withdrawn from quinapril treatment (p < 0.001). Rather than a precipitous deterioration of clinical status or early incidence of adverse events, withdrawal from quinapril was associated with steady worsening of heart failure, beginning 4 to 6 weeks after randomization to placebo. Conclusions. Quinapril is effective and safe for maintaining clinical stability in patients with moderate congestive heart failure. Withdrawal of quinapril from patients with heart failure results in a slow progressive decline in clinical status.

Comparative efficacy of 200, 300 and 400 mg of bepridil for chronic stable angina pectoris

A total of 178 patients participated in a 14-week, multicenter, double-blind, parallel study to evaluate the comparative efficacy and safety of single daily doses of 200, 300 and 400 mg of bepridil hydrochloride and placebo in the treatment of patients with chronic stable angina pectoris. The results showed that weekly angina attacks and nitroglycerin consumption were significantly reduced from baseline levels with all doses of bepridil (p less than 0.01), and the reductions were consistently greater than those in the placebo group. For the 400-mg dose the reductions in angina attacks and nitroglycerin consumption were significantly greater (p less than or equal to 0.05) than those in the placebo group at all but 1 evaluation point. Exercise tolerance improved significantly during bepridil administration (p less than or equal to 0.05), and a significant linear dose response was noted for total exercise time, total work and time to onset of angina. In addition, bepridil was significantly superior to placebo for these parameters at doses of 300 (p less than or equal to 0.05) and 400 mg (p less than or equal to 0.01). There were small reductions in heart rate (mean 3.7 beats/min) and prolongation of QT and QTc intervals (approximately 30 to 40 milliseconds) associated with bepridil treatment. Bepridil was well tolerated by patients in this study. When adverse effects occurred, they most frequently involved the gastrointestinal and central nervous systems. Of the patients receiving bepridil, 6% discontinued therapy because of adverse effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Combination propranolol and bepridil therapy in stable angina pectoris

The safety and efficacy of bepridil plus propranolol therapy were investigated in a placebo-controlled, parallel-design, double-blind trial in 56 patients who were not responding to propranolol alone. Patients entering the study were receiving an average propranolol dosage of 131 mg/day (range 20 to 240). For the first 2 weeks of the study they were given placebo in addition to their propranolol dose, and then were randomized to receive continued placebo plus propranolol or bepridil plus propranolol therapy. The bepridil dosage was adjusted over the 8 weeks of active treatment to an average of 273 mg/day (range 200 to 400). The double-blind treatment period was followed by a 3-week washout period during which all patients received propranolol and placebo. The effects of treatment on the frequency of angina attacks, nitroglycerin consumption, exercise performance (treadmill-modified Bruce protocol) and Holter electrocardiogram (ECG) were assessed. Propranolol and bepridil plasma levels also were obtained. Improved antianginal efficacy and reduced nitroglycerin consumption were noted when bepridil was added to propranolol (p less than 0.01). During 8 weeks of combination treatment, exercise tolerance increased 1.0 +/- 1.2 minutes from a baseline of 7.3 +/- 2.2 with bepridil plus propranolol compared with an increase of 0.02 +/- 1.3 minutes from a baseline of 7.6 +/- 2.9 with placebo plus propranolol (p less than 0.01). With bepridil plus propranolol, there were also increases in exercise time to onset of angina (p less than 0.04), exercise time to 1-mm electrocardiographic ST-segment depression (p less than 0.06) and total work (p less than 0.03) compared with placebo plus propranolol therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Left ventricular relaxation, mitral valve prolapse, and intracardiac conduction in myotonia atrophica: Assessment by digitized echocardiography and noninvasive His bundle recording

Myotonia atrophica, a neuromuscular disease marked by autosomal dominant transmission and delayed relaxation of skeletal muscle, has been associated with cardiac failure, conduction abnormality and mitral prolapse (MVP). In order to determine the relaxation rate of cardiac muscle, left ventricular (LV) size and function, and the presence of MVP, 30 patients with myotonia atrophica were studied using digitized M-mode echocardiography (MME). Intracardiac conduction intervals were determined by noninvasive His bundle recording (HBR) from surface electrodes using a high-resolution, R-wave triggered, signal averaging computer. Neurologically unaffected first-degree relatives of the patients with myotonia atrophica were also studied to determine if cardiac abnormalities may be present in the absence of neurologic manifestations of the disease. Peak normalized diastolic endocardial velocity in patients with myotonia atrophica (3.7 +/- 0.8 sec-1) did not differ from unaffected first-degree relatives (3.8 +/- 0.8 sec-1) or normal subjects (3.6 +/- 0.8 sec-1). Systolic LV function and LV dimensions on MME were normal in both groups. However, MVP was present in 7 of 24 (29%) of patients who could be evaluated, but not in unaffected first-degree relatives. Despite normal LV systolic and diastolic function, infranodal intracardiac conduction was prolonged in patients with myotonia atrophica (average HV interval 50 +/- 5 SD msec) but not in neurologically unaffected relatives (average HV interval 40 +/- 5 msec). Delay in proximal intracardiac conduction was also found in patients with myotonia atrophica (average PH interval 140 +/- 20 msec) but not in neurologically unaffected relatives (average PH interval 115 +/- 6 msec). Hence cardiac findings in myotonia atrophica include proximal and distal conduction delay by external HBR even in the absence of abnormality of the standard 12-lead ECG. There may also be an increased frequency of MVP; however, early diastolic relaxation of the LV is unimpaired, and cardiac manifestations of myotonia are not transmitted independently of neurologic abnormality.

Long-term efficacy of bepridil in patients with chronic stable angina pectoris: Results of a multicenter, placebo-controlled study of extended bepridil use

To evaluate whether bepridil once a day provides effective antianginal therapy during extended use, a placebo-controlled withdrawal study was conducted in 33 patients with chronic stable angina. Each patient studied had previously had a favorable response to short-term administration of bepridil and had been taking the drug once daily for greater than or equal to 9 months of continuous use. Patients were then randomly assigned to receive either continued bepridil or a placebo substitution once daily during a 4-week, double-blind, parallel-group comparison. Dosage for the bepridil group was constantly maintained for each patient at a level observed to be clinically effective. The study consisted of a comparison of angina frequency and nitroglycerin tablet consumption obtained from patient diaries and results from maximal-graded multistage treadmill tests. Patients randomized to continue receiving bepridil remained stable in terms of angina frequency and exercise performance. Discontinuation of long-term bepridil significantly increased angina frequency and nitroglycerin tablet consumption and reduced exercise capacity. Four patients (24%), all receiving placebo treatment, had increases in angina frequency and had the study terminated. Bepridil was reinstituted in these patients with resolution of symptoms and no untoward effects. The results of this placebo-controlled, double-blind, randomized study confirm that bepridil continues to provide antianginal benefit during long-term administration.