[Pimobendan (UDCG 115 BS) in long-term therapy of chronic heart failure]. Double-blind, placebo-controlled study of the efficacy of flosequinan in patients with chronic heart failure. Principal Investigators of the REFLECT Study. Effects of pimobendan on adverse cardiac events and physical activities in patients with mild to moderate chronic heart failure: the effects of pimobendan on chronic heart failure study (EPOCH study). Treatment of severe heart failure: quantity or quality of life? A trial of enoximone. Enoximone Investigators. Effect of oral milrinone on mortality in severe chronic heart failure. The PROMISE Study Research Group. Low-dose enoximone improves exercise capacity in chronic heart failure. Enoximone Study Group. Effect of pimobendan on exercise capacity in patients with heart failure: main results from the Pimobendan in Congestive Heart Failure (PICO) trial. Placebo-controlled trial of flosequinan in moderate heart failure. The possible importance of aetiology and method of analysis in the interpretation of the results of heart failure trials. Oral enoximone therapy in chronic heart failure: a placebo-controlled randomized trial. The Western Enoximone Study Group. A dose-dependent increase in mortality with vesnarinone among patients with severe heart failure. Vesnarinone Trial Investigators. Effectiveness of imazodan for treatment of chronic congestive heart failure. The Imazodan Research Group. Can further benefit be achieved by adding flosequinan to patients with congestive heart failure who remain symptomatic on diuretic, digoxin, and an angiotensin converting enzyme inhibitor? Results of the flosequinan-ACE inhibitor trial (FACET). Effects of vesnarinone on morbidity and mortality in patients with heart failure. Vesnarinone Study Group. Multicenter trial of oral enoximone in patients with moderate to moderately severe congestive heart failure. Lack of benefit compared with placebo. Enoximone Multicenter Trial Group. Beneficial effects of pimobendan on exercise tolerance and quality of life in patients with heart failure. Results of a multicenter trial. The Pimobendan Multicenter Research Group. A comparison of oral milrinone, digoxin, and their combination in the treatment of patients with chronic heart failure.
Pimobendan is a positive inotropic agent with additional calcium-sensitizing effects of the phosphodiesterase III-inhibitor group. In short-term studies, beneficial hemodynamic effects have been demonstrated in patients with congestive heart failure. The aim of this prospective study was to examine the long-term effect of pimobendan (during at least 6 months) on subjective state, hemodynamic parameters, and arrhythmias in patients with congestive heart failure NYHA classes II and III. After double-blind randomization, 24 patients received pimobendan 5 mg bid or placebo orally in addition to a basic therapy (diuretics, digitalis). After 3 months, pimobendan-treated patients showed a significant clinical improvement (p < 0.03). In the placebo group, one patient underwent acute cardiac transplantation due to rapid clinical deterioration; another patient died suddenly after 5 months. No cardiac events occurred in the pimobendan group. In comparison to placebo, no proarrhythmogenic effect of pimobendan was detected. Clinical stabilization of patients in the pimobendan group was not paralleled by improvement of the hemodynamic parameters of left-ventricular performance. The aim of this study was to assess the efficacy of flosequinan in chronic heart failure.
                Flosequinan is a new vasodilator drug that acts by interfering with the inositol-triphosphate/protein kinase C pathway, an important mechanism of vasoconstriction. The drug dilates both peripheral arteries and veins, is orally active and has a long duration of action that permits once-daily dosing. Previous studies have shown that flosequinan produces sustained hemodynamic benefits in heart failure, but large scale studies evaluating its clinical efficacy have not been reported.
                One hundred ninety-three patients with chronic heart failure (New York Heart Association functional class II or III and left ventricular ejection fraction < 40%) receiving digoxin and diuretic drugs were randomly assigned (double-blind) to the addition of flosequinan (100 mg once daily, n = 93) or placebo (n = 100) for 3 months. The clinical status and exercise tolerance of each patient was evaluated at the start of the study and every 2 to 4 weeks during the trial while background therapy remained constant.
                After 12 weeks, maximal treadmill exercise time increased by 96 s in the flosequinan group but by only 47 s in the placebo group (p = 0.022 for the difference between groups). Maximal oxygen consumption increased by 1.7 ml/kg per min in the flosequinan group (n = 17) but by only 0.6 ml/kg per min in the placebo group (n = 23), p = 0.05 between the groups. Symptomatically, 55% of patients receiving flosequinan but only 36% of patients receiving placebo benefited from treatment (p = 0.018). In addition, fewer patients treated with flosequinan had sufficiently severe worsening of heart failure to require a change in medication or withdrawal from the study (p = 0.07). By intention to treat, seven patients in the flosequinan group and two patients in the placebo group died.
                These findings indicate that flosequinan is an effective drug for patients with chronic heart failure who remain symptomatic despite treatment with digoxin and diuretic drugs. The effect of the drug on survival remains to be determined. The long-term beneficial effects of pimobendan in the treatment of chronic heart failure (CHF) have not been established, so the present trial compared pimobendan (1.25 or 2.5mg twice daily) vs placebo in 306 patients with stable New York Heart Association class IIm or III CHF, and a radionuclide or echocardiographic left ventricular ejection fraction (LVEF) < or =45% despite optimal treatment with conventional therapy, for up to 52 weeks in a double-blind protocol. At the end of the 52 weeks of treatment, combined adverse cardiac events had occurred in 19 patients in the pimobendan group (15.9%) vs 33 patients in the placebo group (26.3%). The cumulative incidence of combined adverse cardiac events was 45% lower (95% confidence interval of hazard ratio: 0.31-0.97, log-rank test: p=0.035) in the pimobendan group than in the placebo group. Death and hospitalization for cardiac causes occurred in 12 patients in the pimobendan group (10.1%), vs 19 patients in the placebo group (15.3%), but without significant difference. Treatment with pimobendan also increased the mean Specific Activity Scale score from 4.39+/-0.12 at baseline to 4.68+/-0.15 at 52 weeks (p<0.05). In conclusion, long-term treatment with pimobendan significantly lowered morbidity and improved the physical activity of patients with mild to moderate CHF. To determine the effects of enoximone on mortality and quality of life in patients with severe end stage heart failure.
                A randomised, double blind, placebo controlled trial of the addition of enoximone to conventional treatment. Planned minimum follow up of one year.
                District general hospitals and cardiological referral centres in the United Kingdom.
                Planned 200 patients with severe, symptomatic heart failure despite treatment with diuretics and where appropriate and tolerated angiotensin converting enzyme inhibitors and digoxin.
                The study was ended early by the ethics committee after 151 patients had been recruited because of an excess mortality in the enoximone group: 27 deaths compared with 18 in the placebo group (P < 0.05). Quality of life measured with a disease specific questionnaire showed a clinically significant improvement at week 2 with a mean increase score of 0.48 in the enoximone treated patients compared with 0.14 in those receiving placebo (P = 0.0086). With the Nottingham health profile questionnaire the physical mobility score was improved after three months in the enoximone group, median 21.3 compared with 41.8 in the placebo group (P = 0.008).
                In patients with severe heart failure who remain incapacitated despite conventional treatment enoximone reduced survival but had a beneficial effect on the quality of life. Drugs that improve symptoms in severe end stage heart failure should not be discarded lightly. 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.
                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).
                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.
                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. This study was designed to evaluate the effects of low-dose enoximone on exercise capacity.
                At higher doses the phosphodiesterase inhibitor, enoximone, has been shown to increase exercise capacity and decrease symptoms in heart failure patients but also to increase mortality. The effects of lower doses of enoximone on exercise capacity and adverse events have not been evaluated.
                This is a prospective, double-blind, placebo-controlled, multicenter trial (nine U.S. centers) conducted in 105 patients with New York Heart Association class II to III, ischemic or nonischemic chronic heart failure (CHF). Patients were randomized to placebo or enoximone at 25 or 50 mg orally three times a day. Treadmill maximal exercise testing was done at baseline and after 4, 8 and 12 weeks of treatment, using a modified Naughton protocol. Patients were also evaluated for changes in quality of life and for increased arrhythmias by Holter monitoring.
                By the protocol-specified method of statistical analysis (the last observation carried-forward method), enoximone at 50 mg three times a day improved exercise capacity by 117 s at 12 weeks (p = 0.003). Enoximone at 25 mg three times a day also improved exercise capacity at 12 weeks by 115 s (p = 0.013). No increases in ventricular arrhythmias were noted. There were four deaths in the placebo group and 2 and 0 deaths in the enoximone 25 mg three times a day and enoximone 50 mg three times a day groups, respectively. Effects on degree of dyspnea and patient and physician assessments of clinical status favored the enoximone groups.
                Twelve weeks of treatment with low-dose enoximone improves exercise capacity in patients with CHF, without increasing adverse events. To determine the effects of pimobendan 2.5 and 5 mg daily on exercise capacity in patients with chronic heart failure.
                A randomised, double blind, placebo controlled trial of the addition of pimobendan to conventional treatment with a minimum follow up of 24 weeks.
                Outpatient cardiology clinics in six European countries.
                317 patients with stable symptomatic heart failure, objectively impaired exercise capacity, and an ejection fraction of 45% or lower who were treated with at least an angiotensin converting enzyme inhibitor and a diuretic and who tolerated a test dose of pimobendan.
                Compared with placebo, both pimobendan 2.5 and 5 mg daily improved exercise duration (bicycle ergometry) by 6% (P = 0.03 and 0.05) after 24 weeks of treatment. At that time 63% of patients allocated to pimobendan and 59% of those allocated to placebo were alive and able to exercise to at least the same level as at entry (P = 0.5). No significant effects on oxygen consumption (assessed in a subgroup of patients) and on quality of life (assessed by questionnaire) were observed. Pimobendan was well tolerated. Proarrhythmic effects (24-hour electrocardiography) were not observed. In both pimobendan groups combined the hazard of death was 1.8 (95% confidence interval 0.9 to 3.5) times higher than in the placebo group.
                Pimobendan improves exercise capacity in patients with chronic heart failure who are also on conventional treatment. The balance between benefit and risk of treatment with this compound remains to be established however. One hundred-thirty five patients with moderate heart failure, recruited from 18 centres, were included in a double blind, placebo controlled study to evaluate the effects of flosequinan on symptom limited tread-mill exercise tolerance. Fifteen patients in the placebo group were withdrawn from the study compared with 14 from the group given flosequinan. New York Heart Association classification was improved at week 16 in the flosequinan group relative to those randomised to placebo (P < 0.01). Depending how the other results are analysed flosequinan either appeared to have no effect on symptom limited exercise tolerance in those who completed the study; a suggestion of superiority if an analysis at endpoint is used (P = 0.09), or, if a covariate analysis at endpoint is used, then a significant improvement can be demonstrated (P = 0.04). Subset analysis suggests that the aetiology of the heart failure and the dose of diuretics used might have a major effect on the response to treatment. The best way of analysing clinical trials in heart failure is not clear as the results can be profoundly influenced by the way data from withdrawn patients are handled. The aetiology and diuretic requirement of patients may influence their response to treatment. In a parallel study design, 164 patients with New York Heart Association Functional class II or III heart failure were randomized to receive either enoximone given as 50 mg three times a day, or 100 mg three times a day, or a matching placebo. All patients were receiving digitalis and/or diuretics and had left ventricular ejection fractions less than or equal to 45. Exercise tests were performed after 1, 4, 8, and 12 weeks of treatment. Enoximone produced significantly greater increases in exercise time than placebo treatment at weeks 4 and 8 (p = 0.012, p = 0.029, respectively) but not after 12 weeks. Left ventricular ejection fraction increased significantly after the first dose of enoximone but not after 12 weeks of long-term therapy. Heart failure symptoms and the physicians' evaluations of cardiac status were significantly improved in both enoximone therapy groups during the first 4 weeks of evaluation when compared with evaluations of cardiac status in the placebo group. Diuretic doses were increased more frequently for patients who were receiving a placebo. Adverse events were reported with similar frequency in the placebo and 50 mg enoximone treatment groups; 100 mg enoximone resulted in a significantly greater incidence of adverse events. Mean heart rate and ventricular ectopic activity were not significantly different among the three treatment limbs. Enoximone appears to improve exercise tolerance, ventricular function, and symptoms of heart failure for 4 to 8 weeks. Heart rate, ventricular ectopic activity, and mortality rate were not increased.(ABSTRACT TRUNCATED AT 250 WORDS) Vesnarinone, an inotropic drug, was shown in a short-term placebo-controlled trial to improve survival markedly in patients with severe heart failure when given at a dose of 60 mg per day, but there was a trend toward an adverse effect on survival when the dose was 120 mg per day. In a longer-term study, we evaluated the effects of daily doses of 60 mg or 30 mg of vesnarinone, as compared with placebo, on mortality and morbidity.
                We enrolled 3833 patients who had symptoms of New York Heart Association class III or IV heart failure and a left ventricular ejection fraction of 30 percent or less despite optimal treatment. The mean follow-up was 286 days.
                There were significantly fewer deaths in the placebo group (242 deaths, or 18.9 percent) than in the 60-mg vesnarinone group (292 deaths, or 22.9 percent) and longer survival (P=0.02). The increase in mortality with vesnarinone was attributed to an increase in sudden death, presumed to be due to arrhythmia. The quality of life had improved significantly more in the 60-mg vesnarinone group than in the placebo group at 8 weeks (P<0.001) and 16 weeks (P=0.003) after randomization. Trends in mortality and in measures of the quality of life in the 30-mg vesnarinone group were similar to those in the 60-mg group but not significantly different from those in the placebo group. Agranulocytosis occurred in 1.2 percent of the patients given 60 mg of vesnarinone per day and 0.2 percent of those given 30 mg of vesnarinone.
                Vesnarinone is associated with a dose-dependent increase in mortality among patients with severe heart failure, an increase that is probably related to an increase in deaths due to arrhythmia. A short-term benefit in terms of the quality of life raises issues about the appropriate therapeutic goal in treating heart failure. A 12-week, multicenter, double-blind, randomized, placebo-controlled trial of imazodan, a type III phosphodiesterase inhibitor, was conducted in 147 patients with congestive heart failure to determine clinical efficacy and safety. Patients were randomized to placebo or 2, 5 or 10 mg of imazodan administered twice daily. Patients were maintained on their standard therapy including diuretics, digoxin and an angiotensin-converting enzyme inhibitor. The mean ejection fraction was 23 +/- 10%. Exercise time increased from baseline in all 4 groups. There was no significant difference observed between the placebo group and any of the treated groups with regard to exercise time, ejection fraction, frequency of ventricular premature complexes or ventricular tachycardia. When analyzed by intent to treat, the placebo mortality was 7% (3 of 44) and the imazodan mortality was 8% (8 of 103) (p = not significant). This study failed to demonstrate that imazodan provided any benefit in exercise performance when compared with placebo. Angiotensin converting enzyme inhibitors, diuretics, and digoxin are each effective in treating congestive heart failure, but many patients remain symptom-limited on all three medications. This trial was designed to determine whether the addition of oral flosequinan, a new direct-acting arterial and venous vasodilator with possible dose-dependent positive inotropic effects, improves exercise tolerance and quality of life in such patients.
                In a randomized, double-blind multicenter trial, 322 patients with predominantly New York Heart Association class II or III congestive heart failure and left ventricular ejection fractions of 35% or less, who were stabilized on a diuretic, angiotensin converting enzyme inhibitor, and digoxin, were treated with 100 mg flosequinan once daily, 75 mg flosequinan twice daily, or matching placebo. Efficacy was evaluated with serial measurements of treadmill exercise time, responses to the Minnesota Living With Heart Failure Questionnaire (LWHF), and clinical assessments during a baseline phase and a 16-week treatment period. After 16 weeks, 100 mg flosequinan once daily produced a significant increment in median exercise time (64 seconds at 16 weeks) compared with placebo (5 seconds), whereas the higher-dose flosequinan group did not show a statistically significant increase. Flosequinan (100 mg once daily) also improved the overall LWHF score significantly compared with placebo; both active therapies decreased the physical component, but 75 mg flosequinan twice daily was associated with a trend toward worsening of the emotional component. Most clinical assessments tended to improve on active therapy.
                These results indicate that additional symptomatic benefit can be attained by adding flosequinan to a therapeutic regimen already including a converting enzyme inhibitor. Because in the future most patients will fall into this category, flosequinan is a potential adjunctive agent in the management of severe congestive heart failure. However, because recent evidence indicates that the flosequinan dose studied in the present trial has an adverse effect on survival, the benefit-to-risk ratio must be assessed in individual patients. Inotropic therapy, other than with digitalis glycosides, has had limited success in patients with chronic congestive heart failure. We investigated whether vesnarinone, a new positive inotropic agent, reduces morbidity and mortality and improves the quality of life of patients with symptomatic heart failure.
                Patients receiving concomitant therapy with digoxin (87 percent) and an angiotensin-converting-enzyme inhibitor (90 percent) who had ejection fractions of 30 percent or less were randomly assigned to receive double-blinded therapy with 60 mg of vesnarinone per day, 120 mg of vesnarinone per day, or placebo. Afer 253 patients had been enrolled, randomization to the 120-mg vesnarinone group had to be stopped because of a significant increase in early mortality in this group. Thereafter, patients were randomly assigned only to 60 mg of vesnarinone per day (a total of 239 patients) or placebo (a total of 238 patients).
                Significantly fewer patients in the group receiving 60 mg of vesnarinone than in the group receiving placebo (26 vs. 50 patients; P = 0.003) died or had worsening heart failure during the six-month study period. The reduction in risk was 50 percent (95 percent confidence interval, 20 to 69 percent). Similarly, there was a 62 percent reduction (95 percent confidence interval, 28 to 80 percent) in the risk of dying from any cause among the patients receiving vesnarinone. Furthermore, quality of life improved to a greater extent in the vesnarinone group than in the placebo group over 12 weeks (P = 0.008). The principal side effect associated with vesnarinone was reversible neutropenia, which occurred in 2.5 percent of the patients.
                Six months of therapy with 60 mg of vesnarinone per day resulted in lower morbidity and mortality and improved the quality of life of patients with congestive heart failure. However, a higher dose of vesnarinone (120 mg per day) increased mortality, suggesting that this drug has a narrow therapeutic range; the long-term effects of vesnarinone are unknown. A multicenter double-blind, randomized, placebo-controlled trial of oral enoximone, a phosphodiesterase inhibitor, was conducted in 102 outpatients (50 receiving enoximone and 52 receiving placebo) with moderate to moderately severe congestive heart failure. All were on a long-term regimen of digoxin and diuretics without vasodilators and converting enzyme inhibitors. Symptom score was obtained, and exercise testing was performed monthly for 4 months. There were no differences between groups in symptoms or exercise duration at the end of 4 months. A subgroup undergoing analysis of oxygen consumption with measurement of anaerobic threshold during exercise showed an increase (p less than 0.05) in anaerobic threshold at 1 month with enoximone. (2.7 +/- 0.8 ml O2/kg/min) compared with placebo (-0.8 +/- 1.2 ml O2/kg/min). This improvement was not sustained at 4 months (0.5 +/- 1.7 ml O2/kg/min with enoximone and 0.2 +/- 1.5 ml O2/kg/min with placebo). The dropout rate was significantly higher (p less than 0.02) with enoximone (46%) than with placebo (25%). Adverse effects other than death were slightly, but not significantly, higher with enoximone (32%) than with placebo (22%). During therapy, five deaths occurred in the enoximone group, and none occurred in the placebo group (p less than 0.05). Two deaths were sudden, two were from progressive congestive heart failure, and one was from acute myocardial infarction. With intention-to-treat analysis and inclusion of patients who were removed from therapy because of lack of study drug effect, 10 deaths occurred in the enoximone group, and three occurred in the placebo group (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS) This multicenter trial was conducted to determine the efficacy and safety of pimobendan, an inotropic agent with calcium-sensitizing properties and activity as a phosphodiesterase inhibitor, in patients with heart failure.
                One hundred ninety-eight ambulatory patients with symptoms of moderate to severe heart failure despite therapy with digitalis and diuretics with or without a single vasodilator were randomly assigned to receive either placebo (n = 49) or pimobendan (n = 149) in a double-blind fashion for 12 weeks. A dose range of pimobendan was used including 2.5 (n = 49), 5 (n = 51), or 10 mg/day (n = 49). One hundred fifty-eight (80%) patients were taking a converting enzyme inhibitor (CEI) and 28 (14%) patients were taking a non-CEI vasodilator. At end point, the 5-mg dose of pimobendan significantly increase exercise duration compared with placebo (121.6 +/- 19.1 seconds, p less than 0.001), whereas the 10-mg dose produced an increase of borderline significance (81.1 +/- 19.5 seconds, p = 0.05). Peak VO2 was significantly increased by 2.23 +/- 0.58 ml/kg/min in the 5-mg group (p less than 0.01 versus placebo). Furthermore, quality of life measured with the Minnesota Living With Heart Failure Questionnaire improved by 8.5 +/- 2.3 units in the 5-mg group compared with 1.3 +/- 2.2 units in the placebo group (p less than 0.01). There were a total of 23 all-cause hospitalizations in the placebo group, which was significantly greater compared with 33 in the three groups treated with pimobendan (p less than 0.01). There were no significant differences between the placebo and pimobendan groups with respect to changes in ejection fraction and plasma norepinephrine measured at baseline and at the completion of the 12-week study, proarrhythmic effect, or the number of patients with a significant adjustment in background therapy. Eleven patients died, including three (6%) on placebo and eight (5%) on pimobendan (p = NS). Among all adverse events, headache tended to be more common in the pimobendan groups compared with placebo, with the incidence increasing with dose (p less than 0.05).
                These data demonstrate that pimobendan significantly increases exercise duration, peak VO2, and quality of life in patients with heart failure. Pimobendan appears to be useful adjunctive therapy when added to digitalis, diuretics, and vasodilators. 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.