Magnesium supplementation in patients with congestive heart failure.

OBJECTIVE: To evaluate several potential clinical indicators of magnesium status (diet, blood, urine, 24-hour load retention) in patients with congestive heart failure before, during, and after oral magnesium supplementation. METHODS: Twelve patients with New York Heart Association class II-III heart failure and 12 age and sex matched healthy control subjects were supplemented with 10.4 mmol oral magnesium lactate for 3 months. For the determination of magnesium status, samples of whole blood, serum, plasma, red blood cells, and urine (24-hour) were collected. Four-day dietary intake records were reviewed. A 4-hour IV magnesium load retention study was performed before and 3 months after magnesium supplementation. A non-supplemented control group was similarly studied. RESULTS: At baseline, magnesium intakes for all groups were below the RDA. No significant differences were seen in serum, plasma, ultrafiltrates of serum or plasma or red cell magnesium concentrations among groups over time. At baseline 5/27 subjects (19%) compared to 11/27 subjects (41%) after supplementation demonstrated normal magnesium retentions (< 25%). Magnesium excretions among groups were significantly different during supplementation. Percent magnesium retentions among groups were not different. CONCLUSIONS: Supplementation with 10.4 mmol oral magnesium daily for 3 months did not significantly alter blood levels or magnesium retention; however, patients demonstrated lower retention of magnesium after supplementation. Differences in magnesium retention was not related to basal magnesium intake, blood levels or excretion. Unfortunately, even an intensive effort at characterizing magnesium status did not identify a clinical indicator of utility for differentiating patients with congestive heart failure before, during, and after 3 months of magnesium supplementation.

Timing of ventricular septal rupture after acute myocardial infarction and its relation to thrombolytic therapy.

The clinical and treatment characteristics of 71 patients who had acute myocardial infarction complicated by ventricular septal rupture were assessed retrospectively. A history of hypertension was strongly associated with "early" septal rupture (p < 0.001); other clinical and treatment characteristics, including the use and timing of thrombolytic therapy, were not.

The efficacy and safety of pravastatin in patients aged 60 to 85 years with low-density lipoprotein cholesterol > 160 mg/dl.

This study demonstrated that pravastatin 20 mg once daily significantly lowered total cholesterol (by 19%) and LDL cholesterol by 25%.

First-dose effects of enalapril 2.5 mg and captopril 6.25 mg in patients with heart failure: a double-blind, randomized, multicenter study. The Enalapril-Captopril Investigators.

Significant decreases in blood pressure (BP) may occur when administration of angiotensin-converting enzyme (ACE) inhibitors is initiated for the treatment of heart failure. The purpose of this study was to compare the safety and tolerability of recommended initial doses of the longer-acting ACE inhibitor enalapril (ENAL) with those of the shorter-acting captopril (CAP) in patients with heart failure who were treated concomitantly with digitalis and diuretic agents. We evaluated BP, serum ACE activity, and clinical status when a low, first dose of ENAL (2.5 mg, n = 59) or CAP (6.25 mg, n = 58) was administered in a double-blind, randomized, and parallel fashion to 117 patients with mild to moderate heart failure. BP and serum ACE activity were measured at 30 min and hourly for 8 hours after drug administration. BP decreases were similar for both groups (mean supine BP -6.2/-4.8 mm Hg for ENAL vs -8.3/-6.4 mm Hg for CAP; mean standing BP -9.2/-5.6 mm Hg for ENAL vs -10.0/-4.7 mm Hg for CAP). Although the maximum mean decrease in BP occurred at hours 4 and 5 in the ENAL group and hours 1 and 2 in the CAP group, considerable between-group overlap was observed for individual patients. Decreases in mean serum ACE activity occurred earlier and were of shorter duration in the CAP group. ENAL significantly inhibited serum ACE activity to a greater extent than did CAP at all time points except the 1st hour. Administration of a first dose of ENAL, 2.5 mg or CAP, 6.25 mg to patients with heart failure was well tolerated.

The changing syndrome of heart failure: an annotated review as we approach the 21st century.

EPIDEMIOLOGY: Risk factors for heart failure vary in magnitude, depending on age and sex. Incidence, prevalence, morbidity and mortality are strongly age-related. The presence of hypertension or diabetes among men aged 35-64 years increases the risk fourfold. Electrocardiographic evidence of left ventricular hypertrophy in this group increases the risk 15-fold, independently of the presence of hypertension. Other independent risks include obesity, a high ratio of total to high-density cholesterol, proteinuria, an intraventricular conduction delay or a non-specific repolarization abnormality. Among blacks, the presence of hypertension increases the incidence of heart failure; among whites, the underlying cause is more commonly ischemic heart disease. PATHOPHYSIOLOGY: Impaired cardiac contractility is the primary hemodynamic change in heart failure. Increases in ventricular filling pressure following changes in ventricular diastolic compliance contribute to the symptoms. Neurohormonal changes, particularly those related to activation of the renin-angiotensin-aldosterone system through interactions with the sympathetic nervous system, have been correlated with the severity of the disease and mortality. Drugs that modulate neurohormonal systems have more favorable effects on the outcome of heart disease than those that only affect hemodynamic systems. THERAPY: Patients must be educated towards improved compliance with recommendations on sodium intake, cessation of smoking, weight control, exercise and medication regimens. Current drug therapy includes treatment with diuretics with or without digitalis and can be improved by the use of angiotensin converting enzyme (ACE) inhibitors. Optimal doses of these inhibitors, their use in patients with asymptomatic left ventricular dysfunction and their mechanisms of action are currently being evaluated.

A consensus report on antiarrhythmic drug use.

During the past few years, a number of new antiarrhythmic agents have become available for use in the United States, encainide has been withdrawn from use, and others have had indications for use modified. Therefore, a meeting of arrhythmia specialists was convened in an attempt to develop guidelines for antiarrhythmic therapy. The resultant discussions and guidelines presented in this article address general issues such as the most important antiarrhythmic drug attributes, as well as therapy for particular arrhythmias such as premature ventricular contractions, ventricular tachycardia, ventricular fibrillation, ventricular ectopy, and supraventricular tachyarrhythmias.

Clinical consequences of angiotensin-converting enzyme inhibitor withdrawal in chronic heart failure: a double-blind, placebo-controlled study of quinapril. The Quinapril Heart Failure Trial Investigators.

OBJECTIVES: This study was performed to assess 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. Quinapril hydrochloride, a nonsulfydryl angiotensin-converting enzyme inhibitor, has shown beneficial clinical effects in previous studies. METHODS: After > or = 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 functional class (p = 0.004) and quality of life were improved and signs 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.

A practical approach to the management of heart failure.

The pathophysiology of the serious and disabling problem of heart failure has been confirmed to involve activation of multiple neuroendocrine systems, especially the sympathetic system and renin angiotensin aldosterone system. The results of several large scale clinical trials demonstrate that reduction in morbidity and mortality are possible with currently available drugs. The benefits for the patient can be maximised by early intervention, especially by the family physician as opposed to interventions applied late, which often yield minimal benefit.

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.

Amlodipine combined with beta blockade for chronic angina: results of a multicenter, placebo-controlled, randomized double-blind study.

Amlodipine, a potent long-acting dihydropyridine calcium antagonist, was compared with placebo in a parallel, randomized, double-blind study in 134 patients with chronic stable angina pectoris maintained on beta-adrenergic blocking agents. After a single-blind, two-week placebo period, patients were randomized to receive either amlodipine (2.5, 5, and 10 mg) or placebo once daily for four weeks. The effects of amlodipine on maximal exercise time, work, time to angina onset, and subjective indices including angina frequency, nitroglycerin tablet consumption, and patient and investigator ratings were assessed. Each dose of amlodipine produced increases in exercise time and calculated total work accomplished compared to baseline. Improvements at 5 and 10 mg were significantly greater than placebo which produced no significant change (p less than 0.05). Qualitative improvements in the severity of angina were produced by amlodipine at 5 and 10 mg daily assessed by patient-rating questionnaires (p less than 0.05). Reductions in angina frequency attacks per week and weekly nitroglycerin tablet consumption occurred but were not statistically significant when compared with placebo. Adverse effects observed during amlodipine treatment prompted discontinuation of treatment in only 2 out of 100 patients. Three patients discontinued treatment for reported lack of efficacy. No laboratory abnormalities prompted treatment discontinuation and minor side effects of dizziness, nausea, headache, and fatigue were observed infrequently. The results of this controlled, large-scale multicenter trial suggest that amlodipine significantly increased exercise capacity and was well tolerated when added to the antianginal regimen of patients remaining symptomatic while receiving beta-blocking agents.

Bepridil treatment of chronic stable angina: a review of comparative studies versus placebo, nifedipine, and diltiazem.

The antianginal efficacy of bepridil, a calcium antagonist with an extended plasma elimination half-life, has been compared with placebo and the calcium antagonists nifedipine and diltiazem in patients refractory to diltiazem. The earliest observations in the United States of antianginal effects of bepridil were revealed in a single-blind, multicenter, placebo-controlled trial of 77 patients with chronic stable angina pectoris that demonstrated that bepridil (300 mg/day) improved exercise duration by 26%, from 6.9 +/- 0.4 (standard error of the mean) to 8.7 +/- 0.5 minutes (p less than 0.001), and exercise work by 52%, from 2.7 +/- 0.3 to 4.1 +/- 0.4 x 10(-3) KPM (p less than 0.001), on a standardized treadmill protocol, and it reduced angina frequency by 68%, from 8.5 +/- 1.1 to 2.7 +/- 0.7 attacks per week, and nitroglycerin use by 76% (p less than 0.001). Minor side effects such as nausea, epigastric discomfort, and tremor were infrequent and no major side effects occurred. Double-blind, parallel-design treatment evaluations confirmed beneficial effects of bepridil alone and in combination with beta blockade. Chronic efficacy was confirmed by evaluations up to 24 months in a controlled withdrawal study. Antianginal effects of nifedipine were compared with those of bepridil in a double-blind, parallel group study of 101 patients with chronic stable angina treated for 3 months. Bepridil (mean final dose 284 mg/day; range 200-400 mg/day) produced modest but statistically significantly (p less than 0.05) greater improvements in exercise work, time to angina, or 1 mm ST-segment change than nifedipine (mean final dose 59 mg/day; range 30-120 mg/day).(ABSTRACT TRUNCATED AT 250 WORDS)

Double-blind, dose-response, placebo-controlled multicenter study of nisoldipine. A new second-generation calcium channel blocker in angina pectoris.

BACKGROUND: Nisoldipine is a potent 1:4 dihydropyridine calcium channel antagonist, and doses of 5 or 10 mg administered either once or twice daily have been claimed to exert antianginal effects. There is, however, little information regarding the dose-response relation and whether the drug exerts any consistent effects throughout the dosing interval. In this placebo-controlled, parallel-design study, the dose-response relation of monotherapy with nisoldipine administered twice daily was studied in patients with stable angina pectoris. METHODS AND RESULTS: Two hundred thirty-one patients received single-blind placebo for 2 weeks; of these, 185 patients who reproducibly stopped treadmill exercise because of angina of moderate severity and had greater than or equal to 1 mm ST segment depression during exercise and experienced an average of three episodes of anginal attacks per week were randomized in a double-blind manner to one of the four treatment groups: placebo (n = 48), nisoldipine 2.5 mg (n = 47), nisoldipine 5 mg (n = 44), or nisoldipine 10 mg (n = 46). Nisoldipine or placebo was administered twice daily for 4 weeks and symptom-limited exercise tests were repeated at 2 and 10-14 hours after the double-blind medication. One hundred sixty-eight patients completed the study and 181 patients were valid for efficacy analysis. Compared with double-blind placebo, there were marginally significant trends toward increases for time to onset of angina for the 10-mg-b.i.d. group (83 versus 108 seconds, p = 0.08), time to 1 mm ST segment depression for the 5-mg-b.i.d. group (54 versus 83 seconds, p = 0.08), and total exercise time for the 5- (30 versus 50 seconds, p = 0.10) and 10-mg-b.i.d. (30 versus 58 seconds, p = 0.06) groups at 2 hours after the dose (peak effect) after 4 weeks of therapy. At 10-14 hours after the dose (trough effect), no differences between placebo and any of the nisoldipine doses on any of the exercise parameters were found after 4 weeks of therapy. A subset analysis of patients who stopped exercise within 10 minutes because of angina of moderate severity during single-blind placebo therapy (n = 123) revealed significant increase in total exercise duration and time to 1 mm ST segment depression at 2 hours after the dose in the 5- and 10-mg-b.i.d. dose groups compared with double-blind placebo (p less than 0.04). No significant trough effects, however, were observed even in this subgroup after any of the doses of nisoldipine. The frequency of anginal attacks decreased by 44%, 41%, 30%, and 41% after twice-daily therapy with 2.5 mg, 5 mg, 10 mg nisoldipine, and placebo groups, respectively (p = NS, nisoldipine versus placebo). The incidence of adverse events (minor and major) was 43.8% in the placebo group and 42.6%, 45.5%, and 56.5% in the nisoldipine 2.5-, 5-, and 10-mg-b.i.d. groups, respectively (p = NS compared with placebo). However, four patients developed unstable angina while on nisoldipine therapy (two in the 2.5-mg, one in the 5-mg, and one in the 10-mg-b.i.d. group) and two patients died suddenly in the nisoldipine 10-mg-b.i.d. group. CONCLUSIONS: Monotherapy with 2.5, 5, and 10 mg nisoldipine twice a day was not superior to placebo therapy in treating patients with angina pectoris, and the 10-mg-b.i.d. therapy resulted in a statistically insignificant but clinically important increase in the incidence of serious adverse events.

Effect of oral milrinone on mortality in severe chronic heart failure. The PROMISE Study Research Group.

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.

Can angiotensin converting enzyme (ACE) inhibitors influence the risk of sudden cardiac death in patients with heart failure?

Progression of heart failure ("expected mortality") and sudden cardiac death ("unexpected mortality"), presumably secondary to ventricular arrhythmia, are the major causes for the poor prognosis in chronic heart failure (CHF). Limitations of this classification ultimately stem from inaccuracies in establishing the mechanism of death at the time of death. Elucidation of the determinants of patients prone to sudden death and the effects of treatment modalities on the rate of sudden death remain hidden. Unexpected mortality is probably secondary to arrhythmic death but denotes only that death occurred within some brief interval (arbitrarily less than one hour in most studies) and does not exclude other causes. The demonstrated benefit of ACE inhibitors for improving total mortality as illustrated by the findings of the VHeFT, Captopril Multicenter and CONSENSUS, and the improved event-free survival shown by Munich Mild Heart Failure Trial for low-dose captopril argues strongly for their use in patients with CHF. These agents are confirmed to reduce the risk of death from pump failure; the effects on sudden death are less clear. Although many favorable effects contribute to improved hemodynamics, neuroendocrine and electrolyte status as discussed, at present, it is not possible to predict the precise mechanism by which these agents extend life and whether they reduce the frequency of "sudden" deaths.

A large-scale trial of captopril for mild to moderate heart failure in the primary care setting.

A large-scale, prospective, 8-week, office-based study was conducted to evaluate the effects of adding captopril to a therapeutic regimen of diuretic and digoxin or diuretic alone in the management of patients with mild to moderate congestive heart failure (CHF). A total of 2218 primary care physicians evaluated 6669 patients over the study period for efficacy parameters, which included changes in a modified New York Heart Association (NYHA) functional classification, symptomatology, and daily activity levels. Overall, 63.8% of evaluated patients improved with regard to functional ability, with 19% improving two or more modified NYHA classes. Symptoms of CHF, including dyspnea on exertion, fatigue, and orthopnea and signs, including rales and peripheral edema, were reduced in 86% of these patients: 41.5% demonstrated mild improvement; 30.0%, moderate improvement; and 14.5%, marked improvement. Three parameters, with which patients reported having difficulty at study entry, were assessed serially to evaluate changes in functional capacity; 78.5% of patients reported an increased walking distance, 72.3% had increased capacity for climbing stairs, and 60.2% had improved capacity for individual recreational activities. Adverse experiences were reported in 18.1% of all patients; 4.9% of patients withdrew from the study because of an adverse effect. Combination therapy with captopril and diuretic for CHF was shown to be safe and effective regardless of patient age (less than 70 years vs. greater than or equal to 70 years), duration of heart failure (less than 1 year vs. greater than 1 year), presence of digoxin treatment, or the dosing schedule employed.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute positive inotropic intervention: the phosphodiesterase inhibitors.

Phosphodiesterase inhibitors that are selective for cAMP-specific cardiac and vascular PDE III comprise a new group of agents for the treatment of heart failure, which at present are limited to clinical shortterm intravenous use and research uses only. Although both intravenous amrinone and milrinone are FDA approved, only amrinone is available for general clinical use. Selective phosphodiesterase inhibition produces beneficial actions of positive inotropy and peripheral vasodilation that result from increased cardiac and vascular muscle concentrations of intracellular cAMP and ionic calcium. In addition, a positive lusitropic action (enhancement of cardiac relaxation) has been observed. Neither beta-adrenergic agonist activity nor inhibition of the sodium-potassium ATPase is produced by these agents. The magnitude of hemodynamic improvement generally exceeds that of the cardiac glycosides and is comparable with that of intravenous catecholamines such as dobutamine. The different pharmacodynamic profile of the PDE inhibitors is additive to the effects of cardiac glycosides, complementary and synergistic to the actions of catecholamines, and has been shown to have favorable effects on coronary hemodynamics. As a result there is continued enthusiasm for the short-term intravenous use of amrinone and potentially milrinone in the setting of acute heart failure resulting from systolic dysfunction (after myocardial infarction, open heart surgery, or infectious or toxic myocarditis), heart failure resulting from right ventricular systolic dysfunction, and when patients with severe heart failure await cardiac transplantation. Initiation of treatment with an intravenous bolus followed by a maintenance infusion provides prompt increases in stroke volume and cardiac output and simultaneous reductions in right and left ventricular filling pressures and systemic vascular resistance.(ABSTRACT TRUNCATED AT 250 WORDS)

Doxazosin for the treatment of chronic congestive heart failure: results of a randomized double-blind and placebo-controlled study.

In this study we evaluated the effects of once-daily administration of oral doxazosin in patients with chronic congestive heart failure (CHF). After a stabilization period of at least 2 weeks with digitalis and diuretics, 73 patients with chronic CHF were randomized to receive additionally either doxazosin or placebo in double-blind fashion. Patients underwent weekly dose adjustments with increasing doses of doxazosin (1, 2, 4, 8, and 16 mg daily) or placebo for 5 weeks, and 67 were evaluated for 12 additional weeks on maximally tolerated doses of blinded study drugs. Treatment groups were evaluated with respect to symptoms of heart failure, indexes of quality of life and left ventricular function, frequency and type of arrhythmia, adverse events, and mortality rates. Doxazosin (11.9 +/- 0.9 mg) given once daily produced a favorable trend in the investigators' and patients' assessments of symptomatic change. Doxazosin was associated with a significantly higher level of voluntary submaximal exercise and a favorable trend on left ventricular ejection fraction (increase of 9.8% of the baseline value vs 2.7% with placebo; p = NS). During the 3-month steady-dosing period, patients treated with doxazosin had a significant (p less than 0.004) reduction in ventricular arrhythmias and significantly fewer morbid and mortal cardiac events (including episodes of worsening heart failure severe enough to prompt discontinuation of the study, myocardial infarction, and death). Doxazosin was well tolerated, producing no major side effects and only a slightly higher frequency of minor treatment-related side effects compared with placebo (p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)

ACE inhibitors in the treatment of heart failure.

The renin-angiotensin-aldosterone system (RAAS) has been implicated in the pathogenesis of congestive heart failure (CHF). Abnormal activation of the RAAS adversely affects cardiac performance and impairs functional status, increasing both afterload and preload through direct and indirect mechanisms. Conventional first-line therapy for CHF consists of diuretics and/or digitalis. Diuretics offer rapid relief of symptoms, effective volume control, and ease of administration, but are associated with a number of disadvantages, including further activation of neurohormonal systems resulting in augmented vasoconstriction. Angiotensin-converting enzyme (ACE) inhibitors, which block the RAAS by inhibiting production of angiotensin II from angiotensin I, are emerging as the vasodilators of choice in combination with diuretics with or without concomitant digitalis. Direct comparative studies have shown that ACE inhibitors provide acute and long-term symptomatic, hemodynamic, and exercise-related benefits as well as improved functional class and, possibly, slowed progression of disease with enhanced survival in specific subgroups. Captopril was the first orally effective ACE inhibitor associated with improved exercise tolerance and functional class in large multicenter trials of patients with severe heart failure and mild to moderate heart failure. Enalapril reduced the probability of death in patients with severe heart failure in the CONSENSUS trial. The new ACE inhibitor quinapril has been shown to improve hemodynamic status both acutely and chronically and to produce dose-related improvements in exercise tolerance. ACE inhibitors have a favorable safety profile, although hypotension can occur with initial doses, particularly in volume-depleted patients or at times when excessive initial doses are administered.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical results with oral milrinone in heart failure.

Clinical evaluation of oral milrinone in moderate to severe heart failure has demonstrated pronounced beneficial effects. These effects are achieved through increased cardiac index and exercise tolerance, and reduced ventricular filling pressure and systemic vascular resistance. In a double-blind, multicentre study of 230 patients with moderate to severe failure receiving diuretic therapy, treatment with milrinone or digoxin significantly improved exercise capacity. No additional benefit was obtained using combined treatment with the two drugs. A sub-study of 60 patients showed that milrinone produced a significantly higher peak oxygen consumption during treadmill exercise compared with placebo, and approached a significant improvement over digoxin. Milrinone and digoxin favourably influenced symptoms and quality of life measures, but NYHA class was unaltered. Both treatments were well tolerated, alone or combined. A similar study of 155 patients showed comparable results, with no evidence of tolerance development during chronic (3-month) treatment. Survival during the 3-month studies showed a strong correlation with baseline resting left ventricular ejection fraction and was independent of treatment. Neither treatment adversely affected survival. These studies show that milrinone is a well-tolerated and effective oral agent that provides clinical benefits beyond those obtained with diuretics alone in moderate to severe heart failure.