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Biomedical subjects

M B Fowler

Publications and source records attributed to M B Fowler.

At least 19 recordsLinked to original sources
PubMed2004

The potential impact of soil ingestion on human mineral nutrition.

Geophagia, the intentional and repeated ingestion of soil material, is a complex eating behaviour with incomprehensible aetiology. It is generally assumed that geophagia may help supplement mineral nutrients and thus should not be dissuaded, particularly in subsistence communities. This is largely based on the assumption that a large proportion of mineral nutrients in geophagic materials is potentially available for absorption in the body. We tested this hypothesis on five soils collected from geophagia-prevalent communities by using an in vitro soil ingestion simulation test that is broadly similar to the gastrointestinal (GI) tract. The results show that, despite the soils being rich in mineral nutrients, soil ingestion, inadvertent or through geophagia can potentially reduce the absorption of already bioavailable nutrients, particularly micronutrients such as Fe, Cu and Zn. These in vitro findings, while disagreeing with the commonly held view of geophagia as a source of nutrient supplementation, are consistent with micronutrient deficiency problems observed in clinical nutrition studies conducted amongst geophagic populations. The work also showed that, in some cases, the ingested soils may become a source of Ca, Mg and Mn, although it is not clear why other similar soils should not release any of these mineral nutrients.

Adsorption↗
PubMed2001

Effect of carvedilol on survival in severe chronic heart failure.

BACKGROUND: Beta-blocking agents reduce the risk of hospitalization and death in patients with mild-to-moderate heart failure, but little is known about their effects in severe heart failure. METHODS: We evaluated 2289 patients who had symptoms of heart failure at rest or on minimal exertion, who were clinically euvolemic, and who had an ejection fraction of less than 25 percent. In a double-blind fashion, we randomly assigned 1133 patients to placebo and 1156 patients to treatment with carvedilol for a mean period of 10.4 months, during which standard therapy for heart failure was continued. Patients who required intensive care, had marked fluid retention, or were receiving intravenous vasodilators or positive inotropic drugs were excluded. RESULTS: There were 190 deaths in the placebo group and 130 deaths in the carvedilol group. This difference reflected a 35 percent decrease in the risk of death with carvedilol (95 percent confidence interval, 19 to 48 percent; P=0.00013, unadjusted; P=0.0014, adjusted for interim analyses). A total of 507 patients died or were hospitalized in the placebo group, as compared with 425 in the carvedilol group. This difference reflected a 24 percent decrease in the combined risk of death or hospitalization with carvedilol (95 percent confidence interval, 13 to 33 percent; P<0.001). The favorable effects on both end points were seen consistently in all the subgroups we examined, including patients with a history of recent or recurrent cardiac decompensation. Fewer patients in the carvedilol group than in the placebo group withdrew because of adverse effects or for other reasons (P=0.02). CONCLUSIONS: The previously reported benefits of carvedilol with regard to morbidity and mortality in patients with mild-to-moderate heart failure were also apparent in the patients with severe heart failure who were evaluated in this trial.

Adrenergic beta-Antagonists↗
PubMed2001

Race and the response to adrenergic blockade with carvedilol in patients with chronic heart failure.

BACKGROUND: The benefits of angiotensin-converting-enzyme inhibitors and beta-blockers may be smaller in black patients than in patients of other races, but it is unknown whether race influences the response to carvedilol in patients with chronic heart failure. METHODS: In the U.S. Carvedilol Heart Failure Trials Program, 217 black and 877 nonblack patients (in New York Heart Association class II, III, or IV and with a left ventricular ejection fraction of no more than 0.35) were randomly assigned to receive placebo or carvedilol (at doses of 6.25 to 50 mg twice daily) for up to 15 months. The effects of carvedilol on ejection fraction, clinical status, and major clinical events were retrospectively compared between black and nonblack patients. RESULTS: As compared with placebo, carvedilol lowered the risk of death from any cause or hospitalization for any reason by 48 percent in black patients and by 30 percent in nonblack patients. Carvedilol reduced the risk of worsening heart failure (heart failure leading to death, hospitalization, or a sustained increase in medication) by 54 percent in black patients and by 51 percent in nonblack patients. The ratios of the relative risks associated with carvedilol for these two outcome variables in black as compared with nonblack patients were 0.74 (95 percent confidence interval, 0.42 to 1.34) and 0.94 (95 percent confidence interval, 0.43 to 2.05), respectively. Carvedilol also improved functional class, ejection fraction, and the patients' and physicians' global assessments in both the black patients and the nonblack patients. For all these measures of outcome and clinical status, carvedilol was superior to placebo within each racial cohort (P<0.05 in all analyses), and there was no significant interaction between race and treatment (P> 0.05 in all analyses). CONCLUSIONS: The benefit of carvedilol was apparent and of similar magnitude in both black and nonblack patients with heart failure.

Adrenergic Antagonists↗
PubMed2001

The role of angiotensin receptor blockers in the management of chronic heart failure.

Clinical and basic science research has repeatedly confirmed the importance of the renin-angiotensin-aldosterone system in the pathophysiology of chronic heart failure. Accordingly, blockade of this system by angiotensin-converting enzyme (ACE) inhibitors has assumed a central role in the treatment of heart failure. Recently, angiotensin II receptor blockers (ARBs) have gained prominence as a possible substitute for ACE inhibitors in therapy for heart failure. However, clinical data compiled on this use of ARBs have shown them to be useful only as alternative therapy in ACE inhibitor-intolerant patients. Continuing large-scale clinical investigations may lead to an expansion of their role in therapy for various cardiovascular diseases.

Angiotensin II↗
PubMed2001

Influence of carvedilol on hospitalizations in heart failure: incidence, resource utilization and costs. U.S. Carvedilol Heart Failure Study Group.

BACKGROUND: Carvedilol reduces disease progression in heart failure, but to our knowledge, its effects on hospitalizations and costs have not been evaluated. OBJECTIVES: We examined the effects on hospitalization frequency and costs in the U.S. Carvedilol Heart Failure Trials Program. This program consisted of four concurrent, multicenter, double-blind, placebo-controlled studies involving 1,094 patients with New York Heart Association class II to IV heart failure, which treated patients with placebo or carvedilol for up to 15 months (median, 6.5 months). METHODS: Detailed resource utilization data were collected for all hospitalizations occurring between randomization and the end of follow-up. In-patient care costs were estimated based on observed levels of resource use. RESULTS: Compared with placebo, carvedilol reduced the risk of hospitalization for any reason by 29% (p = 0.009), cardiovascular hospitalizations by 28% (p = 0.034) and heart failure hospitalizations by 38% (p = 0.041). Carvedilol also decreased the mean number of hospitalizations per patient (for cardiovascular reasons 30% [p = 0.02], for heart failure 53% [p = 0.03]). Among hospitalized patients, carvedilol reduced severity of illness during hospital admission, as reflected by shorter length of stay and less frequent use of intensive care. For heart failure hospital admissions, carvedilol decreased mean length of stay by 37% (p = 0.03) and mean number of intensive care unit/coronary care unit days by 83% (p = 0.001), with similar effects on cardiovascular admissions. As a result, estimated inpatient care costs with carvedilol were 57% lower for cardiovascular admissions (p = 0.016) and 81% lower for heart failure admissions (p = 0.022). CONCLUSIONS: Carvedilol added to angiotensin-converting enzyme inhibition reduces hospitalization risk as well as severity of illness and resource utilization during admission in patients with chronic heart failure.

Adrenergic beta-Antagonists↗
PubMed2000

Cardiopulmonary exercise testing and prognosis in severe heart failure: 14 mL/kg/min revisited.

BACKGROUND: Accurately establishing prognosis in severe heart failure has become increasingly important in assessing the efficacy of treatment modalities and in appropriately allocating scarce resources for transplantation. Peak exercise oxygen uptake appears to have an important role in risk stratification of patients with heart failure, but the optimal cutpoint value to separate survivors from nonsurvivors is not clear. METHODS: Six hundred forty-four patients referred for heart failure evaluation over a 10-year period participated in the study. After pharmacologic stabilization at entrance into the study, all participants underwent cardiopulmonary exercise testing. Survival analysis was performed with death as the end point. Transplantation was considered a censored event. Four-year survival was determined for patients who achieved peak oxygen uptake values greater than and less than 10, 11, 12, 13, 14, 15, 16, and 17 mL/kg/min. RESULTS: Follow-up information was complete for 98.3% of the cohort. During a mean follow-up period of 4 years, 187 patients (29%) died and 101 underwent transplantation. Actuarial 1- and 5-year survival rates were 90.5% and 73.4%, respectively. Peak ventilatory oxygen uptake (VO(2)) was an independent predictor of survival and was a stronger predictor than work rate achieved and other exercise and clinical variables. A difference in survival of approximately 20% was achieved by dichotomizing patients above versus below each peak VO(2) value ranging between 10 and 17 mL/kg/min. Survival rate was significantly higher among patients achieving a peak VO (2) above than among those achieving a peak VO (2) below each of these values (P <.01), but each cutpoint was similar in its ability to separate survivors from nonsurvivors. CONCLUSION: Peak VO (2) is an important measurement in predicting survival from heart failure, but whether an optimal cutpoint exists is not clear. Peak VO(2) may be more appropriately used as a continuous variable in multivariate models to predict prognosis in severe chronic heart failure.

Breath Tests↗
PubMed1999

Cost effectiveness of carvedilol for heart failure.

In this study, we examine the cost effectiveness of carvedilol for the treatment of chronic heart failure (CHF). We use a Markov model to project life expectancy and lifetime medical care costs for a hypothetical cohort of patients with CHF who were assumed alternatively to receive carvedilol plus conventional therapy (digoxin, diuretics, and angiotensin-converting enzyme inhibitors) or conventional therapy alone. Patients on carvedilol were assumed to experience a reduced risk of death and hospitalization for CHF, which is consistent with findings from the US Carvedilol Heart Failure Trials Program. The benefits of carvedilol were projected under 2 alternative scenarios. In the first ("limited benefits"), benefits were conservatively assumed to persist for 6 months, the average duration of follow-up in these clinical trials, and then end abruptly. In the other ("extended benefits"), they were arbitrarily assumed to persist for 6 months and then decline gradually over time, vanishing by the end of 3 years. We estimated our model using data from the US Carvedilol Heart Failure Trials Program and other sources. For patients receiving conventional therapy alone, estimated life expectancy was 6.67 years; corresponding figures for those also receiving carvedilol were 6.98 and 7.62 years under the limited and extended benefits scenarios, respectively. Expected lifetime costs of CHF-related care were estimated to be $28,756 for conventional therapy, and $36,420 and $38,867 for carvedilol (limited and extended benefits, respectively). Cost per life-year saved for carvedilol was $29,477 and $12,799 under limited and extended benefits assumptions, respectively. The cost effectiveness of carvedilol for CHF compares favorably to that of other generally accepted medical interventions, even under conservative assumptions regarding the duration of therapeutic benefit.

Adrenergic beta-Antagonists↗
PubMed1998

Clinical, hemodynamic, and cardiopulmonary exercise test determinants of survival in patients referred for evaluation of heart failure.

BACKGROUND: Accurate prognosis in chronic heart failure has become increasingly important in assessing the efficacy of treatment and in appropriately allocating scarce resources for transplantation. Previous studies of severe heart failure have been limited by short follow-up periods and few deaths. OBJECTIVE: To establish clinical, hemodynamic, and cardiopulmonary exercise test determinants of survival in patients with heart failure. DESIGN: Retrospective study. SETTING: Hospital-based outpatient heart failure clinic. PARTICIPANTS: 644 patients referred for evaluation of heart failure over 10 years. MEASUREMENTS: Age, cause of heart failure, body surface area, cardiac index, ejection fraction, pulmonary capillary wedge pressure, left ventricular dimensions, watts achieved during exercise, heart rate, maximum systolic blood pressure, and oxygen uptake (VO2) at the ventilatory threshold and at peak exercise were measured at baseline. Univariate and multivariate analyses were done for clinical, hemodynamic, and exercise test predictors of death. A Cox hazards model was developed for time of death. RESULTS: During a mean follow-up period of 4 years, 187 patients (29%) died and 101 underwent transplantation. Actuarial 1-year and 5-year survival rates were 90.5% and 73.4%, respectively. Resting systolic blood pressure, watts achieved, peak VO2, VO2 at the ventilatory threshold, and peak heart rate were greater among survivors than among nonsurvivors. Cause of heart failure (coronary artery disease or cardiomyopathy) was a strong determinant of death (relative risk for coronary artery disease, 1.73; P< 0.01). By multivariate analysis, only peak VO2 was a significant predictor of death. Stratification of peak VO2 above and below 12, 14, and 16 mL/kg per minute demonstrated significant differences in risk for death, but each cut-point predicted risk to a similar degree. CONCLUSIONS: Peak VO2 outperforms clinical variables, right-heart catheterization data, exercise time, and other exercise test variables in predicting outcome in severe chronic heart failure. Direct measurement of VO2 should be included when clinical or surgical decisions are being made in patients referred for evaluation of heart failure or those considered for transplantation.

Adult↗
PubMed1998

Use of assumed versus measured oxygen consumption for the determination of cardiac output using the Fick principle.

Assumed oxygen consumption (VO2) is increasingly used as a convenient surrogate for measured VO2 for calculation of cardiac output. This substitution is often based on empirical formulae, previously validated only in relatively young patients. To assess the inaccuracy introduced by extrapolating these formulae to older patients, we compared measured VO2 with assumed VO2 in 57 patients. VO2 was measured using an open circuit analyzer. Assumed VO2 was calculated according to the LaFarge or Bergstra formulae. Agreement between both methods was assessed according to the method of Bland and Altman. The mean difference of measured VO2 minus assumed VO2 was 7.9 ml/min/m2 (P < 0.02) using the LaFarge formula, and -15.6 ml/min/m2 (P < 0.0002) using the Bergstra formula across a range of measured VO2 from 70 to 176 ml/min/m2. A systematic error was introduced by assumed VO2 from both formulae of underestimating higher and overestimating lower values of VO2, resulting in poor overall agreement with measured VO2. The same error and poor agreement was found when analyzing subgroups of patients > or =60 or <70 years of age. In summary, use of assumed VO2 introduces large, unpredictable errors in adult patients, suggesting requirement for measurement of VO2 when calculating cardiac output.

Adolescent↗
PubMed1998

Beta-blockers in heart failure. Do they improve the quality as well as the quantity of life?

Heart failure is a common clinical problem in patients with cardiovascular disease. Mortality remains high despite conventional therapy. The morbidity associated with heart failure accounts for numerous hospitalizations and significant health care expenditures. Therapy has been directed at relieving symptoms, augmenting exercise capacity, reducing hospitalizations and improving survival. Randomized clinical trials have shown that angiotensin-converting enzyme (ACE) inhibitors achieve these therapeutic goals and exert a favourable influence on disease progression. Recent clinical trials evaluating metoprolol, bisoprolol and carvedilol have clearly established that judicious use of beta-adrenergic blockers in heart failure patients who have been stabilized favourably influences the natural history of the disease, even when given as additional therapy to patients already receiving ACE inhibitors. Carvedilol is a non-selective beta-adrenergic blocking drug with vasodilatory properties that has been recently approved by the U.S. Food and Drug Administration for use in patients with NYHA functional class II or III heart failure. It was the only agent to produce a statistically significant survival benefit in a pre-specified analysis that included all the patients randomized into the multicentre U.S. Carvedilol Heart Failure Trials Program, irrespective of disease aetiology. As with trials looking at ACE inhibitor therapy, studies involving beta-blocker therapy in patients with heart failure have evaluated the effects of these drugs on hospitalization, NYHA functional class, exercise capacity and survival. In the U.S. Carvedilol Heart Failure Trials Program, the risk of hospitalization for any cause was reduced by 29%, the risk of hospitalization for a cardiovascular cause was reduced by 28% and the risk of dying was reduced by 65%. Thus, carvedilol has been shown in randomized clinical trials to improve the quantity of life and, at least in terms of the incidence of hospitalization, to improve the qualify of life as well. Randomized trials have consistently reported a favourable change in NYHA functional class in patients treated with beta-adrenergic blocking drugs: the majority of patients became less symptomatic. In the U.S. Carvedilol trials, patients and physicians reported (separately) an improvement in global status, and less deterioration when treatment was randomized to carvedilol. The positive influence of such therapy is reflected in a reduction in hospitalizations. In summary, patients with NYHA class II or III who have been stabilized with ACE inhibitors and diuretics can expect an improvement in the quality as well as the quantity of life with beta-blocker therapy.

Adrenergic beta-Antagonists↗
PubMed1997

Effects of beta blockers on symptoms and functional capacity in heart failure.

Beta-adrenergic-blocking drugs ameliorate the progression of disease that usually characterizes heart failure. All of the larger multicenter studies have demonstrated reductions in morbidity, manifested by a reduction in the number of hospitalizations and/or listing for cardiac transplantation, whereas studies with carvedilol have also reported a significant reduction in mortality. The influence of beta-adrenergic blocking drugs on the symptomatic and functional status of patients with heart failure has been more difficult to establish. Almost all trials have reported an improvement in New York Heart Association (NYHA) functional class, with few patients experiencing functional deterioration. Improvement in symptom score was reported in the Metoprolol in Dilated Cardiomyopathy (MDC) trial far patients treated with metoprolol. In patients from the US Carvedilol Heart Failure Trials Program who had heart failure from ischemic and nonischemic etiologies, both patients and physicians reported more improvement and less deterioration in an assessment of global status. More formal instruments to assess quality of life, such as the specific activity scale in the Australia-New Zealand trial of carvedilol (that recruited 30% of patients who bad improved to NYHA stage I) and the Minnesota Quality of Life questionnaire, did not seem sensitive to the clinical benefits observed in these trials. Serial exercise testing similarly does not seem sensitive to the beneficial influence of beta-adrenergic blocking drugs on disease progression, at least in relatively short-term studies.

Adrenergic beta-Antagonists↗
PubMed1997

AT1 and AT2 angiotensin receptor gene expression in human heart failure.

BACKGROUND: The availability of selective antagonists for angiotensin II receptors has focused interest on the gene expression of angiotensin II-receptor subtypes in the human heart. METHODS AND RESULTS: We analyzed expression of the AT1 and AT2 subtypes of the angiotensin II receptor in ventricular myocardium taken from 9 donor hearts before implantation and from 12 patients with heart failure (6 with dilated cardiomyopathy and 6 with ischemic heart disease). Competitive reverse transcription-polymerase chain reaction with synthetic RNA internal standards was used to detect mRNA for both subtypes and to quantify relative differences in levels between failing and non-failing ventricular myocardium. AT1- and AT2-receptor mRNA could be detected in all samples. AT1-receptor gene expression was 2.5-fold greater in nonfailing hearts than in patients with failing hearts (P = .015). There was no significant difference in AT2-receptor mRNA expression in failing and nonfailing hearts. CONCLUSIONS: The level of expression of the angiotensin AT1 receptor appears to decrease in the failing human ventricle whereas the level of AT2 expression is unaffected. These changes parallel the changes found in human ventricular myocardium at the receptor level, suggesting that the changes in receptor level may result from changes in gene expression or mRNA stability.

Adult↗
PubMed1997

A comprehensive management system for heart failure improves clinical outcomes and reduces medical resource utilization.

The effectiveness of heart failure management in clinical practice is limited by physicians' suboptimal utilization of effective medications, patients' poor adherence to dietary sodium limitation and optimal drug therapy, and the lack of systematic monitoring of patients after hospitalization. The present study evaluated the feasibility and safety of MULTIFIT, a physician-supervised, nurse-mediated, home-based system for heart failure management that implements consensus guidelines for pharmacologic and dietary therapy using a nurse manager to enhance dietary and pharmacologic adherence and to monitor clinical status by frequent telephone contact. Fifty-one patients with the clinical diagnosis of heart failure were followed for 138 +/- 44 days. Daily dietary sodium intake fell by 38%, from 3,393 to 2,088 mg (p = 0.0001); average daily medication doses increased significantly (lisinopril: 17 to 23 mg, p <0.001; hydralazine: 140 to 252 mg, p = 0.01). Functional status and exercise capacity improved significantly (p = 0.01). Compared with the 6 months before enrollment and normalized for variable follow-up, the frequency of general medical and cardiology visits declined by 23% and 31%, respectively (both p <0.03); emergency room visits for heart failure and for all causes declined 67% and 53%, respectively (both p <0.001). Hospitalization rates for heart failure and for all causes declined 87% and 74%, respectively (p = 0.001), compared with the year before enrollment. The MULTIFIT system enhanced the effectiveness of pharmacologic and dietary therapy for heart failure in clinical practice, improving clinical outcomes and reducing medical resource utilization.

Aged↗
PubMed1997

Safety and efficacy of carvedilol in severe heart failure. The U.S. Carvedilol Heart Failure Study Group.

BACKGROUND: Many patients remain markedly symptomatic despite optimal current therapy for heart failure. Beta-blockers have often been viewed as contraindicated in this group because of their potential adverse short-term effects on cardiac function. METHODS AND RESULTS: One hundred thirty-one patients with severe congestive heart failure were enrolled into a double-blind, placebo-controlled study of the vasodilating beta-blocker carvedilol. All patients had symptomatic, advanced heart failure while on standard triple therapy, as evidenced by a mean ejection fraction of 0.22, marked reduction in distance traveled in a 6-minute corridor walk test, and severe impairment in quality of life measured by the Minnesota Living With Heart Failure Questionnaire. After a 2-week, open-label test of 6.25 mg twice daily carvedilol, 105 patients were randomized (2:1) to receive either carvedilol (up to 25 mg twice daily, n = 70) or matching placebo (n = 35) for 6 months while background therapy with digoxin, diuretics, and an angiotensin-converting enzyme inhibitor remained constant. Ten patients (8%) did not complete the open-label period because of adverse events and 11.4% in both the carvedilol and placebo groups dropped out in the double-blind phase. The study was terminated early by the Data Safety and Monitoring Board and follow-up evaluation was therefore aborted before the projected number of patients and follow-up time was achieved. Quality of life, which was the primary endpoint, improved similarly in the carvedilol and placebo groups, whereas the global assessment by the physicians and the patient exhibited a better response to carvedilol (P < .05). Hospitalization and mortality rate were too low to evaluate a difference, and exercise time and New York Heart Association classification did not change significantly in response to the drug. Left ventricular ejection fraction rose significantly (+0.09) in the carvedilol group compared with the placebo group (+0.02, P = .004). CONCLUSION: The beta-blocker carvedilol can be safely employed in patients with severe heart failure. Improved left ventricular function with a trend for some improvement in symptoms combined with the experience with the drug in the larger population of less severe patients in this multicenter trial suggests that carvedilol may have a favorable long-term effect in heart failure of diverse severity.

Adrenergic beta-Antagonists↗
PubMed1996

Carvedilol inhibits clinical progression in patients with mild symptoms of heart failure. US Carvedilol Heart Failure Study Group.

BACKGROUND: We tested the hypothesis that carvedilol inhibits clinical progression in patients with mildly symptomatic heart failure due to left ventricular (LV) systolic dysfunction. METHODS AND RESULTS: Patients (n = 366) who had mildly symptomatic heart failure with an LV ejection fraction (LVEF) < or = 0.35, had minimal functional impairment (defined as the ability to walk 450 to 550 m on a 6-minute walk test), and were receiving optimal standard therapy, including ACE inhibitors, were randomized double-blind to carvedilol (n = 232) or placebo (n = 134) and followed up for 12 months. The primary end point was clinical progression, defined as death due to heart failure, hospitalization for heart failure, or a sustained increase in heart failure medications. Clinical progression of heart failure occurred in 21% of placebo patients and 11% of carvedilol patients, reflecting a 48% (P = .008) reduction in the primary end point of heart failure progression (relative risk, 0.52; CI, 0.32 to 0.85). This effect of carvedilol was not influenced by sex, age, race, cause of heart failure, or baseline LVEF. Carvedilol also significantly improved several secondary end points, including LVEF, heart failure score, NYHA functional class, and the physician and patient global assessments. Carvedilol reduced all-cause mortality but had no effects on the Minnesota Living With Heart Failure scale, the distance walked in 9 minutes on a self-powered treadmill, or cardiothoracic index. The drug was well tolerated. CONCLUSIONS: Carvedilol, when added to standard therapy, including an ACE inhibitor, reduces clinical progression in patients who are only mildly symptomatic with well-compensated heart failure.

Adolescent↗
PubMed1996

Carvedilol produces dose-related improvements in left ventricular function and survival in subjects with chronic heart failure. MOCHA Investigators.

BACKGROUND: We conducted a multicenter, placebo-controlled trial designed to establish the efficacy and safety of carvedilol, a "third-generation" beta -blocking agent with vasodilator properties, in chronic heart failure. METHODS AND RESULTS: Three hundred forty-five subjects with mild to moderate, stable chronic heart failure were randomized to receive treatment with placebo, 6.25 mg BID carvedilol (low-dose group), 12.5 mg BID carvedilol (medium-dose group), or 25 mg BID carvedilol (high-dose group). After a 2- to 4-week up-titration period, subjects remained on study medication for a period of 6 months. The primary efficacy parameter was submaximal exercise measured by two different techniques, the 6-minute corridor walk test and the 9-minute self-powered treadmill test. Carvedilol had no detectable effect on submaximal exercise as measured by either technique. However, carvedilol was associated with dose-related improvements in LV function (by 5, 6, and 8 ejection fraction [EF] units in the low-, medium-, and high-dose carvedilol groups, respectively, compared with 2 EF units with placebo, P < .001 for linear dose response) and survival (respective crude mortality rates of 6.0%, 6.7%, and 1.1% with increasing doses of carvedilol compared with 15.5% in the placebo group, P < .001). When the three carvedilol groups were combined, the all-cause actuarial mortality risk was lowered by 73% in carvedilol-treated subjects (P < .001). Carvedilol also lowered the hospitalization rate (by 58% to 64%, P = .01) and was generally well tolerated. CONCLUSIONS: In subjects with mild to moderate heart failure from systolic dysfunction, carvedilol produced dose-related improvements in LV function and dose-related reductions in mortality and hospitalization rate.

Adrenergic beta-Antagonists↗