Meta-analyses of mortality and morbidity effects of an angiotensin receptor blocker in patients with chronic heart failure already receiving an ACE inhibitor (alone or with a beta-blocker)

BACKGROUND: While treatment with either angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs) is clearly superior to placebo in the treatment of heart failure patients, controversy still surrounds the effects of ARBs in patients already receiving an ACEi. Even more controversial is the wisdom of administering ARBs in patients already on an ACEi and beta-blocker. METHODS: We present meta-analyses of the available randomised controlled trials to date (October 2003) of angiotensin II receptor antagonists versus placebo in patients with symptomatic chronic heart failure in which both groups received ACEi. The two largest eligible trials were CHARM-Added and Val-HeFT. We examined two endpoints: mortality and a combined endpoint of mortality and morbidity. RESULTS: In the first meta-analysis, covering all patients regardless of beta-blocker use, we found a significant reduction in the combined endpoint (odds ratio [OR]=0.89; 95% confidence interval [CI] 0.81-0.98), but no significant reduction in mortality itself (OR=0.97; CI: 0.87-1.08). In the second meta-analysis, covering patients concomitantly on beta-blockers, we found no significant effect on mortality (OR=1.08; CI: 0.90-1.29) or on the combined endpoint (OR=0.94; CI: 0.82-1.10). In the third meta-analysis, covering patients not on concomitant beta-blockers, there is clear evidence of a reduction in the combined endpoint (OR=0.83; CI: 0.73-0.94), but not on mortality (OR=0.93; CI: 0.81-1.06). CONCLUSION: There is now good evidence for the use of ARBs to prevent events in patients with heart failure on ACEi who are not suitable for beta-blockers.     

Effects of valsartan on morbidity and mortality in patients with heart failure not receiving angiotensin-converting enzyme inhibitors

OBJECTIVES: A subgroup analysis of the Valsartan Heart Failure Trial (Val-HeFT) was performed to evaluate the effects of the angiotensin II receptor blocker, valsartan, in the patients with chronic heart failure (HF) not receiving angiotensin-converting enzyme (ACE) inhibitors. BACKGROUND: The ACE inhibitors reduce mortality and morbidity in patients with HF. Nonetheless, nearly 20% of potentially eligible patients may not be prescribed ACE inhibitors. RESULTS: Val-HeFT was an international, randomized, double-blinded trial that compared valsartan with placebo when added to the prescribed treatment of patients with HF. The two primary end points of the study were all-cause mortality and the composite of all-cause mortality and morbidity (sudden death with resuscitation, hospital admission for HF, or administration of intravenous inotropic or vasodilator drugs for >or=4 h without hospital admission). Of the 5,010 patients enrolled in the trial, 366 (7.3%) were not treated with ACE inhibitors at baseline. The effects of valsartan on the primary and secondary end points of the study were assessed in this subgroup of patients. RESULTS: Both all-cause mortality and combined mortality and morbidity for patients not treated with ACE inhibitors were significantly reduced in the valsartan treatment group compared with the placebo group (17.3% vs. 27.1%, p = 0.017 and 24.9% vs. 42.5%, p < 0.001, respectively). Consistent with the data on clinical events, patients randomized to valsartan showed improvements in physiologic variables, such as ejection fraction, left ventricular internal diameter in diastole, and plasma neurohormone levels. Permanent discontinuation of study treatment because of adverse experiences was comparable between the two groups. CONCLUSIONS: Val-HeFT has provided the first placebo-controlled outcome data demonstrating a favorable effect of an angiotensin receptor blocker on mortality and morbidity in patients with HF not treated with ACE inhibitors. Based on these results, valsartan appears to be an effective therapy in ACE inhibitor-intolerant patients.     

Effect of Valsartan on hospitalization: results from Val-HeFT

BACKGROUND: Although current therapies have improved heart failure (HF) outcome, hospitalizations continue at high rates. The Valsartan Heart Failure Trial (Val-HeFT) showed that valsartan reduced the risk of first worsening HF hospitalization by 27.5% versus placebo (P <.001). This article analyzes all-cause and investigator-assessed HF hospitalization in Val-HeFT overall and in subgroups defined by preexisting HF therapy. METHODS: Val-HeFT was a randomized, double-blind parallel-arm study in which HF patients (New York Heart Association class II-IV) received either valsartan (n = 2511, force-titrated to 160 mg twice daily) or placebo (n = 2499) in addition to prescribed HF therapy. Total and per patient-year investigator-assessed hospitalizations (all-cause or HF) were analyzed according to prescribed therapy at baseline (angiotensin-converting enzyme inhibitors [ACEI] and beta-blockers [BB]). RESULTS: Hospitalization for worsening HF accounted for 35% of all hospitalizations. There were 2856 and 3106 total all-cause hospitalizations in the valsartan and placebo groups, respectively, an 8% reduction (P =.145). Valsartan significantly reduced the overall number of investigator-assessed HF hospitalizations (-22.4%, P =.002) and reduced HF hospitalizations in the combination therapy subgroups (significant for ACEI+/BB- P =.003 and ACEI-/BB- P =.028) except those receiving both ACEI and BB. The benefit of valsartan versus placebo was more pronounced in reducing the number of patients with recurrent HF hospitalization (-20.6%) than single hospitalizations (-8.7%). CONCLUSIONS: Addition of valsartan to prescribed HF therapy demonstrated significant reductions in HF hospitalizations and was particularly beneficial in reducing recurrent HF hospitalization.     

Valsartan benefits left ventricular structure and function in heart failure: Val-HeFT echocardiographic study

OBJECTIVES: The objective of the study was to evaluate the effect of an angiotensin receptor blocker on left ventricular (LV) structure and function when added to prescribed heart failure therapy. BACKGROUND: The clinical benefit derived from heart failure therapy is attributed to the regression of LV remodeling. METHODS: At 302 multinational sites, 5,010 patients in New York Heart Association (NYHA) classification II to IV heart failure taking angiotensin-converting enzyme inhibitor (ACEI) and/or beta-blocker (BB) were randomized into valsartan and placebo groups and followed for a mean of 22.4 months. Serial echocardiographic measurements of left ventricular internal diastolic diameter (LVIDd) and ejection fraction (EF) were recorded. Total study reproducibility calculated to 90% power at 5% significance defined detectable differences of 0.09 cm for LVIDd and 0.86% for EF. RESULTS: Baseline LVIDd and EF for valsartan and placebo groups were similar: 3.6 +/- 0.5 versus 3.7 +/- 0.5 (cm/m(2)) and 26.6 +/- 7.3 versus 26.9 +/- 7.0 (%). Mean group changes from baseline over time were compared. Significant decrease in LVIDd and increase in EF began by four months, reached plateau by one year, and persisted to two years in valsartan compared with placebo patients, irrespective of age, gender, race, etiology, NYHA classification, and co-treatment therapy. Changes at 18 months were -0.12 +/- 0.4 versus -0.05 +/- 0.4 (cm/m(2)), p < 0.00001 for LVIDd, and +4.5 +/- 8.9 versus +3.2 +/- 8.6 (%), p < 0.00001 for EF. The exception occurred in patients taking both ACEI and BB as co-treatment, in whom the decrease in LVIDd and increase in EF were no different between valsartan and placebo groups. CONCLUSIONS: The Val-HeFT echocardiographic substudy of 5,010 patients with moderate heart failure demonstrated that valsartan therapy taken with either ACEI or BB reversed LV remodeling.     

Morbidity, mortality, physiologic and functional parameters in elderly and non-elderly patients in the Valsartan Heart Failure Trial (Val-HeFT)

Background

The Valsartan Heart Failure Trial (Val-HeFT) demonstrated the favorable effects of the addition of valsartan to prescribed heart failure (HF) therapy on HF hospitalization, and functional and physiological parameters. As the prevalence of HF morbidity and mortality are increased in the elderly, the effect of valsartan in the elderly is of clinical significance.

Methods

In this post-hoc analysis, morbidity, mortality, left ventricular (LV) size and function, brain natriuretic peptide (BNP), aldosterone, norepinephrine (NE), quality of life, and treatment effect with valsartan were examined by subgroups of 2350 elderly (≥ 65 years) and 2660 non-elderly (< 65 years) patients enrolled in Val-HeFT.

Results

While the overall incidence of morbidity and mortality was higher in the elderly, valsartan produced beneficial effects in reducing risk of morbidity in the elderly by 11.8% (P = .07), and the non-elderly by 14.6% (P = .09). Valsartan had no effect on mortality compared to placebo in the non-elderly, 15.2% vs 15.0% (P = .87), and elderly, 25.1% vs 24.0%, (P = .64). Valsartan had statistically significant beneficial effects in both the elderly and non-elderly on LV size and function, BNP, aldosterone and quality of life. Beneficial effects on NE were also observed with valsartan in both subgroups with statistically significant reductions produced in the non-elderly.

Conclusions

Val-HeFT demonstrated that elderly patients present with more advanced HF as evidenced by higher morbidity and mortality along with greater neurohormonal activation. In Val-HeFT, valsartan produced a consistent beneficial effect on morbidity, LV function and size, quality of life, and neurohormonal levels in both the elderly and non-elderly.     

Comment--Val-HeFT and angiotensin-receptor blockers in perspective: A tale of the blind man and the elephant

BACKGROUND: The role of angiotensin-receptor blockers (ARBs) in the therapy of chronic heart failure (CHF) has not been clarified. There are no large placebo-controlled trials with these agents. The second Evaluation of Losartan in the Elderly trial (ELITE-II) compared the ARB losartan with captopril in 3,152 patients >/=60 years old with New York Heart Association (NYHA) class II-IV and left ventricular ejection fraction 相似文献   

Effect of valsartan on quality of life when added to usual therapy for heart failure: results from the Valsartan Heart Failure Trial

BACKGROUND: The effect on quality of life (QOL) of valsartan administered in addition to prescribed background heart failure therapy was assessed as a secondary endpoint in the Valsartan Heart Failure Trial (Val-HeFT). METHODS AND RESULTS: QOL was assessed in 3010 patients receiving either valsartan (160 mg twice daily) or placebo in addition to prescribed background therapy (beta-blockers or angiotensin-converting enzyme inhibitors), using the Minnesota Living with Heart Failure (MLWHF) questionnaire. Treatment differences were compared at intervals to 36 months after randomization and at endpoint (last observation) using analysis of covariance and repeated measures mixed-effects, and at endpoint using a Mantel-Haenszel chi-squared test. Scores lower than baseline were indicative of improved QOL. Valsartan had a significant beneficial effect on the least-square mean change in overall MLWHF score from baseline to study endpoint (+/- standard error) (average followup 23.0 months) compared with placebo (0.19 +/- 0.47 versus 1.94 +/- 0.48; P = .005 respectively). The placebo group was characterized by a deterioration in QOL as the trial progressed. More patients on valsartan reported a clinically meaningful improvement in MLWHF score (a decrease of > or =5 points) than on placebo (34.0% versus 30.2%). CONCLUSION: Valsartan compared to placebo added to prescribed therapy slows progressive worsening of QOL in patients with heart failure.     

Multinational economic evaluation of valsartan in patients with chronic heart failure: results from the Valsartan Heart Failure Trial (Val-HeFT)

Background

The Valsartan Heart Failure Trial (Val-HeFT) compared valsartan versus placebo in 5010 patients taking prescribed background therapy for New York Heart Association class II to IV heart failure. Valsartan reduced the risk of heart failure hospitalization and improved clinical signs and symptoms of heart failure. We sought to compare resource use, costs, and health outcomes among patients taking prescribed therapy for heart failure and randomly assigned to receive valsartan or placebo.

Methods

Measures of resource use were based on data collected during the trial. Unit cost estimates were collected from individual countries and converted to 1999 US dollars. Total costs were estimated for hospitalizations, inpatient and outpatient physician services, ambulance transportation, deaths outside the hospital, and outpatient cardiovascular medications.

Results

Mean follow-up was 23 months. Mean costs for heart failure hospitalizations were $423 lower among patients receiving valsartan (95% CI, −706 to −146). Mean total costs were $9008 for patients receiving valsartan and $8464 for patients receiving placebo, a net incremental cost of $545 (95% CI, −149 to 1148), including the cost of valsartan. There was an overall reduction in total costs of $929 (95% CI, −3243 to 1533) among patients not receiving an ACE inhibitor at baseline but a slight increase in costs of $334 (95% CI, −497 to 1199) among those receiving an ACE inhibitor without a β-blocker and a $1246 increase (95% CI, 54 to 2230) in patients receiving both an ACE inhibitor and a β-blocker at baseline.

Conclusions

Valsartan provided clinical benefits at a mean incremental cost of $285 per year during the trial. In patients not taking ACE inhibitors, valsartan was economically attractive, increasing survival while reducing or marginally increasing overall costs.     

Pharmacological left ventricular reverse remodeling in elderly patients receiving optimal therapy for chronic heart failure

BACKGROUND AND AIMS: In recent years, reversal of established left ventricular (LV) dilatation has been increasingly recognized in middle-aged patients with dilated cardiomyopathy receiving angiotensin-converting enzyme (ACE) inhibitors and/or beta-blockers. We performed this prospective study to evaluate whether optimized therapy for heart failure also induces LV reverse remodeling in older patients. METHODS: One hundred and twenty-four patients aged >70 years with LV ejection fraction <40% underwent clinical and echocardiographic evaluation at baseline and after 1 year. During the early stage of follow-up, pharmacological therapy was optimized. LV reverse remodeling was defined as a reduction in LV end-diastolic volume >25% from baseline to final evaluation. RESULTS: LV reverse remodeling was recognized in 32 patients (26%). Compared to the subjects who did not improve LV geometry, those with reverse remodeling had, at baseline, higher arterial blood pressure, lower serum creatinine levels, shorter duration of symptoms of heart failure, more frequently received beta-blocker therapy and had predominantly nonischemic aetiology. The variables associated with the development of reverse remodeling in the multivariate analysis were shorter duration of symptoms of heart failure (Odds ratio: 7.7; CI: 2.5-23.3, p=0.0001) and beta-blocker therapy (Odds ratio: 6.0; CI: 1.6-23.3, p=0.01). CONCLUSIONS: LV reverse remodeling takes place in elderly as well as in younger heart failure patients. A significant proportion of elderly patients undergoes this favourable process which occurs prevalently in patients receiving beta-blocker therapy with a short history of cardiac disease.     

Effects of carvedilol on left ventricular regional wall motion in patients with heart failure caused by ischemic heart disease. Australia-New Zealand Heart Failure Research Collaborative Group

BACKGROUND: Beta-blocker therapy has been shown to improve left ventricular (LV) ejection fraction and reduce LV volumes in patients with heart failure caused by ischemic heart disease. However, the possible mechanisms of this improvement and the effects of such treatment on regional wall motion have not been established. In a substudy of the Australia-New Zealand trial of carvedilol in patients with heart failure caused by ischemic heart disease, the effects of treatment on LV regional wall motion were assessed using 2-dimensional echocardiography. METHODS AND RESULTS: One hundred nineteen patients from 10 centers were included on this substudy. Patients were randomly assigned to treatment with carvedilol or placebo. Echocardiography was performed before randomization and after 6 and 12 months of treatment. LV regional wall motion was assessed using a semiquantitative scoring system. LV wall motion score index (WMSI) was reduced from 2.40 to 2.29 after 6 and 12 months in the carvedilol group and remained unchanged in the placebo group (2-tailed P = .005, carvedilol vs placebo). The percentage of myocardium with normal function also significantly improved with carvedilol treatment. CONCLUSIONS: Carvedilol improved LV regional WMSI in patients with heart failure caused by ischemic heart disease. These results indicate a mechanism by which beta-blocker therapy may benefit patients with heart failure and are consistent with an intrinsic improvement in LV function after treatment with carvedilol.     

Baseline demographics of the Valsartan Heart Failure Trial. Val-HeFT Investigators

BACKGROUND: The Valsartan Heart Failure Trial (Val-HeFT) is the first large-scale randomized, multinational clinical study to assess the efficacy and safety of valsartan, an angiotensin II receptor blocker, added to conventional therapy, including angiotensin-converting enzyme inhibitors, in heart failure patients. A total of 5010 patients with an ejection fraction <40% have been randomized to either valsartan titrated to 160 mg b.i.d. or to placebo. AIMS: Baseline characteristics of patients in Val-HeFT are presented and compared with other major clinical trials in heart failure. METHODS: Baseline data were collected and summary statistics calculated. RESULTS: The study population has a mean age of 62.7 years and is 80% male, 90.3% white, 6.9% black, and 2.8% Asian. Antecedent coronary heart disease is reported in 57.2% of patients. Angiotensin-converting enzyme inhibitors are prescribed for 92.7% of patients, diuretics for 85.8%, digoxin for 67.3%, and beta-blockers for 35.6%. Subgroup comparisons by age, sex, race and ejection fraction quartile show small differences in baseline characteristics. CONCLUSION: Overall the Val-HeFT population is generally representative of the population of patients with mild to moderate heart failure in industrialized countries.     

Signs and symptoms in chronic heart failure: relevance of clinical trial results to point of care-data from Val-HeFT

BACKGROUND: Clinical trials emphasize mortality and morbidity endpoints. AIMS: To bring relevance of trial results to point of care by examining the prognostic and therapeutic value of individual signs and symptoms (S&S). METHODS: We analysed data from 5010 patients with stable chronic heart failure and left ventricular dysfunction who were participants in the Val-HeFT study. Individual S&S were stratified by severity. Treatment differences between valsartan and placebo were analysed by S&S strata at baseline and endpoint by logistical regression, and an overall S&S score by ANCOVA. Hazard ratios of S&S strata were calculated for mortality and heart failure hospitalisation. Prognostic contributions of S&S to other variables were determined by multivariate analysis. RESULTS: At endpoint, there were significantly fewer valsartan and more placebo patients with severe symptoms. Over time, improvement in the S&S overall score was significantly more favourable for valsartan than placebo. S&S strata were significantly predictive of risk for hospitalisation and death. S&S were each independent and incremental predictors of mortality compared to other variables. Symptom strata separated out moderately symptomatic patients with a mortality rate which was intermediate between that for NYHA Class II and III. CONCLUSION: Risk stratification of individual S&S defined prognosis, identified patients with an intermediate mortality between Class II and III, and treatment benefits of valsartan over placebo.     

Beta-blocker therapy in advanced heart failure: clinical characteristics and long-term outcomes

AIMS: To evaluate the clinical characteristics and long-term outcomes of advanced heart failure patients (NYHA Class IIIb-IV) receiving beta-blocker therapy vs. those patients not receiving beta-blockers at randomization in the FIRST trial, a randomized, double-blind, placebo-controlled trial of epoprostenol vs. usual care in advanced heart failure. METHODS AND RESULTS: The patient population consisted of 471 patients enrolled in FIRST with Class IIIb-IV heart failure, left ventricular ejection fraction (LVEF) of <30%, advanced hemodynamic abnormalities, and standard pharmacologic treatment of ACE-inhibitor, diuretics, and/or digoxin. The study cohort consisted of 448 patients not receiving beta-blockers and 23 patients receiving beta-blockers at randomization for the FIRST trial. Patients in the beta-blocker group had decreased rates of any clinical event (P = 0.03), worsening heart failure (P = 0.001), and death or worsening heart failure (P = 0.0008) than patients not receiving beta-blockers. After adjusting for prognostically important variables, the favorable effect of beta-blockers on worsening heart failure (P = 0.02) and death or worsening heart failure (P = 0.02) persisted. CONCLUSION: Patients with advanced heart failure who receive beta-blocker therapy have a lower rate of hospitalization and are less likely to experience worsening heart failure or death at 6 months than patients who are not treated with beta-blockers. These observational data contribute to the growing body of data demonstrating a favorable effect of beta-blockers on clinical outcomes in heart failure.     

Beta-blockers in congestive heart failure. A Bayesian meta-analysis

PURPOSE: Congestive heart failure is an important cause of patient morbidity and mortality. Although several randomized clinical trials have compared beta-blockers with placebo for treatment of congestive heart failure, a meta-analysis quantifying the effect on mortality and morbidity has not been performed recently. DATA SOURCES: The MEDLINE, Cochrane, and Web of Science electronic databases were searched from 1966 to July 2000. References were also identified from bibliographies of pertinent articles. STUDY SELECTION: All randomized clinical trials of beta-blockers versus placebo in chronic stable congestive heart failure were included. DATA EXTRACTION: A specified protocol was followed to extract data on patient characteristics, beta-blocker used, overall mortality, hospitalizations for congestive heart failure, and study quality. DATA SYNTHESIS: A hierarchical random-effects model was used to synthesize the results. A total of 22 trials involving 10 135 patients were identified. There were 624 deaths among 4862 patients randomly assigned to placebo and 444 deaths among 5273 patients assigned to beta-blocker therapy. In these groups, 754 and 540 patients, respectively, required hospitalization for congestive heart failure. The probability that beta-blocker therapy reduced total mortality and hospitalizations for congestive heart failure was almost 100%. The best estimates of these advantages are 3.8 lives saved and 4 fewer hospitalizations per 100 patients treated in the first year after therapy. The probability that these benefits are clinically significant (>2 lives saved or >2 fewer hospitalizations per 100 patients treated) is 99%. Both selective and nonselective agents produced these salutary effects. The results are robust to any reasonable publication bias. CONCLUSIONS: beta-Blocker therapy is associated with clinically meaningful reductions in mortality and morbidity in patients with stable congestive heart failure and should be routinely offered to all patients similar to those included in trials.     

Plasma N-terminal pro-brain natriuretic peptide and adrenomedullin: prognostic utility and prediction of benefit from carvedilol in chronic ischemic left ventricular dysfunction. Australia-New Zealand Heart Failure Group

OBJECTIVES: We sought to assess plasma concentrations of the amino (N)-terminal portion of pro-brain natriuretic peptide (N-BNP) and adrenomedullin for prediction of adverse outcomes and responses to treatment in 297 patients with ischemic left ventricular (LV) dysfunction who were randomly assigned to receive carvedilol or placebo. BACKGROUND: Although neurohormonal status has known prognostic significance in heart failure, the predictive power of either N-BNP or adrenomedullin in chronic ischemic LV dysfunction has not been previously reported. METHODS: Plasma N-BNP and adrenomedullin were measured in 297 patients with chronic ischemic (LV) dysfunction before randomization to carvedilol or placebo, added to established treatment with a converting enzyme inhibitor and loop diuretic (with or without digoxin). The patients' clinical outcomes, induding mortality and heart failure events, were recorded for 18 months. RESULTS: Above-median N-BNP and adrenomedullin levels conferred increased risks (all p < 0.001) of mortality (risk ratios [95% confidence intervals]: 4.67 [2-10.9] and 3.92 [1.76-8.7], respectively) and hospital admission with heart failure (4.7 [2.2-10.3] and 2.4 [1.3-4.5], respectively). Both of these predicted death or heart failure independent of age, New York Heart Association functional class, LV ejection fraction, previous myocardial infarction or previous admission with heart failure. Carvedilol reduced the risk of death or heart failure in patients with above-median levels of N-BNP or adrenomedullin, or both, to rates not significantly different from those observed in patients with levels below the median value. CONCLUSIONS: In patients with established ischemic LV dysfunction, plasma N-BNP and adrenomedullin are independent predictors of mortality and heart failure. Carvedilol reduced mortality and heart failure in patients with higher pre-treatment plasma N-BNP and adrenomedullin.     

Renin-angiotensin system inhibition prevents type 2 diabetes mellitus. Part 1. A meta-analysis of randomised clinical trials

Most individuals with arterial hypertension or congestive heart failure are insulin-resistant and at a higher risk of developing type 2 diabetes (T2DM). The inhibition of the renin-angiotensin system (RAS), using an angiotensin converting enzyme inhibitor (ACEI) or a selective angiotensin receptor AT1 blocker (ARB), may exert favourable metabolic effects capable of preventing T2DM in high risk individuals. We performed a meta-analysis of randomised clinical trials (RCTs) assessing the effects of RAS inhibition on the incidence of new cases of T2DM in patients with arterial hypertension or congestive heart failure. Ten RCTs with cardiovascular prognosis as primary endpoints analysed the incidence of T2DM as secondary endpoints or as post-hoc analysis after a mean follow-up of 1 to 6 years: five with an ACEI and five with an ARB, compared with a placebo (n = 4) or a reference drug (beta-blocker or diuretic: n = 5; amlodipine: n = 2). Eight RCTs concerned hypertensive patients: STOP Hypertension-2 (lisinopril or enalapril vs beta-blocker or diuretic), CAPPP (captopril vs thiazide or beta-blocker), HOPE (ramipril vs placebo), ALLHAT (lisinopril vs chlorthalidone and lisinopril vs amlodipine), LIFE (losartan vs atenolol), SCOPE (candesartan vs placebo), ALPINE (candesartan vs placebo) and VALUE (valsartan vs amlodipine). Two RCTs concerned patients with congestive heart failure: SOLVD (enalapril vs placebo) and CHARM-overall programme (candesartan vs placebo). Overall, 2 675 new cases of T2DM (7.40%) were observed in the group of 36 167 patients receiving a treatment with ACEI or ARA as compared with 3 842 events (9.63%) in the group of 39 902 control patients. A mean weighed relative risk reduction of new T2DM of 22% (95% CI: 18, 26; p < 0.00001) was observed after RAS inhibition. The beneficial effect was similar with ACEIs and with ARBs as well as in patients with hypertension and in those with heart failure, and was also present whatever the comparator (placebo or beta-blockers/diuretics or amlodipine). The number needed-to-treat to avoid one new case of T2DM averaged 45 patients over 4-5 years. In conclusion, RAS inhibition consistently and significantly reduces the incidence of T2DM in individuals with arterial hypertension or with congestive heart failure. Considering the pandemic of T2DM, such pharmacological approach deserves further attention among the strategies aiming at preventing T2DM.     

Delisting of infants and children from the heart transplantation waiting list after carvedilol treatment

OBJECTIVES: We performed a prospective, randomized, double-blind, placebo-controlled study of carvedilol effects in children with severe, chronic heart failure (HF), despite the use of conventional therapy. BACKGROUND: Little is known about the effects of carvedilol in youngsters with chronic HF and severe left ventricular (LV) dysfunction. METHODS: We conducted a double-blind, placebo-controlled study of 22 consecutive children with severe LV dysfunction. The children had chronic HF and left ventricular ejection fraction (LVEF) <30%. Patients were randomly assigned to receive either placebo (8 patients) or the beta-blocker carvedilol (14 patients) at 0.01 mg/kg/day titrated up to 0.2 mg/kg/day, followed-up for six months. RESULTS: During the follow-up and the up-titration period in the carvedilol group, four patients died and one underwent heart transplantation. In patients receiving carvedilol evaluated after six months, a significant increase occurred in LVEF, from 17.8% (95% confidence interval [CI], 14.1 to 21.4%) to 34.6% (95% CI, 25.2 to 44.0%); p = 0.001. Modified New York Heart Association (NYHA) functional class improved in nine patients taken off the transplant waiting list. All nine patients were alive at follow-up. In the placebo group, during the six-month follow-up, two patients died, and two underwent heart transplantation. Four patients persisted with HF symptoms (NYHA functional class IV). No significant change occurred in LVEF or fractional shortening. CONCLUSIONS: Carvedilol added to standard therapy may reduce HF progression and improve cardiac function, allowing some youngsters to be removed from the heart transplantation waiting list.     

Beta-blockade prevents recurrent gastrointestinal bleeding in well-compensated patients with alcoholic cirrhosis: a multicenter randomized controlled trial

To assess the efficacy of beta-blockers in preventing rebleeding in selected cirrhotic patients and to compare the tolerance, safety and patient compliance of a selective and a nonselective beta-blocker, 94 patients were randomly assigned to propranolol (32 patients), atenolol (32 patients) or placebo (30 patients). Randomization was made at least 15 days after the bleeding episode. Propranolol was given orally at increasing doses until the resting pulse rate was reduced by approximately 25%. Atenolol was given at a fixed dose of 100 mg per day. Patients were followed up for a mean of 357 days. Rebleeding occurred in 14 patients in the placebo group, 10 in the atenolol group and eight in the propranolol group. The incidence of rebleeding was significantly lower in patients receiving propranolol than in those on placebo (propranolol vs. placebo: p = 0.01, logrank test). Atenolol was less effective than propranolol (atenolol vs. placebo: p = 0.065, logrank test). Bleeding-free survival was better for patients on active drugs than for those on placebo (propranolol vs. placebo = p = 0.01, atenolol vs. placebo: p = 0.05, logrank test). Retrospective analysis revealed that, whatever the type of treatment, abstinence from alcohol was crucial in preventing rebleeding. We conclude that beta-blocker treatment is effective in preventing rebleeding from esophageal varices in carefully selected alcoholic cirrhotic patients who survive at least 2 weeks after acute variceal hemorrhage and stop drinking.     

Impact of initiating carvedilol before angiotensin-converting enzyme inhibitor therapy on cardiac function in newly diagnosed heart failure

OBJECTIVES: The purpose of this research was to evaluate the therapeutic value of initiating a beta-blocker before an angiotensin-converting enzyme inhibitor (ACEI) in the treatment of heart failure. BACKGROUND: Although ACEI and carvedilol produce benefits in heart failure, whether the order of initiation of therapy determines the impact on left ventricular (LV) function and New York Heart Association functional class (NYHA FC) has not been determined. METHODS: A single-center, prospective, randomized, open-label study was performed. We evaluated whether initiation of therapy with carvedilol either before (n = 38) or after (n = 40) perindopril therapy in newly diagnosed patients in NYHA FC II to III heart failure with idiopathic dilated cardiomyopathy, with the addition of the alternative agent after six months, determined subsequent changes in NYHA FC and LV function (echocardiography and radionuclide ventriculography). Study drugs were titrated to maximum tolerable doses. RESULTS: There were no differences in baseline characteristics between the study groups. After 12 months 11 patients died (6 in the group where the ACEI was initiated). At 12 months the group receiving carvedilol as initial therapy achieved a higher tolerable dose of carvedilol (43 +/- 17 mg vs. 33 +/- 18 mg, p = 0.03); a lower dose of furosemide (p < 0.05); and better improvements in symptoms (NYHA FC, p < 0.002), LV ejection fraction (radionuclide: 15 +/- 16% vs. 6 +/- 13%, p < 0.05; echocardiographic, p < 0.01), and plasma N-terminal pro-brain natriuretic peptide concentrations (p < 0.02). CONCLUSIONS: As opposed to the conventional sequence of drug use in the treatment of heart failure, initiation of therapy with carvedilol before an ACEI results in higher tolerable doses of carvedilol and better improvements in FC and LV function.     

Prognostic evaluation of neurohumoral plasma levels before and during beta-blocker therapy in advanced left ventricular dysfunction

OBJECTIVES: The study assessed the relative predictive potency of neurohumoral factors in patients with advanced left ventricular (LV) dysfunction during neurohumoral blocking therapy. BACKGROUND: The course of heart failure is characterized by progressive LV deterioration associated with an increase in cardiac (natriuretic peptides) and predominantly extracardiac (norepinephrine, big endothelin [big ET]) hormone plasma levels. METHODS: Plasma hormones were measured at baseline and months 3, 6, 12 and 24 in 91 patients with heart failure (left ventricular ejection fraction [LVEF] <25%) receiving 40 mg enalapril/day and double-blind atenolol (50 to 100 mg/day) or placebo. After the double-blind study phase, patients were followed up to four years. Stepwise multivariate regression analyses were performed with 10 variables (age, etiology, LVEF, symptom class, atenolol/placebo, norepinephrine, big ET, log aminoterminal atrial natriuretic peptide, log aminoterminal B-type natriuretic peptide [N-BNP] and log B-type natriuretic peptide [BNP]). During the study, the last values prior to patient death were used, and in survivors the last hormone level, New York Heart Association class and LVEF at month 24 were used. RESULTS: Thirty-one patients died from a cardiovascular cause during follow-up. At baseline, log BNP plasma level (x2 = 13.9, p = 0.0002), treatment allocation (x2 = 9.5, p = 0.002) and LVEF (x2 = 5.6, p = 0.017) were independently related to mortality. During the study, log BNP plasma level (x2 = 21.3, p = 0.0001) remained the strongest predictive marker, with LVEF (x2 = 11.2, p = 0.0008) log N-BNP plasma level (x2 = 8.9, p = 0.0027) and treatment allocation (x2 = 6.4, p = 0.0109) providing additional independent information. CONCLUSIONS: In patients with advanced LV dysfunction receiving high-dose angiotensin-converting enzyme inhibitors and beta-blocker therapy BNP and N-BNP plasma levels are both independently related to mortality. This observation highlights the importance of these hormones and implies that they will likely emerge as a very useful blood test for detection of the progression of heart failure, even in the face of neurohumoral blocking therapy.