Impact of converting enzyme inhibition on progression of chronic heart failure: results of the Munich Mild Heart Failure Trial.

OBJECTIVE--Neurohormonal activation has major impact on the pathophysiology of congestive heart failure. The Munich Mild Heart Failure Trial was designed to test the hypothesis that interference with the renin-angiotensin system by angiotensin converting enzyme inhibition favourably influences the natural history of heart failure. DESIGN AND PATIENTS--170 patients, median New York Heart Association (NYHA) class II, were randomised to double blind treatment with 25 mg captopril twice a day or placebo in addition to standard treatment for a median observation period of 2.7 years. MAIN OUTCOME MEASURES--Progression of heart failure to NYHA class IV on an optimally adjusted standard treatment, death due to progressive heart failure, and sudden death. RESULTS--Heart failure progressed to class IV in nine patients (10.8%) treated with captopril and in 23 patients (26.4%) treated with placebo (p = 0.01). The mean survival time until this end point was 223 days longer in the captopril group (Kaplan-Meier life table analysis; p = 0.02). Also, progressive deterioration to severe heart failure was a powerful predictor of total mortality and death from heart failure; 80% of deaths due to progressive heart failure occurred after this end point. There were fewer deaths caused by progressive heart failure in the captopril group than in the placebo group (4 v 11; p = 0.10) but similar numbers of sudden deaths (11 v 10). Progressive heart failure was the cause of death in 18.2% of all deaths in the captopril group and 50% in the placebo group. Total heart failure events (the end point on which power calculation was based) were also more common in the placebo group (19 v 32 events) but not significantly so. Total mortality was similar to both groups (22 of 83 v 22 of 87). CONCLUSIONS--Angiotensin converting enzyme inhibition in conjunction with standard therapy early in the course of congestive heart failure slowed the progress of heart failure and thus favourably altered the natural history of the disease.     

Body mass index, prognosis and mode of death in chronic heart failure: results from the Valsartan Heart Failure Trial

AIMS: To assess the relationship between body mass index (BMI), mortality and mode of death in chronic heart failure (CHF) patients; to define the shape of the relationship between BMI and mortality. METHODS AND RESULTS: We performed a post-hoc analysis of 5010 patients from the Valsartan Heart Failure Trial. The end-points of the study were all-cause and cardiovascular mortality. Mortality rate was 27.2% in underweight patients (BMI<22 kg/m2), 21.7% in normal weight patients (BMI 22-24.9 kg/m2), 17.9% in overweight patients (BMI 25-29.9 kg/m2) and 16.5% in obese patients (BMI>30 kg/m2) (p<0.0001). The rates of non-cardiovascular death did not differ among groups. The risk of death due to progressive heart failure was 3.4-fold higher in the underweight than in the obese patients (p<0.0001). Normal weight, overweight and obese patients had lower risk of death as compared with underweight patients (p=0.019, HR 0.76, 95% CI 0.61-0.96; p=0.0005, HR 0.68, 95% CI 0.55-0.84; p=0.003, HR 0.67, 95% CI 0.52-0.88, respectively) independently of symptoms, ventricular function, beta-blocker use, C-reactive protein and brain natriuretic peptide levels. CONCLUSIONS: In CHF patients a higher BMI is associated with a better prognosis independently of other clinical variables. The relationship between mortality and BMI is monotonically decreasing.     

Effect of high- versus low-dose angiotensin converting enzyme inhibition on cytokine levels in chronic heart failure

OBJECTIVES

We examined the effect of long-term treatment with two doses of the angiotensin converting enzyme (ACE) inhibitor enalapril on various immunological variables in patients with chronic congestive heart failure (CHF).

BACKGROUND

Immunological mediators are increasingly recognized to play a pathogenic role in the pathophysiology of CHF. Whether ACE inhibitor therapy modifies immunological variables has not previously been investigated.

METHODS

Seventy-five patients (mean age 52 ± 11 years) with CHF were randomized between low- (5 mg daily) and high-dose (40 mg daily) enalapril in a double-blind trial. Circulating levels of immunological parameters (i.e., proinflammatory cytokines, chemokines and adhesion molecules) were measured at baseline, at 10 weeks and at the end of the study (34 weeks).

RESULTS

All immunological parameters, except soluble interleukin (IL)-6 receptor, were increased in CHF compared with 21 healthy controls. During the study immunoreactive IL-6 levels decreased (p < 0.05) and soluble IL-6 receptor increased (p < 0.05) during high-dose but not during low-dose enalapril therapy. Furthermore, IL-6 bioactivity decreased only during the high-dose (p < 0.001), resulting in a significant difference in change during treatment between the two dosage groups (p < 0.001). This decrease in IL-6 bioactivity was significantly associated with decreased interventricular septum thickness as assessed by echocardiography (r = 0.56, p = 0.013). No other variables changed during treatment.

CONCLUSIONS

In patients with severe CHF, high-dose enalapril therapy is associated with a significant decrease in IL-6 activity. However, despite treatment with a high-dose ACE inhibitor, a persistent immune activation exists in these patients which may be of importance for the progression of CHF.     

Digoxin use and heart failure outcomes: results from the Valsartan Heart Failure Trial (Val-HeFT)

Several retrospective studies have raised concerns regarding digoxin therapy in select subgroups of heart failure patients. To assess the impact of digoxin therapy on outcomes in the current era of heart failure therapy, the authors analyzed data representing 5010 patients enrolled in the Valsartan Heart Failure Trial (Val-HeFT) to examine the relationship of baseline digoxin use and all-cause mortality, first morbid event, and heart failure hospitalizations. At baseline, 3374 patients (67%) were receiving digoxin therapy and 1636 (33%) were not. Patients receiving digoxin had features of worse heart failure with higher New York Heart Association class and lower blood pressure, ejection fraction, and β-blocker use (32.1% vs 40.8%). Digoxin use was associated with worse mortality (21.1 vs 15.0%, P<.001), first morbid event (34.6 vs 21.7, P<.001), and HF hospitalization rate (19.1 vs 10.1%, P<.001). After adjustment for baseline group differences including medical therapy and baseline rhythm, patients receiving digoxin remained at a higher risk for all-cause mortality (hazard ratio [HR], 1.28; 95% confidence interval [CI], 1.05-1.57), first morbid event (HR, 1.35; 95% CI, 1.15-1.59), and heart failure hospitalization (HR, 1.41; 95% CI, 1.12-1.78). These results remained materially unchanged with propensity matched analysis. No benefit with digoxin use was observed in this study, underscoring the need to reassess the role of digoxin in the contemporary management of 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.     

Influence of angiotensin converting enzyme inhibition on pump function and cardiac contractility in patients with chronic congestive heart failure.

Eleven patients with coronary artery disease and chronic heart failure were studied before and three months after the angiotensin converting enzyme inhibitor enalapril was added to their frusemide medication. The following were measured: left ventricular pressure and volume with transient occlusion of the inferior vena cava, radionuclide angiography, and hormone concentrations in plasma. As in other reported studies, the clinical condition of the patients improved and their exercise tolerance increased moderately. Addition of enalapril reduced end diastolic and systolic pressure, reduced ventricular volume, and concomitantly increased the ejection fraction. The end systolic pressure-volume relation shifted to the left as it did in a similar animal study. In the animal study unloading by a vasodilator did not induce a leftward shift, so it can be inferred that in the present study unloading combined with a decrease in the angiotensin concentration was instrumental in remodelling the heart. Though unloading was expected to have a beneficial effect on the oxygen supply/demand ratio of the heart, the patients still showed the same drop in the ejection fraction during exercise as they did before treatment with enalapril, and early diastolic filling did not improve. Normally, regression of cardiac dilatation is only found if pump function improves; the present study showed that unloading in combination with angiotensin converting enzyme inhibition reshapes the ventricle without improving intrinsic pump function.     

Transient renal dysfunction during initial inhibition of converting enzyme in congestive heart failure.

Treatment with captopril in resistant normotensive congestive heart failure is associated with a pronounced reduction in blood pressure, particularly after the first dose. The effects of this reduction on renal function were assessed in 10 patients at the beginning of and during chronic treatment (at one week and three months). Renal plasma flow and glomerular filtration rates were measured by isotope clearance during water diuresis. The first dose of captopril (25 mg) led to a pronounced fall in renal plasma flow and glomerular filtration rates together with a decrease in mean arterial pressure; this fall correlated with baseline plasma renin activity. These changes were paralleled by decreases in water and sodium excretion. In contrast, by the end of the first week of treatment a similar fall in mean arterial pressure occurred together with a pronounced increase in renal plasma flow; the glomerular filtration rate was maintained and there was no decrease in water and sodium excretion. This new response pattern recurred after three months of treatment. The difference in response at different stages of treatment may reflect the balance between the different mechanisms influencing kidney dynamics in heart failure and their alteration by converting enzyme inhibition. The sustained increase in renal plasma flow during chronic treatment with captopril may account for the continued control of heart failure in these patients.     

Impact of dopamine infusion on renal function in hospitalized heart failure patients: results of the Dopamine in Acute Decompensated Heart Failure (DAD-HF) Trial

BackgroundWorsening renal function (WRF) and hypokalemia related to diuretic use for acute decompensated heart failure (ADHF) are common and associated with poor prognosis. Low-dose dopamine infusion improves renal perfusion; its effect on diuresis or renal function specifically in ADHF is not known.Methods and ResultsSixty consecutive ADHF patients (age 75.7 ± 11.2 years; 51.7% female; left ventricular ejection fraction 35.3 ± 12.1%) were randomized, after receiving a 40 mg intravenous furosemide bolus, to either high-dose furosemide (HDF, 20 mg/h continuous infusion for 8 hours) or low-dose furosemide combined with low-dose dopamine (LDFD, furosemide 5 mg/h plus dopamine 5 μg kg^?1 min^?1 continuous infusion for 8 hours). Both strategies were compared for total diuresis, WRF (defined as a rise in serum creatinine of >0.3 mg/dL from baseline to 24 hours), electrolyte balance, and 60-day postdischarge outcomes. Mean hourly excreted urine volume (272 ± 149 mL in HDF vs 278 ± 186 mL in LDFD group; P = .965) and changes in dyspnea score (Borg index: ?4.4 ± 2.1 in HDF group vs ?4.7 ± 2.0 in LDFD group; P = .575) during the 8 hours of protocol treatment were similar in the two groups. WRF was more frequent in the HDF (n = 9; 30%) than in the LDFD group (n = 2; 6.7%; P = .042). Serum potassium changed from 4.3 ± 0.5 to 3.9 ± 0.4 mEq/L at 24 hours (P = .003) in the HDF group and from 4.4 ± 0.5 to 4.2 ± 0.5 mEq/L at 24 hours (P = .07) in the LDFD group. Length of stay and 60-day mortality or rehospitalization rates (all-cause, cardiovascular, and worsening HF) were similar in the two groups.ConclusionsIn ADHF patients, the combination of low-dose furosemide and low-dose dopamine is equally effective as high-dose furosemide but associated with improved renal function profile and potassium homeostasis.Clinical Trial Registration InformationClinicalTrials.gov Identifier: NCT00937092 (http://clinicaltrials.gov/ct2/show/NCT00937092)     

Comparison between angiotensin receptor antagonism and converting enzyme inhibition in heart failure

This study was designed to assess the influence of the activation status of the renin angiotensin system (RAS) on the hemodynamic effects of EXP 3174 (an angiotensin AT1 receptor antagonist) and enalaprilat (an angiotensin converting enzyme inhibitor) in tachycardia-induced heart failure. Thirteen dogs were chronically instrumented to measure left ventricular (LV) pressure, its first time derivative (LV dP/dt), atrial and aortic pressures, and cardiac output. EXP 3174 (0.1 mg/kg, iv) or enalaprilat (1 mg/kg, iv) were administered in conscious dogs with heart failure induced by right ventricular pacing (250 beats/min, 3 weeks). EXP 3174 and enalaprilat produced significant vasodilation but the effects of EXP 3174 on mean aortic pressure (MAP), cardiac output, and total peripheral resistance (TPR) were only 50% of those produced by enalaprilat. When dogs were grouped according to their baseline plasma renin activity (PRA) values, in dogs with normal PRA (0.5 ± 0.1 ng/ml/h) EXP 3174 did not produce significant change in MAP and TPR, while enalaprilat decreased significantly MAP and TPR. In contrast, in dogs with high PRA (6.7 ± 3.2 ng/ml/h), EXP 3174 produced significant reductions in MAP and TPR, which were similar to those produced by enalaprilat. Thus, in conscious dogs with heart failure, enalaprilat is effective whether the RAS is activated or not. In contrast, EXP 3174 is effective only when the RAS is activated. These results may help in the choice of inhibitors of the RAS in heart failure. Received: 22 September 1998, Returned for revision: 14 October 1998, Revision received: 23 November 1998, Accepted: 8 December 1998     

Influence of angiotensin converting enzyme inhibition on pump function and cardiac contractility in patients with chronic congestive heart failure

Eleven patients with coronary artery disease and chronic heart failure were studied before and three months after the angiotensin converting enzyme inhibitor enalapril was added to their frusemide medication. The following were measured: left ventricular pressure and volume with transient occlusion of the inferior vena cava, radionuclide angiography, and hormone concentrations in plasma. As in other reported studies, the clinical condition of the patients improved and their exercise tolerance increased moderately. Addition of enalapril reduced end diastolic and systolic pressure, reduced ventricular volume, and concomitantly increased the ejection fraction. The end systolic pressure-volume relation shifted to the left as it did in a similar animal study. In the animal study unloading by a vasodilator did not induce a leftward shift, so it can be inferred that in the present study unloading combined with a decrease in the angiotensin concentration was instrumental in remodelling the heart. Though unloading was expected to have a beneficial effect on the oxygen supply/demand ratio of the heart, the patients still showed the same drop in the ejection fraction during exercise as they did before treatment with enalapril, and early diastolic filling did not improve. Normally, regression of cardiac dilatation is only found if pump function improves; the present study showed that unloading in combination with angiotensin converting enzyme inhibition reshapes the ventricle without improving intrinsic pump function.     

慢性心力衰竭治疗中血管紧张素转换酶抑制剂的应用

慢性心力衰竭传统的治疗主要是针对心脏的血流动力学异常,采用“强心、利尿、扩血管”的治疗方案。然而大规模、多中心、随机双盲、安慰剂对照的临床试验结果却表明正性肌力药和单纯的血管扩张剂虽可产生短期的血流动力学效应,但长期治疗却增加病死率和病残率。随着对“心室重构是心衰发生、发展机制”认识的逐步深入,以及神经内分泌拮抗剂——血管紧张素转换酶抑制剂(ACEI)和β-受体阻滞剂等成功地降低心     

Transient renal dysfunction during initial inhibition of converting enzyme in congestive heart failure

Treatment with captopril in resistant normotensive congestive heart failure is associated with a pronounced reduction in blood pressure, particularly after the first dose. The effects of this reduction on renal function were assessed in 10 patients at the beginning of and during chronic treatment (at one week and three months). Renal plasma flow and glomerular filtration rates were measured by isotope clearance during water diuresis. The first dose of captopril (25 mg) led to a pronounced fall in renal plasma flow and glomerular filtration rates together with a decrease in mean arterial pressure; this fall correlated with baseline plasma renin activity. These changes were paralleled by decreases in water and sodium excretion. In contrast, by the end of the first week of treatment a similar fall in mean arterial pressure occurred together with a pronounced increase in renal plasma flow; the glomerular filtration rate was maintained and there was no decrease in water and sodium excretion. This new response pattern recurred after three months of treatment. The difference in response at different stages of treatment may reflect the balance between the different mechanisms influencing kidney dynamics in heart failure and their alteration by converting enzyme inhibition. The sustained increase in renal plasma flow during chronic treatment with captopril may account for the continued control of heart failure in these patients.     

Effectiveness of converting enzyme inhibition (enalapril) for mild congestive heart failure

The present study investigates the effectiveness of converting enzyme inhibition (CEI) on cardiac performance of patients with congestive heart failure (New York Heart Association functional class II). Outpatients (n = 12) were treated with enalapril, 5 to 10 mg twice daily, in addition to stable doses of digitalis and diuretic drugs. Before and after 4 and 12 weeks of treatment a treadmill exercise test and echocardiography were performed. Maximal oxygen uptake and exercise tolerance increased significantly and mean arterial pressure at rest and on exertion decreased significantly. Heart rate did not change. Left ventricular end-diastolic diameter decreased significantly. Serum angiotensin converting enzyme activity was reduced to nearly 0; plasma renin concentration, which was already elevated, increased further. Plasma norepinephrine levels did not change significantly. Treatment was tolerated well by all patients. CEI decreased preload and afterload, suggesting that they might have had an inappropriately elevated arteriolar and venous tone owing to a moderately stimulated renin angiotensin system and sympathetic nervous system. These conditions may lead to further deterioration of cardiac performance. By means of CEI one may be able to interrupt these pathogenetic mechanisms, relieving the already damaged heart from inappropriate elevations of preload and afterload and delaying or even preventing further deterioration of cardiac performance.     

血管紧张素转换酶抑制剂对心力衰竭患者心率变异性昼夜节律的影响

本文对43例心力衰竭患者进行了24h心率变异性(HRV)昼夜节律分析，并对部分患者以血管紧张素转换酶抑制剂(ACEI)治疗，通过治疗前后HRV昼夜节律分析比较，初步探讨ACEI对心力衰竭病人自主神经活性昼夜节律的影响。     

Long-term treatment of chronic heart failure by an inhibitor of angiotensin converting enzyme

We studied the hemodynamic, echocardiographic, phonomechanographic and hormonal changes during acute (25 mg) and chronic (6 months--75 to 225 mg/day) treatment of 10 patients with congestive cardiac failure due to cardiomyopathy with dilatation with SQ 14 225 (Captopril). The following changes were observed after the single dose: an increase in cardiac output (p less than 0,001), in stroke volume (p less than 0,01), a reduction in heart rate (p less than 0,01), in peripheral resistance (p less than 0,001) and pulmonary capillary pressure (p less than 0,001). There were no significant changes in end systolic or end diastolic left ventricular internal diameter. Plasma renin activity increased (p less than 0,001); there was a concurrent fall in serum aldosterone (NS): the plasma concentration of converting enzyme decreased (p less than 0,001). There was a correlation between the increase in peripheral resistance under basal conditions and the basal plasma renin activity (R = 0,72, p less than 0,02). The decrease in peripheral resistance after captopril also correlated with basal plasma renin activity (R = 0,89, p less than 0,01). After six months continuous therapy, the hemodynamic effect was sustained and was accompanied by a significant symptomatic improvement. Left ventricular internal end systolic and end diastolic diameters decreased (p less than 0,01 and p less than 0,01 respectively). The pre-ejectional period decreased (p less than 0,05). Serum aldosterone fell significantly (p less than 0,001) as did plasma renin activity (p less than 0,01); the serum level of converting enzyme remained low with respect to its initial value. These results show that captopril may be useful in severe cardiac failure without tolerance during long-term administration. No renal or hematological toxicity was observed in this group of patients.     

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.