Class II-IV Chronic Heart Failure Research Articles

Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial

Angiotensin II type 1 receptor blockers have favourable effects on haemodynamic measurements, neurohumoral activity, and left-ventricular remodelling when added to angiotensin-converting-enzyme (ACE) inhibitors in patients with chronic heart failure (CHF). We aimed to find out whether these drugs improve clinical outcome. Between March, 1999, and November, 1999, we enrolled 2548 patients with New York Heart Association functional class II-IV CHF and left-ventricular ejection fraction 40% or lower, and who were being treated with ACE inhibitors. We randomly assigned patients candesartan (n=1276, target dose 32 mg once daily) or placebo (n=1272). At baseline, 55% of patients were also treated with beta blockers and 17% with spironolactone. The primary outcome of the study was the composite of cardiovascular death or hospital admission for CHF. Analysis was done by intention to treat. The median follow-up was 41 months. 483 (38%) patients in the candesartan group and 538 (42%) in the placebo group experienced the primary outcome (unadjusted hazard ratio 0.85 [95% CI 0.75-0.96], p=0.011; covariate adjusted p=0.010). Candesartan reduced each of the components of the primary outcome significantly, as well as the total number of hospital admissions for CHF. The benefits of candesartan were similar in all predefined subgroups, including patients receiving baseline beta blocker treatment. The addition of candesartan to ACE inhibitor and other treatment leads to a further clinically important reduction in relevant cardiovascular events in patients with CHF and reduced left-ventricular ejection fraction.

Deceleration time of early filling in patients with left ventricular systolic dysfunction: Functional and prognostic independent value

Background Although diastolic function parameters have been mentioned as significant predictors of functional capacity and prognosis in patients with left ventricular (LV) systolic dysfunction, it has not been fully elucidated whether they keep an independent predictive value when multiple parameters from a wide variety of examinations are considered. Methods We prospectively studied 60 patients with New York Heart Association (NYHA) class II-IV chronic heart failure symptoms and LV ejection fraction <0.4. At the time of entry into the study, demographic data and functional class were obtained, and usual Doppler echocardiographic, radionuclide ventriculographic, cardiopulmonary exercise testing and hemodynamic variables were determined. Deceleration time of early filling (DT) and NYHA functional class were the only independent predictors of functional capacity as assessed by means of peak oxygen uptake (peak Vo2). Mean follow-up was 21 ± 6 months, and event-free survival was defined as the absence of cardiac death, urgent cardiac transplantation, or hospital admission requiring inotropic or mechanical support. Results Multivariate Cox analysis showed that DT (P =.008), peak Vo2 (P =.01), and NYHA class (P =.02) were independent predictors of event-free survival at 1 year. Patients in the lowest tertile of DT (<130 ms) had a significantly lower event-free survival than patients in the intermediate (44% vs 80%, P =.03) and in the highest tertile (44% vs 83%, P =.02). Patients with both a DT <130 milliseconds and a peak Vo2 <14 mL/kg/min had the highest rate of events at 1 year (83% vs 22% for the remaining patients, relative risk 3.75, P <.001). Conclusions In patients with LV systolic dysfunction, DT is a powerful independent predictor of functional capacity and prognosis among a wide variety of variables. A shortened DT (<130 ms) identifies a subgroup of patients with a worse outcome, especially when combined with a reduced peak Vo2 (<14 mL/kg/min). (Am Heart J 2002;143:1101-6.)

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

EDITOR SUMMARY 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 ≤40% and did not establish the efficacy of the ARB or its equivalent to angiotensin-converting enzyme inhibitor. The Valsartan Heart Failure Trial was designed to determine whether addition of valsartan improved the outcomes of patients receiving standard therapy for heart failure, which in most cases included an ACE inhibitor. Methods and Results: A total of 5,010 patients with NYHA class II-IV CHF and ejection fraction <40% were assigned to receive 160 mg valsartan or placebo twice daily. The 2 coprimary end points were all-cause mortality and the composite of mortality and morbidity, defined as the incidence of hospitalization for heart failure, resuscitated sudden death, or receipt of intravenous inotropic or vasodilator therapy for at least 4 hours (with hospitalizations accounting for 94% of the nonfatal end points). Mortality was similar in the 2 groups, but the combined mortality and morbidity end point was 13.2% lower with valsartan (relative risk, 0.87; 95% confidence interval, 0.77-0.97; P.009), primarily because of a reduction in the number of patients hospitalized for CHF (13.8% v 18.2%). There were improvements in several secondary end points, including ejection fraction, signs and symptoms of CHF, and quality of life with valsartan. Of note is that analyses of subgroups defined according to background therapy at baseline showed highly significant interactions. For instance, the small subgroup of 366 patients (7%) who were not receiving ACE inhibitors had a 33% reduction in mortality and a 44% decrease in mortality and morbidity, whereas the morbidity and mortality benefit of valsartan observed in the overall trial was no longer significant in patients receiving background ACE inhibitor therapy (relative risk, 0.90; P.10). The larger subgroup of patients receiving both an ACE inhibitor and a β-blocker at baseline had a statistically significant 42% increase in mortality with valsartan (P.009) and a trend toward an increase in the mortality and morbidity composite (P.10). Conclusions: When added to standard therapy, valsartan has no overall effect on mortality and produces a modest (13.2%) reduction in morbidity and mortality. However, this benefit is much larger in patients not receiving concomitant ACE inhibitor therapy and statistically not significant in those who are taking ACE inhibitors. Somewhat troublesome is the finding of significant increase in mortality with valsartan in patients receiving both ACE inhibitor and β-blocker therapy. (Prepared by Journal of Cardiac Failure editors.) A Randomized Trial of the Angiotensin-Receptor Blocker Valsartan in Chronic Heart Failure (Val-HeFT). N Engl J Med 2001;345:1667-1675

ADEPT: Addition of the AT1 receptor antagonist eprosartan to ACE inhibitor therapy in chronic heart failure trial: Hemodynamic and neurohormonal effects

Background Persistent activation of the renin-angiotensin-aldosterone-system (RAAS) is known to occur in patients with chronic heart failure (CHF) despite treatment with angiotensin-converting enzyme inhibitor (ACE) therapy. When added to ACE inhibitors, angiotensin II type 1 (AT1) antagonists may allow more complete blockade of the RAAS and preserve the beneficial effects of bradykinin accumulation not seen with AT1 receptor blockade alone. Methods Thirty-six patients with stable New York Heart Association class II-IV CHF receiving ACE inhibitor therapy were randomly assigned in a double-blind manner to receive either eprosartan, a specific competitive AT1 receptor antagonist (400 to 800 mg daily, n = 18) or placebo (n = 18) for 8 weeks. The primary outcome measure was left ventricular ejection fraction (LVEF) as measured by radionuclide ventriculography, and secondary measures were central hemodynamics assessed by Swan-Ganz catheterization and neurohormonal effects. Results There was no change in LVEF with eprosartan therapy (mean relative LVEF percentage change [SEM] +10.5% [9.3] vs +10.1% [5.0], respectively; difference, 0.4; 95% confidence interval [CI], –20.8 to 21.7; P =.97). Eprosartan was associated with a significant reduction in diastolic blood pressure and a trend toward a reduction in systolic blood pressure compared with placebo (–7.3 mm Hg [95% CI, –14.2 to –0.4] diastolic; –8.9 mm Hg [95% CI, –18.6 to 0.8] systolic). No significant change in heart rate or central hemodynamics occurred during treatment with eprosartan compared with placebo. A trend toward an increase in plasma renin activity was noted with eprosartan therapy. Eprosartan was well tolerated, with an adverse event profile similar to placebo, whereas kidney function remained unchanged. Conclusions When added to an ACE inhibitor, eprosartan reduced arterial pressure without increasing heart rate. There was no change in LVEF after 2 months of therapy with eprosartan. (Am Heart J 2001;141:800-7.)