Rationale and design of the valsartan heart failure trial: A large multinational trial to assess the effects of valsartan, an angiotensin-receptor blocker, on morbidity and mortality in chronic congestive heart failure

doi:10.1016/S1071-9164(99)90038-6

Journal of Cardiac Failure

Volume 5, Issue 2, June 1999, Pages 155-160

https://doi.org/10.1016/S1071-9164(99)90038-6 Get rights and content

Abstract

Background: To investigate the role of persistent angiotensin activity despite angiotensinconverting enzyme inhibitor therapy in the progression of heart failure, the Valsartan Heart Failure Trial has been designed to investigate the effect of the angiotensin-receptor blocker, valsartan, on morbidity and mortality.

Methods and Results: Nearly 5,000 patients with New York Heart Association classes II to IV heart failure, while receiving all standard therapy, are being randomized to treatment with valsartan, 160 mg twice daily, or placebo in a worldwide study. Follow-up will be continued until 906 deaths have been recorded. Additional end points will include the need for hospitalization, other major morbid events, quality-of-life measurement, changes in neurohormone levels, and changes in left ventricular size and function. Substudies will explore exercise tolerance, arrhythmias, and magnetic resonance imaging.

Conclusion: This study should help establish the role of angiotensin-receptor blockade in the treatment of heart failure.

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Malnutrition syndrome, but not body mass index, is associated to worse prognosis in heart failure patients
2011, Clinical Nutrition
Many studies have suggested that obese patients with chronic heart failure have a better prognosis than leaner patients. The main purpose of this study was to assess the prognostic value of body mass index in patients with chronic heart failure, independently of other poor prognosis parameters.
This retrospective study included 405 heart failure patients. Anthropometric, body composition, clinical, biochemical, and echocardiographic data were collected from all patients. Patients were classified as: underweight (<20 kg/m²), normal (20–24.9 kg/m²), overweight (25–29.9 kg/m²), and obese (≥30 kg/m²). The endpoints were all-cause and cardiovascular mortality.
Cox regression analysis on all-cause mortality showed that normal weight patients were at significantly lower risk of death [RR = 0.231 (CI_95% 0.085–0.627)] as compared with obese patients, while underweight and overweight categories did not show a significantly different risk compared with the reference category. Age, gender, ejection fraction, systolic heart failure, angiotensin II receptor blockers use, hemoglobin levels, and handgrip strength were independent predictors of all-cause mortality. Cardiovascular deaths showed the same trend.
A lower body mass index does not predict all-cause and cardiovascular mortality among chronic heart failure patients, independently of other nutritional, body composition, and clinical status parameters.
Changes in metabolic profile and population of skeletal muscle fibers of mice overexpressing calsequestrin: Influence of losartan
2011, Acta Histochemica
In heart failure, exertional fatigue of skeletal muscles can occur. A transgenic mouse overexpressing calsequestrin can be regarded as an animal model of heart failure. The aims of the present study were to investigate, whether at the time of cardiac failure the composition of fiber types of skeletal muscles was altered, what kind of alterations in glycolytic and oxidative enzyme activities occurred in different muscle fiber types and whether these were affected by the administration of the angiotensin II receptor blocker, losartan. Hemodynamic parameters were determined using a working heart preparation. Four groups of mice were investigated: wild-type (WT) mice and transgenic (TG) mice overexpressing calsequestrin, with and without losartan treatment. Enzyme activities were measured in homogenates of Rectus femoris muscle and in muscle fibers, which were typed by their metabolic profile. Calcineurin expression was measured by Western blotting. Succinate dehydrogenase activity was increased by 275% in R. femoris muscle homogenates of TG compared to WT mice. This was due to a 57% increase in slow oxidative fibers, which was accompanied by an increased calcineurin expression in TG muscles. This increase was attenuated by losartan treatment. With respect to glycerol-3-phosphate-dehydrogenase (GPDH), no difference was evident comparing WT and TG. Treatment with losartan resulted in a down-regulation of GPDH in WT and TG. In conclusion, changes in skeletal muscles occur in this mouse model of heart failure and these changes were antagonized by losartan. In contrast to heart failure patients, in the mouse model a shift to the oxidative phenotype of skeletal muscle was noted, possibly due to enhanced calcineurin expression.
Waon therapy improves the prognosis of patients with chronic heart failure
2009, Journal of Cardiology
We developed a Waon therapy (soothing warm therapy) and have previously reported that repeated Waon therapy improves hemodynamics, peripheral vascular function, arrhythmias, and clinical symptoms in patients with chronic heart failure (CHF). The aim of this study was to investigate the effect of Waon therapy on the prognosis of CHF patients.
We studied 129 patients with CHF in NYHA functional class III or IV who were admitted to our hospital between January 1999 and March 2001. In the Waon therapy group, 64 patients were treated with a far infrared-ray dry sauna at 60 °C for 15 min and then kept on bed rest with a blanket for 30 min. The patients were treated daily for 5 days during admission, and then at least twice a week after discharge. In the control group, 65 patients, matched for age, gender, and NYHA functional class, were treated with traditional CHF therapy. The follow-up time was scheduled for 5 years.
Recent, complete follow-up data on each patient were obtained. The overall survival rate was 84.5% (Kaplan–Meier estimate). Twelve patients died in the control group and 8 patients died in the Waon therapy group at 60 months of follow-up. Cardiac events due to heart failure or cardiac death occurred in 68.7% of the control group but only 31.3% of the Waon therapy group (P < 0.01) at 60 months of follow-up.
Waon therapy reduced cardiac events in patients with CHF. This therapy is a promising non-pharmacological treatment for CHF.
Incremental value of renal function in risk prediction with the Seattle Heart Failure Model
2009, American Heart Journal
Impaired renal function portends poor heart failure (HF) outcomes. The Seattle Heart Failure Score (SHFS), a multimarker risk assessment tool, however does not incorporate renal function. In this study, we assessed the incremental value of renal function over the SHFS in patients with advanced HF on contemporary optimal treatment.
Blood urea nitrogen (BUN), serum creatinine (sCr), BUN/sCr ratio, and estimated glomerular filtration rate were assessed in survival models with SHFS as the base model among 443 patients with HF (52 ± 12 years, male 68.5%, white 52.4%, ejection fraction 0.18 ± 0.08). Incremental value of renal function was assessed by changes in the likelihood ratio χ² and the area under the receiver operating characteristic curves for 1-, 2-, and 3-year event prediction.
During a median follow-up of 21 months, 108 (24.5%) of 443 patients had an event (death [n = 92], urgent transplantation [n = 13], or ventricular assist device implantation [n = 3]). All renal parameters individually were associated with outcome (BUN, P < .001; sCr, P < .001; BUN/sCr ratio, P = .006; and estimated glomerular filtration rate, P = .006); however, only BUN was an independent predictor of events in multivariable analyses. Addition of BUN improved the predictive ability of SHFS (Δlikelihood ratio χ² 5.03, P = .025); however, the increase in the area under the receiver operating characteristic curve was marginal (year 1, 0.786 to 0.791; year 2, 0.732 to 0.741; year 3, 0.745 to 0.754; all P > .2).
Among the various renal function parameters, BUN had the strongest association with outcomes in patients with advanced HF. However, the incremental value of renal function over the SHFS for risk determination was marginal.
Clinical, Neurohormonal, and Inflammatory Markers and Overall Prognostic Role of Chronic Obstructive Pulmonary Disease in Patients With Heart Failure: Data From the Val-HeFT Heart Failure Trial
2007, Journal of Cardiac Failure
Chronic obstructive pulmonary disease (COPD) and heart failure are major causes of death and disability. Because little information is available about the population of patients with both syndromes, we assessed the characteristics and the independent contribution of COPD to outcomes in patients with stable chronic heart failure.
The clinical, neurohormonal, and echocardiographic characteristics of the 5010 patients enrolled in the Valsartan Heart Failure Trial were compared in patients with or without COPD. The prognostic value of COPD was tested by multivariate Cox proportional hazard models.
Patients with COPD were older, more symptomatic, and less likely to be receiving beta-blocker therapy, and had a higher mortality (27.4% vs. 18.4%, P < .0001). Echocardiographic parameters were not different, and brain natriuretic peptide was only minimally increased. Norepinephrine, inflammatory markers, cardiac troponin T, and creatinine values were significantly higher. After adjustment, COPD no longer predicted all-cause mortality but remained predictive of noncardiovascular mortality (hazard ratio 2.50; 95% confidence interval: 1.58–3.96; P < .0001) and hospitalizations, especially noncardiovascular (hazard ratio 1.71; 95% confidence interval; 1.43–2.06; P < .0001).
Patients with COPD are more symptomatic and have worse outcomes that are not explained by poorer left ventricular function. After adjustment for demographic, clinical, biohumoral, and treatment variables, COPD is a weak predictor of all-cause mortality but a strong predictor of noncardiovascular events. Awareness and optimized treatment of heart failure and COPD may reduce the clinical burden of these patients.
ACE2: A novel therapeutic target for cardiovascular diseases
2006, Progress in Biophysics and Molecular Biology
Hypertension afflicts over 65 million Americans and poses an increased risk for cardiovascular morbidity such as stroke, myocardial infarction and end-stage renal disease resulting in significant mortality. Overactivity of the renin–angiotensin system (RAS) has been identified as an important determinant that is implicated in the etiology of these diseases and therefore represents a major target for therapy. In spite of the successes of drugs inhibiting various elements of the RAS, the incidence of hypertension and cardiovascular diseases remain steadily on the rise. This has lead many investigators to seek novel and innovative approaches, taking advantage of new pathways and technologies, for the control and possibly the cure of hypertension and related pathologies. The main objective of this review is to forward the concept that gene therapy and the genetic targeting of the RAS is the future avenue for the successful control and treatment of hypertension and cardiovascular diseases. We will present argument that genetic targeting of angiotensin-converting enzyme 2 (ACE2), a newly discovered member of the RAS, is ideally poised for this purpose. This will be accomplished by discussion of the following: (i) summary of our current understanding of the RAS with a focus on the systemic versus tissue counterparts as they relate to hypertension and other cardiovascular pathologies; (ii) the newly discovered ACE2 enzyme with its physiological and pathophysiological implications; (iii) summary of the current antihypertensive pharmacotherapy and its limitations; (iv) the discovery and design of ACE inhibitors; (v) the emerging concepts for ACE2 drug design; (vi) the current status of genetic targeting of the RAS; (vii) the potential of ACE2 as a therapeutic target for hypertension and cardiovascular disease treatment; and (viii) future perspectives for the treatment of cardiovascular diseases.

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^☆: Supported in part by a grant from Novartis.

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Drugs in clinical trialRationale and design of the valsartan heart failure trial: A large multinational trial to assess the effects of valsartan, an angiotensin-receptor blocker, on morbidity and mortality in chronic congestive heart failure☆

Abstract

Am Heart J

Lancet

Lancet

Am J Cardiol

J Card Fail

Effects of enalapril on mortality in severe congestive heart failure

New Engl J Med

Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure

N Engl J Med

A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure

N Engl J Med

The effect of captopril on mortality and morbidity in patients with left ventricular dysfunction following myocardial infarction: Results of the Survival and Ventricular Enlargement (SAVE) trial

N Engl J Med

A clinical trial of the angiotensin-converting enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction

N Engl J Med

Role of the renin-angiotensin system in the systemic vasoconstriction of chronic congestive heart failure

Circulation

[SAR'] Angiotensin II receptor-mediated stimulation of protein synthesis in chick heart cells

Am J Physiol

Drugs in clinical trial
Rationale and design of the valsartan heart failure trial: A large multinational trial to assess the effects of valsartan, an angiotensin-receptor blocker, on morbidity and mortality in chronic congestive heart failure☆