Predictors of Congestive Heart Failure after Treatment with an Endothelin Receptor Antagonist

Abstract

Background and objectives The Avosentan on Time to Doubling of Serum Creatinine, End Stage Renal Disease or Death (ASCEND) trial tested the renoprotective effect of the endothelin receptor antagonist avosentan in patients with diabetes and nephropathy, but the study was terminated due to an excess of congestive heart failure (CHF) events in the avosentan arms, likely due to fluid retention. The aim of this study was to identify risk markers of CHF after treatment with avosentan.Design, setting, participants, & measurements In a post hoc analysis of the ASCEND trial (N=1392 participants), we assessed which baseline characteristics predicted CHF risk during avosentan treatment. Furthermore, postrandomization changes between baseline and the first available measurement of body weight and hemoglobin were examined as potential clinical indicators of fluid retention for their relationship with CHF development.Results Relative to placebo, avosentan increased CHF risk (hazard ratio, 2.76; 95% confidence interval, 1.68 to 4.54). The avosentan-related CHF risk was higher with lower baseline cholesterol levels (P interaction=0.003) and concomitant statin use (P interaction=0.06), whereas it was lower with a lower estimated GFR (P interaction=0.04). Patients allocated to avosentan had a median body weight increase of 0.6 kg (interquartile range, 0.0 to 2.0 kg) and a median hemoglobin decrease of 1.4 g/dl (interquartile range, 22.1 to 20.7 g/dl) at the first postrandomization measurement. The body weight increase induced by avosentan was associated with CHF development (P interaction=0.04), whereas hemoglobin decrease was not (P interaction=0.64). The increase in body weight was particularly pronounced in patients with a cardiovascular disease history and in patients using statins. ConclusionsIn avosentan-treated patients, body weight increase, but not hemoglobin decrease, was associated with CHF development, indicating that close body weight monitoring could provide an early signal of CHF development in future trials with endothelin receptor antagonists.

Diabetic Kidney Disease: Pathophysiology and Therapeutic Targets

“…Although the trial was stopped prematurely due to an excess of cardiovascular events in the intervention group, there was a dose-dependent reduction in albuminuria in the avosentan group [ 95 ] when compared to the placebo arm. A post hoc analysis of the ASCEND trial found that the increased events of congestive heart failure (CHF) were preceded by increases in body weight and that future trials with ET-1 receptor antagonists would benefit from close monitoring of body weight to sooner identify any potential CHF development [ 96 ]. In a more recent study, data from two-phase 2b, randomized, double-blind, placebo-controlled trials in patients with type 2 diabetes with overt nephropathy were pooled to compare concomitant atrasentan and RAS-inhibitor use with a placebo group.…”

Long-Term Effect of Endothelin Receptor Antagonism With Bosentan on the Morbidity and Mortality of Patients With Severe Chronic Heart Failure

“…However, the finding of delayed benefit was based on a post hoc analysis of a small number of events observed in a subgroup of patients-characteristics that increase the likelihood of the play of chance. No biphasic response was seen in a dose-ranging trial with the more endothelin type A (ET A ) receptor-selective antagonist enrasentan (18), which noted an excess early risk of worsening heart failure, which persisted for the duration of follow-up (Figure 5).The mechanisms leading to early worsening heart failure in patients treated with endothelin antagonists(17,19,25) have not been fully elucidated.Receptor antagonism may interfere with the positive inotropic and negative lusitropic effects of endothelin(26) or may have adverse effects on neurohormonal activation or cardiac remodeling(27). In addition, endothelin receptor antagonists dilate the pulmonary arterioles(28), and thus, may interfere with the restraint that pulmonary vasoconstriction normally exerts on blood flow into the lungs and the transudation of fluid into alveoli when pulmonary venous pressures are increased(29,30).In the current trial and earlier studies(17,19,21), however, early worsening heart failure was related to fluid retention.…”

Rationale and protocol of the Study Of diabetic Nephropathy with AtRasentan (SONAR) trial: A clinical trial design novel to diabetic nephropathy

“…If at any time during the study there is an interruption of or decrease in ACE inhibitor/ARB dose, resumption of the previous dose is attempted within 1 month, in line with the investigator’s medical judgment. ERAs may induce sodium retention in some patients . The investigator may increase the diuretic dose as needed in the presence of signs and symptoms of fluid overload (eg, peripherial edema, dyspnea or orthopnea).…”