When the planned 42-month trial was prematurely terminated after a median follow-up of just four months, patients who received avosentan were more likely to have fluid overload and congestive heart failure than those who received placebo, according to Giancarlo Viberti, MD, of King's College London School of Medicine, and colleagues.
There was also a nonsignificant trend toward higher mortality in patients taking 25 or 50 mg a day of avosentan (4.6% and 3.6%) than in those taking placebo (2.6%), the researchers reported in the March issue of the Journal of the American Society of Nephrology.
"Despite its potent albuminuria-lowering effect, it is clear that avosentan at the doses [used in this study] in a population of patients with type 2 diabetes and 3 to 4 chronic kidney disease stage is not a viable therapeutic option," Viberti and his colleagues wrote.
Eberhard Ritz, MD, of Ruperto Carola University in Heidelberg, Germany, and René Wenzel, of Hospital Zell am See in Austria, agreed in an accompanying editorial, but said endothelin receptor blockers might still have a role to play in some patients.
"Should we continue to use [endothelin receptor] blockers in all proteinuric kidney disease?" they asked.
"Presumably, yes, particularly in earlier stages of diabetic (and possibly nondiabetic) nephropathy," they said, citing evidence from animal studies and smaller trials in humans. "But watch out for clear contraindications (stages 3 and 4 chronic kidney disease and preexisting heart disease), and monitor patients carefully."
In addition, they said, it is unclear whether lower doses of avosentan could be effective in patients with overt diabetic nephropathy while avoiding serious side effects.
Avosentan had been shown to reduce proteinuria in short-term proof-of-concept studies, but whether this resulted in slowing or stopping the progressive loss of renal function in the long term had not been investigated. (See Experimental Endothelin Antagonist Reduces Diabetic Kidney Disease)
To answer that question, Viberti and his colleagues initiated the ASCEND trial, a double-blind, placebo-controlled trial conducted at 551 centers in 36 countries.
Overall, 1,392 patients with type 2 diabetes and stage 3 to 4 chronic kidney disease were randomized to placebo or one of the two doses of avosentan.
All continued standard treatment, which included angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or a combination of the two drug classes.
At the time the trial was stopped, there was no difference between the three groups in the primary outcome, a composite of time to doubling of serum creatinine, end-stage renal disease, or death: 8.1% and 8.6% with the low and high doses of avosentan and 9.6% with placebo.
The reductions in albumin-to-creatinine ratio, a secondary endpoint, were significantly greater in the avosentan groups: 44.3% with the lower dose and 49.3% with the higher dose versus 9.7% with placebo (P<0.0001 for both).
Also, the percentage of patients who achieved the target blood pressure of less than 130/80 mm Hg was higher in the avosentan groups (66.9% and 62.6% versus 50%).
But those findings were overshadowed by higher rates of fluid overload in the 25-mg/day (44.8%) and 50-mg/day (45.8%) doses of avosentan than with placebo (30.7%) (P≤0.0001 for both).
Rates of congestive heart failure were similarly elevated at 5.9%, 6.1%, and 2.2%, respectively (P≤0.05 for both).
Anemia was more frequent in the avosentan groups, and those on active treatment were more likely to discontinue treatment because of adverse events (19.6% and 18.2% versus 11.5%, P≤0.02 for both).
Speedel Pharma, Switzerland, sponsored the study and appointed the contract research organization, Quintiles, for study set-up, initiation, management, monitoring, laboratory analyses, data management, and statistical analysis.
Two of the study authors were employees of Speedel Pharma. Viberti and the rest of the authors reported receiving honoraria for consultancy with the sponsor.
The editorialists did not make any financial disclosures.
- Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner
Journal of the American Society of NephrologySource Reference: Mann J, et al "Avosentan for overt diabetic nephropathy" J Am Soc Nephrol 2010; 21: 527-35.
Journal of the American Society of NephrologySource Reference: Ritz E, Wenzel R "Endothelin receptor antagonists in proteinuric renal disease: every rose has its thorn" J Am Soc Nephrol 2010; DOI: 10.1681/ASN.2010010047.