Adding the renin inhibitor aliskiren to standard hypertension treatment in type 2 diabetes patients with comorbid kidney or cardiovascular disease did not reduce serious cardiovascular or renal events, according to a multinational study of more than 8,000 patients.
The findings from ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints) were presented at Kidney Week 2012 and simultaneously published online Nov. 3 in the New England Journal of Medicine.
Data from previous studies suggest that the direct renin inhibitor aliskiren, when combined with an angiotensin-receptor blocker (ARB), was associated with a greater decrease in albuminuria than ARB treatment alone in patients with diabetic renal disease, said Dr. Hans-Henrik Parving of the University of Copenhagen and his colleagues. However, the effect on renal and cardiovascular outcomes of combining aliskiren with an ARB or an angiotensin-converting–enzyme (ACE) inhibitor is unknown, they said.
To determine the safety of a dual renin–angiotensin–aldosterone system (RAAS) blockade, the researchers randomized 8,606 adults at 838 centers in 36 countries to receive standard treatment plus aliskiren or a placebo. Complete data were available for 8,561 patients enrolled between October 2007 and June 2010. Eligible patients had type 2 diabetes and were taking either an ARB or ACE inhibitor (N. Engl. J. Med. 2012, Nov. 3 [doi:10.1056/NEJMoa1208799]).
The average age of the patients was 65 years, and approximately one-third were female. Baseline demographics were similar between the two groups. After 2 months, 84% of the aliskiren patients were taking the maximum dose of 300 mg.
The primary composite outcome included death from cardiovascular causes, cardiac arrest with resuscitation, myocardial infarction (fatal or nonfatal), stroke (fatal or nonfatal), unplanned hospitalization for heart failure, end-stage renal disease (death attributable to kidney failure or loss of kidney function), and doubling of baseline serum creatinine. Any one patient "may have had multiple cardiovascular or renal events of different types," the researchers noted.
After a median follow-up of approximately 2.5 years, 783 patients in the aliskiren group (18%) and 732 in the placebo group (17%) met the primary end point, though the difference was not statistically significant (P = .12)
Aliskiren patients showed significantly lower systolic and diastolic blood pressures and higher mean reductions in urinary albumin-to-creatinine ratios after 6 months than placebo patients. However, significantly more aliskiren patients than placebo patients had hyperkalemia (39% vs. 29%, respectively) and hypotension (12% vs. 8%, respectively).
The number of deaths from any cause was not significantly different between the aliskiren and placebo groups (119 and 102, respectively).
Significantly more aliskiren patients than placebo patients discontinued the study drug due to an adverse event (13% vs. 10%). The most common adverse event was hyperkalemia, followed by renal impairment and hypotension.
"The overall lack of benefit with regard to the primary composite cardiovascular and renal outcome was observed across all the predefined subgroups," the researchers said.
Two trials of aliskiren in combination with another renin-angiotensin system blocker in heart failure patients are ongoing, the researchers said.
However, "the present study documented more adverse events in the aliskiren group than in the placebo group without clinical benefits to offset them, which underscores the need to go beyond surrogate biomarkers and obtain risk-benefit data from clinical end-point trials to better inform clinical decisions," they said.
Novartis supported the study. Dr. Parving has received funding from Novartis, served on the speakers bureau for Novartis and Sanofi, and has served as a consultant for Abbott, Reata, and Takeda.