November 9th, 2013
Yet Another Blow to Combination Renin-Angiotensin-Aldosterone System Blockade
ACE inhibitors and angiotensin-receptor blockers have been found to effectively slow progression of kidney disease. It has been theorized that dual blockade of the renin-angiotensin-aldosterone system (RAAS) might prove even more beneficial, but these hopes have not been realized. Now a new trial published in the New England Journal of Medicine throws further cold water on the once-promising hypothesis.
In the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial, Linda Fried and colleagues randomized type 2 diabetics with proteinuric kidney disease already receiving the angiotensin-receptor blocker losartan to either the ACE inhibitor lisinopril or placebo. The trial was stopped early by the data and safety monitoring committee due to safety concerns and the low likelihood that the trial would be able to yield a significant difference in the primary end point.
In the end, 1,448 patients were randomized and followed for 2.2 years. The primary endpoint — decline in estimated glomerular filtration rate (GFR), end-stage renal disease (ESRD), or death — occurred in 152 patients in the monotherapy group versus 132 in the combination group (hazard ratio for combination therapy: 0.88, CI 0.70-1.12, p=0.30). There was a trend toward benefit for the secondary endpoint of GFR decline and ESRD (HR 0.78, CI 0.58-1.05 p=0.10). There were no significant differences in mortality or cardiovascular events.
There was a significant increase in risk for hyperkalemia and acute kidney injury in the combination group compared with the monotherapy group:
- hyperkalemia: 6.3 versus 2.6 events per 100 person-years (p<0.001)
- acute kidney injury: 12.2 versus 6.7 events per 100 person-years (p<0.001)
The authors note that the results are consistent with the ONTARGET trial, in which the combination of an ACE inhibitor and an ARB also resulted in an increased risk for adverse events. Combination therapy also proved unsafe in the ALTITUDE trial, which tested the direct renin inhibitor aliskiren in addition to an ACE inhibitor or an ARB.
In an accompanying editorial, Dick de Zeeuw wonders whether these trials indicate the end of the dual therapy hypothesis. He writes that these “failed” trials “suggest that improvement in surrogate markers — lower blood pressure or less albuminuria — does not translate into risk reduction.” Combination therapy “can be resuscitated only if we can show renal and cardiovascular protection in a defined group of patients in whom the desired decreases in blood pressure, albuminuria, or both are achieved without major increases in potassium levels or other side effects.”