RANDOMIZED PLACEBO-CONTROLLED TRIAL OF EFFECT OF RAMIPRIL ON DECLINE IN GLOMERULAR-FILTRATION RATE AND RISK OF TERMINAL RENAL-FAILURE IN PROTEINURIC, NONDIABETIC NEPHROPATHY

Background In diabetic nephropathy, angiotensin-converting-enzyme (ACE ) inhibitors have a greater effect than other antihypertensive drugs o n proteinuria and the progressive decline in glomerular filtration rat e (GFR). Whether this difference applies to progression of nondiabetic proteinuric nephropathies is not clear. The Ramipril Efficacy In Neph ropathy study of chronic nondiabetic nephropathies aimed to address wh ether glomerular protein traffic influences renal-disease progression, and whether an ACE inhibitor was superior to conventional treatment, with the same blood-pressure control, in reducing proteinuria, limitin g GFR decline, and preventing endstage renal disease. Methods In this prospective double-blind trial, 352 patients were classified according to baseline proteinuria (stratum 1: 1-3 g/24 h; stratum 2: greater th an or equal to 3 g/24 h), and randomly assigned ramipril or placebo pl us conventional antihypertensive therapy targeted at achieving diastol ic blood pressure under 90 mm Hg. The primary endpoint was the rate of GFR decline. Analysis was by intention to treat. Findings At the seco nd planned interim analysis, the difference in decline in GFR between the ramipril and placebo groups in stratum 2 was highly significant (p =0.001). The Independent Adjudicating Panel therefore decided to open the randomisation code and do the final analysis in this stratum (stra tum 1 continued in the trial). Data (at least three GFR measurements i ncluding baseline) were available for 56 ramipril-assigned patients an d 61 placebo-assigned patients. The decline in GFR per month was signi ficantly lower in the ramipril group than the placebo group (0.53 [0.0 8] vs 0.88 [0.13] mL/min, p=0.03). Among the ramipril-assigned patient s, percentage reduction in proteinuria was inversely correlated with d ecline in GFR (p=0.035) and predicted the reduction in risk of doublin g of baseline creatinine or endstage renal failure (18 ramipril vs 40 placebo, p=0.04). The risk of progression was still significantly redu ced after adjustment for changes in systolic (p=0.04) and diastolic (p =0.04) blood pressure, but not after adjustment for changes in protein uria. Blood-pressure control and the overall number of cardiovascular events were similar in the two treatment groups. Interpretation In chr onic nephropathies with proteinuria of 3 g or more per 24 h, ramipril safely reduces proteinuria and the rate of GFR decline to an extent th at seems to exceed the reduction expected for the degree of blood-pres sure lowering.