Background. The Ramipril Efficacy In Nephropathy (REIN) study found that in patients with chronic nephropathies and proteinuria of 3 g or more per 24 h, ramipril safely reduced the rate of decline of the glomerular filtration rate (GFR) and halved the combined risk of doubling of serum creatinine or end-stage renal failure (ESRF), as compared with placebo plus conventional antihypertensive drugs at the same level of blood pressure control. At the end of the core study patients continued on or shifted to ramipril and were formally enrolled into the REIN follow-up study. Methods. 97 patients entered the follow-up study. Patients originally randomised to ramipril continued with the same daily dose (n = 51), whereas those originally on placebo plus conventional antihypertensive drugs switched to ramipril after the first visit of the follow-up study (n = 46). Ramipril (1.25 to 5.00 mg/day) and conventional antihypertensive therapy were targeted at achieving diastolic blood pressure under 90 mmHg. The main efficacy variables were GFR decline and ESRF (need for dialysis). Analysis was by intention to treat. Findings. During the follow-up study the mean rate of GFR decline per month decreased from 0.44 (SD 0.54) mL/min per 1.73 m2 in the core study to 0.10 (0.50) mL/min per 1.73 m2 in patients originally randomised to ramipril (p = 0.017), and from 0.81 (1.12) to 0.14 (0.87) mL/min per 1.73 m2 in those originally randomised to placebo plus conventional antihypertensive therapy (p = 0.017). At the final visit, mean absolute GFR values were 12 mL/min per 1.73 m2 higher (33% better) in patients randomised to ramipril than in those assigned placebo (n = 26 and 17, respectively: 35.5 [19.0] vs 23.8 [9.4] mL/min per 1.73 m2, p = 0.01). 19 of the patients originally on ramipril versus 35 switched from placebo to ramipril progressed to ESRF (p = 0.027) during the whole observation period; of these, six (8%) versus 14 (16%) reached that endpoint during the follow-up study; and the risk ratios were 1.86 (95% CI 1.07-3.26) over the whole observation period and 2.95 (1.13-7.68) during follow-up. Beyond follow-up at month 36, the incidence of ESRF was zero in patients originally randomised to ramipril but 30% in patients on placebo plus conventional antihypertensive therapy. Interpretation. In patients with chronic nephropathy and high risk of rapid progression to ESRF, ramipril reversed the tendency of GFR to decline with time. Moreover, a treatment period of sufficient duration (≤ 36 months) eliminated the need for dialysis. Even patients previously treated with antihypertensive drugs other than angiotensin-converting-enzyme inhibitors benefited from shifting to ramipril.
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