Rationale and design of a study to evaluate management of proteinuria in patients at high risk for vascular events: the IMPROVE trial

Abstract

Declining kidney function predicts increasing cardiovascular risk in people with hypertension. Microalbuminuria is a marker for cardiovascular risk and declining kidney function. Agents that block the renin-angiotensin-aldosterone system (RAAS), notably angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), reduce proteinuria and microalbuminuria, lower blood pressure and slow the progression of proteinuric kidney disease. Evidence is accumulating that the combination of an ACE inhibitor and an ARB is the optimal means of RAAS blockade in this setting, slowing the progression of nephropathy independently of blood pressure lowering to a greater degree than can be achieved using maximum approved doses of either agent alone. However, the emerging therapeutic potential of ACE inhibitor/ARB combination therapy in hypertensive kidney disease requires further characterization. The Irbesartan in the Management of PROteinuric patients at high risk for Vascular Events trial aims to determine definitively whether the combination therapy of an ARB, irbesartan and an ACE inhibitor, ramipril, is more effective than ramipril alone in reducing the urinary albumin excretion rate in patients at high cardiovascular risk with hypertension and proteinuria or microalbuminuria.

Treatment of microalbuminuria in hypertensive subjects with elevated cardiovascular risk: Results of the IMPROVE trial

“…of 0.73 used in the planning of the study. 22 Results for the two secondary, supportive analyses were consistent with the primary efficacy analysis. No earlier postrandomization data were collected for the first of these analyses and in the second, the inclusion of subjects with an AER of o20 mg/min had no significant effect on the results.…”

“…Providing similar blood pressure, control was achieved in both treatment groups; it was assumed that any difference that emerged with respect to reductions in albuminuria would likely reflect differences in the therapeutic model of RAAS blockade working independently of blood pressure control. 22 As our results show, the study failed to meet its primary end point. It is important to stress that the study had a number of limitations, not least the fact that the study ended up being underpowered-despite careful planningand that it failed to recruit patients with high levels of albuminuria.…”

Antihypertensive Combination Therapy: Optimizing Blood Pressure Control and Cardiovascular Risk Reduction

“…The combination of an ACE inhibitor and an ARB has demonstrated improvement in proteinuria and reduction in the progression to ESRD, compared with ACE inhibitor or ARB monotherapy in nondiabetic renal disease 20 . Similar studies are ongoing, using similar combinations in diabetic and nondiabetic proteinuria 27 . Other studies have shown the benefit of combination therapy on cognition with the ACE inhibitor perindopril plus the diuretic indapamide 28 .…”

Cardiac biomarkers: myths, facts and future horizons

“…All diabetics subjects should undergo screening for microalbuminuria, in order to detect the earliest signs of diabetic nephropathy [22]. There are substantial observational data regarding the association between urinary albumin excretion and increased CVD risk and mortality in people with diabetes and hypertension [22][23][24].…”