Drug Topics - January 14, 2008 - (Page 37) 37 Table 3 Clinical trials of ARBs in diabetic/nondiabetic kidney disease Trial RENAAL Regimens Losartan 50-100 mg, placebo Irbesartan 300 mg, amlodipine 10 mg, placebo Renal end point Doubling of baseline serum creatinine level, progression to ESRD, or death Doubling of baseline serum creatinine level, progression to ESRD, or death Results 16% risk reduction with losartan to placebo 35% reduction of proteinuria Irbesartan 20% reduction compared with placebo and 23% compared with amlodipine Reduction of proteinuria: 33%-irbesartan 10%-placebo 6%-amlodipine 39% relative risk reduction in the irbesartan groups compared with placebo Reduction of proteinuria: 38%-irbesartan 300 mg 24%-irbesartan 150 mg 2%-placebo IDNT IRMA-2 Irbesartan 150 mg, irbesartan 300 mg, placebo Onset of diabetic nephropathy nephropathy by 20% compared with placebo and 23% compared with amlodipine. The irbesartan group (300mg/day) reduced the relative risk of doubling of serum creatinine by 33% compared with placebo and 37% versus the amlodipine group (10mg/day). The relative risk of end-stage renal disease in the irbesartan group was no different than the amlodipine group or placebo. Proteinuria was significantly reduced by 33% for the irbesartan group compared with the amlodipine group (6%) and placebo group (10%). Amlodipine was associated with a 6% increase in proteinuria versus baseline. Patients in the irbesartan group had a significantly lower rate of adverse events compared with the amlodipine and placebo groups. There was no significant difference among the treatment groups in secondary cardiovascular outcomes. The most common reason for discontinuation of irbesartan and amlodipine were cardiovascular events, which were evenly distributed among the different treatment groups. The IRMA 2 trial consisted of subjects with Type 2 diabetes, persistent microalbuminuria, normal renal function, and hypertension. Some 590 subjects were randomized to irbesartan 150mg/day to 300mg/day, or placebo (conventional antihypertensive therapy – diuretics, beta-blockers, calcium channel blockers, alpha blockers, and centrally acting agonists). The irbesartan group demonstrated a 39% relative risk reduction compared with placebo for development of diabetic nephropathy. Irbesartan reduced urinary albumin excretion by 24% in the 150mg group and 38% in the 300mg group, whereas placebo reduced microalbuminuria by only 2%. Systolic BP and proteinuria reduction was significant for the 300mg irbesartan group compared with the 150mg group and placebo. BP reduction in the placebo group and irbesartan 150mg group was similar. Nonfatal adverse events and discontinuation rates were similar between the irbesartan groups and placebo. ACE inhibitor and angiotensin II receptor blocker combination therapy Blocking the activity of angiotensin II has shown to be of great importance for preserving renal function and reducing proteinuria. ACEIs inhibit the production of angiotensin II in the RAAS, but not in other pathways. ARBs bind to the AT1 receptor blocking the activity of angiotensin II. The rationale for using an ACEI and ARB concomitantly is due to a mechanism where angiotensin II and aldosterone return to pretreatment levels following chronic use of ACEIs. The theory of combination therapy for dual blockade has been studied to determine if there is a higher degree of improvement in kidney function and decrease in proteinuria. Data on the combination of ACEIs and ARBs are limited. The two studies that will be discussed are the combination treatment of angiotensin-II receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease (COOPERATE) trial and the candesartan and lisinopril microalbuminuria (CALM) study. In the COOPERATE trial, patients with nondiabetic chronic nephropathy and persistent proteinuria >0.3g/24 hours were randomly assigned to trandolapril 3mg/day, losartan 100mg/day, or a combination of both drugs. The trial was halted three years early because the effectiveness of combination therapy was already clear. There were similar BP reductions between the three treatment groups, but combination therapy demonstrated a significantly greater reduction of proteinuria. Combination therapy reduced proteinuria by 75.6% compared with trandolapril (44.3%) and losartan (42%). Time to doubling of serum creatinine or end-stage renal disease was significantly less with combination therapy than either losartan or trandolapril monotherapy. Frequency of adverse effects did not significantly differ between groups, but there was a slightly higher incidence of hyperkalemia and dry cough in the trandolapril and combination groups compared with the losartan group.
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