A meta-analysis 3 included 42 RCTs with 14 576 patients with diabetes. Dual renin-angiotensin-aldosterone system (RAAS) blockade therapy was associated with significant decreases in blood pressure, albuminuria, and proteinuria. However, dual therapy was not superior to monotherapy in terms of reductions in all-cause mortality, cardiovascular mortality, or progression to end-stage renal disease (ESRD). Significant increases in serum potassium and rates of hyperkalemia and hypotension were more common in patients treated with dual therapy. However, glomerular filtration rates (GFR) did not decrease significantly with dual therapy. In subgroup analysis, an angiotensin-converting enzyme inhibitor (ACEI) plus an angiotensin-receptor blocker (ARB) or a direct renin inhibitor (DRI) plus an ACEI/ARB did not significantly increase the risk of hyperkalemia, hypotension, and adverse events, and the risk of hypotension increased significantly within the normotensive subgroup but not within the hypertensive subgroup.
A meta-analysis 2 included 59 (25 crossover and 34 parallel-arm) RCTs comparing the efficacy and safety of combined vs. single RAAS blockade therapy in CKD with 4 975 patients. Combination of ACE inhibitor (ACEi) and angiotensin receptor blocker (ARB) were used in 81% of studies. Combined RAAS blockade therapy was associated with a significant net decrease in glomerular filtration rate (GFR) (-1.8ml/min or ml/min/1.73 m(2); P = 0.005), albuminuria (-90mg/g of creatinine; P = 0.001 or -32mg/day; P = 0.03), and proteinuria (-291mg/g; P = 0.003 or -363mg/day; P < 0.001). Combined RAAS blockade therapy was associated with a 9.4% higher rate of regression to normoalbuminuria and a 5% higher rate of achieving the blood pressure (BP) goal (as defined in individual trials). However, combined RAAS blockade therapy was associated with a significant net increase in serum potassium level, a 3.4% higher rate of hyperkalemia, and a 4.6% higher rate of hypotension. There was no effect on doubling of the serum creatinine level, hospitalization, or mortality.
A systematic review 4 included 9 studies with a total of 13 050 dialysis patients. Compared with single blockade, combined combined RAAS blockade significantly reduced all-cause mortality (OR 0.71, 95% CI 0.54 to 0.93, p = 0.01), while cardiovascular mortality remained unchanged (OR 0.85, 95% CI 0.45 to 1.59, p = 0.61). Combined blockade tended to increase odd of hypotension but not odd of hyperkalemia (OR 1.54, 95% CI 1.00 to 2.38, p = 0.05; OR 0.89, 95% CI 0.76 to 1.05, p = 0.17, respectively). Further mediation analysis indicated that hypotension might exert a suppression effect on the survival benefit of ACEi plus ARB treatment on cardiovascular mortality.
In the COOPERATE study 1 336 Japanese patients with non-diabetic renal disease were randomized to receive either a combination of trandolapril 3 mg/d and losartan 100 mg/d, or trandolapril alone, or losartan alone. Ten (11%) of 85 patients on combination treatment reached the combined end point of time to doubling of serum creatinine concentration or end-stage renal disease, compared to 20 (23%) of 85 on trandolapril alone (HR 0.38, 95% CI 0.18 to 0.63) or to 20 (23%) of 86 on losartan alone (HR 0.40, 95% CI 0.17 to 0.69). Frequency of side effects with combination treatment was the same as with trandolapril alone.
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