Combination therapy with ACE inhibitors and angiotensin II receptor blockers in chronic renal disease: New therapeutic world beyond blood pressure reduction
Authors: Naoyuki Nakao, Makoto Sakai, Akira Fujimori, Masfumi Fukagawa
Journal: Kidney International (2005)

To the Editor: We read the recent article by Wolf et al comprehensively reviewing pathophysiology and indication of combination therapy with angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers in chronic renal disease1.Wolf G. Ritz E. Combination therapy with ACE inhibitors and angiotensin II receptor blockers to halt progression of chronic renal disease: Pathophysiology and indications.Kidney Int. 2005; 67: 799-812Google Scholar. As one author of the COOPERATE study, I would like to comment on several issues quoted by them. First, because the COOPERATE study was the fixed dose-design, during a run-in period, the dose of trandolapril had been adjusted to reach a maximal reduction in proteinuria, but not in blood pressure (BP). We had noticed that the maximally licensed dose of trandolapril (up to 2 mg/day) was not sufficient to reduce proteinuria maximally, which required 3 mg daily. Therefore, we determined 3 mg of trandolapril in the core COOPERATE study2.Nakao N. Yoshimura A. Morita H. et al.Combination treatment of angiotensin-II receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease (COOPERATE): A randomised controlled trial.Lancet. 2003; 361: 117-124Google Scholar. Second, as Wolf et al speculated, 24-hour BP might be different among 3 groups. In this issue, we have recently published the results of the COOPERATE-ABP substudy3.Nakao N. Seno H. Kasuga H. et al.Effects of combination treatment with losartan and trandolapril on office and ambulatory blood pressures in non-diabetic renal disease: A COOPERATE-ABP substudy.Am J Nephrol. 2004; 24: 543-548Google Scholar. In this substudy, 92 patients enrolled in the COOPERATE trial underwent 24-hour ambulatory blood pressure (ABP) monitoring at randomization and at month 6, year 1, year 2, and year 3 on randomized treatment. Both office blood pressure (OPB) and ABP were similarly reduced among 3 groups at all measurement points and throughout the whole study period. No significant correlation between the change in 24-hour ABP and the change in proteinuria was seen. Therefore, ABPM did not seem to have any benefits over OBP. Third, the study agents were administrated 3 times a day, and the dose on each arm was gradually and carefully up-titrated Figure 1 . Therefore, it seems unlikely that a difference at the time of peak actions of the agents might be attributable to the superior antiproteinuric effect in the combination therapy. The COOPERATE-ABP substudy did not detect any difference of daily BP profile3.Nakao N. Seno H. Kasuga H. et al.Effects of combination treatment with losartan and trandolapril on office and ambulatory blood pressures in non-diabetic renal disease: A COOPERATE-ABP substudy.Am J Nephrol. 2004; 24: 543-548Google Scholar. Last, both OBP and ABP were not selected as a significant risk factor in Cox-multivariable model for renal survival2.Nakao N. Yoshimura A. Morita H. et al.Combination treatment of angiotensin-II receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease (COOPERATE): A randomised controlled trial.Lancet. 2003; 361: 117-124Google Scholar , 3.Nakao N. Seno H. Kasuga H. et al.Effects of combination treatment with losartan and trandolapril on office and ambulatory blood pressures in non-diabetic renal disease: A COOPERATE-ABP substudy.Am J Nephrol. 2004; 24: 543-548Google Scholar. In conclusion, combination therapy with ACE inhibitors and angiotensin II receptor blockers can halt progression of chronic renal disease beyond BP reduction.