Combination treatment of angiotensin-II receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease (COOPERATE): a randomised controlled trial.
BACKGROUND
Present angiotensin-converting-enzyme inhibitor treatment fails to prevent progression of non-diabetic renal disease. We aimed to assess the efficacy and safety of combined treatment of angiotensin-converting-enzyme inhibitor and angiotensin-II receptor blocker, and monotherapy of each drug at its maximum dose, in patients with non-diabetic renal disease.


METHODS
336 patients with non-diabetic renal disease were enrolled from one renal outpatient department in Japan. After screening and an 18-week run-in period, 263 patients were randomly assigned angiotensin-II receptor blocker (losartan, 100 mg daily), angiotensin-converting-enzyme inhibitor (trandolapril, 3 mg daily), or a combination of both drugs at equivalent doses. Survival analysis was done to compare the effects of each regimen on the combined primary endpoint of time to doubling of serum creatinine concentration or end-stage renal disease. Analysis was by intention to treat.


RESULTS
Seven patients discontinued or were otherwise lost to follow-up. Ten (11%) of 85 patients on combination treatment reached the combined primary endpoint compared with 20 (23%) of 85 on trandolapril alone (hazard ratio 0.38, 95% CI 0.18-0.63, p=0.018) and 20 (23%) of 86 on losartan alone (0.40, 0.17-0.69, p=0.016). Covariates affecting renal survival were combination treatment (hazard ratio 0.38, 95% CI 0.18-0.63, p=0.011), age (1.30, 1.03-2.29, p=0.009), baseline renal function (1.80, 1.02-2.99, p=0.021), change in daily urinary protein excretion rate (0.58, 0.24-0.88, p=0.022), use of diuretics (0.80, 0.30-0.94, p=0.043), and antiproteinuric response to trandolapril (0.81, 0.21-0.91, p=0.039). Frequency of side-effects with combination treatment was the same as with trandolapril alone.


CONCLUSIONS
Combination treatment safely retards progression of non-diabetic renal disease compared with monotherapy. However, since some patients reached the combined primary endpoint on combined treatment, further strategies for complete management of progressive non-diabetic renal disease need to be researched.
Nakao
Naoyuki
N
Division of Nephrology, Showa University Fujigaoka Hospital, Yokohama, Japan. nakao@ce.catv.ne.jp
Yoshimura
Ashio
A
Morita
Hiroyuki
H
Takada
Masyuki
M
Kayano
Tsuguo
T
Ideura
Terukuni
T
D000328:Adult; D000368:Aged; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007211:Indoles / Q000009:adverse effects / Q000627:therapeutic use*; D007674:Kidney Diseases / Q000188:drug therapy*; D007677:Kidney Function Tests; D019808:Losartan / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D007211:Indoles; C052035:trandolapril; D019808:Losartan