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Combination treatment of angiotensin-II receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease (COOPERATE): a randomised controlled trial
Naoyuki Nakao, Ashio Yoshimura, Hiroyuki Morita, Masyuki Takada, Tsuguo Kayano, Terukuni Ideura
Introduction
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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 endstage renal disease. Analysis was by intention to treat.
According to the 2000 annual data report of the Japanese Society for Dialysis Therapy, more than 206 000 individuals are on renal replacement treatment (about 0·2% of the Japanese population).1 The number of patients newly treated for end-stage renal disease was 32 018, whereas 18 938 dialysis patients died, mostly due to cardiovascular events. In the past decade, the number of patients with end-stage renal disease rose at a constant rate of 7% per year. The annual cost of dialysis and other treatments exceeds US$10 billion (5·2% of the national health-care budget). Although diabetic renal disease became a leading cause of end-stage renal disease in 1998 (36·6%), non-diabetic renal disease remains the major underlying cause of this disorder—32·5% chronic glomerulonephritis, 7·6% nephrosclerosis, and 2·4% polycystic kidney disease. Thus, halting of progression of non-diabetic renal disease is an essential goal for patients and society. Presently, no treatment guidelines for nondiabetic renal disease are available. Much experimental and clinical evidence has been published that suggests the renin-angiotensin-aldosterone system (RAAS) has an important role in progression of non-diabetic disease.2–7 Results of meta-analyses agree that angiotensin-converting-enzyme inhibitors are more effective than conventional antihypertensive drugs at delaying of progression of non-diabetic renal disease.8–10 For example, Jafar and colleagues9 pooled a large amount of data for non-diabetic patients from 11 randomised controlled trials and calculated the relative risk of progression of the disease in those treated with angiotensin-converting-enzyme inhibitors (0·70, 95% CI 0·55–0·88). The researchers concluded that these drugs should be the antihypertensive treatment of choice in nondiabetic renal disease. Data from survival curves, however, showed that about 20% of patients treated with angiotensin-converting-enzyme inhibitors reached combined endpoints (doubling of baseline serum creatinine concentration or end-stage renal disease) by year 3 of intervention. Results of the REIN stratum 2 long-term follow-up study4 showed that no more events (progression to endstage renal disease) arose in patients treated with angiotensin-converting-enzyme inhibitors than in those with advanced renal failure and heavy proteinuria after 36 months of treatment with ramipril. The same authors have reported that this occurrence could arise in patients with daily baseline proteinuria of less than 3 g, after 48 months’ follow-up.5 These findings suggest that patients who survive the initial periods of treatment with angiotensin-converting-enzyme inhibitors have almost total remission of chronic renal disease. Therefore, to improve management of non-diabetic patients with progressive renal disease, possible strategies should include attempts to reduce the number of patients failing to survive during the initial period of the intervention.
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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.
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Summary
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Findings 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 sideeffects with combination treatment was the same as with trandolapril alone.
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Interpretation 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 nondiabetic renal disease need to be researched.
Lancet 2003; 361: 117–24. Published online Dec 17, 2002 http://image.thelancet.com/extras/01art11215web.pdf
Division of Nephrology, Showa University Fujigaoka Hospital, Yokohama, Japan (Prof T Ideura MD, A Yoshimura MD, H Morita MD, N Nakao MD); and Division of Nephrology, Gen Gen-Do Kimitsu Hospital, Kimitsu (M Takada MD, T Kayano MD) Correspondence to: Dr Naoyuki Nakao, Division of Nephrology, Showa University, Fujigaoka Hospital, 1-30 Fujigaoka, Aoba-Ku, Yokohama 227-8501, Japan (e-mail:
[email protected])
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Patients and methods
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Procedures Of 336 eligible patients, 35 were excluded (ten needed dialysis immediately and 25 were unwilling to participate). The remaining 301 patients entered a single-blind 18 weeks’ run-in period, during which time we ascertained the maximum dose of trandolapril. Participants were not told which drug and what dose they were given. We measured change in daily urinary protein excretion as a marker of the amount of renoprotection obtained from trandolapril. Any antihypertensive drugs, including angiotensin-converting-enzyme inhibitors, were discontinued for 3 weeks. We then asked the participants to take 0·5 mg trandolapril daily. This dose was increased by 1 mg every 3 weeks, up to a final dose of 6 mg per day. We measured daily proteinuria excretion three times consecutively, at the end of each 3-week period. We noted that once the dose had reached 3 mg per day, renoprotection reached its plateau, with a mean percentage change in daily excretion of urinary protein of –44·7% (95% CI –21·4 to –54·2). Thus, 3 mg of trandolapril was chosen as the maximum renoprotective dose for our study. We also recorded during this prerandomisation period that some patients did not respond adequately to trandolapril (defined as low responders). Change in daily urinary protein excretion in these patients was –3% to –7%, compared with the remaining responsive patients, with a mean percentage change of –44·7% (95% CI –21·4 to –54·2%). These findings prompted us to classify participants in our trial—with –7% as a cut-off— for restricted randomisation and statistical analysis. Since losartan was not commercially available in Japan during the run-in period, 100 mg was estimated to be the maximum dose needed for organ protection, on the basis of other work.16 During this run-in period, safety and adherence were repeatedly assessed to identify patients with adverse reactions to angiotensin-converting-enzyme inhibitors. After this run-in period, angiotensin-converting-enzyme inhibitors were discontinued for 3 weeks. Thereafter, to keep the effect of baseline blood pressure on surrogate markers and primary endpoints to a minimum, we intensively reduced blood pressure levels to less than 130/80 mm Hg, with many antihypertensive drugs, excluding angiotensin-converting-enzyme inhibitors and angiotensin-II receptor blockers. These drugs included long-acting dihydropyridine calcium-channel blockers, diuretics, alpha 1-blockers, and centrally acting drugs. To confirm the underlying renal disease, we did renal biopsy. Any polymorphism in the angiotensin-converting enzyme (ACE) gene was also established in all patients (Special Research Laboratory, Tokyo, Japan). All patients were requested to restrict sodium intake to below 5–7 g daily and to eat 0·5–0·7 g protein per kg of bodyweight daily. We assessed dietary adherence by measurement of daily urinary urea and sodium excretion. Nutritionists, without knowledge of the process of this trial, periodically gave nutritional advice, especially about foods rich in potassium. Patients were stratified by three variables that could affect renal outcome: baseline renal function rate (less than or equal to or more than a calculated glomerular
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Patients We did a double-blind, randomised clinical trial at the Gen Gen-Do Kimitsu Hospital outpatient renal department, the catchment area of which was three cities near Tokyo—Kisarazu, Kimitsu, and Futtsu in Chiba Prefecture; the total population of these three cities was 266 903 in 1999. Because no other kidney-disease care providers are available in this area, we had the chance to investigate a typical cohort of renal diseases. Between July 1996, and May, 1998, consecutive renal patients, all Japanese, were screened with inclusion and exclusion criteria. Most of these patients were referred to the renal department by their family doctors requesting further management of the renal disease (median concentration of serum creatinine at referral was 186 mol/L). Inclusion criteria were: age 18–70 years; chronic nephropathy, as defined by a serum creatinine concentration of 133–398 mol/L (normal range 44–150 mol/L) or calculated glomerular filtration rate of 20–70 mL/min per 1·73 m2 (normal range 90–130 mL/min per 1·73 m2), with variation of less than 30% during at least three consecutive measurements;15 non-diabetic renal disease, as established by history, physical examination, urinalysis, serum biochemistry tests, and renal biopsy (in most patients); persistent proteinuria, as defined by urinary protein excretion exceeding 0·3 g per 24 h (normal range 0–0·06 g/24 h), for a minimum of 3 months after the first consultation, without evidence of urinary-tract infection or overt heart failure (New York Heart Association [NYHA] class III–IV); and no history of allergic reaction to drugs, especially angiotensin-converting-enzyme inhibitors. Exclusion criteria were: immediate need for renal replacement therapy; treatment-resistant oedema; need for treatment with corticosteroids, non-steroidal antiinflammatory drugs, or immunosuppressive drugs; proteinuria greater than 10 g per day and hypoalbuminaemia less than 28 g/L (normal range 36–50 g/L); renovascular hypertension; malignant hypertension, myocardial infarction, or cerebrovascular accident in the year preceding the trial; severe peripheral vascular disease;
severe congestive heart failure (NYHA III–IV); chronic hepatic disease (rise of serum aminotransferase concentration); connective-tissue disease; obstructive uropathy; cancer; chronic pulmonary disease; drug or alcohol misuse; pregnancy; and breastfeeding. Gen Gen-Do ethics committees approved the protocol, and every eligible patient gave informed written consent.
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Despite administration of the maximum dose of angiotensin-converting-enzyme inhibitors, reduction of proteinuria is highly variable between individuals, which can lead to different outcomes.11 Even patients initially benefiting from the renoprotective properties of these drugs can deteriorate suddenly after a period of several years, with impairment in renal function.12 These findings suggest that monotherapy with angiotensin-convertingenzyme inhibitors is insufficient for complete inhibition of the RAAS, which would prevent or halt progression of non-diabetic renal disease. Therefore, other pharmacological or non-pharmacological interventions should be combined with this regimen.11 We postulated that complete inhibition of the RAAS would be most beneficial in management of progressive non-diabetic renal disease, and might be achieved by dual blockage with angiotensin-II receptor blockers and angiotensin-converting-enzyme inhibitors. To prove this hypothesis, we aimed to compare the efficacy of three treatments—monotherapy with an angiotensin-II receptor blocker (losartan), monotherapy with an angiotensinconverting-enzyme inhibitor (trandolapril), and the combination of these drugs—on renal survival. Losartan and trandolapril have been reported to have renoprotective effects beyond those explained by their antihypertensive effects.13,14
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filtration rate of 45 mL/min per 1·73 m2); baseline half-dose of a calcium-channel blocker and to measure proteinuria excretion (
