- Email: [email protected]
The COOPERATE trial
CORRESPONDENCE
COMMENTARY
CORRESPONDENCE e-mail submissions to [email protected]
The COOPERATE trial Sir—Naoyuki Nakao and colleagues (Jan 11, p 117)1 suggest that, for patients with non-diabetic renal disease, combination treatment with 3 mg trandolapril and 100 mg losartan is better than monotherapy with regard to the combined primary endpoint of time to doubling of serum creatinine or end-stage renal disease. However, this assumption rests on a small number of absolute events (10 vs 20), and some questions that could affect the main message of the trial remain so far unanswered. The dose of trandolapril does not seem to be the maximum. The recommended maximum daily dose of trandolapril in most countries is 4–8 mg. In the TRACE study,2 in patients with left-ventricular dysfunction after myocardial infarction, a target dose of 4 mg per day was used. Therefore it would have been of interest to use 6 mg of trandolapril (and 200 mg of losartan) in this longterm trial in comparison with 3 mg of trandolapril and 100 mg of losartan. Alternatively, a combination treatment with 1·5 mg of trandolapril and 50 mg of losartan could have been used. The extent of blinding in this “double-blind” trial is unclear. Unblinded comparisons could introduce bias, for example in the time of implementation of dialysis. What were the reasons for starting dialysis in the three and seven patients in the monotherapy groups and the one patient in the combination therapy group? What happened to the renal function of patients who were lost to follow-up? In an intention-to-treat analysis, these patients would need to be counted as if they had reached an endpoint. What are the results of such an analysis? The authors alluded to a group of about 13% who were low responders to trandolapril. However, no detailed results of this subgroup have been given. What was the proportion of patients reaching an endpoint, and what was the proteinuria response to treatment during this long-term trial? Bernd Krüger, Carsten Böger, Mike Stubanus, Michael Fischereder, *Bernhard K Krämer
1054
Klinik und Poliklinik für Innere Medizin II— Nephrologie, University of Regensburg, 93042 Regensburg, Germany (e-mail: [email protected]) 1
2
Nakao N, Yoshimura A, Morita H, Takada M, Kayano T, Ideura T. Combination treatment of angiotensin-II receptor blocker and angiotensinconverting-enzyme inhibitor in non-diabetic renal disease (COOPERATE): a randomised controlled trial. Lancet 2003; 361: 117–24. Published online Dec 17, 2002. http://image.thelancet.com/ extras01art11215web.pdf. Køber L, Torp-Pedersen C, Carlsen JE, et al. A clinical trial of the angiotensinconverting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 1995; 333: 1670–76.
Sir—The results of the COOPERATE study1 show that the combination of a maximum dose of trandolapril and losartan was more effective than the maximum dose of each drug alone in retarding serum creatinine doubling in patients with moderate renal failure. This renoprotective effect was independent of blood pressure control, even though the proteinuria reduction decreased gradually over time only in the trandolapril group. Although comparable restriction of salt and protein was advised and monitored in all patients, urinary excretion of sodium and urea were not reported. It would be interesting to have these data to confirm that renal protection was also independent of salt and protein intake—variables known to increase proteinuria and therefore to accelerate progression of renal failure2,3 in some patients. Additional use of diuretics has been shown to independently slow the progression of renal failure by 20%. Diuretics have long been known to initially reduce glomerular filtration rate (GFR) and proteinuria, but they can also prevent long-term decline in GFR to the same extent as angiotensin-converting-enzyme (ACE) inhibitors.4 Conversely, calcium antagonists can transiently improve GFR (in relation to the afferent arterial vasodilatation), but in patients with proteinuria, they are not as protective as ACE inhibitors
in the long term in diabetic and nondiabetic patients with moderate renal failure.5 We would be interested to know the proportion and dose of these two drugs used in each group. Since the incidence of hyperkalaemia was 8·5% in the combination and trandolapril groups, and since the use of diuretics potentiates the protective effect of ACE inhibitors combined with angiotensin-II-receptor blockade, we suggest that the preferred drug to give with the combination of ACE inhibitor and angiotensin-II-receptor blocker would have been a diuretic rather than a dihydropyridine. Since most patients had IgA nephropathy, the superiority of ACE inhibition plus angiotensin-II-receptor blockade cannot be extrapolated to non-proteinuric nephropathies such as nephroangiosclerosis with proteinuria less than 300 mg, in which ramipril has not been shown to be better than amlodipine in preventing progression of renal failure. Claire Presne, Janette Mansour, Raïfah Makdassi, Gabriel Choukroun, *Albert Fournier Nephrology Department, CHU Amiens, 80084 Amiens Cedex 1, France (e-mail: [email protected]) 1
2
3
4
5
Nakao N, Yoshimura A, Morita H, Takada M, Kayano T, Ideura T. Combination treatment of angiotensin II receptor blocker and angiotensinconverting-enzyme inhibitor in non-diabetic renal disease (COOPERATE): a randomised controlled trial. Lancet 2003; 361: 117–24. Published online Dec 17, 2002. http://image.thelancet. com/extras/01art1125web.pdf. Gansevoort RT, de Zeeuw D, de Jong PE. Long-term benefits of the antiproteinuric effect of angiotensin-converting enzyme inhibition in nondiabetic renal disease. Am J Kidney Dis 1993; 22: 202–06. Gansevoort RT, de Zeeuw D, de Jong PE. Additive antiproteinuric effect of ACE inhibition and a low-protein diet in human renal disease. Nephrol Dial Transplant 1995; 10: 497–504. Walker W, Hermann J, Anderson J. Randomized double blinded trial of enalapril versus hydrochlorothiazide on GFR in diabetic nephropathy. Hypertension 1993; 22: 410 (abstr). Agodoa LY, Appel L, Bakris GL, et al. Effect of ramipril vs amlodipine on renal outcomes in hypertensive nephrosclerosis: a randomized controlled trial. JAMA 2001; 285: 2719–28.
THE LANCET • Vol 361 • March 22, 2003 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.
COMMENTARY
CORRESPONDENCE e-mail submissions to [email protected]
The COOPERATE trial Sir—Naoyuki Nakao and colleagues (Jan 11, p 117)1 suggest that, for patients with non-diabetic renal disease, combination treatment with 3 mg trandolapril and 100 mg losartan is better than monotherapy with regard to the combined primary endpoint of time to doubling of serum creatinine or end-stage renal disease. However, this assumption rests on a small number of absolute events (10 vs 20), and some questions that could affect the main message of the trial remain so far unanswered. The dose of trandolapril does not seem to be the maximum. The recommended maximum daily dose of trandolapril in most countries is 4–8 mg. In the TRACE study,2 in patients with left-ventricular dysfunction after myocardial infarction, a target dose of 4 mg per day was used. Therefore it would have been of interest to use 6 mg of trandolapril (and 200 mg of losartan) in this longterm trial in comparison with 3 mg of trandolapril and 100 mg of losartan. Alternatively, a combination treatment with 1·5 mg of trandolapril and 50 mg of losartan could have been used. The extent of blinding in this “double-blind” trial is unclear. Unblinded comparisons could introduce bias, for example in the time of implementation of dialysis. What were the reasons for starting dialysis in the three and seven patients in the monotherapy groups and the one patient in the combination therapy group? What happened to the renal function of patients who were lost to follow-up? In an intention-to-treat analysis, these patients would need to be counted as if they had reached an endpoint. What are the results of such an analysis? The authors alluded to a group of about 13% who were low responders to trandolapril. However, no detailed results of this subgroup have been given. What was the proportion of patients reaching an endpoint, and what was the proteinuria response to treatment during this long-term trial? Bernd Krüger, Carsten Böger, Mike Stubanus, Michael Fischereder, *Bernhard K Krämer
1054
Klinik und Poliklinik für Innere Medizin II— Nephrologie, University of Regensburg, 93042 Regensburg, Germany (e-mail: [email protected]) 1
2
Nakao N, Yoshimura A, Morita H, Takada M, Kayano T, Ideura T. Combination treatment of angiotensin-II receptor blocker and angiotensinconverting-enzyme inhibitor in non-diabetic renal disease (COOPERATE): a randomised controlled trial. Lancet 2003; 361: 117–24. Published online Dec 17, 2002. http://image.thelancet.com/ extras01art11215web.pdf. Køber L, Torp-Pedersen C, Carlsen JE, et al. A clinical trial of the angiotensinconverting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 1995; 333: 1670–76.
Sir—The results of the COOPERATE study1 show that the combination of a maximum dose of trandolapril and losartan was more effective than the maximum dose of each drug alone in retarding serum creatinine doubling in patients with moderate renal failure. This renoprotective effect was independent of blood pressure control, even though the proteinuria reduction decreased gradually over time only in the trandolapril group. Although comparable restriction of salt and protein was advised and monitored in all patients, urinary excretion of sodium and urea were not reported. It would be interesting to have these data to confirm that renal protection was also independent of salt and protein intake—variables known to increase proteinuria and therefore to accelerate progression of renal failure2,3 in some patients. Additional use of diuretics has been shown to independently slow the progression of renal failure by 20%. Diuretics have long been known to initially reduce glomerular filtration rate (GFR) and proteinuria, but they can also prevent long-term decline in GFR to the same extent as angiotensin-converting-enzyme (ACE) inhibitors.4 Conversely, calcium antagonists can transiently improve GFR (in relation to the afferent arterial vasodilatation), but in patients with proteinuria, they are not as protective as ACE inhibitors
in the long term in diabetic and nondiabetic patients with moderate renal failure.5 We would be interested to know the proportion and dose of these two drugs used in each group. Since the incidence of hyperkalaemia was 8·5% in the combination and trandolapril groups, and since the use of diuretics potentiates the protective effect of ACE inhibitors combined with angiotensin-II-receptor blockade, we suggest that the preferred drug to give with the combination of ACE inhibitor and angiotensin-II-receptor blocker would have been a diuretic rather than a dihydropyridine. Since most patients had IgA nephropathy, the superiority of ACE inhibition plus angiotensin-II-receptor blockade cannot be extrapolated to non-proteinuric nephropathies such as nephroangiosclerosis with proteinuria less than 300 mg, in which ramipril has not been shown to be better than amlodipine in preventing progression of renal failure. Claire Presne, Janette Mansour, Raïfah Makdassi, Gabriel Choukroun, *Albert Fournier Nephrology Department, CHU Amiens, 80084 Amiens Cedex 1, France (e-mail: [email protected]) 1
2
3
4
5
Nakao N, Yoshimura A, Morita H, Takada M, Kayano T, Ideura T. Combination treatment of angiotensin II receptor blocker and angiotensinconverting-enzyme inhibitor in non-diabetic renal disease (COOPERATE): a randomised controlled trial. Lancet 2003; 361: 117–24. Published online Dec 17, 2002. http://image.thelancet. com/extras/01art1125web.pdf. Gansevoort RT, de Zeeuw D, de Jong PE. Long-term benefits of the antiproteinuric effect of angiotensin-converting enzyme inhibition in nondiabetic renal disease. Am J Kidney Dis 1993; 22: 202–06. Gansevoort RT, de Zeeuw D, de Jong PE. Additive antiproteinuric effect of ACE inhibition and a low-protein diet in human renal disease. Nephrol Dial Transplant 1995; 10: 497–504. Walker W, Hermann J, Anderson J. Randomized double blinded trial of enalapril versus hydrochlorothiazide on GFR in diabetic nephropathy. Hypertension 1993; 22: 410 (abstr). Agodoa LY, Appel L, Bakris GL, et al. Effect of ramipril vs amlodipine on renal outcomes in hypertensive nephrosclerosis: a randomized controlled trial. JAMA 2001; 285: 2719–28.
THE LANCET • Vol 361 • March 22, 2003 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.