Dual blockade of the renin–angiotensin system compared with a 50% increase in the dose of angiotensin-converting enzyme inhibitor: effects on proteinuria and blood pressure

Priscilla Kincaid-Smith1,2, Kenneth F. Fairley1 and David Packham1

1 Epworth Hospital, Richmond, Victoria and 2 University of Melbourne, Parkville, Australia

Correspondence and offprint requests to: Priscilla Kincaid-Smith, Epworth Hospital, Richmond, Victoria, Australia. Email: priscillk{at}epworth.org.au



   Abstract
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Several publications in the past 2 years have demonstrated that combined angiotensin-converting enzyme inhibitors (ACEI) and angiotensin-II receptor antagonist (AIIRA) are more effective in reducing blood pressure and proteinuria in patients with chronic renal disease than ACEI or AIIRA alone. This study compares the effect of increasing the ACEI dose by 50% with that of adding an AIIRA to a standard ACEI dose.

Methods. This study was designed as part of a previous comparison of ACEI with ACEI plus candesartan. Directly after completion of the randomized intervention periods of that study, the dose of ACEI was increased by 50% in all patients. Proteinuria and blood pressure were compared in both groups of patients in the three periods, on standard ACEI, on ACEI plus candesartan and on a dose of ACEI increased by 50%.

Results. No significant differences in the primary end-point proteinuria or secondary end-points were observed when the ACEI dose was increased by 50%. Proteinuria was 1.8 g in 24 h on candesartan and ACEI and 2.4 g in 24 h when the ACEI dose was increased by 50% (P<0.02). Systolic blood pressure was 126.6 mmHg on candesartan and ACEI and 134.47 mmHg when the ACEI dose was increased by 50% (P<0.002). Diastolic blood pressure, serum creatinine, urea and potassium were not different between groups.

Conclusions. Standard ACEI plus candesartan is more effective in reducing systolic blood pressure and proteinuria than a 50% increase in ACEI dose. This has implications for the prevention of renal failure in chronic renal disease.

Keywords: angiotensin-converting enzyme inhibitors; angiotensin-II receptor antagonists; hypertension; proteinuria



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
We previously reported [1] a randomized controlled trial in which addition of candesartan to angiotensin-converting enzyme inhibitor (ACEI) treatment in 60 patients with chronic renal disease reduced proteinuria and systolic and diastolic blood pressure. The protocol for the randomized study included a final 3 month intervention period in which the ACEI dose was increased by 50% in all patients. We compared the effect of this increase in ACEI dose with the previous period on standard ACEI treatment and with the period when candesartan was added to standard ACEI treatment. As reducing proteinuria and blood pressure slow progression in chronic renal disease, it seemed important to determine whether in clinical practice increasing the dose of ACEI by 50% or adding an AIIRA antagonist achieved a greater reduction in these parameters in chronic renal disease.



   Subjects and methods
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
This was an observational study comparing three 3 month periods: one on standard dose ACEI, one on a 50% increased dose of ACEI and one on a standard dose ACEI plus candesartan (Figure 1). Of the 58 subjects who completed the initial crossover trial, 54 completed this further 3 month period on the 50% higher ACEI dose. Three patients required dialysis and one died of a myocardial infarction.



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Fig. 1. In the study design, patients were randomized to two treatment sequences. Thirty patients were randomized to the two groups and crossed over after 3 months. In the final 3 month intervention period, the dose of ACEI was increased by 50% in all patients. Only 54 were available for the third 3 month period, because two were lost to follow-up, one died of myocardial infarction and three required dialysis.

 
As reported in the previous publication [1], a diagnosis of chronic renal disease was based on specific features on a renal biopsy or radiology in the initial 60 patients and baseline characteristics were similar in the two randomized intervention groups.

The ACEI dose that the patients were receiving at entry to the trial was considered to be the appropriate dose for blood pressure control (Table 1). In patients with normal blood pressures where ACEI was given to reduce proteinuria, doses were lower to avoid postural hypotension.


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Table 1. Daily dose of ACEI in 60 patients

 
The primary end-point of the study was urine protein excretion, which was measured every 2 weeks. Secondary end-points included systolic and diastolic blood pressure measured at the beginning and end of each intervention period. Serum urea, creatinine and potassium were also measured at these times. In the analysis, two comparisons were made between the values 3 months after the higher dose of ACEI: firstly, between the values after 3 months on standard ACEI and candesartan and, secondly, between the values after 3 months on the standard dose of ACEI.

The average 24 h urine protein, blood pressure, urea, creatinine and potassium measurements were compared using a paired t-test or a non-parametric equivalent. There were no defined stopping rules.

Ethical approval was granted by the Research and Ethics Committee at Epworth Hospital.



   Results
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Of the original 58 patients, 54 patients were included in this observational study.

There was no significant difference in the primary end-point of proteinuria or in any of the secondary end-points when standard ACEI treatment was compared with the period when ACEI dose was increased by 50% (P>0.3; Table 2).


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Table 2. Primary and secondary end-points during standard ACEI therapy on a 50% increased dose of ACEI and on ACEI plus candesartan

 
When the period on ACEI with candesartan was compared with a period on 50% increase in ACEI dose, there were significant differences in proteinuria and in systolic blood pressure. Proteinuria was 1.8 g/24 h on candesartan together with ACEI and 2.4 g/24 h when the ACEI dose was increased by 50%. This gave a difference of 0.57 g/24 h [95% confidence interval (CI): 0.1–1.0; P<0.02]. Urine protein levels varied considerably, but there was a tendency to fall slowly over the 3 month period without reaching a steady level on any regimen. Systolic blood pressure was 126.7 mmHg on candesartan plus ACEI and 134.47 mmHg when ACEI dose had been increased by 50%. This gave a difference of 7.6 mmHg (CI: 3.1–12.2; P<0.002). Diastolic blood pressure, serum creatinine, urea and potassium did not show significant differences between the groups.

Only one patient showed side effects requiring cessation of treatment. This was a cough, which developed when the ramipril was increased from 10 to 15 mg daily.



   Discussion
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
At the time that this study was planned there was no information as to whether combined ACEI and AIIRA reduced blood pressure and proteinuria more than ACEI alone and no information about the effect of increasing ACEI doses above ‘recommended’ maximum doses. We chose a 50% increase in ACEI rather than double the dose because of the private practice setting of the study.

Our study showed that no reduction in proteinuria or blood pressure occurred when the standard ACEI dose was increased by 50%. In contrast, we saw a rise in both proteinuria and systolic blood pressure when candesartan was ceased and the ACEI dose was increased by 50%. These results provide further support for the efficacy of combined ACEI and AIIRA and indicate that little gain can be expected from increasing the ACEI dose by 50% in patients receiving the doses listed in Table 1.

We have not been able to find another study that makes the comparison between the effects of increasing the dose of ACEI by 50% and adding AIIRA in a group of patients with chronic renal disease. In the run-in period in the COOPERATE study [2], doubling the dose of trandolapril from 3 to 6 mg for a short period did not reduce urine protein. Laverman et al. [3] found a variable relationship between reduction of proteinuria by both losartan and lisinopril in different subjects. They divided their subjects into three groups on the basis of different responses. Dual therapy achieved a significant additional reduction in proteinuria. In diabetic nephropathy [4], dual blockade of the renin–angiotensin syndrome proved superior to a maximum dose of ACEI.

We used proteinuria as a surrogate marker of progression as it is the best independent predictor of progression in non-diabetic renal disease [5]. We predicted that combined ACEI and AIIRA would slow progression on the basis of the reduction in proteinuria and blood pressure that we observed [1]. This has now been tested in the COOPERATE study [2], a double blind randomized trial in 263 patients with chronic renal disease, which demonstrated that whereas only 11% of patients on combined ACEI and AIIRA reached the end-points of doubling of the serum creatinine or end-stage renal failure in 3 years, 23% of those on either monotherapy reached these primary end-points in 3 years (P<0.02).

Our study has limitations. Because of the private practice setting and restriction of consultations to the usual intervals, we were unable to change drugs or doses of ACEI or assess optimal doses. In spite of this, in keeping with our policy most patients (45) were on maximum doses of ACEI. A further limitation was the lack of washout periods between the three intervention periods in Figure 1. This would have required extra visits and incurred additional costs.

One important aspect of our study is that it was conducted as part of routine management of patients in private practice and our results on safety and efficacy are therefore applicable to management in this context. The only funding required for this study was payment for additional urine protein tests, which would not normally have been performed as part of routine management.



   Acknowledgments
 
This study was designed and carried out by the three authors. Hoechst Division of Aventis and AstraZeneca Pharmaceuticals provided the ramipril and the candesartan tablets used in this study and paid for the additional urine protein studies. Professor C.K. Fairley provided valuable advice about the design and analysis of the study and Mrs Noel Wyres collated the data for analysis.

Conflict of interest statement. None declared.



   References
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

  1. Kincaid-Smith P, Fairley K, Packham D. Randomized controlled crossover study of effect on proteinuria and blood pressure of adding an angiotensin II receptor antagonist to an angiotensin converting enzyme inhibitor in normotensive patients with chronic renal disease and proteinuria. Nephrol Dial Transplant 2002; 17: 597–661[Abstract/Free Full Text]
  2. Nakao N, Yoshimura A, A H Morita 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: 117–124[CrossRef][ISI][Medline]
  3. Laverman GD, Navis G, Henning R, de Jong P, deZeeu D. Dual renin–angiotensin system blockade at optimal doses for proteinuria. Kidney Int 2002; 62: 1020–1025[CrossRef][ISI][Medline]
  4. Jacobsen P, Andersen S, Rossing K, Jensen B, Parving H-H. Dual blockade of renin–angiotensin system versus maximal recommended dose of ace inhibition in diabetic nephropathy. Kidney Int 2003; 63: 1874–1880[CrossRef][ISI][Medline]
  5. Ruggenenti P, Perua A, Mosconi L, Pisone R, Remuzzi G. Urinary protein excretion rate is the best predictor of ESRF in non-diabetic chronic nephropathies. Kidney Int 1998; 53: 1209–1216[CrossRef][ISI][Medline]
Received for publication: 16. 2.04
Accepted in revised form: 2. 6.04