Dual renin-angiotensin system (RAS) blockade using ACE-inhibitor plus angiotensin-receptor blocker (ARB) has uncertain benefits and significant potential harms in chronic kidney disease (CKD), according to the authors of a Comment article in Archives of Internal Medicine. In consequence, they recommend that the combination should not be used for the average CKD patient in the community.
The authors briefly note the epidemiology of CKD and discuss the physiological rational behind dual RAS blockade in these patients. They note that its use appears to be increasing in primary care, but comment that the mechanism behind its use is still speculative. They then discuss the evidence for use, particularly the landmark COOPERATE trial that randomised patients with non-diabetic kidney disease to losartan, trandolapril, or both. While 11% of the combination group reached the study endpoint (doubled serum creatinine or ESRD) after three years, 23% of those on the individual drugs alone did so. Although the results appear impressive, a number of questions have subsequently arisen over the study that cast doubt on their robustness.
A further problem with COOPERATE and other trials of combined RAS blockade is that the patients involved mostly had primary glomerulonephropathic diseases, however in most patients with kidney failure it is consequent on diabetes or hypertension.
A meta-analysis recently examined the question: this excluded COOPERATE due to concerns over statistical reporting, however it still found a potential benefit for dual blockade. The authors of the comment note that in two of the large studies included, patients in the combination groups had lower blood pressure than those in the monotherapy groups, raising doubts over whether the effect was purely due to better blood pressure control. They also comment on issues raised by the authors of the meta-analysis – there is no robust evidence on appropriate dose escalation and limited evidence on adverse effects with the combination.
More recently, a large (n>25,000) relevant study has reported. The ON-TARGET trial compared dula blockade with monotherapy in patients with vascular risk factors. Renal outcomes were secondary (to all-cause mortality), however both primary and secondary outcomes were found to occur with combination treatment compared to monotherapy. While there are still some concerns over the results of this study, the authors suggest that it should still raise caution over use of dual RAS blockade.
They conclude that while there is no doubt over the benefits of ACE-inhibitor or ARB monotherapy in the treatment of CKD, they question the notion that dual blockade is superior. Although there is some physiological rationale, the harms may outweigh the benefits and until more efficacy and safety data are available they suggest that it should not be used by the general practitioner.
Arch Intern Med 2009; 169: 1015-8 (link to extract)