Several trials have investigated the effect of combination therapy on diabetic and nondiabet-ic proteinuria. Conclusions from these trials are limited by their small sample size and by measurement of intermediate outcomes without mortality data. The largest trial, COOPERATE, was conducted in Japan and included 336 patients with nondiabetic renal disease.7 The investigators found that significantly fewer patients receiving combination therapy reached the combined primary endpoint of time to doubling of serum creatinine or end-stage renal disease compared with patients receiving monotherapy. The CALM study included 199 patients with hypertension, micro-albuminuria, and type 2 diabetes mellitus, and demonstrated significantly greater attenuation of urinary albumin/creatinine ratio and significantly improved blood pressure control with combination therapy compared with either therapy alone.8
Another trial, ONTARGET, is being conducted to assess the impact of ACE inhibitor or ARB monotherapy and combination therapy on reducing cardiovascular risk; it includes a combined primary endpoint of morbidity and mortality. The study involves 23,400 high-risk patients and will have a follow-up period of 5.5 years. This trial enrolls patients who have coronary disease, cere-brovascular disease, peripheral vascular disease, or diabetes with end-organ damage (inclusion and exclusion criteria are based upon those used in the HOPE study).
Recommendations from others
We were unable to find to find any recommendations regarding the addition of ARB drugs to ACE inhibitors.
CLINICAL COMMENTARY
Adding ARBs to ACE inhibitors: Good in theory, but clinical evidence is still weak
David Kilgore, MD
Tacoma Family Medicine, Tacoma, Wash
There is good evidence of the benefits of angiotensin inhibition in multiple diseases, so it is logical to ask if adding receptor blockers adds further benefit. For now, it appears that the addition of an ARB to an ACE inhibitor is an idea that sounds good in theory, but needs more data to prove its clinical benefit and safety.
The clinical evidence for the combo in heart failure and hypertension is weak, since mortality data are lacking and there is the troubling association with increased mortality in the presence of beta blockers. Using the combination is not currently recommended by the major national guidelines for those areas (eg, American Heart Association, Joint National Committee VII). Although the benefit for patients with proteinuria appears promising, we still await evidence for decreasing mortality. Given cost and the combination’s uncertain benefit, it would be prudent to wait until the completion of studies currently in progress before we embrace it.