I gave a lecture at a nephrology conference recently on angiotensin blockade in kidney protection. At the beginning of the talk I posed the question: how many people in the audience use dual blockade, that is, both an ACE inhibitor and an angiotensin receptor blocker (ARB). Nearly 50% of the audience raised their hand. I then went on to present the COOPERATE study that had been pubished by Nakao and co-workers in the Lancet in 2003.
As I discussed the paper, I invited people in the audience to come up to the microphone and comment on the paper – “findings too good to be true”, “dual blockade doesn’t work” were some of the remarks. Interestingly, no-one mentioned the fact that the paper had been retracted by the Lancet because of mistakes or perhaps pure fabrication (as suggested by Kunz et al and others). Stuart Linas had a nice review in CJASN that reviews the evidence on dual blockade (combination therapy).
The most influential study on dual blockade is the ONTARGET study published in 2008 in NEJM. It showed increased risk with dual blockade. Briefly, ONTARGET recruited 25,620 patients with either pre-existing vascular disease or diabetes and randomly assigned patients to either ramipril, telmisartan, or the combination of ramipril and telmisartan. Patients were followed for 4.5 years. The primary outcome was a composite of CV death, MI, stroke, or hospitalized CHF. There were multiple secondary endpoints.
The key findings of ONTARGET are as follows:
- No hint of benefit for any endpoint with combination therapy
- Trend toward increased risk of death, 1.07 (0.98-1.16), with combination therapy
- Many more adverse events with combination therapy
In 2011, there was a secondary analysis of ONTARGET published in Circulation. The analysis comprised of 5623 patients with eGFR<60 and/or proteinuria
- Combination therapy reduced proteinuria to a greater degree than monotherapy
- Combination therapy significantly increased the incidence of ESRD or doubling of Scr (0.79 vs. 0.56 % per year)
- Combination therapy significantly increased the incidence of ESRD (2.7 vs. 1.6 % per year) among patients with both eGFR<60 and proteinuria
Why should there be increased risk with dual blockade? Non-one really knows.
What should one do? For starters, avoid dual blockade because it is unclear that it works and there appears to be increased risk.