dual RAS blockade not beneficial but harmful

The question arises occasionally as to whether there is an advantage of dual blockade of the renin angiotensin system, especially in cases of patients with heart failure or severe proteinuria.  The rationale of dual blockade is that ACE inhibitors by themselves lead to incomplete and often transient RAS blockade in most patients because of a physiologic escape mechanism/alternative pathway, and the objectives of RAS blockade are to decrease cardiac remodeling, reduce endothelial dysfunction, and decrease renal dysfunction by decreasing the putative nephrotoxic effects of severe proteinuria.  Dual blockade has been mostly achieved through the combination of an ACE inhibitor and an angiotensin receptor blocker (ARB), or the combination of an ARB/ACE-I with the direct renin inhibitor aliskiren.  There was meta-analysis in the BMJ recently of 33 randomized controlled trials with 68K patients with a mean age of 61 and followed a mean of 52 weeks  (see chf dual RAS blockade bmj 2013 in dropbox or BMJ 2013;346:f360 doi: 10.1136/bmj.f360), with the major indications for the dual blockade being congestive heart failure and hypertension.  Results:
    --No overall benefit for all-cause mortality, although there was a trend to a decrease in the subgroup with heart failure but a significant 7% increase  in the subgroup without heart failure (i.e., mostly in those treated for hypertension)
    --No benefit in cardiovascular mortality
    --In the subgroup with heart failure, there was an 18% decrease in hospital admissions
    --However, dual therapy was associated with the 55% increase in the risk of hyperkalemia (defined as a potassium greater than 5.5), a 41% increase in the risk of renal failure (defined as a creatinine above 2 or a doubling of the creatinine), and a 66% increased risk of hypotension.
so, the bottom line is that dual RAS blockade seems only to help in decreasing hospitalizations in patients who have heart failure.  In terms of severe proteinuria, the COOPERATE trial did find that dual therapy led to a decrease in renal failure, spurring many of us on to advocate aggressive dual therapy in this circumstance.  However, this study was ultimately retracted and the ONTARGET study found that the combination of the ARB telmsartan and ACE-I ramipril decreased albuminuria, but led to more renal dysfunction.  So, yet again, what seemed mechanistically to be an attractive therapy (dual RAS blockade), ultimately proved not to be clinically beneficial, except perhaps in decreasing hospitalizations in patients with severe heart failure.  Although dual blockade does decreased blood pressure, I am unaware of any study showing positive clinical outcomes with this therapy and the increase in all-cause mortality in patients in this meta-analysis with dual therapy not for a heart failure indication (which is mostly in patients with hypertension) was associated with an increase in all-cause mortality

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