CardioExchange Archive

The enormous success of ACE inhibitors in hypertension and heart failure spurred hope that adding a second drug to block the renin-angiotensin system would yield improved outcomes. Although definitive evidence supporting dual blockade of the renin-angiotensin system has never been found, more than 200,000 patients in the U.S. currently receive this therapy. Now a large new meta-analysis suggests that dual blockade results in no improvement in mortality, but is associated with an increase in important adverse events.

In a paper published online in BMJ, Harikrishna Makani and colleagues at Columbia University and New York University performed a meta-analysis of more than 68,000 patients who were enrolled in clinical trials comparing dual blockade of the renin-angiotensin system with monotherapy. They found no significant difference between the groups for all-cause mortality or cardiovascular (CV) mortality, although dual blockade was associated with a significant 18% reduction in hospital admission for heart failure (HF):

• All-cause mortality: RR 0.97, CI 0.89-1.06
• CV mortality: RR 0.96, CI 0.88-1.05
• HF admission: RR 0.82, CI 0.74-0.92

However, any neutral or positive effect was offset by significant increases in hyperkalemia, hypotension, and renal failure. People on dual blockade were also more likely to withdraw from therapy because of adverse events:

• Hyperkalemia: RR 1.55, CI 1.32-1.82
• Hypotension: RR1.66, CI 1.38-1.98
• Renal failure: RR 1.41, CI 1.09-1.84
• Withdrawal due to adverse events: RR 1.27, CI 1.21-1.32

The authors note that nearly all the data supporting dual blockade “are based on evidence from surrogate endpoints,” showing, for instance, that dual blockade reduced proteinuria or reduced the risk of end-stage renal disease or the time to doubling of serum creatinine. The authors write:

The present data evolving from studies with dual blockade of the renin-angiotensin system should be a reminder that many purported benefits of such therapy was solely based on data using surrogate endpoints. Surrogate endpoints not uncommonly fail to emulate hard outcomes endpoints and leapfrogging from surrogate data cannot substitute for the exposure of patients in clinical outcome studies.

They conclude:

Although dual blockade of the renin-angiotensin system may have seemingly beneficial effects on certain surrogate endpoints, it failed to reduce mortality and was associated with an excessive risk of adverse events such as hyperkalaemia, hypotension, and renal failure when compared with monotherapy. The overall risk to benefit ratio argues against the use of dual therapy.