The present analysis evaluating the long term efficacy and safety of dual blockade of the renin-angiotensin system failed to show any benefit for all cause mortality and cardiovascular mortality with dual therapy compared with monotherapy. This is the most comprehensive review of literature evaluating both the safety and outcomes of dual therapy. Although compared with monotherapy dual therapy was associated with a reduction in admissions to hospital for heart failure mainly in the cohort with heart failure, the risks of hyperkalaemia, hypotension, renal failure, and withdrawal owing to drug related adverse events were significantly increased. Given these facts it may appropriately be asked why dual therapy was and still is extensively used to treat many patients with hypertension and heart failure. With the exception of the CHARM Added trial,18
most if not all data making dual therapy attractive are based on evidence from surrogate endpoints.
reported “encouraging” evidence that dual therapy reduced proteinuria by an incremental 20-25% compared with monotherapy. The COOPERATE study48
even showed that dual therapy with trandolapril and losartan reduced the risk of the primary endpoint (time to doubling of serum creatinine level or end stage renal disease) by 60% better than monotherapy, thereby becoming one of the most widely quoted studies by the Lancet
After such seemingly robust evidence many physicians accepted that reduction of albuminuria or proteinuria was synonymous with nephroprotection. In the CHARM Added trial,18
in a cohort of 2548 patients with heart failure, dual blockade of the renin-angiotensin system (candesartan and ACE inhibitor) significantly reduced the primary outcome of cardiovascular death or admission to hospital for worsening of heart failure. As a consequence, dual therapy became more and more used in patients with hypertension, diabetes, and heart failure resistant to treatment.
The importance of dual therapy began to change with publication of the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET).50
Similar to other studies, in this study the surrogate endpoint albuminuria was reduced with dual therapy compared with monotherapy. However, a significant doubling of creatinine level and dialysis in the combination arm (despite less albuminuria) argued against a nephroprotection by dual therapy. More recently, authors51
found several inconsistencies in COOPERATE, eventually leading to retraction of the study by the Lancet
In heart failure, the safety issue remained a major concern with dual therapy. In the CHARM Added trial, hyperkalaemia was almost five times more common and increased creatinine levels twice as common with dual therapy than with monotherapy. A meta-analysis53
in over 18
000 patients with left ventricular dysfunction showed a significantly increased risk of adverse events of dual therapy compared with monotherapy, leading to the discontinuation of dual therapy. Given the adverse effects and lack of consistent survival benefits, the addition of an angiotensin receptor blocker to ACE inhibitor therapy in patients with heart failure should perhaps be reserved only for selected patients who continue to have symptoms while receiving monotherapy and cannot tolerate mineralocorticoid antagonists.
Several trials have shown a beneficial effect of aliskiren in combination with ACE inhibitors or angiotensin receptor blockers in patients with heart failure or diabetic nephropathy on surrogate endpoints, such as in proteinuria,41
left ventricular hypertrophy,39
and neurohormonal changes.36
Our analysis showed a significantly increased risk of hyperkalaemia with combination therapy with aliskiren compared with monotherapy. Similar results were also found in a recent meta-analysis of 10 studies with over 4800 patients.54
The ALTITUDE trial46
was terminated early because of an increased risk of adverse outcomes (stroke, hypotension, and hyperkalaemia) when aliskiren was combined with ACE inhibitors or angiotensin receptor blockers. As to the mechanism of hypotension, one author suggested that blockade of the renin-angiotensin-aldosterone system could trigger the Bezold-Jarisch reflex sensitised by withdrawal of the effect of angiotensin II.55
More extensive blockade of the renin-angiotensin system with two drugs could lead to a reduction in sympathetic outflow from the brainstem and excessive vagal tone causing prolonged hypotension and bradycardia. Conceivably this mechanism might account for the higher incidence of stroke and hypotension in patients receiving dual therapy.55
Regulatory agencies such as the Food and Drug Administration and European Medicines Agency56
recommended avoiding aliskiren in patients with diabetes or moderate to severe renal dysfunction who are already taking ACE inhibitors or angiotensin receptor blockers. Of note, the VA NEPHRON-D multicentre trial57
to assess the effect of combination of losartan and lisinopril compared with losartan alone, on the progression of kidney disease in 1850 patients with diabetes and overt proteinuria was terminated recently for similar reasons to those of ALTITUDE.
The present data evolving from studies with dual blockade of the renin-angiotensin system should be a reminder hat 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.
Strengths and limitations of this meta-analysis
Our paper had several limitations. As with other meta-analyses, given the lack of data in each trial, we did not adjust our analysis for adherence to therapy. Also, the results are subject to limitations inherent to any meta-analysis based on pooling of data from different trials with different duration, doses of drugs, definitions for safety outcomes, and patient groups. Analysis of safety events is also prone to several biases since the data vary in each study for quality, incidence, severity, and adjudication. The reporting may also be influenced by expectations of the investigators, sponsors, and patients. Despite all the limitations, this is the most comprehensive analysis evaluating the safety and efficacy of dual blockade of the renin-angiotensin system. Despite significant heterogeneity among the studies, there was no evidence of publication bias visually and by Egger’s test. The results were fairly consistent among various subgroups.
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.
What is already known on this topic
- Dual blockade of the renin-angiotensin system (RAS) is extensively used for treatment of resistant forms of heart failure, hypertension, diabetic nephropathy, and proteinuria
- The efficacy and safety of dual RAS blockade, however, remains controversial
What this study adds
- Although dual RAS blockade reduced admissions to hospital for heart failure (mainly in patients with heart failure), it had no effect on all cause or cardiovascular mortality
- Compared with monotherapy, dual therapy was associated with a significant increase in adverse events such as hyperkalaemia, hypotension, and renal failure
- These considerations of risk-benefit argue against the routine use of dual therapy