The Sudden Demise of Dual Renin-Angiotensin System Blockade or the Soft Science of the Surrogate End Point

Physicians have embraced the concept of dual renin-angiotensin system (RAS) blockade hoping that it would translate into better blood pressure control as well as incremental nephroprotective and cardioprotective effects. With regard to blood pressure, a small additional fall with dual RAS blockade was observed when compared with that seen in monotherapy. Numerous studies have shown a reduction of albuminuria with dual RAS blockade. However, the recent findings in the ONTARGET (Renal Outcomes With Telmisartan, Ramipril, or Both, in People at High Vascular Risk) study of significantly more doubling of the creatinine and dialysis in the combination arm despite lesser albuminuria emphasized the fallacy of surrogate end points and argue against nephroprotective effects of dual RAS blockade. In heart failure, dual RAS blockade was associated with more hypotension, worsening of renal function, and hyperkalemia than was angiotensin-converting enzyme inhibitor therapy alone. In conclusion, recent outcome and safety data have shattered the halo of dual RAS blockade for hypertension, nephroprotection, and heart failure. Unless data emerge to the contrary, dual RAS blockade should no longer be used in clinical practice.