Our understanding of the complexities and inter-related pathways of the renin-angiotensin-aldosterone system continues to evolve. Which drugs to use, when, and how, are everyday questions faced by clinicians in the ambulatory setting. Combining these classes, for the purpose of enhancing renin-angiotensin-aldosterone system blockade and incremental blood pressure, nephroprotective, and cardioprotective effects, logically has emerged as an area for scientific inquiry and clinical use. Despite the lack of evidence on safety and efficacy in most disease states, dual therapy has been embraced as a treatment option. Most studies of angiotensin-converting enzyme (ACE) inhibitor and angiotensin receptor blocker (ARB) combination therapy in the treatment of hypertension have limitations. In contrast, combination ACE inhibitor-ARB therapy in systolic heart failure has been addressed in several large randomized controlled trials. Until recently, there has been limited and conflicting evidence for the use of combination therapy for the prevention or management of nephropathy. Based on the new evidence, combination ACE inhibitor-ARB therapy in the treatment and management of hypertension, heart failure, and nephropathy should be limited.

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