An Issue of Dependence: Implications From the Aliskiren in the Evaluation of Proteinuria in Diabetes (AVOID) Trial

T he direct renin inhibitor aliskiren is a new antihypertensive agent that appears to be equivalent to other agents in blood pressure reduction.It is well tolerated, has a long half-life, and has a sustained duration of action.At present, aliskiren as monotherapy is not widely used despite these potential benefits.There are many other available options for the treatment of hypertension with demonstrated morbidity and mortality outcomes and economic advantages.The role of aliskiren as part of combination therapy is, however, evolving.Two-or three-drug therapy is necessary for many hypertensive patients, and rational combinations to maximize blood pressure control and influence comorbid conditions should continue to be identified.The characteristics of aliskiren and the broader application of this new class of medications will require further assessment and demonstration of long-term effects, particularly before treatment practices will change.The recently published Aliskiren in the Evaluation of Proteinuria in Diabetes (AVOID) study evaluated the potential renoprotective effect of direct renin inhibition in patients with hypertension, type 2 diabetes, and proteinuria.Aliskiren, titrated to maximum doses over 6 months, or placebo were added to full-dose angiotensin II receptor blocker (ARB) (losartan) and antihypertensive therapy with other agents in 599 patients.The primary outcome was reduction in the urinary albumin-to-creatinine ratio. 1 Parving and colleagues 1 concluded that aliskiren may have renoprotective effects independent of blood pressure lowering in this patient population that was already receiving treatment with currently recommended renoprotective therapy, an ARB.1,2 While this conclusion is plausible, we contend that the authors provide insufficient discussion on the contribution of several dependent variables, including the long-term effect of losartan, potential differences in 24-hour blood pressure between groups and, in particular, confounding baseline demographics.Theoretically, as observed with the combination of angiotensin-converting enzyme inhibitors (ACEIs) and aldosterone antagonists in heart failure, optimization of renin-angiotensin system (RAS) inhibition may potentially offer benefits, particularly in patients with comorbid diseases.Treatment with an ACEI or ARB has been reported to provide benefits in the treatment of diabetic nephropathy.The rationale for attempting more complete blockade by combining agents targeting the RAS relates to the recognition of angiotensin-converting enzyme-independent pathways and further generation of angiotensin II by these pathways or to the