ONTARGET still OFF-TARGET?

Several large randomized, controlled trials have demonstrated that interruption of the renin-angiotensin-aldosterone system with angiotensin-converting enzyme inhibition (ACEi) or angiotensin receptor blockade (ARB) delays the progression of renal and cardiovascular disease.1,–,6 These beneficial effects of ACEis and ARBs are likely to be mediated through reductions in blood pressure and albuminuria: the more blood pressure or albuminuria is reduced in the initial months after start of therapy, the more reduction in renal or cardiovascular events is observed during the subsequent years.7,–,9 Although ACEi and ARB are effective protective agents, the residual risk in these populations for either renal or cardiovascular risk is still very high. This residual risk appears to be determined by the residual high blood pressure and albuminuria in these studied populations. Many studies and their recent meta-analyses have shown that one can further reduce blood pressure and albuminuria by combining ACEi and ARB therapies.10,–,12 Therefore, one would expect that such dual therapy would offer further renal and cardiovascular protection. The ONTARGET (Ongoing Telmisartan Alone and in Combination With Ramipril Global End Point Trial) trial was designed to investigate this question, and it showed, surprisingly, in its primary analysis that dual therapy had no additional effect on either cardiovascular or renal outcomes.13,14Article see p 1098How can we explain the lack of an enhanced effect of dual therapy in the ONTARGET trial? Angiotensin-converting enzyme inhibition …