Many questions remain as to the therapeutic advantage of drugs that block the RAS in patients with heart disease, kidney disease, and/or diabetes mellitus. Although ONTARGET does not answer these questions, it does document two important points: RAS blockers are effective for lowering BP, and they are among the best-tolerated medications for treating BP.

Additional non-hemodynamic advantages of these medications may also be relevant, as numerous investigators have described pleiotropic benefits of these drugs that may, for example, improve endothelial function. Other benefits may be related to more effective reduction of central aortic pressure. Although these points are theoretical, they need to be examined in future clinical trials.

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ONTARGET also raises intriguing questions as to why dual RAS blockade was not more effective than using an ACE inhibitor or ARB alone. One might argue that this study was not designed to measure BP, and therefore, the BP readings may not be entirely reflective of what the patients experienced during the course of follow-up. 

Another thought is that, mechanistically, these drugs may not be that much different from one another, so that using the two together may not provide an incremental opportunity to reduce vascular events. Although it is fair to say that it is pointless to use both an ACE inhibitor and an ARB, it is possible that some patient populations, perhaps those with CKD and proteinuria, may benefit from this approach. 

There is a large ongoing study at VA hospitals exploring the use of an ACE inhibitor and an ARB together in proteinuric patients with kidney disease. Hopefully, this study will provide more important answers about the pros and cons of dual RAS blockade and implications about safety.

In summary, ONTARGET has added substantially to our understanding about the management of CVD in high-risk patients. It provides clear evidence that ACE inhibitors and ARBs are interchangeable. As such, we now have two therapeutic alternatives that can be used as part of an effective BP-lowering regimen to reduce the risk of cardiovascular events.

Dr. Weir is professor of nephrology and director of the Nephrology Division at the University of Maryland School of Medicine in Baltimore.