Of fads, fashion, surrogate endpoints and dual RAS blockade.
BACKGROUND
Dual renin-angiotensin system (RAS) blockade, mostly by combining an angiotensin converting enzyme (ACE) inhibitor with an angiotensin receptor blocker (ARB), is increasingly used in patients with hypertension and diabetes and/or proteinuria and in those with resistant heart failure. However, in the zest of achieving greater nephroprotection and cardioprotection, even patients with uncomplicated essential hypertension are not uncommonly treated with dual RAS blockade.


METHODS
In 2003 the COOPERATE trial, seemed to confirm that dual RAS blockade was beneficial and that proteinuria reduction was synonymous with nephroprotection. This study had to be withdrawn recently attesting to the suspicion that the data looked to good to be true. Moreover, the large prospective ONTARGET data argue against a nephroprotective effect of dual RAS blockade and together with renal findings from ACCOMPLISH, cast doubt on albuminuria/proteinuria being a reliable surrogate endpoint for renal outcome. Although in heart failure, dual RAS blockade had some benefit without reducing mortality, there remains a distinct safety issue with regard to hyperkalemia and elevated creatinine. Neither in ischaemic heart disease nor in left ventricular hypertrophy had dual RAS blockade any benefits when compared with single RAS blockade. Of note, the combination of an ACE inhibitor with an ARB was recently shown to reduce the risk of dementia. All dual RAS blockade may be created equal and the combination of valsartan with aliskiren, a direct renin inhibitor will be evaluated in diabetic patients in the prospective, randomized ALTITUDE study.


CONCLUSIONS
For the time being, given the adverse effects and lack of consistent survival benefits, the use of dual RAS blockade should be avoided unless ironclad data emerge to the contrary.
Messerli
Franz H
FH
Division of Cardiology, St. Luke's and Roosevelt Hospitals, Columbia University College of Physicians and Surgeons, 1000 Tenth Avenue, New York, NY, USA. messerli.f@gmail.com
Staessen
Jan A
JA
Zannad
Faiez
F
D000368:Aged; D057911:Angiotensin Receptor Antagonists / Q000627:therapeutic use*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D003072:Cognition Disorders / Q000517:prevention & control; D003327:Coronary Disease / Q000188:drug therapy*; D003704:Dementia / Q000517:prevention & control; D003925:Diabetic Angiopathies / Q000188:drug therapy*; D004359:Drug Therapy, Combination; D005260:Female; D006333:Heart Failure / Q000188:drug therapy*; D006801:Humans; D006973:Hypertension / Q000188:drug therapy*; D008297:Male; D016032:Randomized Controlled Trials as Topic; D012084:Renin-Angiotensin System / Q000187:drug effects; D009626:Terminology as Topic; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors