ACE Inhibitor + ARB = Effective Therapy?

January 1, 2007

Q:Do evidence-based data support combination therapy with anangiotensin-converting enzyme (ACE) inhibitor and an angiotensin IIreceptor blocker (ARB)?

Q:Do evidence-based data support combination therapy with anangiotensin-converting enzyme (ACE) inhibitor and an angiotensin IIreceptor blocker (ARB)?A:The availability of 2 distinct classes of drugs that effectively suppress therenin-angiotensin-aldosterone system inevitably leads to the questionof whether a combination of these agents provides benefits beyond thoseobserved with monotherapy. Although some small studies have demonstratedthe effectiveness of an ACE inhibitor and an ARB in combination, no largeprospective trials have compared these drug classes with each other or evaluatedthem when used together.Recommendations for study design. Study results have been difficultto assess because there is no objective definition of additive effects. A properlyconducted study should ascertain the optimal dose response of drug A beforedrug B is added to the regimen. For example, if blood pressure response isbeing used as the surrogate marker of effectiveness of an ACE inhibitor orARB, the dosage of drug A would be titrated to the maximum tolerated dosageor the dosage at which no further reduction in blood pressure was observed.At this point, drug B would be added and titrated appropriately to determinethe maximum combined effect of the 2 agents.Other surrogate markers can be used in evaluating ACE inhibitors andARBs. For example, in patients with either diabetic or nondiabetic progressiverenal disease, the rate of decline in glomerular filtration rate or quantitative proteinuriacan be used as a surrogate marker of effectiveness. In patients withcongestive heart failure (CHF), improvement in treadmill exercise time and reductionin frequency of hospitalizations for CHF have been used as surrogatemarkers of effectiveness.In clinical practice, few medications are prescribed at optimum or maximummanufacturer's recommended dosages. Many physicians hesitate to uptitratemedications, even within their recommended dosage ranges and in theabsence of adverse effects. ACE inhibitors and ARBs are usually prescribed atlow to moderate dosages. In patients with CHF, low blood pressure may limitoptimum dosing of these agents. In patients with renal disease and significantazotemia, up-titration may also be limited by excessive rises in serum creatinineconcentration associated with drug-induced decreases in glomerular filtrationrate. In the presence of these comorbidities, clinicians are understandablyreluctant to up-titrate drug dosages. These factors limit the achievementof maximum dose responses with both classes of agents.Inconclusive evidence. Two recent studies illustrate the difficulty of determiningwhether truly additive effects of ACE inhibitors and ARBs are seen onselected surrogate disease markers. One study sought to determine the effectsof combination therapy on proteinuria in normotensive patients with IgA nephropathy.1 Eight patients were successively given an ACE inhibitor alone, theARB losartan alone, combination therapy, and single-agent therapy at a doubled dosage. Both the ACE inhibitor and losartan significantly reduced proteinuria;doubled dosages did not reduce it further. Combination therapy reduced proteinuriato a much greater degree than either agent alone.The authors hypothesized that combination therapy had an additive, dosedependentantiproteinuric effect, independent of the drug-related reduction inblood pressure. However, they could not definitively conclude that the antiproteinuriceffect of combination therapy was unrelated to reduction in bloodpressure.The maximum doses of ACE inhibitors used in this study were well belowthe maximum recommended dosages for the treatment of hypertension andmay not represent optimum dosages. It is unclear whether, if the maximumeffective dose responses had been attained, the apparent additive effect of combinationtherapy would have been the same.The second study included more than 5000 patients with CHF who weregiven the ARB valsartan in addition to the standard therapeutic regimen.2 Ninety-three percent of the participants were taking an ACE inhibitor when valsartanwas added. After 27 months of follow-up, there was a 13% reduction in combinedall-cause mortality and morbidity and a 27.5% reduction in heart failurehospitalizations in the valsartan group.The authors concluded that valsartan had an additive effect when combinedwith standard therapy. However, there was no protocol control over thedosage or dose titration of ACE inhibitors used in the study, and many patientswith CHF cannot tolerate higher doses of ACE inhibitors. Therefore, it is riskyto assume that the results were attributable to combination therapy.A final caveat. My purpose here is to encourage a critical review of clinicalstudies. Be wary of study designs and results that do not appear to support theauthor's conclusions.Current evidence suggests that there may be significant advantages tocombination therapy with ACE inhibitors and ARBs. However, before we canmake a definitive assessment, we need clinical trials that are properly designedto ensure appropriate titration to maximum tolerated or effective dosages, aswell as to determine the potential magnitude of benefit and delineate safetyconcerns.




Russo D, Pisani A, Balletta MM, et al. Additive antiproteinuric effect of converting enzyme inhibitor andlosartan in normotensive patients with IgA nephropathy.

Am J Kidney Dis

. 1999;33:851-856.


Cohn JN, Tognoni G, for the Valsartan Heart Failure Trial (Val-HeFT) Investigators. A randomized trial ofthe angiotensin-receptor blocker valsartan in chronic heart failure.

N Engl J Med

. 2001;345:1667-1675.