to the editor: We found this article to be well written and comprehensive; however, we feel the need to respond to the author’s statement that “ARBs [angiotensin receptor blockers] can safely be added to ACE [angiotensin-converting enzyme] inhibitors.” The authors reference the Candesartan in Heart Failure: Assessment of Reduction in Mortality and morbidity (CHARM) study ¹ to support the statement; however, this overly simplified statement may lead many family physicians to routinely employ this treatment regimen and may unintentionally lead to adverse consequences.

In the Valsartan Heart Failure Trial (Val-HeFT) the combination of valsartan and an ACE inhibitor decreased hospitalizations but did not improve mortality.² However, mortality was increased when such a combination was used in conjunction with beta blockers, which are also recommended as concomitant therapy in patients with heart failure.

The Valsartan in Acute Myocardial Infarction Trial (VALIANT)³ and the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTAR-GET)⁴ showed that ARBs are not superior to an ACE inhibitor, and that the addition of an ARB to a full dose of an ACE inhibitor “was associated with additional adverse effects, including hypotension and renal dysfunction.”⁵ The impact of such a dual treatment regimen on serum potassium and renal function cannot be over emphasized. Although ONTARGET did suggest that an ACE/ARB combination may benefit patients with heart failure, a full dose of an ACE inhibitor was not used. It is important when initiating an ACE/ARB regimen that the “right amount” of medication is used and that the amount is based on clinical trials.

We agree that the combination of an ACE inhibitor and an ARB may benefit appropriately chosen patients with heart failure. However, the treatment of heart failure is complex. A decision about starting combination therapy requires overall consideration of the patient’s cardiovascular status (best used in patients with recurrent hospitalizations and nephrotic syndrome); should not be entered into routinely; and is best made in consultation with a heart failure specialist.

in reply: Drs. Wexler and Feldman express concern about the safety of combining angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) in patients with heart failure with regard to renal dysfunction, hyperkalemia, and concomitant beta blockade. Although we agree that this combination should be prescribed with caution, their concerns need to be placed in context.

Individually, ACE inhibitors and ARBs significantly increase average serum creatinine in patients with heart failure. In the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS), serum creatinine at least doubled in 11 percent of patients receiving enalapril (Vasotec) compared with 3 percent of the control group.¹ In the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM)-Alternate trial, serum creatinine at least doubled in 5.5 percent of patients receiving candesartan (Atacand) versus 1.6 percent of the control group.²

In contrast, the addition of an ARB to an ACE inhibitor is associated with comparatively small changes in renal function. In the CHARM-Added trial, serum creatinine at least doubled in 7 percent of ARB-added patients compared with 6 percent of the control group.³ A meta-analysis combining data from four randomized clinical trials found that serum creatinine increased by 0.5 mg per dL (40 μmol per L) in 3.3 percent of the ARB-added patients.⁴ Thus, de novo initiation of an ACE inhibitor appears to pose a larger renal risk than the subsequent addition of an ARB to an ACE inhibitor. Similarly, the risk of hyperkalemia in combining an ARB with an ACE inhibitor is low.⁵

Drs. Wexler and Feldman noted that subgroup analysis of the Valsartan Heart Failure Trial (ValHeFT) suggested combining an ARB, an ACE inhibitor, and a beta blocker might increase mortality. However, a similar analysis in CHARM-Added found that this subgroup gained the greatest benefit.³ Importantly, few patients in either CHARM or ValHeFT received aldosterone antagonists (i.e., spironolactone [Aldactone]).^2,3,5 Thus, the effects of combining an ARB with an ACE inhibitor and an aldosterone antagonist have not been studied.

We would like to caution readers about generalizing the results of the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET), a trial of patients with vascular disease or high-risk diabetes that excluded patients with heart failure, and The Valsartan in Acute Myocardial Infarction Trial (VALIANT), a trial of patients post myocardial infarction, to patients with chronic heart failure.^6,7 In ONTARGET and VALIANT, combining an ARB with an ACE inhibitor produced no clinical benefit. In contrast, in patients with chronic heart failure, combination therapy decreased hospitalizations by 27 percent in ValHeFT and by 17 percent in CHARM.^2,3,5

We thank Drs. Wexler and Feldman for emphasizing caution about combination drug therapy. However, we maintain that based on the data from ValHeFT and CHARM-Added, ARBs can be safely combined with ACE-inhibitors in patients with heart failure without serious risk of renal failure or hyperkalemia and regardless of background beta blocker therapy. Finally, in many patients, ACE inhibitors should first be combined with aldosterone antagonists, and the combination of an ACE inhibitor, aldosterone antagonist, and ARB carries an unknown risk.