The renin-angiotensin-aldosterone system (RAAS) plays an important role in cardiovascular regulation, cardiovascular remodeling, and blood pressure (BP) control. These actions are mediated through the generation of angiotensin II, the final active peptide of the RAAS cascade. Drugs that interfere with the generation or action of angiotensin II at the receptor level, such as direct renin blockers, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARBs), decrease BP and reverse the remodeling effects of angiotensin II. Because these drugs act at different levels of RAAS cascade, it was proposed from experimental data that their combination could have a synergistic effect and amplify their overall effect. Studies in spontaneously hypertensive rats by Menard et al suggested this assumption, because the combination of enalapril and losartan exerted a greater systolic BP-lowering effect and a greater reduction in left ventricular weight than monotherapy with either drug. However, the combination doses used were low, and when higher doses of the single drugs were used, the reduction in systolic BP was not different from the combination treatment. The rationale for the dual-drug blockade of the RAAS was based on the observation that ACE inhibitor monotherapy was associated with an escape phenomenon due to angiotensin II returning toward pretreatment levels after prolonged administration of an ACE inhibitor and also of angiotensin II being generated by non-ACE-mediated pathways. This led to the hypothesis that adding an ARB to an ACE inhibitor will result in a complete blockade of the RAAS, because ARBs block the action of angiotensin II at the angiotensin II receptor type 1 level, irrespective of the mechanism of its generation, and thus will enhance their cardioprotective, renoprotective, and BP-lowering effects. A Medline search of relevant reports in English published from 1990 to 2009 was conducted, using the terms “combination of converting enzyme inhibitors with ARBs,” “renin inhibitors,” “dual RAAS blockade,” “hypertension,” “heart failure,” and “renal disease.” Of these reports, 12 were selected, including meta-analyses, for this concise review.

Antihypertensive Effects

The basic tenet for the combination of blockers of the RAAS was the different mechanism of action on the RAAS cascade, as demonstrated in Figure 1 . ACE inhibitors block the conversion of angiotensin I to angiotensin II and lead to high levels of angiotensin I, which could be converted to angiotensin II by non-ACEs and lead to the escape phenomenon. The action of generated angiotensin II could be blocked downstream at its angiotensin II receptor type 1 receptor level by ARBs, which also could generate additional vasodilatation by allowing angiotensin II to stimulate the unoccupied angiotensin II receptor type 2. This combination and the dual action of ARBs could also enhance their antiremodeling effects. This possible synergistic effect of the combination of ACE inhibitors and ARBs was suggested by experimental and clinical studies. In the study by Mogensen et al in 199 patients with hypertension, diabetes, and microalbuminuria, the administration of candesartan 16 mg/day, lisinopril 20 mg/day, and their combination for 12 weeks decreased diastolic BP by 9.5, 9.7, and 16.3 mm Hg, respectively, and the decrease in diastolic BP with the combination was significantly greater than that with monotherapy with either drug (p <0.001). In another randomized, double-blind study, 1,096 patients with hypertension were treated for 8 weeks with either lisinopril 40 mg/day or the combination of lisinopril 20 mg/day and candesartan 32 mg/day. The combination therapy had an overall reduction in BP of 3.1/1.7 mm Hg compared to monotherapy. Hyperkalemia (serum potassium ≥6.0 mEq/L) was seen in 2.0% of lisinopril-treated patients and in 1.6% of combination-treated patients. In a meta-analysis of studies combining ACE inhibitors with ARBs versus monotherapy, Doulton et al criticized these studies for being either small or of too short duration to the long-term benefits and risks. They concluded that the 4/3 mm Hg reduction in BP does not justify their combination for the treatment of uncomplicated hypertension and might increase the long-term risks. Their concerns were justified by the recently published Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET), in which 25,620 high-risk patients with cardiovascular disease and diabetes were randomized to telmisartan 80 mg/day, ramipril 10 mg/day, or their combination and followed for a median of 56 months. The reductions in BP was 6.4/4.3, 7.4/5.0, and 9.8/6.3 mm Hg for telmisartan, ramipril, and combination therapy, respectively (p = NS), and the cardiovascular outcomes were similar among the 3 treatment groups, whereas the incidence of renal failure and hyperkalemia were greater in the combination group (p <0.001). Studies with the recently approved direct renin inhibitor aliskiren in combination with the ARB valsartan have shown greater BP reductions with the combination therapy compared to monotherapy with the component drugs. In 1 study, 1,123 patients with hypertension were randomized to various single doses of aliskiren (75, 150, and 300 mg), valsartan (80, 160, and 320 mg), or their combination and followed for 8 weeks. The difference in BP reduction between the combination therapy (aliskiren 300 mg/day and valsartan 320 mg/day) was 2.99/0.67 mm Hg compared to aliskiren 300 mg/day and 1.53/1.65 mm Hg compared to valsartan 320 mg/day (p = NS for both). In the other study, 1,797 patients with hypertension were randomized to aliskiren 150 mg/day up-titrated to 300 mg/day, valsartan 160 mg/day up-titrated to 320 mg/day, their combination, or placebo. The placebo-corrected BP difference of the high-dose combination compared to aliskiren 300 mg/day was 4.2/3.2 mm Hg and for valsartan 320 mg/day was 4.4/2.5 mm Hg. These combination studies and another open-label monotherapy study of 601 patients with hypertension treated for 6 months with the combination of aliskiren 300 mg/day and valsartan 320 mg/day for 6 months were safe with respect to renal dysfunction or hyperkalemia.

Generation of angiotensin II through the classic and alternative pathways and blockade of the RAAS system by the various RAAS blockers.

Adapted with permission from J Clin Hypertens .