Curr Hypertens Rep (2015) 17:511 DOI 10.1007/s11906-014-0511-3
ANTIHYPERTENSIVE AGENTS: MECHANISMS OF DRUG ACTION (M ERNST, SECTION EDITOR)
Dual Renin-Angiotensin-Aldosterone Blockade: Promises and Pitfalls Steven G. Chrysant & George S. Chrysant
# Springer Science+Business Media New York 2014
Abstract Single renin-angiotensin-aldosterone system (RAAS) blockade has been shown to be effective and safe for the treatment of hypertension, coronary heart disease (CHD), heart failure (HF), diabetes, and chronic kidney disease (CKD) with proteinuria. Due to the action of RAAS blockers at various levels of the RAAS cascade, it was hypothesized that dual RAAS blockade would result in more complete inhibition of angiotensin II (Ang II) production and be more effective in blocking its detrimental cardiovascular remodeling effects. Unfortunately, several clinical trials in patients with hypertension, CHD, HF, and CKD with proteinuria have demonstrated no superiority of dual versus single RAAS blockade, but a higher incidence of adverse events. Based on these findings, dual RAAS blockade is no longer recommended for the routine treatment of various cardiovascular diseases, except diabetic nephropathy with proteinuria and HF with reduced ejection fraction. All the new information gathered from studies within the last 3 years will be presented in this review.
Keywords RAAS blockade . Hypertension . Coronary heart disease . Heart failure . Diabetes . Chronic kidney disease . Angiotensin II . Diabetic nephropathy . Proteinuria
This article is part of the Topical Collection on Antihypertensive Agents: Mechanisms of Drug Action S. G. Chrysant (*) College of Medicine, University of Oklahoma, 5700 Mistletoe Court, Oklahoma City, OK 73142, USA e-mail: [email protected] G. S. Chrysant INTEGRIS Baptist Medical Center, Oklahoma City, OK, USA
Introduction The renin-angiotensin-aldosterone system (RAAS) plays an important role in cardiovascular homeostasis, blood pressure (BP) regulation, and cardiovascular remodeling [1]. The RAAS exerts its effects through angiotensin II (Ang II), which is the final product of the RAAS cascade [2–5]. Consequently, drugs that either interfere with its generation, or its action at either the renin level, angiotensin I level, or its receptor level, such as direct renin inhibitors (DRIs), angiotensin-converting enzyme (ACE) inhibitors, or angiotensin receptor blockers (ARBs), respectively, will decrease the BP and prevent or reverse the cardiovascular remodeling effects of Ang II [1, 4–8]. As these drugs act at different levels of the RAAS cascade, it was hypothesized that their combination could have a synergistic or additive effect. Studies in spontaneously hypertensive rats by Menard et al. [9] suggested that the combination of low doses of the ACE inhibitor enalapril with the ARB losartan exerted a greater systolic BP (SBP) effect and a greater reduction in left ventricular weight than low doses of the individual drugs. However, when the dose of the individual drugs was increased, these differences were no longer present. This study demonstrated that low-dose combination of two drugs acting at different levels of the RAAS cascade is better than a low dose of a component drug. But when the dose of the component drug is increased, the difference in the magnitude of action is eliminated, which means that perhaps the combination of two drugs from the same class in low doses is not better than a higher dose of a component drug. For this review, a Medline search of the English language literature was conducted on the effectiveness and possible pitfalls of the dual combination of inhibitors of RAAS in patients with hypertension, coronary heart disease (CHD) with left ventricular dysfunction (LVD), heart failure (HF), and chronic kidney disease (CKD) with proteinuria for the last 3 years (2011–2013). From the review of 58 abstracts, 16
511, Page 2 of 10
pertinent papers were selected for inclusion in this concise review and they will be discussed together with collateral literature. Pharmacodynamic Effects of RAAS Blockers The RAAS blockers include the DRIs, the ACE inhibitors, and the ARBs. The difference among these drugs is their action at the different levels of the RAAS cascade as demonstrated in Fig. 1. The DRIs like aliskiren act at the first level of the RAAS cascade by blocking the action of renin on the angiotensinogen substrate by cleaving 10 amino acids and producing the decapeptide angiotensin I (Ang I), a weak vasoconstrictive substance. Their administration is associated with a significant reduction of plasma renin activity (PRA), Ang I, Ang II, plasma aldosterone, and BP [10]. The ACE inhibitors act at the second level of the RAAS cascade by blocking the action of ACE from cleaving eight amino acids from Ang I and converting it to octapeptide angiotensin II (Ang II), a potent vasoconstrictor. Their administration is associated with a significant decrease of plasma Ang II and
Curr Hypertens Rep (2015) 17:511
aldosterone and a significant increase in plasma bradykinin levels, since the ACE is identical to kininase II, which degrades bradykinin to its inactive metabolites. The combined effect results in a significant decrease of BP and prevention or reversal of the adverse cardiovascular remodeling effects of Ang II [1]. The ARBs act at the last level of the RAAS cascade by blocking the attachment of Ang II to its angiotensin 1 receptor (AT1) through which it exerts its vasoconstrictive and cardiovascular remodeling effects. In contrast to ACE inhibitors, the ARBs block the effects the Ang II produced by other enzymes as well, like chymase, which escape the ACE. In addition, the ARBs being highly selective for the AT1 receptor allow the Ang II to be attached and stimulate its other free receptor (AT2), resulting in a dual beneficial, vasodilating, and antiremodeling cardiovascular effect [11]. As was demonstrated from the pharmacodynamic actions of the various RAAS blockers, there were good theoretical reasons for the combination of two RAAS blockers for a greater RAAS blockade and better clinical outcomes in patients with hypertension and other cardiovascular diseases. This hypothesis was tested experimentally in 2009 by Menard et al. [9] in spontaneously hypertensive rats (SHR), who demonstrated that the combination of the ACE inhibitor enalapril and the ARB losartan resulted in a greater reduction of BP and left ventricular mass than either component drug given alone at the same dose. The publication of this study led to increased utilization of dual RAAS blockade for the treatment of hypertension, CHD, HF, and diabetes mellitus with renal failure and proteinuria and was incorporated into several national and international guidelines [12, 13•, 14•]. Antihypertensive Effects of Dual RAAS Blockade
Fig. 1 The figure depicts the levels of action of the various RAAS blockers. The DRIs act at the level of renin by blocking its action on angiotensinogen and the generation of Ang I. The ACE inhibitors act at the level of Ang I by blocking the action of ACE and the conversion of Ang I to Ang II. They also block the degradation of bradykinin by blocking the action of kininase II, which is similar to ACE. The ARBs act at the last level of RAAS cascade by interfering with attachment of Ang II to its preferred receptor AT1. The figure also shows that Ang II is produced through alternate pathways, which escape the action of ACE inhibitors, but not the action of ARBs
Based on the mechanism of action of the various RAAS blockers, it made good clinical sense to combine them for a more complete RAAS blockade with the expectation of better outcomes from the treatment of patients with moderate to severe hypertension. However, the results of several small and large clinical trials using a combination of two RAAS blockers were not impressive compared to the effect of either component drug given alone. The data from several major clinical trials of dual RAAS blockade for the treatment of hypertension are listed in Table 1 and will be briefly discussed here. The study by Solomon et al. [7] was a multicenter, randomized, double-blind trial of 465 patients with hypertension (BP 146/89 mmHg) and LVH and with a mean age of 59 years. These patients were randomized to treatment with either aliskiren 300 mg/day, losartan 100 mg/day, or their combination and were followed for 9 months. The primary objective was to compare the change from baseline in left ventricular mass index (LVMI) with the combination of aliskiren and losartan, and the secondary objective was to determine that aliskiren was noninferior to losartan in reducing the LVMI.
Curr Hypertens Rep (2015) 17:511
Page 3 of 10, 511
Table 1 Clinical trials using dual RAAS blockade for the treatment of hypertension Study
Study Patients (no.) Age (years) F-U (weeks) BP (mmHg) Drugs (mg) (design)
Change (mmHg) BP diff (mmHg)
Solomon et al. [7]
DB
565
59
36
Weir et al. [15]
OL
5446
58
8
Izzo et al. [16]
OL
1096
54
8
Yusuf et al. [17]
DB
26,620
66
672
Pool et al. [18]
DB
1123
56
8
Oparil et al. [19]
DB
1797
53
8
601
55
54
Chrysant et al. [20] OL
146/89 146/89 146/89 156/97
Alis 300 Los 100 Alis 300+Los 100 Cand 16–32
−6.5/3.8 −5.5/3.7 −7.0/5.0 −18.7/13.1
156/97 149/97 149/97 142/82 142/82 142/82 153/99 153/99 153/99 154/100 154/100 154/100 150/96
Cand+ACEI Lisin 20 Lisin 20+Cand 160 Ram 10 Telm 80 Ram 10+Telm 80 Alis 300 Val 320 Alis 300+Val 320 Alis 150 Val 160 Alis 150+Val 160 Alis 300+Val 320
−15.3/10.0 −15/12 −21/16 −6.4/4 −7.5/5 −9.8/6 −15/12 −17/11 −18/13 −13/9 −13/10 −17/1 −20.5/13.4
+0.5/1.2 +1.5/1.3 −3.4/3.1 +6/4 +3.4/2 +2.3/1 +3/1 +1/1 +4/3 +4/2
The (+) sign indicates the additional decrease of BP by the dual RAAS blockade compared to single blockade. The (−) sign indicates a greater decrease of BP by the single RAAS blockade compared to dual RAAS blockade DB double-blind, OL open label, F-U follow-up, Alis aliskiren, Cand candesartan, Enal enalapril, Los losartan, Ram ramipril, Telm telmisartan, Val valsartan, BP diff additional BP decrease with dual blockade versus single RAAS blockade
The study showed that the BP was reduced significantly and similarly by all treatment groups (6.5/4.6, 5.5/3.7, and 6.6/3.8 by aliskiren, losartan, and their combination, respectively). The LVMI was also decreased significantly and similarly from baseline by all treatment groups (4.9, 4.8, and 5.8 g/m2), respectively, with aliskiren, losartan, and the combination therapy. Therefore, this study did not show any superiority of dual versus single RAAS blockade. The study by Weir et al. [15] was an open-label, clinical experience study of 8 week duration. This study included 5465 hypertensive patients (BP 156/97 mmHg) either naive to treatment or uncontrolled with treatment hypertension with a mean age of 58 years. These patients were randomized to treatment with candesartan cilexetil 16–32 mg/day alone or as add-on to background therapy with an ACE inhibitor. Candesartan given as monotherapy in 51 % of patients reduced BP by 18.7/13.1 mmHg, and as add-on to ACE inhibitor in 49 % of patients, it reduced it further by 15.3/10 mmHg. The BP response to treatment was independent of age or race. The drugs were well tolerated, and hypotension was infrequent (0.2 %) with candesartan alone and (0.8 %) with the combination therapy. This study showed the superiority of dual versus single RAAS blockade, but it was an open-label study and the patients were receiving background therapy with several other drugs.
The study by Izzo et al. [16] was a combination of two separate randomized, double-blind studies (the AMAZE trials). These studies included 1096 hypertensive patients (BP 149/97 mmHg), uncontrolled on lisinopril 20 mg/day, and were randomized 1:1 to receive either lisinopril 40 mg/day for 8 weeks or the addition of candesartan 16 mg/day to background lisinopril therapy for 2 weeks, followed by 32 mg/day for an additional 6 weeks. Study 1 (n=538) demonstrated a decrease in trough sitting BP (sBP) by 6.2/5.9 mmHg with lisinopril monotherapy 40 mg/day and by 11.6/8.3 mmHg with the combination treatment (p5.5 mmol/l occurred in 283/8576 (3.2 %) in the ramipril, 287/8542 (3.4 %) in the telmisartan, and in 480/8502 (5.6 %) in the combination group (pmono Comb=mono
Val 80×2+Cap 50×3 versus Val 160×2 versus Cap 50×3 Ali 300+ACEI, ARB versus PL+ACEI, ARB Cand 4–8+En 20 versus En 20 versus Cand 4–16 Val 320 versus ACEI versus PL Cand 8+En 20 versus PL±ACEI ACEI+ARB versus ACEI, ARB Ali 150+ACEI versus PL+ACEI, ARB Ali 150+ACEI, ARB versus PL+ACEI, ARB
LVD left ventricular dysfunction, AHF acute heart failure, HF heart failure, NYHAC New York Heart Association class, ACEI angiotensin-converting enzyme inhibitor, Ali aliskiren, Cand candesartan, En enalapril, Val valsartan, Comb combination, mono monotherapy, PL placebo
958/4909 (19.5 %) patients in the captopril, and 941/4885 (19.3 %) patients in the combination group reached the primary endpoint with no difference between the three treatment groups. However, the patients in the drug combination group experienced the most drug-related side effects. Similar results were reported in a study by Solomon et al. [36], which included 820 patients with acute MI and EF≤ 45 %, with a mean age of 59 years. These patients were randomized to aliskiren 150 mg/day, titrated to 300 mg/day (n=423), or placebo (n=397) in addition to their background therapy, which included ACE inhibitors or ARBs, 2 to 8 weeks post-MI and were followed for 36 weeks. The primary endpoint of the study was the change in left ventricular endsystolic volume (LVESV), and the secondary endpoints were the change in left ventricular end-diastolic volume (LVEDV) and left ventricular EF, which were evaluable in 343 patients in the aliskiren group and in 329 patients in the placebo group. Aliskiren reduced the LVESV and LVEDV by 4.4±16.8 and 3.3 ±19.3 ml, respectively, compared to placebo, which decreased them by 3.5±16.3 and 1.7±19.6 ml, respectively (p=ns). Also, no significant differences were noted between the two treatment groups in the secondary composite endpoint of cardiovascular death, hospitalization for HF, reduction in EF>6 points, hypotension, or increase in serum creatinine (Scr), or potassium levels. The study by McKelvie et al. [37], the Randomized Evaluation Strategies for Left Ventricular Dysfunction (RESOLVD), included 441 patients, with a mean age of 65 years, who were randomized to treatment with candesartan 4–16 mg/day (n=327), enalapril 20 mg/day (n=109), or candesartan 4– 8 mg+enalapril 20 mg/day (n=332) and were followed for 43 months. This study showed that the combination therapy was better than monotherapy in preventing left ventricular remodeling or increasing the EF by 0.025 % compared with 0.015 % for monotherapy, respectively. Also, the combination therapy increased the end-systolic (ESV) and end-
diastolic volume (EDV) by 1.0 and 8.0 ml, respectively, compared with an increase of 18 and 27 ml, respectively, for candesartan and by 7 and 23 ml, respectively, for enalapril (p
ANTIHYPERTENSIVE AGENTS: MECHANISMS OF DRUG ACTION (M ERNST, SECTION EDITOR)
Dual Renin-Angiotensin-Aldosterone Blockade: Promises and Pitfalls Steven G. Chrysant & George S. Chrysant
# Springer Science+Business Media New York 2014
Abstract Single renin-angiotensin-aldosterone system (RAAS) blockade has been shown to be effective and safe for the treatment of hypertension, coronary heart disease (CHD), heart failure (HF), diabetes, and chronic kidney disease (CKD) with proteinuria. Due to the action of RAAS blockers at various levels of the RAAS cascade, it was hypothesized that dual RAAS blockade would result in more complete inhibition of angiotensin II (Ang II) production and be more effective in blocking its detrimental cardiovascular remodeling effects. Unfortunately, several clinical trials in patients with hypertension, CHD, HF, and CKD with proteinuria have demonstrated no superiority of dual versus single RAAS blockade, but a higher incidence of adverse events. Based on these findings, dual RAAS blockade is no longer recommended for the routine treatment of various cardiovascular diseases, except diabetic nephropathy with proteinuria and HF with reduced ejection fraction. All the new information gathered from studies within the last 3 years will be presented in this review.
Keywords RAAS blockade . Hypertension . Coronary heart disease . Heart failure . Diabetes . Chronic kidney disease . Angiotensin II . Diabetic nephropathy . Proteinuria
This article is part of the Topical Collection on Antihypertensive Agents: Mechanisms of Drug Action S. G. Chrysant (*) College of Medicine, University of Oklahoma, 5700 Mistletoe Court, Oklahoma City, OK 73142, USA e-mail: [email protected] G. S. Chrysant INTEGRIS Baptist Medical Center, Oklahoma City, OK, USA
Introduction The renin-angiotensin-aldosterone system (RAAS) plays an important role in cardiovascular homeostasis, blood pressure (BP) regulation, and cardiovascular remodeling [1]. The RAAS exerts its effects through angiotensin II (Ang II), which is the final product of the RAAS cascade [2–5]. Consequently, drugs that either interfere with its generation, or its action at either the renin level, angiotensin I level, or its receptor level, such as direct renin inhibitors (DRIs), angiotensin-converting enzyme (ACE) inhibitors, or angiotensin receptor blockers (ARBs), respectively, will decrease the BP and prevent or reverse the cardiovascular remodeling effects of Ang II [1, 4–8]. As these drugs act at different levels of the RAAS cascade, it was hypothesized that their combination could have a synergistic or additive effect. Studies in spontaneously hypertensive rats by Menard et al. [9] suggested that the combination of low doses of the ACE inhibitor enalapril with the ARB losartan exerted a greater systolic BP (SBP) effect and a greater reduction in left ventricular weight than low doses of the individual drugs. However, when the dose of the individual drugs was increased, these differences were no longer present. This study demonstrated that low-dose combination of two drugs acting at different levels of the RAAS cascade is better than a low dose of a component drug. But when the dose of the component drug is increased, the difference in the magnitude of action is eliminated, which means that perhaps the combination of two drugs from the same class in low doses is not better than a higher dose of a component drug. For this review, a Medline search of the English language literature was conducted on the effectiveness and possible pitfalls of the dual combination of inhibitors of RAAS in patients with hypertension, coronary heart disease (CHD) with left ventricular dysfunction (LVD), heart failure (HF), and chronic kidney disease (CKD) with proteinuria for the last 3 years (2011–2013). From the review of 58 abstracts, 16
511, Page 2 of 10
pertinent papers were selected for inclusion in this concise review and they will be discussed together with collateral literature. Pharmacodynamic Effects of RAAS Blockers The RAAS blockers include the DRIs, the ACE inhibitors, and the ARBs. The difference among these drugs is their action at the different levels of the RAAS cascade as demonstrated in Fig. 1. The DRIs like aliskiren act at the first level of the RAAS cascade by blocking the action of renin on the angiotensinogen substrate by cleaving 10 amino acids and producing the decapeptide angiotensin I (Ang I), a weak vasoconstrictive substance. Their administration is associated with a significant reduction of plasma renin activity (PRA), Ang I, Ang II, plasma aldosterone, and BP [10]. The ACE inhibitors act at the second level of the RAAS cascade by blocking the action of ACE from cleaving eight amino acids from Ang I and converting it to octapeptide angiotensin II (Ang II), a potent vasoconstrictor. Their administration is associated with a significant decrease of plasma Ang II and
Curr Hypertens Rep (2015) 17:511
aldosterone and a significant increase in plasma bradykinin levels, since the ACE is identical to kininase II, which degrades bradykinin to its inactive metabolites. The combined effect results in a significant decrease of BP and prevention or reversal of the adverse cardiovascular remodeling effects of Ang II [1]. The ARBs act at the last level of the RAAS cascade by blocking the attachment of Ang II to its angiotensin 1 receptor (AT1) through which it exerts its vasoconstrictive and cardiovascular remodeling effects. In contrast to ACE inhibitors, the ARBs block the effects the Ang II produced by other enzymes as well, like chymase, which escape the ACE. In addition, the ARBs being highly selective for the AT1 receptor allow the Ang II to be attached and stimulate its other free receptor (AT2), resulting in a dual beneficial, vasodilating, and antiremodeling cardiovascular effect [11]. As was demonstrated from the pharmacodynamic actions of the various RAAS blockers, there were good theoretical reasons for the combination of two RAAS blockers for a greater RAAS blockade and better clinical outcomes in patients with hypertension and other cardiovascular diseases. This hypothesis was tested experimentally in 2009 by Menard et al. [9] in spontaneously hypertensive rats (SHR), who demonstrated that the combination of the ACE inhibitor enalapril and the ARB losartan resulted in a greater reduction of BP and left ventricular mass than either component drug given alone at the same dose. The publication of this study led to increased utilization of dual RAAS blockade for the treatment of hypertension, CHD, HF, and diabetes mellitus with renal failure and proteinuria and was incorporated into several national and international guidelines [12, 13•, 14•]. Antihypertensive Effects of Dual RAAS Blockade
Fig. 1 The figure depicts the levels of action of the various RAAS blockers. The DRIs act at the level of renin by blocking its action on angiotensinogen and the generation of Ang I. The ACE inhibitors act at the level of Ang I by blocking the action of ACE and the conversion of Ang I to Ang II. They also block the degradation of bradykinin by blocking the action of kininase II, which is similar to ACE. The ARBs act at the last level of RAAS cascade by interfering with attachment of Ang II to its preferred receptor AT1. The figure also shows that Ang II is produced through alternate pathways, which escape the action of ACE inhibitors, but not the action of ARBs
Based on the mechanism of action of the various RAAS blockers, it made good clinical sense to combine them for a more complete RAAS blockade with the expectation of better outcomes from the treatment of patients with moderate to severe hypertension. However, the results of several small and large clinical trials using a combination of two RAAS blockers were not impressive compared to the effect of either component drug given alone. The data from several major clinical trials of dual RAAS blockade for the treatment of hypertension are listed in Table 1 and will be briefly discussed here. The study by Solomon et al. [7] was a multicenter, randomized, double-blind trial of 465 patients with hypertension (BP 146/89 mmHg) and LVH and with a mean age of 59 years. These patients were randomized to treatment with either aliskiren 300 mg/day, losartan 100 mg/day, or their combination and were followed for 9 months. The primary objective was to compare the change from baseline in left ventricular mass index (LVMI) with the combination of aliskiren and losartan, and the secondary objective was to determine that aliskiren was noninferior to losartan in reducing the LVMI.
Curr Hypertens Rep (2015) 17:511
Page 3 of 10, 511
Table 1 Clinical trials using dual RAAS blockade for the treatment of hypertension Study
Study Patients (no.) Age (years) F-U (weeks) BP (mmHg) Drugs (mg) (design)
Change (mmHg) BP diff (mmHg)
Solomon et al. [7]
DB
565
59
36
Weir et al. [15]
OL
5446
58
8
Izzo et al. [16]
OL
1096
54
8
Yusuf et al. [17]
DB
26,620
66
672
Pool et al. [18]
DB
1123
56
8
Oparil et al. [19]
DB
1797
53
8
601
55
54
Chrysant et al. [20] OL
146/89 146/89 146/89 156/97
Alis 300 Los 100 Alis 300+Los 100 Cand 16–32
−6.5/3.8 −5.5/3.7 −7.0/5.0 −18.7/13.1
156/97 149/97 149/97 142/82 142/82 142/82 153/99 153/99 153/99 154/100 154/100 154/100 150/96
Cand+ACEI Lisin 20 Lisin 20+Cand 160 Ram 10 Telm 80 Ram 10+Telm 80 Alis 300 Val 320 Alis 300+Val 320 Alis 150 Val 160 Alis 150+Val 160 Alis 300+Val 320
−15.3/10.0 −15/12 −21/16 −6.4/4 −7.5/5 −9.8/6 −15/12 −17/11 −18/13 −13/9 −13/10 −17/1 −20.5/13.4
+0.5/1.2 +1.5/1.3 −3.4/3.1 +6/4 +3.4/2 +2.3/1 +3/1 +1/1 +4/3 +4/2
The (+) sign indicates the additional decrease of BP by the dual RAAS blockade compared to single blockade. The (−) sign indicates a greater decrease of BP by the single RAAS blockade compared to dual RAAS blockade DB double-blind, OL open label, F-U follow-up, Alis aliskiren, Cand candesartan, Enal enalapril, Los losartan, Ram ramipril, Telm telmisartan, Val valsartan, BP diff additional BP decrease with dual blockade versus single RAAS blockade
The study showed that the BP was reduced significantly and similarly by all treatment groups (6.5/4.6, 5.5/3.7, and 6.6/3.8 by aliskiren, losartan, and their combination, respectively). The LVMI was also decreased significantly and similarly from baseline by all treatment groups (4.9, 4.8, and 5.8 g/m2), respectively, with aliskiren, losartan, and the combination therapy. Therefore, this study did not show any superiority of dual versus single RAAS blockade. The study by Weir et al. [15] was an open-label, clinical experience study of 8 week duration. This study included 5465 hypertensive patients (BP 156/97 mmHg) either naive to treatment or uncontrolled with treatment hypertension with a mean age of 58 years. These patients were randomized to treatment with candesartan cilexetil 16–32 mg/day alone or as add-on to background therapy with an ACE inhibitor. Candesartan given as monotherapy in 51 % of patients reduced BP by 18.7/13.1 mmHg, and as add-on to ACE inhibitor in 49 % of patients, it reduced it further by 15.3/10 mmHg. The BP response to treatment was independent of age or race. The drugs were well tolerated, and hypotension was infrequent (0.2 %) with candesartan alone and (0.8 %) with the combination therapy. This study showed the superiority of dual versus single RAAS blockade, but it was an open-label study and the patients were receiving background therapy with several other drugs.
The study by Izzo et al. [16] was a combination of two separate randomized, double-blind studies (the AMAZE trials). These studies included 1096 hypertensive patients (BP 149/97 mmHg), uncontrolled on lisinopril 20 mg/day, and were randomized 1:1 to receive either lisinopril 40 mg/day for 8 weeks or the addition of candesartan 16 mg/day to background lisinopril therapy for 2 weeks, followed by 32 mg/day for an additional 6 weeks. Study 1 (n=538) demonstrated a decrease in trough sitting BP (sBP) by 6.2/5.9 mmHg with lisinopril monotherapy 40 mg/day and by 11.6/8.3 mmHg with the combination treatment (p5.5 mmol/l occurred in 283/8576 (3.2 %) in the ramipril, 287/8542 (3.4 %) in the telmisartan, and in 480/8502 (5.6 %) in the combination group (pmono Comb=mono
Val 80×2+Cap 50×3 versus Val 160×2 versus Cap 50×3 Ali 300+ACEI, ARB versus PL+ACEI, ARB Cand 4–8+En 20 versus En 20 versus Cand 4–16 Val 320 versus ACEI versus PL Cand 8+En 20 versus PL±ACEI ACEI+ARB versus ACEI, ARB Ali 150+ACEI versus PL+ACEI, ARB Ali 150+ACEI, ARB versus PL+ACEI, ARB
LVD left ventricular dysfunction, AHF acute heart failure, HF heart failure, NYHAC New York Heart Association class, ACEI angiotensin-converting enzyme inhibitor, Ali aliskiren, Cand candesartan, En enalapril, Val valsartan, Comb combination, mono monotherapy, PL placebo
958/4909 (19.5 %) patients in the captopril, and 941/4885 (19.3 %) patients in the combination group reached the primary endpoint with no difference between the three treatment groups. However, the patients in the drug combination group experienced the most drug-related side effects. Similar results were reported in a study by Solomon et al. [36], which included 820 patients with acute MI and EF≤ 45 %, with a mean age of 59 years. These patients were randomized to aliskiren 150 mg/day, titrated to 300 mg/day (n=423), or placebo (n=397) in addition to their background therapy, which included ACE inhibitors or ARBs, 2 to 8 weeks post-MI and were followed for 36 weeks. The primary endpoint of the study was the change in left ventricular endsystolic volume (LVESV), and the secondary endpoints were the change in left ventricular end-diastolic volume (LVEDV) and left ventricular EF, which were evaluable in 343 patients in the aliskiren group and in 329 patients in the placebo group. Aliskiren reduced the LVESV and LVEDV by 4.4±16.8 and 3.3 ±19.3 ml, respectively, compared to placebo, which decreased them by 3.5±16.3 and 1.7±19.6 ml, respectively (p=ns). Also, no significant differences were noted between the two treatment groups in the secondary composite endpoint of cardiovascular death, hospitalization for HF, reduction in EF>6 points, hypotension, or increase in serum creatinine (Scr), or potassium levels. The study by McKelvie et al. [37], the Randomized Evaluation Strategies for Left Ventricular Dysfunction (RESOLVD), included 441 patients, with a mean age of 65 years, who were randomized to treatment with candesartan 4–16 mg/day (n=327), enalapril 20 mg/day (n=109), or candesartan 4– 8 mg+enalapril 20 mg/day (n=332) and were followed for 43 months. This study showed that the combination therapy was better than monotherapy in preventing left ventricular remodeling or increasing the EF by 0.025 % compared with 0.015 % for monotherapy, respectively. Also, the combination therapy increased the end-systolic (ESV) and end-
diastolic volume (EDV) by 1.0 and 8.0 ml, respectively, compared with an increase of 18 and 27 ml, respectively, for candesartan and by 7 and 23 ml, respectively, for enalapril (p
