A systematic review and meta-analysis of aliskiren and angiotension receptor blockers in the management of essential hypertension

Article A systematic review and meta-analysis of aliskiren and angiotension receptor blockers in the management of essential hypertension Journal of the Renin-Angiotensin- Aldosterone System 12(2) 102 112 The Author(s) 2010 Reprints and permission: sagepub.co.uk/journalspermissions.nav DOI: 10.1177/1470320310381912 jra.sagepub.com Zhenfeng Zheng 1, Huilan Shi 2, Junya Jia 1, Dong Li 1 and Shan Lin 1 Abstract Aliskiren is a novel antihypertensive agent and the first direct renin inhibitor (DRI) in clinical use. Several clinical trials have compared DRI with angiotensin receptor blockers (ARBs) in the management of essential hypertension. However, systematic comparison of efficacy and safety between DRIs and ARBs is still lacking. We reviewed randomized controlled trials (RCTs) comparing aliskiren with ARBs for net reduction of blood pressure from baseline, achieved rate of control, and incidences of common and serious adverse events. Weighted mean differences (WMD) and relative risk (RR) with 95% confidence intervals (CI) were calculated for continuous and dichotomous data, respectively. Seven RCTs with 5488 patients were included in this meta-analysis. We compared the efficacy of aliskiren and ARBs in reducing systolic blood pressure (SBP) and diastolic blood pressure (DBP). No differences were found between the two groups. Aliskiren combined with ARBs was superior to aliskiren monotherapy at the maximum recommended dose on SBP and DBP reduction. (WMD -4.80, 95% CI -6.22-3.39, p < 0.0001; WMD -2.96, 95% CI -4.63-1.28, p = 0.0001; respectively). Similar results were found with aliskiren combined with ARBs versus ARB monotherapy (WMD -4.43, 95% CI -5.91-2.96, p < 0.0001; WMD -2.40; 95% CI -3.41-1.39, p < 0.0001; respectively). No differences were found in adverse events between the aliskiren and ARB groups. Similar results were found with aliskiren and ARB combination therapy and its respective monotherapy. We conclude that aliskiren s BP-lowering capabilities were comparable to those of ARBs. Aliskiren and ARB combination therapy provided more effective BP reduction than each respective monotherapy without increasing adverse events. Keywords Aliskiren, angiotensin receptor blocker, direct rennin inhibitor, hypertension, meta-analysis Introduction The renin angiotensin aldosterone system (RAAS) plays a key role in the regulation of blood pressure (BP) and volume homeostasis, acting primarily via the effects of the octapetide hormone angiotensin (Ang) II. Excessive RAAS activity is a major underlying cause of many pathological states because Ang II increases BP and exerts direct growth-promoting effects on tissues that lead to end-organ damage. 1-3 Its importance in diseases such as hypertension, congestive heart failure and chronic renal failure has long been recognized, and it has also been established that inhibition of the RAAS is an effective way to intervene in the pathogenesis of these disorders. 4-6 Indeed, RAAS inhibitors, such as angiotensin converting enzyme (ACE) inhibitors and angiotensin AT 1 - receptor blockers (ARBs), have proved to be highly successful treatments for hypertension, heart failure, and related cardiovascular disorders. The shortcomings of RAAS blockade do exist, but there are difference of pharmacological agents in ARB, ACE inhibitor and DRI. The incidence of adverse event in RAAS blockade is low in therapy dosage. ACE inhibitors block the formation of Ang II but also cause a reactive increase in the concentrations of Ang I that can subsequently be converted to Ang II by other pathways, such as the chymase system. ARBs specifically block the AT-1 receptors, leaving other types of AT receptors (e.g. AT 2 R and AT 4 R) that might be involved in some important regulatory 1 Department of Nephrology, The First Affiliated Hospital of Tianjin Medical University, China 2 Department of Radiology, The First Affiliated Hospital of Tianjin Medical University, China Corresponding author: Zhenfeng Zheng, Department of Nephrology, The First Affiliated Hospital of Tianjin Medical University, No.154, Anshan road, Heping district, Tianjin 300052, People s Republic of China. Email: zhengzhenfeng@126.com

Zheng et al. 103 functions of the endothelium and vascular smooth muscle, open to unopposed potential stimulation by Ang II. 7 Along with the incomplete blockade of the RAAS, both ACE inhibitors and ARBs lead to a substantial compensatory raise in circulating active renin and angiotensin peptides that may eventually limit their therapeutic potential. In a landmark paper published more than 50 years ago, Skeggs et al. 8 first suggested that inhibition of Ang I generation from angiotensinogen was the therapeutic approach most likely to succeed because renin was the initial and ratelimiting step of the RAAS. The first renin inhibitor was synthesized more than 30 years ago. 9 Orally active renin inhibitors were developed in the 1980s, including enalkiren, remikiren, ditekiren and zanikiren. Unfortunately, poor absorption from the gastrointestinal tract, short half-life and low potency prevented further development of these compounds. Aliskiren is the first in a new class of orally active, nonpeptide, low molecular weight renin inhibitors. It was discovered through a co-mbination of molecular modeling and crystallographic structure analysis. 10 Aliskiren is a potent inhibitor of renin, with an IC 50 (concentration inhibiting 50% of activity) of 0.6 nmol/l. After an oral dose, the bioavailability of aliskiren is 2.5%. High aqueous solubility and high affinity for renin compensates for the low absolute bioavailability. A terminal half-life of 23 36 h makes the drug suitable for once-daily administration. An increasing number of clinical trials have compared the antihypertensive efficacy and tolerability of aliskiren with placebo, hydrochlorothiazide, ARBs, ACE inhibitors and calcium channel blockers. Aliskiren has also been evaluated as both monotherapy and combination therapy in the treatment of hypertension. The primary aim of the present study is to systematically assess the antihypertensive efficacy and safety of aliskiren in comparison with ARBs in mild-tomoderate hypertensive patients. Methods Trial inclusion and exclusion criteria We developed inclusion criteria for this review which included the following absolute requirements: adult population; clear diagnosis of primary hypertension; randomized controlled trials; follow-up of at least 4 weeks; objectives of the study precisely defined; clear description of inclusion and exclusion criteria; treatment and control group comparable at entry; clear description of withdrawals and dropouts; raw data available; statistical method described clearly in English. The exclusion criteria included hypertension with coronary disease, stroke, congestive heart failure, secondary hypertension, poorly controlled diabetes mellitus, chronic kidney failure, administration of any ACE inhibitors or ARB or other antihypertensive agents within 2 weeks, and unavailable data. Search techniques We developed a protocol for the review and followed standard QUOROM reporting guidelines. 11 We performed electronic searches of the Cochrane Central Register of Controlled Trials (Cochrane Library Issue1, 2010), MEDLINE and Pre-MEDLINE (1966 March 2010), EMBASE (1980 March 2010), review articles, prospective trial registers, relevant trials and abstracts from hypertension meetings, randomized controlled trials (RCTs) and quasi-rcts comparing any benefits of aliskiren and angiotensin receptor blockers for the treatment essential hypertension. The following medical subject heading terms and text words were used: aliskiren, spp100, renin inhibitor, randomized controlled trials, essential hypertension, blood pressure, angiotensin receptor blockers. Reference lists of retrieved reports were checked. Data collection Included trials were evaluated independently by two of the reviewers. For studies that could possibly have been RCTs, or in the case of disagreement between the two reviewers, the full articles were obtained. In turn, the same reviewers, who were not blinded to authorship or journal, compiled an ad hoc questionnaire and independently reviewed these articles. The questionnaires were then cross-checked, and disagreement was resolved by consensus or by a third reviewer. Agreement between reviewers on inclusion was evaluated using a kappa statistic. Strength of agreement as evaluated by the kappa statistic was defined as slight (0.00 0.20), fair (0.21 0.40), moderate (0.41 0.60), substantial (0.61 0.80) or almost perfect (0.81 1.00). 12 The following general descriptive information was extracted from each trial: number, age, gender and ethnicity of participants; hypertension duration; baseline trough seated systolic blood pressure (SBP) and diastolic blood pressure (DBP); number of participants randomized assigned to each intervention; duration of follow-up; number of drop outs or withdrawals because of adverse events or unwillingness to continue; change from baseline of seated SBP and DBP; response rate and control rate based on achievement of target BP; and the incidence of adverse events. Quality assessment Trials were inspected for three principal aspects of the randomization process: (1) generation of allocation sequence; (2) allocation concealment; and (3) blinding. In generation of allocation sequence, the approaches would be considered as computer, random number table, shuffled cards or tossed coins. Allocation concealment strategies would be considered as central randomization, numbered or coded containers, and sequentially numbered, opaque, sealed

104 Journal of the Renin-Angiotensin-Aldosterone System 12(2) envelopes. We also assessed whether the analysis was by intention-to-treat or not and the completeness of followup. The following Cochrane quality checklist was compiled: (1) allocation concealment: adequate/unclear/ inadequate; (2) blinding: blinding of investigators (yes/no/ not stated), blinding of participants (yes/no/not stated), blinding of outcome assessors (yes/no/not stated), blinding of data analysis (yes/no/not stated); (3)intention-to-treat: (A) yes; specifically reported by investigators that intention-to-treat analysis was undertaken and this was confirmed on study assessment; (B) yes; not stated, but confirmed on study assessment; (C) no; not reported and lack of intention-to-treat analysis confirmed on study assessment; (D) no; stated, but not confirmed on study assessment; and (E) not stated; unable to be determined on study assessment. Study quality was assessed using the Jadad scale. 13 The Jadad scale was designed to examine elements of clinical studies that may lead to bias. A 5-point scoring system described and summarized as follows: was the study described as randomized? (1 = yes; 0 = no); was the study described as double-blind? (1 = yes; 0 = no); was there a description of withdrawals and dropouts? (1 = yes; 0 = no); was the method of randomization well described and appropriate? (1 = yes; 0 = no); was the method of double-blinding well described and appropriate? (1 = yes; 0 = no). A score of 0 2 reflects low quality, a score of 3 4 indicates moderate quality and a score of 5 represents a high-quality study. Dosage categorizing BP data were pooled for the ARBs by categorizing individual doses as proportions of the manufacturers maximum recommended daily dose (Max). When analyzed as a class (by categorizing the individual ARBs according to proportion of the manufacturer s maximum recommended dose), the lowest dose with near maximal BP lowering efficacy was the maximum recommended dose. Statistical analysis This meta-analysis combined data at study level and not at individual patient level. Outcome data were synthesized using weighted mean differences (WMD) for continuous data and relative risk (RR) for dichotomous data. We tested for heterogeneity using the Cochran Q test and quantified the degree of heterogeneity with the I 2 statistic. The I 2 statistic ranges from 0 100% and measures the degree of inconsistency across studies in a meta-analysis as low, moderate, and high to I 2 values of 25%, 50%, and 75%, respectively. 14 Because the Q test was a low-power test, α level was set at 0.10. A random-effect model or fixed-effect model was elected according to the Q test. It was still possible that important trials had not been published and thus Figure I. QUOROM flow diagram ACEI, angiotensin converting enzyme inhibitor; CCB, calcium channel blocker; HCTZ, hydrochlorothiazide; RCT, randomized controlled trial would not be included in this meta-analysis. We used the funnel plots to detect and visualize the publication bias. The publication bias test was performed by Egger s test. 15 This meta-analysis was performed using STATA 10.0 (StataCorp, College Station, TX, USA). Results Description of studies The original search produced a total of 71 articles; following initial review of titles and abstracts, 16 potentially relevant references were identified. The abstracts of these 26 articles were reviewed and full articles were retrieved. Of theses, seven articles met the inclusion criteria. 16-22 The retrieved flow and characteristics of the included studies are shown in the Figure 1 and Table 1. Three studies

Zheng et al. 105 Table 1. Characteristics of the studies included in the meta-analysis Investigator Participants Intervention Drop out ITT analysis Jadad score Stanton 2003 16 226 A double-blind, active comparator, randomized, parallel-group study. Aliskiren 37.5 mg, 75 mg, 150 mg, 300 mg and Losartan 100 mg for 4 weeks Gradman 652 A multicenter, randomized, double-blind, placebo-controlled 2005 17 parallel-group study. Aliskiren 150 mg, 300 mg, 600 mg, irbesartan 150 mg and placebo for 8 weeks Jordan 2007 18 489 A multicenter, randomized, double-blind, placebo-controlled parallel-group study. Aliskiren 150 mg/hctz 25 mg, irbesartan 150 mg/hctz 25 mg, amlodipine 5 mg/hctz 25 mg for 4 weeks, and the doses of aliskiren, irbesartan and amlodipine doubled for another 4 weeks, placebo/hctz 25 mg for 8 weeks Oparil 2007 19 1776 A multicenter, randomized, double-blind, placebo-controlled parallel-group, dose-escalation study. Aliskiren 150 mg, valsartan 160 mg for 4 weeks, and forced titration to double dose for another 4 weeks, placebo for 8 weeks Pool 2007 20 1123 A multicenter, randomized, double-blind, placebo-controlled parallel-group study. Aliskiren 75 mg, 150 mg, 300 mg, valsartan 80 mg, 160 mg, 320 mg, aliskiren/valsartan 75 mg/80 mg, 150 mg/160 mg, 300 mg/320 mg, valsartan/hctz 160 mg/12.5 mg for 8 weeks Yarows 2008 21 581 A multicenter, randomized, double-blind, placebo-controlled study. Aliskiren 150 mg valsartan 160 mg, aliskiren/valsartan 150 mg/160 mg for 4 weeks, and double the dose for further 4 weeks. Placebo for 8 weeks Geiger 2009 22 641 A randomized, double-blind, parallel-group, active-control, doseescalation study. Aliskiren/HCTZ 150 mg/25 mg, valsartan/hctz 160 mg/25 mg, aliskiren/valsartan /HCTZ 150 mg/160 mg/25 mg for 4 weeks, and double the dose for further 4 weeks 14 5 3 66 5 5 41 4 5 196 5 5 89 5 3 14 4 3 58 5 3 Abbreviations: ITT, intent-to-treat; HCTZ, hydrochlorothiazide randomized patients to fixed-dose therapy and four studies were up-titration trials during double-blind treatment. Efficacy of aliskiren versus ARBs in blood pressure reduction Aliskiren versus ARBs in 1/2 Max dose. We analyzed three RCTs with 566 patients for the SBP and DBP reduction efficacy of aliskiren and ARBs at half Max dose at the end of the follow-up. No difference was found in the reduction of SBP and DBP of the two groups. (WMD 2.10, 95% CI -0.30 4.51, p = 0.09; WMD 0.40, 95% CI -1.09 1.90, p = 0.60; respectively). No difference was found in the BP control rate of the two groups (RR 0.86, 95% CI 0.51 1.45, p = 0.57), See Figure 2. Aliskiren versus ARBs at Max dose. We analyzed five RCTs with 1955 patients on the SBP and DBP reduction efficacy of aliskiren and ARBs at Max dose at the end of the followup. No difference was found in the reduction of SBP and DBP in the two groups (WMD 0.35, 95% CI -0.95 1.64, p = 0.60; WMD 0.38, 95% CI -1.06 1.82, p = 0.60; respectively). No difference was found in the BP control rate of the two groups (RR 1.03, 95% CI 0.92 1.15, p = 0.62), see Figure 3. Aliskiren combined with ARBs versus aliskiren or ARB monotherapy at Max dose. Four studies were included comparing SBP and DBP reduction aliskiren in combination with ARBs and aliskiren or ARBs monotherapy at Max dose. Aliskiren combined ARBs was superior to aliskiren monotherapy at Max dose on SBP and DBP reduction (WMD -4.80, 95% CI -6.22-3.39, p < 0.0001; WMD -2.96, 95% CI -4.63-1.28, p = 0.0001; respectively). Aliskiren combined with ARBs was superior to aliskiren monotherapy at Max dose in terms of BP control (RR 1.45, 95% CI 1.30 1.63, p < 0.0001). Aliskiren combined with ARBs was also superior to ARB monotherapy at Max dose in SBP and DBP reduction (WMD -4.43, 95% CI -5.91-2.96, p < 0.0001; WMD -2.40, 95% CI -3.41-1.39, p < 0.0001; respectively), see Figure 4. Aliskiren combined with ARBs was also superior to ARB

106 Journal of the Renin-Angiotensin-Aldosterone System 12(2) Figure 2. Forest plot of net blood pressure reduction from baseline of aliskiren 150 mg and half Max ARBs. (a) Comparison of net diastolic blood pressure (DBP). (b) Comparison of net systolic blood pressure (SBP). (c) Comparison of blood pressure controlled rate. monotherapy at Max dose in BP control (RR 1.44, 95% CI 1.28 1.61, p < 0.0001). Safety of aliskiren versus ARBs in blood pressure reduction Aliskiren versus ARBs at Max dose. We also compared common adverse events, discontinuation due to adverse event, any serious adverse events and several common adverse events related to aliskiren and ARBs treatment. Unfortunately, not all trials included in the systematic review provided full descriptions of this information. The incidence of any adverse events, discontinuation due to adverse event and any serious adverse events were similar (RR 0.91, 95% CI 0.80 1.03, p = 0.12; RR 0.74, 95% CI 0.40 1.35, p = 0.32; RR 1.10, 95% CI 0.58 2.10, p = 0.78, respectively). No obvious difference was found in the results of the two groups. The most common adverse events related to treatment were dizziness, headache, fatigue, nasopharyngitis, back pain, nausea, diarrhea, edema, infection, hypokalemia and hyperkalemia. The incidence of these adverse events was comparable between aliskiren and ARBs (see Table 2).

Zheng et al. 107 Figure 3. Forest plot of net blood pressure reduction from baseline of aliskiren 300 mg and Max ARBs. (a) Comparison of net diastolic blood pressure (DBP). (b) Comparison of net systolic blood pressure (SBP). (c) Comparison of blood pressure controlled rate. Aliskiren combined ARBs versus Aliskiren or ARBs monotherapy in Max dose. When comparing aliskiren combined with ARBs with aliskiren monotherapy at Max dose, the incidence of any adverse events and discontinuation due to adverse events was comparable between two groups (RR 1.04, 95% CI 0.90 1.19, p = 0.61; RR 0.79, 95% CI 0.36 1.73, p = 0.56, respectively). It was interesting that the incidence of any serious adverse events in the combination group was lower than that of the aliskiren monotherapy group (RR 0.37, 95% CI 0.15 0.91, p = 0.03). The incidence of common adverse events was comparable between combination therapy and aliskiren monotherapy except for fatigue (RR 2.24, 95% CI 1.03 4.90, p = 0.04) and hyperkalemia (RR 1.92, 95% CI 1.04 3.54, p = 0.04). Comparing aliskiren combined with ARBs to ARB monotherapy at Max dose, no differences were found in all adverse events,

108 Journal of the Renin-Angiotensin-Aldosterone System 12(2) Figure 4. Aliskiren 300 mg and Max ARBs combination therapy versus respective monotherapy. (a) Comparison of net diastolic blood pressure between combination therapy and aliskiren monotherapy. (b) Comparison of net systolic blood pressure between combination therapy and aliskiren monotherapy. (c) Comparison of net diastolic blood pressure between combination therapy and ARBs monotherapy. (d) Comparison of net systolic blood pressure between combination therapy and ARBs monotherapy.

Zheng et al. 109 Table 2. Aliskiren 300 mg versus ARB double dosage: effect on adverse events Category RR 95%CI p-value Any AE 0.91 0.80 1.03 0.12 Discontinuation due to AE 0.74 0.40 1.35 0.32 Any SAE 1.10 0.58 2.10 0.78 Dizziness 0.56 0.31 1.02 0.06 Headache 0.65 0.41 1.03 0.06 Fatigue 0.52 0.22 1.22 0.13 Nasopharyngitis 0.97 0.62 1.54 0.91 Back pain 0.50 0.17 1.49 0.22 Nausea 0.88 0.33 2.32 0.80 Diarrhea 0.94 0.24 3.68 0.93 Edema 0.60 0.07 4.84 0.63 Infection 1.09 0.26 4.51 0.91 Hypokalemia 0.68 0.41 1.14 0.14 Hyperkalemia 0.93 0.51 1.70 0.82 Abbreviations: ARB, angiotensin receptor blockers; RR, relative risk; CI, confidence interval; AE, adverse events; SAE, serious adverse events discontinuation due to adverse events, any serious adverse events and common adverse events (see Table 3). Publication bias analysis We performed the publication bias analysis with Egger s test. No evidence for publication bias were found in reduction of SBP (p = 0.783) and DBP (p = 0.349). Discussion The results of our meta-analysis clearly demonstrate that once-daily oral treatment with the novel renin inhibitor aliskiren lowered BP effectively in patients with mild-tomoderate hypertension. Aliskiren monotherapy at doses of 150 mg to 300 mg daily provided similar reductions in DBP and SBP compared with ARBs at recommended half Max dose and Max dose. These results provide convincing evidence that renin inhibition with aliskiren monotherapy provides 24-h BP lowering comparable with ARB monotherapy in patients with mild-to-moderate hypertension. The reductions in DBP and SBP were 9 10 mmhg and 10 12 mmhg, respectively, for aliskiren at 150 mg. When the dosage was up-titrated to 300 mg, aliskiren reduced DBP and SBP by 9 12 mmhg and 13 17 mmhg, respectively. Importantly, aliskiren 300 mg lowered BP more effectively and brought more patients to target BP levels compared with aliskiren 150 mg. These results indicate that up-titration of the dose of aliskiren could be used for additional BP lowering in patients who did not achieve BP control with aliskiren 150 mg. The combination of the maximum therapeutic doses of aliskiren and ARBs provided clinically meaningful and significant reductions in BP over and above that achieved with either of the component monotherapies. Similarly, the combination of the recommended starting doses of aliskiren and ARBs also showed significant reductions in BP over and above that achieved with either monotherapy. The average reductions of DBP and SBP were 11 16 mmhg and 17 22 mmhg for aliskiren 300 mg combined with Max dose ARBs. To explain these data, it might be considered that the RAAS was a self-regulating system which was Table 3. Aliskiren combined with ARB on double dosage versus respective monotherapy Category Combined therapy versus aliskiren Combined therapy versus ARB RR 95%CI p-value RR 95%CI p-value Any AE 1.04 0.90 1.19 0.61 0.91 0.80 1.04 0.15 Discontinuation due to AE 0.79 0.36 1.73 0.56 0.57 0.27 1.24 0.16 Any SAE 0.37 0.15 0.91 0.03 0.44 0.18 1.12 0.09 Dizziness 1.57 0.78 3.14 0.20 0.70 0.41 1.20 0.20 Headache 1.36 0.82 2.25 0.23 0.80 0.51 1.23 0.31 Fatigue 2.24 1.03 4.90 0.04 1.12 0.57 2.22 0.74 Nasopharyngitis 0.82 0.46 1.46 0.49 0.68 0.39 1.20 0.18 Back pain 1.54 0.40 5.94 0.53 1.00 0.26 3.84 0.99 Nausea 1.38 0.54 3.52 0.50 1.26 0.50 3.13 0.62 Diarrhea 0.79 0.19 3.31 0.75 0.71 0.16 3.17 0.66 Edema - - - - - - Infection 1.18 0.27 5.12 0.83 0.98 0.18 5.28 0.98 Hypokalemia 1.13 0.62 2.07 0.68 0.65 0.39 1.10 0.11 Hyperkalemia 1.92 1.04 3.54 0.04 1.38 0.79 2.42 0.25 Abbreviations: ARB, angiotensin receptor blockers; RR, relative risk; CI, confidence interval; AE, adverse events; SAE, serious adverse events

110 Journal of the Renin-Angiotensin-Aldosterone System 12(2) controlled by negative feedback inhibition. The stimulation of the AT 1 receptors by Ang II immediately suppressed the release of renin from the juxtaglomerular cells. Angiotensin receptor blockade stimulated renin production by inhibiting the action of Ang II on AT 1 receptors. Such compensatory activation of the RAAS may limit the efficacy of AT 1 receptor blockers, and therefore the simultaneous administration of a direct renin inhibitor such as aliskiren may produce a better antihypertensive response. The combination of the maximum therapeutic doses was of particular clinical relevance, since patients not achieving BP control with an ACE inhibitor or ARB were generally titrated to a higher dose before additional drugs were used. For example, up-titration of ACE inhibitor therapy was showed to be as effective in reducing BP as adding an ARB to the lower ACE inhibitor dose. In the AMAZE studies, addition of high-dose candesartan 32 mg to lisinopril 20 mg provided little additional reduction in BP over up-titration to maximum dose lisinopril 40 mg. 23 Whether or not the combination therapy with a different RAAS blocker provided a synergistic effect was still a paradoxical problem. In an 8-week, multicenter, randomized, double-blind, placebo-controlled trial, 20 Pool and colleagues studied the efficacy of BP reduction by aliskiren and valsartan at different dosages. They also compared the efficacy of lowering of BP between monotherapy and combination therapy of the two agents. At the end of 8-week follow-up, the trough mean sitting DBP was decreased by 10.3 mmhg and 10.5 mmhg in the aliskiren 75 mg group and valsartan 80 mg group, respectively. When the dosages were doubled, the trough mean sitting DBP values were decreased by 10.3 mmhg and 11.0 mmhg in the aliskiren 150 mg group and valsartan 160 mg group, respectively. It was interesting that the reduction of trough mean sitting DBP in the aliskiren 75 mg combined with valsartan 80 mg group was superior to that seen in the aliskiren 150 mg monotherapy group. The results showed a significant fall in BP with aliskiren 75 mg and valsartan 80 mg combination therapy, similar to that achieved with higher doses of each monotherapy (aliskiren 300 mg or valsartan 320 mg), whereas aliskiren 75 mg or valsartan 80 mg monotherapy did not decrease BP significantly compared with placebo. These results might be indicative of additivity or synergy of the low-dose aliskiren and valsartan combination in hypertensive patients. On the other hand, aliskiren and valsartan combination therapy at Max dosage did not provide the same additive BP-lowering magnitude as their combination therapy at low dosage. In the aliskiren 300 mg and valsartan 320 mg monotherapy group, the trough mean sitting DBP values were decreased by 12.3 mmhg and 11.3 mmhg, respectively. Their combination therapy only provided a reduction of 12.9 mmhg in trough mean sitting DBP. Although the higher-dose combination therapy (aliskiren 150 mg/valsartan 160 mg and aliskiren 300 mg/ valsartan 320 mg) provided numerically superior BP reductions compared with the respective monotherapies, these differences were not statistically significant. The difference of the BP-lowering effect in combination therapy between low dosage and high dosage might be due to the limited binding sites of renin and angiotensin II type-1 receptor for aliskiren and ARBs, respectively In clinical practice, a stepwise antihypertensive therapy approach was a routine regimen. A single antihypertensive agent was used in initiating therapy, and additional drugs were added if BP was not adequately controlled. This leads to the achievement of BP goal in a timelier manner, especially for patients with BP > 20 mmhg above systolic goal or 10 mmhg above diastolic goal. Sustained BP elevation potentially increases the risk of developing or worsening organ damage. The JNC 7 24 and the ESH/ESC 25 guidelines recommend the initiation of two-drug treatment for patients whose BP is above 160/100 mmhg, or for those with diabetes or coronary heart disease. However, in some special clinical scenarios such as coronary disease, stroke, congestive heart failure, secondary hypertension, poorly controlled diabetes mellitus and chronic kidney failure, the data for using two RAAS blockers was still lacking. Giving aliskiren and ARB simultaneously for the treatment of patients who do not adequately respond to a single drug treatment should be carefully monitored. Aliskiren treatment showed a good safety and tolerability profile in these studies. At either 150 mg or 300 mg, aliskiren treatment was associated with a relatively low incidence of adverse events, similar to that seen in the ARB groups. The placebo-like tolerability of aliskiren is of major clinical importance, because concern over potential adverse effects is an important factor in patient non-compliance with antihypertensive therapy. 26 The combination of aliskiren and ARBs showed similar tolerability to the individual monotherapies. Our meta-analysis showed that the incidence of any adverse event, discontinuation due to adverse event and any serious adverse event was comparable between the combination therapy group and the respective monotherapy groups. Inhibition of the RAAS may lead to increases in serum potassium levels, so combining two renin angiotensin inhibitors hypothetically could increase the potential for hyperkalemia. In our meta-analysis, serum potassium levels of > 5.5 mmol/l were more frequent in the aliskiren/ ARB combination group (0.6 4.0%) than in the aliskiren monotherapy group (1.5 2.0%). However, most increases were transient, with potassium levels returning to normal without discontinuation of these drugs. Only a few patients (0.5 0.8%) receiving the combination therapy exhibited a serum potassium level of 6.0 mmol/l. Of increasing interest is the possibility that the antihypertensive agents used for blocking the RAAS may be used for organ protection. According to the results of ONTAGET 27, the authors suggest that the combination of ARB and ACE inhibitor dose not bring more benefits for

Zheng et al. 111 organ protection. However, Parving and colleagues demonstrated that adding aliskiren to a background therapy of losartan produced greater reduction in proteinuria than losartan alone in hypertensive patients with type 2 diabetes mellitus and nephropathy. 28 As the degree of proteinuria is closely associated with the rates of renal and cardiovascular events, these data suggest a potential clinical benefit of an aliskiren and ARB combination. The combination of aliskiren and an ARB might have a different organ-protective effect from the ARB and ACE inhibitor combination. In conclusion, once-daily oral treatment with the direct renin inhibitor aliskiren provided antihypertensive efficacy comparable with an ARB, with similar safety and tolerability in patients with hypertension. The introduction of aliskiren into clinical medicine is of particular interest because of the novel mechanism of action. Until outcomes data become available, there is as yet no evidence base to justify replacing an ACE inhibitor or ARB with aliskiren for end-organ protection in patients. Aliskiren does however represent an attractive new option as an add-on therapy for achieving BP goals. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Conflict of interest The authors have declared no conflict of interest. References 1. Dzau VJ. Theodore Cooper Lecture. Tissue angiotensin and pathobiology of vascular disease: a unifying hypothesis. Hypertension 2001; 37: 1047 1052. 2. Maibaum J and Feldman DL. Renin inhibitors as novel treatments for cardiovascular disease. Expert Opin Ther Patents 2003; 13: 589 603. 3. Zaman MA, Oparil S and Calhou DA. Drugs targeting the renin-angiotensin-aldosterone system. Nat Rev Drug Discov 2002; 1: 621 636. 4. Ruggenenti P, Perna A, Gherardi G, Garini G, Zoccali C, Salvadori M, et al. Renoprotective properties of ACEinhibition in non-diabetic nephropathies with non-nephrotic proteinuria. Lancet 1999; 354: 359 364. 5. Flather MD, Yusuf S, Køber L, Pfeffer M, Hall A, Murray G, et al. Long-term ACE-inhibitor therapy in patients with heart failure or left-ventricular dysfunction: a systematic overview of data from individual patients. ACE-Inhibitor Myocardial Infarction Collaborative Group. Lancet 2000; 355: 1575 1581. 6. Turnbull F. Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectively designed overviews of randomised trials. Lancet 2003; 362: 1527 1535. 7. Watanabe T, Barker TA and Berk BC. Angiotensin II and the endothelium: diverse signals and effects. Hypertension 2005; 45: 163 169. 8. Skeggs LT Jr, Kahn JR, Lentz K and Shumway NP. The preparation, purification, and amino acid sequence of a polypeptide renin substrate. J Exp Med 1957; 106: 439 453. 9. Gross F, Lazar J and Orth H. Inhibition of the renin-angiotensinogen reaction by pepstatin. Science 1971; 175: 656. 10. Wood JM, Maibaum J, Rahuel J, Grütter MG, Cohen NC, Rasetti V, et al. Structure-based design of aliskiren, a novel orally effective renin inhibitor. Biochem Biophys Res Commun 2003; 308: 698 705. 11. Moher D, Cook DJ, Eastwood S, Olkin I, Rennie D and Stroup DF. Improving the quality of reports of meta-analysis of randomized controlled trials: the QUOROM statement. Quality of reporting of meta-analysis. Lancet 1999; 354: 1896 1900. 12. Landis JR and Koch GG. The measurement of observer agreement for categorical data. Biometrics 1977; 33: 159 174. 13. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996; 17: 1 12. 14. Higgins JP, Thompson SG, Deeks JJ and Altman DG. Measuring inconsistency in meta-analysis. Br Med J 2003; 327: 557 560. 15. Egger M, Davey Smith G, Schneider M and Minder C. Bias in the meta-analysis detected by a simple, graphical test. Br Med J 1997; 315: 629 634. 16. Stanton A, Jensen C, Nussberger J and O Brien E. Blood pressure lowering in essential hypertension with an oral renin inhibitor, aliskiren. Hypertension 2003; 42: 1137 1143. 17. Gradman AH, Schmieder RE, Lins RL, Nussberger J, Chiang Y and Bedigian MP. Aliskiren, a novel orally effective renin inhibitor, provides dose-dependent antihypertensive efficacy and placebo-like tolerability in hypertensive patients. Circulation 2005; 111: 1012 1018. 18. Jordan J, Engeli S, Boye SW, Le Breton S and Keefe DL. Direct Renin inhibition with aliskiren in obese patients with arterial hypertension. Hypertension 2007; 49: 1047 1055. 19. Oparil S, Yarows SA, Patel S, Fang H, Zhang J and Satlin A. Efficacy and safety of combined use of aliskiren and valsartan in patients with hypertension: a randomised, doubleblind trial. Lancet 2007; 370: 221 229. 20. Pool JL, Schmieder RE, Azizi M, Aldigier JC, Januszewicz A, Zidek W, et al. Aliskiren, an orally effective renin inhibitor, provides antihypertensive efficacy alone and in combination with valsartan. Am J Hypertens 2007; 20: 11 20. 21. Yarows SA, Oparil S, Patel S, Fang H and Zhang J. Aliskiren and valsartan in stage 2 hypertension: subgroup analysis of a randomized, double-blind study. Adv Ther 2008; 25: 1288 1302. 22. Geiger H, Barranco E, Gorostidi M, Taylor A, Zhang X, Xiang Z, et al. Combination therapy with various combinations of aliskiren, valsartan, and hydrochlorothiazide in hypertensive patients not adequately responsive to hydrochlorothiazide alone. J Clin Hypertens (Greenwich) 2009; 11: 324 332. 23. Izzo JL Jr, Weinberg MS, Hainer JW, Kerkering J and Tou CK. Antihypertensive efficacy of candesartan-lisinopril in combination vs. up-titration of lisinopril: the AMAZE trials. J Clin Hypertens (Greenwich) 2004; 6: 485 493.

112 Journal of the Renin-Angiotensin-Aldosterone System 12(2) 24. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003; 289: 2560 2572. 25. Mancia G, De Backer G, Dominiczak A, Cifkova R, Fagard R, Germano G, et al. 2007 Guidelines for the management of arterial hypertension: the task force for the management of arterial hypertension of the European Society of Hpertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens 2007; 25: 1105 1187. 26. Neutel JM, Smith DH and Weber MA. Low-dose combination therapy: an important first-line treatment in the management of hypertension. Am J Hypertens 2001; 12: 286 292. 27. The ONTARGET Investigators. Telmisartan, ramipril or both in patients at high risk for vascular events. N Engl J Med 2008; 358: 1547 1559. 28. Parving HH, Persson F, Lewis JB, Lewis EJ, Hollenberg NK and AVOID Study Investigators. Aliskiren combined with losartan in type 2 diabetes and nephropathy. N Engl J Med 2008; 358: 2433 2446.