Comparison of the Efficacy of Candesartan and Losartan: a Meta-Analysis of Trials in the Treatment of Hypertension

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Journal of Human Hypertension (2010) 24, 525–531 & 2010 Macmillan Publishers Limited All rights reserved 0950-9240/10 www.nature.com/jhh ORIGINAL ARTICLE Comparison of the efficacy of candesartan and losartan: a meta-analysis of trials in the treatment of hypertension

PA Meredith, LS Murray and GT McInnes Department of Medicine & Therapeutics, Division of Cardiovascular & Medical Sciences, Gardiner Institute, Western Infirmary, Glasgow, Scotland, UK

Informed by the findings from prospective observational included in the analysis using a random effect model. studies and randomized outcome trials, guidelines for Mean changes in SBP and DBP were compared for each the management of hypertension acknowledge that drug alone and after stratification for dose and for the benefit of treatment can be attributed largely to combination with hydrochlorothiazide (HCTZ). On the blood pressure (BP) reduction. Therefore, quantification basis of all the data, the weighted mean difference of differential BP lowering of different agents within favoured candesartan—3.22 mm Hg (95% confidence classes of anti-hypertensives is of practical importance. interval (CI) 2.16, 4.29) for SBP and 2.21 mm Hg (95% CI The objective of this analysis was to compare the 1.34, 3.07) for DBP. These findings were consistent efficacy of candesartan and losartan with respect to when analyses according to dose and combination with reduction in systolic and diastolic BP (SBP and DBP). HCTZ were carried out. Thus, it can be concluded that at A systematic literature search of databases from 1980 to currently recommended doses, candesartan is more 1 October 2008 identified 13 studies in which candesartan effective than losartan in lowering BP. and losartan were compared in randomized trials in Journal of Human Hypertension (2010) 24, 525–531; hypertensive patients. Data from 4066 patients were doi:10.1038/jhh.2009.99; published online 17 December 2009

Keywords: angiotensin II type 1 receptor blockers; anti-hypertensive treatment; randomized controlled trials; losartan; candesartan; benzimidazoles

Introduction five major classes of anti-hypertensive agents are suitable for the initiation and maintenance of anti- Placebo-controlled trials in mild–moderate hyper- hypertensive treatment, and furthermore suggest that, tension and meta-analyses arising from these trials because many patients require more than one drug, clearly established the benefits of treating hyperten- 1 emphasis on identification of the first class of drugs to sion to reduce cardiovascular (CV) events. The most be used is often futile.4 This advice fails to acknowl- recent analysis from the Blood Pressure Lowering edge the fact that there may be significant differences Treatment Trialists’ Collaboration (BPLTTC) has in the magnitude of the anti-hypertensive responses confirmed that all commonly used blood pressure between drugs within a given class. (BP)-lowering treatments reduce the risk of major CV Losartan was the first angiotensin II receptor events, and that larger reductions in BP produce 2 blocker (ARB) to be approved for clinical use, and larger reductions in CV risk. However, data from a number of other ARBs have subsequently been national surveys and other sources suggest a high licensed for the treatment of hypertension. It has prevalence of uncontrolled hypertension, with up been suggested that all ARBs lower BP to a similar to two-thirds of individuals with hypertension being 3 extent when administered at the usual recom- inadequately treated. All current hypertension mended doses for the treatment of hypertension, treatment guidelines agree that the major benefit of and in addition that, at these recommended doses, treatment is associated with improved BP control. The the dose response for BP reduction with all ARBs is European guidelines (ESH/ESC, 2007) suggest that all relatively flat.5 This position was challenged by an analysis of the dose–response relationships for Correspondence: Dr P Meredith, Department of Medicine & various ARBs, which showed a significant differ- Therapeutics, Division of Cardiovascular & Medical Sciences, entiation in the achieved BP reductions.6 However, Gardiner Institute, Western Infirmary, Glasgow, Scotland, G11 both analyses were potentially compromised, 6NT, UK. E-mail: [email protected] because only data from disparate studies submitted Received 22 September 2009; revised and accepted 1 November to the Food and Drug administration (FDA) for 2009; published online 17 December 2009 regulatory and licensing purposes were considered. Comparison of the anti-hypertensive effects of candesartan and losartan PA Meredith et al 526 The ARBs have potentially important differences metabolic syndrome and chronic kidney disease; in pharmacokinetic and pharmacodynamic charac- (iii) intervention—candesartan versus losartan— teristics. For instance, losartan and candesartan used as monotherapy or in fixed combination with cilexetil are both pro-drugs, but while losartan hydrochlorothiazide (HCTZ); and (iv) BP reported at requires cytochrome P450-mediated biotransforma- baseline and at end point or intermediate end point. tion to yield the active moiety EXP-3174,7 cande- In some instances, the publications involved the sartan cilexetil is rapidly converted to candesartan same group or subgroup of patients. To avoid by ester hydrolysis during absorption from the duplication, only data from the most recent series gastrointestinal tract.8 In vitro studies have shown were included in the analysis. that candesartan acts as an insurmountable antagonist and is able to virtually eliminate the AT1 9 receptor-mediated effects of angiotensin II. Com- Statistical analysis pared with other widely used ARBs, candesartan The outcome measure was assessed on an intention 9 shows high binding affinity for the AT1 receptor, to treat basis, with the intention to treat population that is, B80-fold higher than losartan and 10-fold comprising all randomized patients who received higher than EXP 3174. Insurmountable antagonism study medication and in whom a valid baseline provides long-lasting suppression of the renin– measurement was available. angiotensin–aldosterone system, and it is suggested Weighted mean difference (WMD) was calculated that this accounts for the magnitude of the anti- for the reduction in BP. Studies that reported the hypertensive efficacy of candesartan and for its mean values and standard deviation (s.d.) of change sustained duration of effect.10 from baseline in systolic BP (SBP) and diastolic BP To determine whether the pharmacological char- (DBP), or obtained these values by contacting with acteristics of candesartan offer advantages over the the authors, used these values directly. When papers first in class ARB, losartan, with respect to anti- reported standard error (s.e.) but not s.d., the s.d. hypertensive efficacy, we undertook a meta-analysis was calculated using the formula s.d. ¼ s.e. Â (N)0.5. of all studies in which the two agents were The studies in which the mean values and s.d. or s.e. compared directly in hypertensive patients. of change from baseline were not reported, the authors of the study were contacted to obtain these data. When mean BP reduction (BPR) and s.d.s Methods could not be obtained, these were computed using the formula BPR ¼ BPbaseline–BPend point and Search criteria 2 2 0.5 SDBPR ¼ (s.d.baseline þ s.d.end point) . The aim was to identify all randomized controlled The statistical analysis was performed using trials in which the anti-hypertensive effects of RevMan software version 5, provided by the Co- candesartan were compared with those of losartan chrane Information Management System,11 using the in hypertensive patients. The search strategy was methodology described by DerSimonian and focused on the reports of clinical trials of cande- Laird.12 Given the disparate sample sizes and sartan versus losartan, which were identified clinical characteristics among the study groups, an through a systematic search of PubMed (from 1966 assumption that heterogeneity could be present to 1 October 2008), Embase (from 1980 to 1 October even when no statistical significance was identified 2008) and the Cochrane library (from 1 October 2008 was made, and thus, a random effects model with onwards). The search combined terms related to inverse variance was fitted to the data. The results candesartan and losartan (including MeSH search are reported with 95% confidence intervals (CIs). using exp ‘benzimidazoles’, exp ‘tetrazoles’ and exp The w2-test was applied to all the comparisons to ‘benzoates’, and keyword search using words ‘can- evaluate the evidence of heterogeneity of treatment desartan’, ‘Blopress’, ‘Amias’, ‘Kenzen’, ‘Atacand’, effects between studies and a Z-test was performed ‘Ratacand’, ‘losartan’, ‘Cozaar’, ‘Hyzaar’). to test the overall effect. We also searched the reference lists of original To evaluate the impact of potential methodologi- reports and meta-analyses of studies involving ARBs cal differences of various randomized clinical trials (retrieved through the electronic searches) to identi- on the results of this meta-analysis, a sensitivity fy studies that were not yet included in the analysis was performed. computerized databases.

Results Trial eligibility For a trial to be eligible for inclusion in the meta- The initial search process identified 48 studies that analysis, it was required to meet a number of could potentially have been included in the analy- selection criteria, including (i) randomized clinical sis, and of these, a total of 13 randomized controlled trials, including quasi-randomized clinical trials; (ii) trials met the pre-specified criteria for inclusion in patients with hypertension, with or without the this meta-analysis.13–25 A total of 4066 patients were simultaneous presence of other diseases such as included in the analysis, and the design and patient

Journal of Human Hypertension Comparison of the anti-hypertensive effects of candesartan and losartan PA Meredith et al 527 Table 1 Design and patient characteristics of randomized clinical trials included in the meta-analysis

Study Candesartan Losartan Candesartan Losartan Study design Duration Mean age Sex reference (n) (n) dose (mg) dose (mg) (mg) (weeks) (years) (percentage M/F)

Andersson et al.13 82 83 8 50 RDB/PG 8 60 57/43 Andersson et al.13 84 83 16 50 RDB/PG 8 59 62/38 Baguet et al.14 87 89 8 50 RDB/PG 8 54 58/42 Bakris et al.15 322 332 32 100 RDB/PG 8 54 58/42 Gradman et al.16 162 170 16/32 50/100 RDB/PG/T 8 56 58/42 Koenig17 81 79 16 HCTZ 50 HCTZ RDB/PG 6 58 47/53 Koh et al.18 31 32 16 100 R/PG 8 49 77/23 Lacourciere et al.19 109 106 8 50 RDB/PG 4 55 63/47 Lacourciere et al.19 106 100 16 100 RDB/PG/FT 8 55 63/47 Manolis et al.20 462 449 8/16 50/100 RDB/PG/FT 12 51 51/49 Matsuda et al.21 17 15 4 25 R/PG 96 54 50/50 Nishimura et al.22 12 11 2-12 25-100 R/PG/T 4 56 56/44 Ohman et al.23 151 148 16 HCTZ 50 HCTZ RDB/PG 12 — 52/48 Rayner et al.24 25 27 8/16 50/100 R/PG/T 24 — 40/60 Vidt et al.25 307 304 32 100 RDB/PG/FT 8 56 49/51

Abbreviations: F, female; FT, forced titrated; HCTZ, hydrochlorothiazide (25 mg); M, male; PG, parallel group; RDB, randomized double blind; T, titrated. characteristics of randomized clinical trials in- 2.49 mm Hg (95% CI 1.52, 3.47; Po0.001) (Figure 4) cluded in the meta-analysis are shown in Table 1. and 7.03 mm Hg (95% CI 4.26, 9.80; Po0.001) The majority of the trials had a randomized, double- (Figure 5), respectively. blind, parallel group design. In two of the trials,13,19 Analysis of the DBP data from the trials produced two doses of candesartan were compared with a results that were compatible with those for SBP single dose of losartan. In these two trials, the (Table 2). Significant BP differentials favouring comparison of the two drugs was treated as candesartan were noted for all the trials with independent evaluations. WMD in DBP of 2.21 mm Hg (95% CI 1.34, 3.07) The initial analysis focused on the comparison of and a Z-value ¼ 4.99 (Po0.00001) (Table 2). Similar candesartan and losartan in all the trials identified, statistically significant differences in DBP were including those employing a fixed-dose combina- apparent for the subgroup analyses of monotherapy, tion of the two drugs with HCTZ. There was a ‘low-dose’, ‘high-dose’ and combination therapy significantly greater reduction in SBP with the use with HCTZ (Table 2). However, with the DBP of candesartan when compared with losartan (13 analyses, statistically significant heterogeneity was trials, 4066 patients) with a WMD in SBP of detected for a number of the analyses. 3.22 mm Hg (95% CI 2.16, 4.29; Po0.001) (Figure 1). Sensitivity analyses were undertaken to evaluate On the basis of the w2-test, there was no evidence of the effect of individual trials on the overall findings statistically significant heterogeneity in the trials for SBP and DBP. Sequential removal of individual included in the analysis (Figure 1). trials did not significantly modify the overall findings. Despite the lack of evidence of statistical heterogeneity, because the doses of drug used in different trials included in the analysis are disparate, further Discussion analyses were performed on the basis of subdivision by dose. These were classified by use of mono- The results of the meta-analysis of data derived from therapy: ‘low-dose’ (4 and 8 mg candesartan and 25 13 randomized clinical trials reveal that candesartan and 50 mg losartan); ‘high-dose’ (12, 16 and 32 mg treatment produces a greater reduction in SBP and candesartan and 100 mg losartan); and combination DBP when compared with treatment with losartan at with HCTZ. The results of these analyses are shown the currently recommended doses. This differential in Figures 2–5. All these analyses were consistent was apparent even when the database was divided and showed statistically superior SBP reductions on the basis of the administered dose. These with candesartan when compared with losartan, and findings are consistent with an earlier analysis that with no evidence of heterogeneity in the analyses. suggested that there was a significant differentiation With monotherapy, there was WMD in SBP, favour- in the achieved BP reductions with various ARBs, ing candesartan of 2.57 mm Hg (95% CI 1.71, 3.44; with candesartan producing greater BP reductions Po0.001) (Figure 2). Comparison of the ARBs at over the full therapeutic dose–response relationship ‘low-dose’ revealed a WMD in SBP of 2.74 mm Hg when compared with losartan and valsartan.6 These (95% CI 0.83, 4.64) and a Z-value ¼ 2.81 (P ¼ 0.005) findings are contrary to the suggestion that all ARBs (Figure 3). Corresponding figures for comparison of lower BP to a similar extent when administered at the ARBs at ‘high-dose’ and combination therapy their usual recommended doses for the treatment of with HCTZ produced values of WMD in SBP of hypertension.6

Journal of Human Hypertension Comparison of the anti-hypertensive effects of candesartan and losartan PA Meredith et al 528 Candesartan Losartan Mean Difference Mean Difference Study or Subgroup Mean SD Total Mean SD Total Weight 95% CI 95% CI Andersson et al 1998 15.7 24.5 82 12.3 22.1 83 2.1% 3.40 [-3.72, 10.52] Andersson et al 1998 16.9 24.3 84 12.3 22.1 83 2.1% 4.60 [-2.44, 11.64] Baguet et al 2006 10.8 11.3 87 8.8 8.9 89 8.7% 2.00 [-1.01, 5.01] Bakris et al 2001 13.3 14.8 322 9.8 14.2 332 12.6% 3.50 [1.28, 5.72] Gradman et al 1999 11.9 14.5 162 10 14.6 170 8.2% 1.90 [-1.23, 5.03] Koenig et al 2000 32.2 12.8 81 23.8 12.7 79 5.8% 8.40 [4.45, 12.35] Koh et al 2004 22.1 12.1 31 22.7 12.4 32 2.8% -0.60 [-6.65, 5.45] Lacourciere et al 1999 12.3 10.7 109 8.4 10.5 106 9.4% 3.90 [1.07, 6.73] Lacourciere et al 1999 14.5 11.8 106 10.3 11.5 100 8.0% 4.20 [1.02, 7.38] Manolis et al 2000 15.8 12.2 462 14.4 11.7 449 17.5% 1.40 [-0.15, 2.95] Matsuda et al 2003 14.2 9.7 17 15.2 10.4 15 2.1% -1.00 [-8.00, 6.00] Nishimura et al 2005 11.4 10 12 7.9 8.1 11 1.9% 3.50 [-3.91, 10.91] Ohman et al 2000 19.4 16.9 151 13.7 17.4 148 5.9% 5.70 [1.81, 9.59] Rayner et al 2006 25.8 18.3 25 17.7 15.6 27 1.3% 8.10 [-1.18, 17.38] Vidtet al 2001 13.4 15.1 307 10.1 14.9 304 11.7% 3.30 [0.92, 5.68]

Total (95% CI) 2038 2028 100.0% 3.22 [2.16, 4.29]

Heterogeneity: Tau2 = 1.06; Chi2 = 19.19, df = 14 (P = 0.16); I2 = 27% Test for overall effect: Z = 5.92 (P < 0.00001) -20 -10 0 10 20 Favours Losartan Favours Candesartan Figure 1 Comparison of the effects of candesartan and losartan on reduction in systolic blood pressure—all trials.

Candesartan Losartan Mean Difference Mean Difference Study or Subgroup Mean SD Total Mean SD Total Weight 95% CI 95% CI Andersson et al 1998 15.7 24.5 82 12.3 22.1 83 1.5% 3.40 [-3.72, 10.52] Andersson et al 1998 16.9 24.3 84 12.3 22.1 83 1.5% 4.60 [-2.44, 11.64] Baguet et al 2006 10.8 11.3 87 8.8 8.9 89 8.2% 2.00 [-1.01, 5.01] Bakris et al 2001 13.3 14.8 322 9.8 14.2 332 15.0% 3.50 [1.28, 5.72] Gradman et al 1999 11.9 14.5 162 10 14.6 170 7.6% 1.90 [-1.23, 5.03] Koh et al 2004 22.1 12.1 31 22.7 12.4 32 2.0% -0.60 [-6.65, 5.45] Lacourciere et al 1999 12.3 10.7 109 8.4 10.5 106 9.2% 3.90 [1.07, 6.73] Lacourciere et al 1999 14.5 11.8 106 10.3 11.5 100 7.3% 4.20 [1.02, 7.38] Manolis et al 2000 15.8 12.2 462 14.4 11.7 449 30.8% 1.40 [-0.15, 2.95] Matsuda et al 2003 14.2 9.7 17 15.2 10.4 15 1.5% -1.00 [-8.00, 6.00] Nishimura et al 2005 11.4 10 12 7.9 8.1 11 1.4% 3.50 [-3.91, 10.91] Rayner et al 2006 25.8 18.3 25 17.7 15.6 27 0.9% 8.10 [-1.18, 17.38] Vidtet al 2001 13.4 15.1 307 10.1 14.9 304 13.1% 3.30 [0.92, 5.68]

Total (95% CI) 1806 1801 100.0% 2.57 [1.71, 3.44] Heterogeneity: Tau2 = 0.00; Chi2 = 9.24, df = 12 (P = 0.68); I2 = 0% Test for overall effect: Z = 5.86 (P < 0.00001) -20-10 0 10 20 Favours Losartan Favours Candesartan Figure 2 Comparison of the effects of candesartan and losartan on reduction in systolic blood pressure—monotherapy trials.

Candesartan Losartan Mean Difference Mean Difference Study or Subgroup Mean SD Total Mean SD Total Weight 95% CI 95% CI Anderssonet al 1998 15.7 24.5 82 12.3 22.1 83 7.2% 3.40 [-3.72, 10.52] Baguetet al 2006 10.8 11.3 87 8.8 8.9 89 40.1% 2.00 [-1.01, 5.01] Lacourciereet al 1999 12.3 10.7 109 8.4 10.5 106 45.3% 3.90 [1.07, 6.73] Matsuda et al 2003 14.2 9.7 17 15.2 10.4 15 7.4% -1.00 [-8.00, 6.00]

Total (95% CI) 295 293 100.0% 2.74 [0.83, 4.64] Heterogeneity: Tau2 = 0.00; Chi2 = 2.01, df = 3 (P = 0.57); I2 = 0% Test for overall effect: Z = 2.81 (P = 0.005) -10 -5 0 5 10 Favours Losartan Favours Candesartan Figure 3 Comparison of the effects of candesartan and losartan on reduction in systolic blood pressure—‘low-dose’ trials.

It is well established that individuals with hypertensive patients is to reduce events such as elevated BP are at greater risk for CV or cerebrovas- stroke, myocardial infarction and heart failure. cular events and the primary aim of treating Epidemiological evidence and findings from

Journal of Human Hypertension Comparison of the anti-hypertensive effects of candesartan and losartan PA Meredith et al 529 Candesartan Losartan Mean Difference Mean Difference Study or Subgroup Mean SD Total Mean SD Total Weight 95% CI 95% CI Bakris et al 2001 13.3 14.8 322 9.8 14.2 332 19.2% 3.50 [1.28, 5.72] Gradman et al 1999 11.9 14.5 162 10 14.6 170 9.7% 1.90 [-1.23, 5.03] Koh et al 2004 22.1 12.1 31 22.7 12.4 32 2.6% -0.60 [-6.65, 5.45] Lacourciere et al 1999 14.5 11.8 106 10.3 11.5 100 9.4% 4.20 [1.02, 7.38] Manolis et al 2000 15.8 12.2 462 14.4 11.7 449 39.5% 1.40 [-0.15, 2.95] Nishimura et al 2005 11.4 10 12 7.9 8.1 11 1.7% 3.50 [-3.91, 10.91] Rayner et al 2006 25.8 18.3 25 17.7 15.6 27 1.1% 8.10 [-1.18, 17.38] Vidt et al 2001 13.4 15.1 307 10.1 14.9 304 16.8% 3.30 [0.92, 5.68]

Total (95% CI) 1427 1425 100.0% 2.49 [1.52, 3.47] Heterogeneity: Tau2 = 0.00; Chi2 = 6.86, df= 7 (P = 0.44); I2 = 0% Test for overall effect: Z = 5.01 (P < 0.00001) -20 -10 0 10 20 Favours Losartan Favours Candesartan Figure 4 Comparison of the effects of candesartan and losartan on reduction in systolic blood pressure—‘high-dose’ trials.

Candesartan Losartan Mean Difference Mean Difference Study or Subgroup Mean SD Total Mean SD Total Weight 95% CI 95% CI

Koenig et al 2000 32.2 12.8 81 23.8 12.7 79 49.2% 8.40 [4.45, 12.35] Ohman et al 2000 19.4 16.9 151 13.7 17.4 148 50.8% 5.70 [1.81, 9.59]

Total (95% CI) 232 227 100.0% 7.03 [4.26, 9.80] Heterogeneity: Tau2 = 0.00; Chi2 = 0.91, df = 1 (P = 0.34); I2 = 0% Test for overall effect: Z = 4.97 (P < 0.00001) -10 -5 0 5 10 Favours Losartan Favours Candesartan Figure 5 Comparison of the effects of candesartan and losartan on reduction in systolic blood pressure—‘HCTZ combination’ trials.

Table 2 Comparison of the effects of candesartan and losartan on reduction in diastolic blood pressure

Candesartan (n) Losartan (n) WMD (mm Hg) 95% CI Test of overall Test of heterogeneity (mm Hg) effect Z (P) w2 (P)

All trials 2038 2028 2.21 1.34, 3.07 4.99 (o0.00001) 32.15 (0.004) Monotherapy trials 1806 1801 1.76 1.03, 2.50 4.70 (o0.00001) 18.05 (0.11) ‘Low-dose’ trials 295 293 2.02 0.81, 3.23 3.27 (0.001) 0.44 (0.93) ‘High-dose’ trials 1427 1425 1.63 0.59, 2.67 3.06 (0.002) 15.77 (0.03) ‘HCTZ combination’ trials 232 227 4.34 0.82, 7.87 2.41 (0.02) 4.99 (0.03)

Abbreviations: CI, confidence interval; HCTZ, hydrochlorothiazide (25 mg); WMD, Weighted mean difference. outcome trials indicate that the relative risk of CV 0.75) and of B35% in stroke (relative risk 0.65), at events is related to BP levels in a continuous and the age 65 years. The results of our analyses suggest linear manner.26 Thus, there is a sound rationale for that candesartan monotherapy could increase the suggesting that when all other factors are equal, it is DBP reduction by an additional 1.8 mm Hg when logical, when initiating anti-hypertensive treatment, compared with losartan. Adopting the previously to use within any given drug class, the agent most published methodology,29 it can be shown that this likely to produce the greatest BP reduction. It could additional BP response could reduce coronary heart be argued that small differences in BP reduction in disease events by 32% (because 0.756.8/5 ¼ 0.68), an individual patients are of little consequence, and a additional 7% points, and reduce stroke by 44% recent meta-analysis has suggested that differences (0.656.8/5 ¼ 0.56), an additional 9% points. On the in efficacy between drugs within a class are likely to basis of the differential in DBP with the combination be ‘small and clinically unimportant’.27 However, therapy using HCTZ (4.3 mm Hg), similar considera- there is compelling evidence on a population basis tions predict that coronary heart disease events that this is not the case. A meta-analysis of 61 cohort would be reduced by 41% and stroke by 55%. studies, supported by a meta-analysis of 147 Despite the BP differentials, it could be argued randomized trials,27,28 suggests that when a single that there is no data from randomized outcome trials BP-lowering drug at a standard dose reduces DBP by that support the contention that there are mean- B5 mm Hg, there is a resulting reduction of B25% ingful differences between the drugs. The LIFE in risk of coronary heart disease events (relative risk (Losartan Intervention For Endpoint reduction in

Journal of Human Hypertension Comparison of the anti-hypertensive effects of candesartan and losartan PA Meredith et al 530 hypertension) trial30 showed that with equal BP Conflict of interest control, a losartan-based regimen was superior in reducing CV end points (mainly stroke) to an The analyses presented were supported by a grant atenolol-based regimen in patients with left ventri- from Takeda Pharmaceuticals, which carried cular hypertrophy. Similar, but statistically non- no restrictions regarding the publication of the significant, results were obtained in the SCOPE analysis. Peter Meredith and Gordon McInnes have (Study On Cognition And Prognosis In The Elderly) received honoraria for consultancy, advisory board study,31 in which candesartan was compared with attendance and speaker fees from a number of HCTZ in elderly patients. The apparent discrepancy pharmaceutical companies, including AstraZeneca, between the studies is probably due to the inade- Bayer, Boehringer Ingelheim, GSK, MSD, Pfizer and quate statistical power of SCOPE, in which the Takeda. protocol had to be changed during the course of the study for ethical reasons, and the disparate nature of the populations studied. Furthermore, a putative References placebo comparison of the SCOPE and LIFE32 suggested that there were no differences between 1 Collins R, Peto R, MacMahon S, Hebert P, Fiebach NH, Eberlein KA et al. Blood pressure, stroke, and coronary the trials, and if anything, the outcomes in SCOPE heart disease: part 2. Short-term reductions in blood were slightly better than those in LIFE. There are no pressure: overview of randomised drug trials in their outcome trials in which losartan and candesartan epidemiological context. Lancet 1990; 335: 827–838. have been directly compared. However, the ‘Real 2 Blood Pressure Lowering Treatment Trialists’ Colla- Life’ study33 has recently compared the two agents boration. Effects of different regimens to lower blood in a cohort study, conducted in selected primary pressure on major cardiovascular events in older and care centres in Sweden. Candesartan was associated younger adults: meta-analysis of randomised trials. Br with a lower risk of CV disease, heart failure and Med J 2008; 336: 1121–1123. peripheral artery disease compared with losartan, 3 Wolf-Maier K, Cooper RS, Kramer H, Banegas JR, with no evidence of a differential BP reduction Giampaoli S, Joffres MR et al. Hypertension treatment and control in five European countries, Canada, and between the treatment groups. the United States. Hypertension 2004; 43: 10. The results obtained from our meta-analysis are 4 Mancia G, De Backer G, Dominiczak A, Cifkova R, subject to the limitations that are inherent in any Fagard R, Germano G et al. 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