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

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