Journal of Human (2009) 23, 339–349 & 2009 Macmillan Publishers Limited All rights reserved 0950-9240/09 $32.00 www.nature.com/jhh ORIGINAL ARTICLE versus angiotension- converting enzyme inhibitors in the treatment of hypertension: a meta-analysis of randomized controlled trials

Z Zou1,3, G-L Xi2,3, H-B Yuan1, Q-F Zhu1 and X-Y Shi1 1Department of Anesthesiology, Changzheng Hospital, Second Military Medical University, Shanghai, People’s Republic of China and 2Center for New Drug Evaluation, Institute of Basic Medical Science, Second Military Medical University, Shanghai, People’s Republic of China

Telmisartan and -converting enzyme inhibi- 0.33–2.62). Telmisartan also showed a greater DBP tors (ACEIs) are both effective and widely used response rate than (relative risk (RR) 1.15, antihypertensive drugs targeting –angiotensin– 95% CI 1.05–1.26), (RR 1.34, 95% CI 1.11–1.61) aldosterone system. The study aimed to estimate the and (RR 1.22, 95% CI 1.05–1.41). There was efficacy and tolerability of telmisartan in comparison no statistical difference in DBP reduction or therapeutic with different ACEIs as monotherapy in the treatment of response rate between telmisartan and (WMD hypertension. Cochrane Central Register of Controlled À0.30, 95% CI À0.65 to 0.05; RR 0.99, 95% CI 0.80–1.23, Trials, PubMed and Embase were searched for relevant respectively). Telmisartan had fewer drug-related studies. A meta-analysis of all randomized controlled adverse events than enalapril (RR 0.57, 95% CI 0.44–0.74), trials fulfilling the predefined criteria was performed. A ramipril (RR 0.44, 95% CI 0.26–0.75), lisinopril (RR 0.70, random-effect model was used to account for hetero- 95% CI 0.56–0.89) and perindopril (RR 0.52, 95% CI geneity among trials. Twenty-eight randomized con- 0.28–0.98). The meta-analysis indicates that telmisartan trolled trials involving 5157 patients were ultimately provides a superior BP control to ACEIs (enalapril, identified out of 721 studies. Telmisartan had a greater ramipril and perindopril) and has fewer drug-related diastolic blood pressure (DBP) reduction than enalapril adverse events and better tolerability in hypertensive (weighted mean difference (WMD) 1.82, 95% confidence patients. interval (CI) 0.66–2.99), ramipril (WMD 3.09, 95% CI Journal of Human Hypertension (2009) 23, 339–349; 1.94–4.25) and perindopril (WMD 1.48, 95% CI doi:10.1038/jhh.2008.132; published online 6 November 2008

Keywords: telmisartan; angiotensin II type 1 receptor blockers; angiotensin-converting enzyme inhibitors; antihyper- tensive agents

Introduction Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II type 1 receptor blockers Hypertension is a major risk factor for myocardial (ARBs) are two kinds of effective and widely used infarction, congestive , stroke, end-stage 1 antihypentisive drugs targeting renin–angiotensin– renal disease and even sudden death. Benefits of aldosterone system. ACEIs prevent the generation of consistent reduction of blood pressure (BP) to 2 angiotensin II from angiotensin I, while ARBs exert prevent end-organ damages are well established. their vasodilatation effect at the receptor level by However, only 34% patients with hypertension are inhibiting the binding of angiotensin II to the type 1 adequately controlled to a BP of p140/90 mm Hg, receptors, irrespective of whether angiotensin II is despite the fact that the importance of BP control 3 generated by renin–angiotensin cascade or in local has been recognized. tissues by other pathways. The direct blockade of angiotensin II to the type 1 receptors might be more Correspondence: Professor X-Y Shi, Department of Anesthesio- effective than the indirect blockade of ACEIs. Unlike lgoy, Changzheng Hospital, Second Military Medical University, ACEIs, ARBs do not disrupt the degeneration of 415 Fengyang Road, Shanghai 200003, People’s Republic of other peptides such as , which may cause China. persistent dry cough and . The ARB E-mail: [email protected] 3These authors contributed equally to this study. telmisartan is an orally active and potent nonpep- Received 1 August 2008; revised 5 October 2008; accepted 5 tide selective AT1 antagonist with a long terminal October 2008; published online 6 November 2008 elimination half-life of about 24 h in the patients Meta-analysis comparing telmisartan with ACEIs Z Zou et al 340 with hypertension.4 Telmisartan is an effective 2008). The search combined the terms related to antihypertensive agent that provides smooth control ‘telmisartan’ (‘Micardis’, ‘Pritor’) with the terms of BP, with a low rate of adverse events profile related to ACEIs (‘’, ‘’, ‘benaze- compared with placebo,4–6 and without cough that is prilat’, ‘’, ‘ceranapril’, ‘’, ‘cilaza- frequently associated with ACEIs.6 In addition, the prilat’, ‘’, ‘enalapril’, ‘’, lipophilic nature of its molecule should enhance its ‘’, ‘fosinoprilic acid’, ‘’, ‘libenza- tissue penetration compared with other ARBs.7 pril’, ‘lisinopril’, ‘’, ‘moveltipril’, ‘altio- Telmisartan 80 mg given once daily provides a better pril’, ‘’, ‘perindopril’, ‘perindoprilat’, BP control than 50 mg or 80 mg.8,9 ‘’, ‘’, ‘ramipril’, ‘ramiprilat’, Telmisartan provides numerically greater weighted ‘’, ‘’, ‘’, ‘ average reductions of diastolic BP (DBP) and hydrochloride’, ‘teprotide’, ‘’, ‘’), systolic BP (SBP) than and using Boolean operators and database-specific cilexetil.10 syntax. We also searched the reference lists of the The findings of the Ongoing Telmisartan Alone original reports and meta-analyses of studies invol- and in Combination with Ramipril Global Endpoint ving ARBs (retrieved through the electronic Trial (ONTARGET) show that the combination of searches) to identify studies, which had not yet telmisartan with ramipril is associated with more been included in the computerized databases. adverse events without an increase in benefits in patients with vascular disease or high-risk dia- betes.11 Aiming to evaluate which drug was more eligible for patients with hypertension, we under- Trials selection took a systematic review and meta-analysis to Studies meeting the following selection criteria determine the clinical efficacy and tolerability were included in this meta-analysis: (1) study of telmisartan in comparison with ACEIs as mono- design: prospective randomized controlled clinical therapy in the treatment of hypertension. trials; (2) population: patients with hypertension, with or without other diseases such as metabolic syndrome and chronic kidney diseases; (3) inter- Methods ventions: telmisartan versus ACEIs, used as mono- therapy and (4) outcome variables: at least one of BP, We tried to identify and include all randomized therapeutic BP response rates, mortality, cerebro- controlled trials carried out to assess the efficacy cardiovascular event rates, adverse events, with- and tolerability associated with the use of telmisar- drawal and cough was reported. Two reviewers (ZZ, tan compared with ACEIs in patients with hyper- GLX) independently assessed the eligibility of a trial tension. to be included in our meta-analysis, and this was checked by another author (XYS). To avoid duplica- Outcome measures tion, only the data from the latest series were The primary efficacy variable was the reduction included if the same group of patients were involved from the baseline to the end of treatment in clinical in different reports. DBP and SBP. Second efficacy variables included the following: therapeutic response rates of DBP and SBP (DBP o90 mm Hg and/or a reduction of X10 mm Hg, 24-h mean ambulatory DBP Data extraction o85 mm Hg and/or a reduction from baseline of Data were independently abstracted for each identi- X10 mm Hg; SBP o140 mm Hg and/or a reduction fied trials by two researchers (ZZ, GLX), and any of X10 mm Hg, 24-h mean ambulatory SBP disagreement was resolved by discussion. Data o130 mm Hg and/or a reduction from baseline of were extracted from each study with a predesigned X10 mm Hg); reductions from baseline in ambula- review form. The following data were included: the tory DBP and SBP in 24-h, the last 6-h, daytime and authors of each study, the year of publication, the night time periods; and rate of cerebro-cardiovascu- design of the trial, the duration of the study, the lar events. We also assessed the tolerability of the number of the patients, the age of the patients, sex, drugs by considering overall rates of withdrawal, baseline SBP/DBP values, end point SBP/DBP withdrawal for adverse events, the number of values, changes from baseline in SBP and DBP, the patients experiencing adverse events, and the ambulatory SBP and DBP values and therapeutic relationship between such events and the drugs response rates of SBP and DBP. In addition, we administered to patients. retrieved the number or proportion of adverse events, withdrawals, mortality and cerebro-cardio- vascular events. Only the data associated with Search strategy monotherapy were retrieved if the patients received We searched the Cochrane Central Register of monotherapy as well as a combination of other Controlled Trials (Cochrane Library Issue 2, 2008), antihypertensive drugs once they were reported PubMed (up to 7 June 2008), Embase (1980 to June separately.

Journal of Human Hypertension Meta-analysis comparing telmisartan with ACEIs Z Zou et al 341 Qualitative assessment Studies identified from literature search The studies were appraised independently by two (n= 716) and hand search (n=5) authors (ZZ, GLX) based on the standard criteria (generation of allocation concealment, intention-to- Excluded (n=552) treat analysis, blinding and loss to follow-up), and Duplicate citations (n=161) additional quantitative quality was assessed by Not clinical controlled trials (n=391) using the scoring system developed by Jadad,12 appropriately modified according to the treatments Studies obtained for full paper review (n=169) under study. The quality scoring system was as follows: (1) Was the study described as randomized Excluded (n=140) Not randomized trials (n=31) (1 ¼ yes, 0 ¼ no)? (2) Was the study described as Not patients with hypertension (n=33) double-blind or prospective, randomized, open- No monotherapy (n=14) label, blinded-end point (PROBE)13 (1 ¼ yes, No ACEI control arm (n=62) 0 ¼ no)? (3) Was there a description of withdrawals and dropouts (1 ¼ yes, 0 ¼ no)? (4) Was the method Studies provisionally included (n=29) of randomization well described and appropriate (1 ¼ yes, 0 ¼ no)? (5) Was the method of double-blind Studies with no data on outcome variables (n=1) well described and appropriate (1 ¼ yes, 0 ¼ no)? (6) Deduct 1 point if methods for randomization or Studies included in final analysis (n=28) blinding were inappropriate. Telmisartan vs enalapril (n=13) Telmisartan vs ramipril (n=6) Telmisartan vs lisinopril (n=4) Telmisartan vs perinopril (n=5) Statistical analysis Not all of the trials reported on all the outcomes of Figure 1 The diagram showing studies eligible for inclusion in interest to our analysis. We undertook separate the meta-analysis. meta-analyses for each comparison and outcome. We combined the data by using a random-effect tan was compared with enalapril in 13 trials, with model on the assumption that variation in clinical ramipril in 6 trials, with lisinopril in 4 trials and characteristics and sample sizes in the study groups with perindopril in 5 trials. produced heterogeneity. All included trials were prospective randomized We summarized dichotomous data as relative risk controlled clinical trials. One trial had the maxi- (RR) and continuous data as weighted mean differ- mum Jadad score of 5, 7 had a score of 4, 7 had a ence (WMD). When the authors reported mean BP score of 3, 7 had a score of 2 and 6 had 1. Allocation reduction and standard deviation (s.d.) from the concealment was adequate in 2 trials, inadequate in baseline to the end of treatment, we retrieved them 7 trials (open label) and unclear in the remaining directly. When the authors reported standard error trials. Thirteen trials were double blind and six were (s.e.) instead of s.d., we calculated s.d. by using the single blind, with no report in the remaining trials. 1/2 formula: s.d. ¼ s.e. Â (N) . When mean BP reduc- Finally, intention-to-treat principle was used to tion and its s.d. were not available, we computed analyse the patients in 10 trials. Characteristics of them by using the methods given by Cochrane the included trials were shown in Table 1. 14 handbook version 4.2.6. The statistical analysis In one trial,5 in which the patients were rando- was carried out with RevMan version 4.2. mized to receive telmisartan 40, 80, 120 mg or enalapril 20 mg, we did not extract the data of telmisartan 40 and 120 mg to avoid potential Sensitivity analysis duplication. So did in another trial.15 To evaluate the effect of methodological character- istics of studies on the results of this meta-analysis, the impact of the components of such characteristics Telmisartan versus enalapril on our meta-analysis was assessed by sensitivity Thirteen trials involving 1682 patients compared analysis. telmisartan with enalapril.5,15–26 There was a greater reduction in both DBP and SBP with the use of Results telmisartan as compared with enalapril. Therapeutic response rates of DBP and SBP favored telmisartan The flow diagram (Figure 1) showed the process of (RR 1.15, 95% confidence interval (CI) 1.05–1.26; RR identifying studies eligible for inclusion in the meta- 1.18, 95% CI 1.02–1.38, respectively). There was analysis. We obtained 169 full papers from 721 significant difference that favored telmisartan in studies for detail evaluation. A total of 28 studies adverse events, drug-related adverse events and were included for final analysis, involving 5157 cough. Two patients suffered from angioedema in patients. Among the included studies, 21 were in the enalapril group.15,22 There was no difference in English, 5 in Chinese, 1 in French and 1 in Russian. severe adverse events (RR 0.57, 95% CI 0.11–2.88). Fourteen trials were multi-center studies. Telmisar- No death or cerebro-cardiovascular event was

Journal of Human Hypertension ora fHmnHypertension Human of Journal 342

Table 1 Characteristics of randomized clinical trials included in the meta-analysis

Study Number Mean age Sex (M/F) Center Length Severity of Dosage Quality (years) hypertension grade Telmisartan ACEIs eaaayi oprn emsra ihACEIs with telmisartan comparing Meta-analysis Telmisartan versus enalapril Alcocer et al.19 68 60 19/49 Multi-center 8 weeks Mild-to-moderate 80 mg 20 mg 1 Amerena et al.17 516 52 332/184 Multi-center 12 weeks Mild-to-moderate 40–80 mg 10–20 mg 3 Andreeva et al.21 30 56 19//11 Single-center 12 weeks Mild-to-moderate 20–80 mg 5–10 mg 1 Chen et al.16 147 51 77/70 Single-center 6 weeks Mild-to-moderate 40 mg 10 mg 4 Chen et al.25 35 45 20/15 Single-center 16 weeks Mild-to-moderate 80–160 mg 10–20 mg 3 Hannedouche et al.18 71 53 52/19 Multi-center 12 weeks Mild-to-moderate 40–80 mg 10–20 mg 4 Huang et al.24 106 60 55/51 Single-center 32 weeks Mild-to-moderate 40–80–160 mg 10–20 mg 2 Karlberg et al.20 278 71 118/160 Multi-center 26 weeks Mild-to-moderate 20–40–80 mg 5–10–20 mg 4 Lewandowski 26 32 40 30/2 Single-center 8 weeks Mild-to-moderate 40–80 mg 10–20 mg 1 23

Lu et al. 86 73.6 45/41 Single-center 8 weeks Mild-to-moderate 80 mg 10 mg 3 Zou Z Neutel et al.22 86 51 65/21 Multi-center 8 weeks Severe 80–160 mg 20–40 mg 2 5

Smith et al. 83 51 57/26 Multi-center 4 weeks Mild-to-moderate 80 mg 20 mg 5 al et Smith et al.15 144 54 85/59 Multi-center, 12 weeks Mild-to-moderate 80 mg 20 mg 4

Telmisartan versus ramipril Celik et al.30 100 52 56/44 Single-center 6 months Mild-to-moderate 80 mg 10 mg 1 Lacourciere et al.29 812 53 543/269 Multi-center 14 weeks Mild-to-moderate 40–80 mg 2.5–5–10 mg 3 Poirier et al.28 35 61 27/8 Multi-center 8 weeks Mild-to-moderate 80 mg 2.5–5–10 mg 3 Schmieder et al.31 87 59 61/26 Multi-center 9 weeks Mild-to-moderate 40–80 mg 5–10 mg 4 Wang et al.32 46 52 28/18 Single-center 8 weeks Mild-to-moderate 40 mg 2.5 mg 2 Williams et al.27 801 54 479/322 Multi-center 14 weeks Mild-to-moderate 80 mg 2.5–5–10 mg 3

Telmisartan versus lisinopril Lacourciere et al.6 57 59 23/34 Multi-center 8 weeks Mild-to-moderate 80 mg 20 mg 4 Neutel et al.33 578 53 383/195 Multi-center 52 weeks Mild-to-moderate 40–80–160 mg 10–20–40 mg 4 Sengul et al.35 219 57 82/137 Single-center 52 weeks Mild-to-moderate 80 mg 20 mg 2 Stergiou et al.34 32 50 26/6 Single-center 10 weeks Mild-to-moderate 80 mg 20 mg 2

Telmisartan versus perindopril Ghiadoni et al.36 57 51 36/21 Single-center 6 months Mild-to-moderate 80–160 mg 2–4 mg 1 Nalbantgil et al.37 60 51 35/25 Single-center 6 weeks Mild-to-moderate 80 mg 4 mg 2 Peng et al.40 120 75.3 65/55 Single-center 8 months Mild-to-moderate 80–160 mg 4–8 mg 3 Ragot et al.38 435 55 238/197 Multi-center 12 weeks Mild-to-moderate 40–80 mg 4–8 mg 2 Remkova et al.39 36 56 11/25 Single-center 1 month Mild-to-moderate 40 mg 5 mg 1 Meta-analysis comparing telmisartan with ACEIs Z Zou et al 343 Table 2 Mean clinical BP reduction

Interventions DBP WMD (95% CI) SBP WMD (95% CI)

Telmisartan versus enalapril 1.82 (0.66, 2.99) 3.63 (1.59, 5.68) Telmisartan versus ramipril 3.09 (1.94, 4.25) 2.95 (À0.39, 6.29) Telmisartan versus lisinopril À0.30 (À0.65, 0.05) À1.09 (À1.58, À0.61) Telmisartan versus perindopril 1.48 (0.33, 2.62) 1.67 (À1.09, 4.43)

Abbreviations: BP, blood pressure; 95% CI, 95% confidence interval; DBP, diastolic BP; SBP, systolic BP; WMD, weighted mean difference. A random-effect model was used to calculate WMD and 95% CI. reported in both groups (Tables 2 and 3, Figures 2 ramipril group (RR 0.60, 95% CI 0.38–0.96). No and 3). death, angioedema or cerebro-cardiovascular event was reported in both groups (Tables 2 and 3, Figures 2 and 3). Sensivity analysis Sensitivity analysis was performed to evaluate the effects of methodological characteristics on the Sensitivity analysis analysis of clinical DBP reduction and therapeutic There was no statistical difference in DBP reduction response of DBP. We divided the studies according between the two groups on the analysis of studies to the administration of drugs. Studies only includ- only including fixed dosage in random-effect model ing fixed dosage or titration-to-response showed (WMD 2.51, 95% CI À0.64 to 5.67). However, the significant decrease of DBP, which favored telmi- difference was significant, which favored telmisar- sartan (WMD 2.27, 95% CI 0.59–3.95; WMD 1.50, tan in fixed-effect model (WMD 3.03, 95% CI 95% CI 0.24–2.76, respectively). In one trial,22 the 1.27–4.79, test for heterogeneity: Q ¼ 2.42, P ¼ 0.12, patients with severe hypertension were included. I2 ¼ 59%). There was statistical difference that We reanalysed the results after excluding that trial favored telmisartan in studies including only titra- and found there was a greater DBP reduction in the tion-to-response: DBP reduction (WMD 3.14, 95% CI telmisartan group (WMD 2.11, 95% CI 1.01, 3.20). 1.61–4.68) and therapeutic response rate of DBP (RR Studies only including titration-to-response showed 1.38, 95% CI 1.08–1.75). The analysis including a greater DBP response rate in telmisartan group (RR only high-quality trials also showed that a signifi- 1.17, 95% CI 1.04–1.31). After excluding the trial cant decrease of DBP that favored telmisartan (WMD with severe hypertension, we also found a greater 3.14, 95% CI 1.61, 4.68). DBP response rate in the telmisartan group (RR 1.15, 95% CI 1.05–1.26). The analysis including only high-quality trials (Jadad score 43) also showed a Telmisartan versus lisinopril significant decrease of DBP that favored telmisartan Four trials involving 886 patients compared telmi- (WMD 1.99 95% CI 1.01, 2.97). sartan with lisinopril.6,33–35 There was no statistical difference in DBP reduction and therapeutic response rate of DBP between the two groups. There Telmisartan versus ramipril was a greater SBP reduction that favored lisinopril. Six trials involving 1881 patients compared telmi- There was no statistical difference between the two sartan with ramipril.27–32 There was a greater DBP groups in both ambulatory DBP and SBP reduction, reduction that favored telmisartan. Therapeutic including 24-h, daytime and night-time periods. response rates of DBP and SBP favored telmisartan More drug-related adverse events and coughs oc- (RR 1.34, 95% CI 1.11–1.61; RR 1.16, 95% CI 1.08–1.24, curred in the lisinopril group. Two patients suffered respectively). As to ambulatory data, all the DBP from angioedema33 and no death or cardio-cerebro- reductions of mean 24-h, the last 6-h, daytime and vascular event was reported in both groups (Tables 2 night time periods favored telmisartan (WMD 2.48, and 3, Figures 2 and 3). 95% CI 1.60–3.35; WMD 2.93, 95% CI 1.95–3.92; WMD 3.16, 95% CI 1.65–4.68; WMD 3.20, 95% CI 0.29–6.10, respectively). The SBP reductions of Telmisartan versus perindopril mean 24-h, the last 6-h, daytime and night time Five trials involving 708 patients compared telmi- periods also favored telmisartan (WMD 3.33, 95% CI sartan with perindopril.36–40 There was a greater 2.15–4.51; WMD 4.09, 95% CI 2.66–5.53; WMD 3.82, DBP reduction and therapeutic response rate of DBP 95% CI 1.93–5.71; WMD 4.05, 95% CI 2.11–5.98, in the telmisartan group. There was no statistical respectively). There was statistical difference that difference in SBP reduction and therapeutic favored telmisartan in drug-related adverse events, response rate of SBP between the two groups adverse events-related withdrawal rate and cough. (WMD 1.67, 95% CI À1.09 to 4.43; RR 1.24, 95% There were more severe adverse events in the CI 0.90–1.72, respectively). More drug-related adverse

Journal of Human Hypertension Meta-analysis comparing telmisartan with ACEIs Z Zou et al 344 events and coughs occurred in the perindopril group (Tables 2 and 3, Figures 2 and 3). 0.00001 0.00001 0.00001 P-value o o o

Sensitivity analysis There was no statistical difference on the analysis of studies by titration-to-response in DBP reduction in random-effect model (WMD 0.98, 95% CI À1.00 to 2.97). However, the difference was significant in fixed-effect model (WMD 1.25, 95% CI 0.01–2.50; 0.24 (0.14, 0.42) test for heterogeneity: Q ¼ 1.37, P ¼ 0.24, I2 ¼ 27%). Considering the overall tolerability, we found that telmisartan caused fewer adverse events, drug- a related adverse events, adverse events-related with- value RR (95% CI) drawals and coughs than the four ACEIs. The overall P- possibility of drug-related adverse events was 10.4% in telmisartan group and 15.8% in ACEIs group, the overall adverse events-related withdrawal rate was 3.1% in the telmisartan group and 5.6% in the ACEIs group, and the overall possibility of cough 0%). was 1.7% in the telmisartan group and 8.8% in the ¼ 2 I ACEIs group. There were two patients in the lisinopril group and two in the enalapril group, 0.91, respectively, who suffered from angioedema, while ¼

P no patient in the telmisartan group suffered from it. value RR (95% CI)

P- Discussion Hypertension is currently one of the leading causes of morbidity and mortality in the world.41 Despite the numerous drugs available for the treatment of hypertension, an adequate control of high BP has

0.04; test for heterogeneity: not yet been achieved in the vast majority of patients ¼

P with hypertension. This meta-analysis focused on the two kinds of widely used antihypertensive drugs. The results of this meta-analysis revealed that telmisartan pro- vided a superior control of BP to enalapril, perindo-

value RR (95% CI) pril and ramipril, as evidenced by a greater DBP P- reduction and therapeutic DBP response rate than the three ACEIs. Earlier meta-analysis of 61 pro- spective observational studies involving one million patients with no earlier vascular diseases revealed that in each age group, the proportional difference in the risk of vascular death associated with a given absolute difference in BP was similarly down to at

RR (95% CI) least 115/75 mm Hg, below which there was no obvious relationship.42 A reduction in SBP of 2–3 mm Hg should have translated into a risk reduction of 4–5%.11 The findings of ONTARGET showed that mean BP was slightly lower in the telmisartan group than in the ramipril group (0.9/0.6 mm Hg). However, concomitant antihyper- tensive drugs such as b-blockers and might influence the direct comparison of antihypertensive effect between the two drugs.11 After excluding

Tolerability of telmisartan versus ACEIs the interference of other antihypertensive drugs, a greater reduction of DBP 1.82, 3.09, 1.48 mm Hg and SBP 3.63, 2.95, 1.67 mm Hg compared with enala- The difference was significant in fixed-effect model (RR 0.59, 95% CI 0.36, 0.99, Interventions Adverse events (any reason) Withdrawal (any reason) Withdrawal (adverse events) Cough Table 3 Abbreviations: ACEIs, angiotensin-converting enzymeA inhibitors; random-effect 95% modela CI, was 95% used confidence to interval; calculate NR, RR not and reported; 95% RR, CI. relative risk. Telmisartan versus enalapril 0.76 (0.64, 0.91) 0.002 0.77 (0.55, 1.07) 0.12 0.61 (0.36, 1.02) 0.06 Telmisartan versus ramiprilTelmisartan versus lisinoprilTelmisartan versus perindoprilTelmisartan versus ACEIs 0.65 (0.34, 0.87 1.24) 0.92 (0.52, (0.36, 1.44) 2.33) 0.78 (0.66, 0.19 0.91) 0.58 0.85 0.94 0.003 (0.71, 0.83 1.24) (0.62, 1.11)pril, 0.85 NR (0.72, 0.66 1.01) 0.20 ramipril 0.07 0.64 (0.40, 0.36 1.01) (0.08, 1.72) and 0.62 (0.46, 0.85) 0.06 0.20 perindopril 0.002 0.13 (0.06, 0.35 0.26) (0.20, 0.61) NR 0.23 (0.17, 0.33) was 0.0002 found in the 0.17 (0.05, 0.66) 0.010

Journal of Human Hypertension Meta-analysis comparing telmisartan with ACEIs Z Zou et al 345

Figure 2 Comparison of the effect of telmisartan and angiotensin-converting enzyme inhibitors (ACEIs) on therapeutic response of diastolic blood pressure (DBP). RR, relative risk; 95% CI, 95% confidence interval; N, number of patients. present meta-analysis, which might have clinical cing BP analysed by meta-analytical approach also benefits that favored telmisartan in the long run. revealed that telmisartan provided numerically From the results of this meta-analysis, telmisartan greater weighted average reductions of DBP and was significantly more effective than ramipril in SBP than enalapril and ramipril, which paralleled reducing BP throughout the 24-h dosing interval, our findings.10 The findings of ONTARGET showed daytime, night time and particularly during the last that telmisartan was equivalent to ramipril in the 6 h. The incidence of cerebro-cardiovascular events, patients with vascular diseases or high-risk diabetes. such as myocardial infarction, stroke and myocar- However, telmisartan monotherapy might show an dial ischaemia, peaks in the early morning hours, increase in benefits to patients with hypertension in which coincides with the sharp rise of BP, occurring the long run with its better lowering BP effect, upon arising and awakening from overnight sleep without the interference of so many other antihy- and also with the waning pharmacodynamic effect pertensive drugs in the ONTARTGET.11 of antihypertensive drugs taken once daily in the This meta-analysis revealed that the incidence of morning.43,44 In addition, the increased BP varia- drug-related adverse events, especially cough, was bility is independently associated with increased significantly lower in telmisartan compared with all target-organ damage and cardiovascular events.45,46 the included four ACEIs. Although most adverse The ARB telmisartan might be of benefit with events were mild-to-moderate, telmisartan may smooth and sustained 24-h BP. On the contrary, result in better compliance as compared to the ramipril produced a significant reduction that was noncompliance or withdrawal of the treatment by restricted to the period corresponding to its peak ACEIs because of chronic, dry cough.47 Thus, effect.28 Efficacy of antihypertensive drugs in redu- telmisartan might provide a better long-term BP

Journal of Human Hypertension Meta-analysis comparing telmisartan with ACEIs Z Zou et al 346

Figure 3 Comparison of the drug-related adverse events of telmisartan and angiotensin-converting enzyme inhibitors (ACEIs). RR, relative risk; 95% CI, 95% confidence interval; N, number of patients.

control. The incidence of cough in ACEIs treatment meta-analysis, such as severity of hypertension and was 8.8% in 2043 patients, parallel to the findings of quality of trials were also evaluated. the post-marketing surveillance of over 47 000 One limitation of this meta-analysis was that our patients in France, which revealed that 11.3% in analysis of outcome variables was based on data women and 7.8% in men treated with perindopril pooled from studies of different durations. Some had a cough.48 caution was therefore required in their interpreta- tion. Another limitation of this meta-analysis is no report of cerebro-cardiovascular event in this meta- Strengths and limitations of the meta-analysis analysis because of comparatively short duration of In contrast to an earlier review that identified three the included studies. In addition, some of the studies,49 we examined 28 clinical trials, using a included studies were poorly reported, with six wider range of clinically relevant outcome variables, trials scored 1 by Jadad score system. and focused on direct comparison of treatments with telmisartan and ACEIs as monotherapy, pre- cluding the interference of other drugs. To avoid the Recommendations for future research to inform clinical potential influence of differences in administration practice procedures, we performed separate meta-analyses Our meta-analysis shows that there is much evi- on fixed dose or titration-to-response. Other factors dence available to help deal with how telmisartan is that could potentially influence the results of this compared in terms of efficacy and tolerability with

Journal of Human Hypertension Meta-analysis comparing telmisartan with ACEIs Z Zou et al 347 ACEIs in the treatment of hypertension. Some References comparative data are available for telmisartan to inform clinical practice. However, the lack of key 1 Rosamond W, Flegal K, Furie K, Go A, Greenlund K, comparative data such as the rate of cerebro- and Haase N et al. Heart disease and stroke statistics—2008 update: a report from the American Heart Association cardiovascular events and mortality leaves doctors, Statistics Committee and Stroke Statistics Subcommit- commissioners and the public confused about how tee. Circulation 2008; 117: e25–146. to use these drugs in relation to standard practice. 2 Wang JG, Staessen JA, Franklin SS, Fagard R, Gueyffier Pragmatic well-designed randomized controlled F. Systolic and diastolic blood pressure lowering as trials with long duration are needed to compare the determinants of cardiovascular outcome. 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