Updated Meta-Analysis of Antihypertensive Drugs (PDF)

Clin Drug Invest 2007; 27 (11): 735-753 ORIGINAL RESEARCH ARTICLE 1173-2563/07/0011-0735/$44.95/0...

Clin Drug Invest 2007; 27 (11): 735-753 ORIGINAL RESEARCH ARTICLE 1173-2563/07/0011-0735/$44.95/0 © 2007 Adis Data Information BV. All rights reserved. Updated Meta-Analytical Approach to the Efficacy of Antihypertensive Drugs in Reducing Blood Pressure J.P. Baguet,1 B. Legallicier,2 P. Auquier3 and S. Robitail3 1 Cardiology and Hypertension Unit, Grenoble University Hospital, Grenoble, France 2 Nephrology Unit, Rouen University Hospital, Rouen, France 3 Department of Public Health, University of Marseille, Marseille, France Abstract Background and objective: Despite advances in the treatment of hypertension, control rates continue to be suboptimal in both Europe and the US. Strategies that improve hypertension control are therefore urgently needed. This study aimed to assess the relative efficacies of various antihypertensive drugs commonly used in France in reducing systolic and diastolic blood pressure (SBP and DBP) by using a meta-analytical approach. This update of a previously published meta-analytical approach extends the number of drugs evaluated from 13 to 19. Methods: A total of 80 randomised, controlled trials published between 1973 and 2007 involving 10 818 patients were selected for inclusion in the meta-analytical approach. Data were examined for 19 drugs, and 16 drugs were included in the analysis: hydrochlorothiazide, indapamide sustained-release (SR), atenolol, amlodipine, lercanidipine, manidipine, enalapril, ramipril, trandolapril, candesartan cilexetil, irbesartan, losartan, olmesartan medoxomil, telmisartan, valsartan and aliskiren. Weighted average reductions in SBP and DBP over a period of 8–12 weeks were calculated for each drug from information on both the mean and the variability in BP reduction. No trials evaluating furosemide, spironolactone or cicletanine satisfied the inclusion criteria for this analysis. Results: The average weighted reductions in SBP over 8–12 weeks were most marked with diuretics, and in particular indapamide SR 1.5 mg/day (mean change from baseline –22.2mm Hg), which reduced SBP to a greater extent than any of the other drugs evaluated (at any dosage considered). Average weighted reduc- tions in DBP were generally similar with all classes of antihypertensives and ranged from –11.4mm Hg with the β-adrenoceptor blocker atenolol and calcium channel antagonists to –10.3mm Hg with the angiotensin II type 1 receptor antagonists. Conclusion: This new analysis supports the results of the earlier investigation, in that indapamide SR 1.5 mg/day appeared to be the most effective drug for producing significant reductions in SBP within 8–12 weeks, which is an essential element in optimising cardiovascular prevention among hypertensive patients. The clinical application of these results should take into consideration all the limitations discussed in this analysis. 736 Baguet et al. Introduction the available clinical trial data for various common- ly used antihypertensives to assess their compara- Hypertension is a highly prevalent condition and tive efficacies. The present study updates a previ- is the leading cause of cardiovascular disease world- ously published analysis of 72 clinical trials involv- wide. In Europe, the prevalence of hypertension is ing the use of 11 drugs, and extends this number to as high as 44%, while in the US, epidemiological 16, including trandolapril, manidipine and a number data for the period 1999–2002 indicated a preva- of newer agents such as olmesartan medoxomil, lence of 28.6%.[1,2] Currently, hypertension is esti- telmisartan and the renin inhibitor aliskiren. mated to affect approximately 1 billion people worldwide, and as the population ages, this number Materials and Methods can be expected to increase even further. More- over, despite advances in treatment of the condition, Antihypertensive Drugs Analysed hypertension control rates continue to be suboptimal in both Europe and the US, as in other parts of the The antihypertensive drugs considered for poten- world.[1,4,5] Strategies that improve control rates and tial inclusion in the updated analysis were those prevent the condition arising are therefore urgently commonly used to treat hypertension in France, needed. including: (1) the diuretics cicletanine, furosemide, Numerous clinical trials have established the effi- hydrochlorothiazide, indapamide sustained-release cacy of antihypertensive therapies in reducing the (SR) and spironolactone; (2) the β-blocker atenolol; incidence of cardiovascular disease morbidity and (3) the CCAs amlodipine, lercanidipine and mortality. However, effective use of blood pressure manidipine; (4) the ACE inhibitors enalapril, (BP)-lowering drugs requires their optimal selection ramipril and trandolapril; (5) the ARBs candesartan for individual patients and careful follow-up to en- cilexetil, irbesartan, losartan, olmesartan medox- sure that the goals of therapy are being met.[3,6] omil, telmisartan and valsartan; and (6) a member of Several classes of drugs are available to treat hyper- a new class soon to be available in France, the renin tension, including diuretics, β-adrenoceptor antago- inhibitor aliskiren. Dosages of the candidate drugs nists (β-blockers), calcium channel antagonists that were considered are shown in table I. (CCAs), angiotensin-converting enzyme (ACE) in- hibitors, angiotensin II type 1 receptor antagonists Data Source (angiotensin receptor blockers [ARBs]), α-adreno- Controlled clinical trials involving the candidate ceptor antagonists, central antihypertensive drugs drugs published over the period 1 January 1973 to and renin inhibitors, the choice of which is depen- 25 May 2007 were identified via the PubMed dent on the clinical situation, efficacy and tolerabili- database (US National Library of Medicine, Wash- ty/acceptability to the patient. The Seventh Report ington, DC, USA). Only randomised, double-blind of the Joint National Committee on Prevention, De- trials where the drugs were used as monotherapy, tection, Evaluation, and Treatment of High Blood either at a fixed daily dosage or in increasing dos- Pressure (JNC 7) guidelines state that diuretics con- ages, were considered. Combination therapies were stitute an effective first-line treatment and are the excluded from the analysis. Initially, abstracts of the primary class recommended for first-line treatment trials were identified and then analysed to determine of hypertension in the US. their concordance with the inclusion and exclusion Clearly, efficacy in lowering both systolic and criteria defined in the study protocol (see below). diastolic BP (SBP and DBP) is considered the most important criterion in any clinical setting, but Inclusion and Exclusion Criteria equivalent efficacy among the available agents can- not be assumed in all situations. To address this The inclusion criteria for selection of studies for issue, we undertook a meta-analytical approach to analysis were evaluation of antihypertensive therapy © 2007 Adis Data Information BV. All rights reserved. Clin Drug Invest 2007; 27 (11) Updated Meta-Analysis on Antihypertensive Drugs 737 Table I. Antihypertensive drugs and dosages considered for inclusion in the analysis Drug class Generic name Dosage Diuretics Cicletanine 50–100 mg/day Furosemide 20–40 mg/day Hydrochlorothiazide 12.5–50 mg/day Indapamide SR 1.5 mg/day Spironolactonea 50–100 mg/day β-Blocker Atenolol 50–100 mg/day Calcium channel antagonists Amlodipine 5–10 mg/day Lercanidipine 10–20 mg/day Manidipine 10 mg/day ACE inhibitors Enalapril 20–40 mg/day Ramipril 2.5–10 mg/day Trandolapril 2 mg/day ARBs Candesartan cilexetil 8–16 mg/day Irbesartan 150–300 mg/day Losartan 50–100 mg/day Olmesartan medoxomil 20–40 mg/day Telmisartan 40–80 mg/day Valsartan 80 mg/day Renin inhibitor Aliskiren 150–300 mg/day a Potassium-sparing diuretic. ACE = angiotensin-converting enzyme; ARBs = angiotensin II type 1 receptor antagonists; β-Blocker = β-adrenoceptor antagonist; SR = sustained-release. in patients with mild or moderate essential hyperten- quality, a descriptive analysis of the features of each sion (SBP 140–179mm Hg and/or DBP 90–109mm trial and the characteristics of the patient popula- Hg, as defined in current international guidelines) tions studied was performed by taking into account: and patient age >18 years. Exclusion criteria were (1) controls incorporated in the trial design; (2) ran- severe hypertension, equivalence or non-inferiority dom allocation of treatments; (3) double-blind con- studies, crossover studies, use of dosages outside ditions (treatment and follow-up); (4) descriptions each drug’s current registration recommendations, of patient selection and dropouts during the trial; studies conducted in patients with only isolated sys- (5) ITT analysis; and (6) the absence of other biases. tolic hypertension, and trials conducted only in For trials meeting the criteria for inclusion in the Black patients, in whom the superior BP-lowering analysis, the efficacy of treatment was evaluated via efficacy of diuretics and CCAs is well established. measurements of SBP and DBP at the start of the trial (baseline) and after 8 or 12 weeks of therapy. Data Collection and Evaluation The meta-analytical approach therefore compared the efficacy of each antihypertensive drug in reduc- The following information was gathered for each ing SBP and DBP over this period of time. trial: trial acronym, date of publication, description of the treatments administered, characteristics of the Analysis Method patients enrolled, duration of the washout period, sizes of the treatment groups, number of patients lost A descriptive analysis of the methodological to follow-up, use of intention-to-treat (ITT) analy- quality of the trials and the characteristics of the sis, and the mean and variation of SBP and DBP at populations studied was performed. baseline and at the intermediate and final assess- The trials were thus classified according to the ments for each group. To ensure methodological grid proposed by Cucherat and the grid proposed © 2007 Adis Data Information BV. All rights reserved. Clin Drug Invest 2007; 27 (11) 738 Baguet et al. by Jadad et al., which assess the following six Giles and Robinson as no information on varia- methodological parameters: controlled trial, random bility was provided. However, this was considered allocation of treatments, double-blind follow-up, the best available evidence on olmesartan medox- dropout rate, ITT analysis and absence of other omil, and this meant that the results of two other biases. studies [12,13] could not be combined with these data. The analysis method used was based on calcula- Therefore, the results for olmesartan medoxomil are tion of the sum weighted for the trial size. To based solely on the meta-analysis of Giles and calculate the mean BP reduction for a set of drugs Robinson. The mean BP reductions by this thera- evaluated, the combined data were weighted for the peutic class in the studies selected are quite similar trial size using the following formula: (BP reduction to those reported in the ARB meta-analysis of Fabia [trial 1] number of patients [trial 1] +…+ BP re- et al. duction [trial n] number of patients [trial n])/total number of patients (trial 1 +…+ trial n). Weighted Average Blood Pressure Reductions Results All results from clinical trials included are shown A total of 2780 abstracts were identified from the in tables III and IV. Results for drug classes and PubMed search and analysed for their suitability for individual drugs within each class are shown in table inclusion in the analysis. Abstracts and articles were III, while table IV provides results for individual rejected if they failed to comply with the inclusion drugs by dosage. and exclusion criteria defined in the protocol, or if Across all patients, SBP was reduced by 14.5mm mean changes in SBP and DBP were not reported Hg and DBP by 10.7mm Hg over the 8- to 12-week between baseline and 8–12 weeks after the start of period. While the data reported in tables III and IV treatment together with the confidence intervals do not reflect outcomes from direct, head-to-head (CIs) associated with the changes in BP. Application comparative trials or any formal comparisons be- of these criteria resulted in exclusion of 2151 ab- tween drugs, appraisal of the change from baseline stracts (77%), and 549 of the 629 studies that had in SBP and DBP achieved by each drug and drug been considered further (87%). class allows some appreciation of their relative effi- A total of 80 trials involving 10 818 patients were cacy since all data are derived from studies of gener- selected for inclusion. The number of studies relat- ally similar design. Results for the various drug ing to each drug and the numbers of patients classes (table III) showed that diuretics, CCAs and analysed at the various dosages used are shown in ACE inhibitors produced the most marked reduc- table II. Brief details of the characteristics of each tions in SBP from baseline (–19.2mm Hg, –16.4mm individual trial, including mean patient ages, sex Hg and –15.6mm Hg, respectively). Reductions in ratios and BP measurement intervals are provided in DBP were of generally similar magnitude with appendix 1. Additional details relating to the new all antihypertensive classes but were most marked studies that were included in the updated analysis with the β-blocker atenolol, CCAs and diuretics are given in appendix 2. (–11.4mm Hg, –11.4mm Hg and –11.1mm Hg, re- Although the diuretics cicletanine, furosemide spectively). and spironolactone were considered for inclusion, Among the diuretics, indapamide SR produced a none of the studies relating to these agents satisfied more marked effect than hydrochlorothiazide on all inclusion criteria to allow their incorporation. both SBP (–22.2mm Hg vs –17.3mm Hg, respec- Hence, no results are reported for these drugs and a tively) and DBP (–11.7mm Hg vs –10.7mm Hg, total of 16 drugs were included in the analysis. In the respectively) [table III]. case of the ARB olmesartan medoxomil, calculation For the other drug classes (table IV), the greatest of CIs was not possible from the meta-analysis of BP-lowering efficacy was exhibited by manidipine © 2007 Adis Data Information BV. All rights reserved. Clin Drug Invest 2007; 27 (11) Updated Meta-Analysis on Antihypertensive Drugs 739 Table II. Total numbers of patients analysed in the studies selected for analysis (further details are provided in appendix 1) Drug class Drug Dosage (mg/day) No. of studies Total no. of patients Diuretics Cicletanine ND Furosemide ND Hydrochlorothiazide ≤25 4 317 Hydrochlorothiazide 12.5–50 2 94 Hydrochlorothiazide 50 1 56 Indapamide SR 1.5 3 265 Spironolactone ND β-Blockers Atenolol 50 4 321 Atenolol 50–100 14 483 Calcium channel antagonists Amlodipine 5 3 340 Amlodipine 5–10 14 1400 Amlodipine 10 2 75 Lercanidipine 10–20 1 89 Manidipine 10 1 183 ACE inhibitors Enalapril 20 2 116 Enalapril 20–40 1 21 Ramipril 2.5–5 1 17 Trandolapril 2 1 30 ARBs Candesartan cilexetil 8 2 151 Candesartan cilexetil 8–16 4 749 Candesartan cilexetil 16 2 144 Irbesartan 150 2 287 Irbesartan 150–300 7 563 Irbesartan 300 1 140 Losartan 50 9 569 Losartan 50–100 12 2310 Losartan 100 2 162 Olmesartan medoxomila 20 3 769 Olmesartan medoxomil 40 1 195 Telmisartan 40–80 1 164 Telmisartan 80 1 244 Valsartan 80 6 544 Renin inhibitor Aliskiren 150 1 178 Aliskiren 300 1 175 a Two studies of olmesartan medoxomil 20 mg/day involving 333 patients could not be included in the meta-analysis because there was no statistical means of combining the data with those of the third study (since CIs could not be calculated for the latter). ARBs = angiotensin II type 1 receptor antagonists; β-Blockers = β-adrenoceptor antagonists; CIs = confidence intervals; ND = no study satisfied the inclusion criteria, or the data reported were insufficient to allow incorporation into the meta-analysis; SR = sustained-release. among the CCAs (reductions in SBP and DBP tively, at 40 mg/day). At a dosage of 300 mg/day, –17.5mm Hg and –13.7mm Hg, respectively), the renin inhibitor aliskiren produced similar reduc- enalapril 20–40 mg/day among the ACE inhibitors tions in SBP and DBP to atenolol at dosages of (reductions in SBP and DBP –21.0mm Hg and 50–100 mg/day (table IV); however, at the lower –14.0mm Hg, respectively), and olmesartan medox- omil among the ARBs (reductions in SBP and DBP dosage of 150 mg/day, aliskiren was less effective in –15.1mm Hg and –12.2mm Hg, respectively, at 20 lowering SBP than atenolol 50 mg/day (–12.1mm mg/day, and –17.6mm Hg and –13.1mm Hg, respec- Hg vs –14.2mm Hg, respectively). © 2007 Adis Data Information BV. All rights reserved. Clin Drug Invest 2007; 27 (11)  Table III. Weighted average reductions of systolic and diastolic BP by drug class and by individual drugs 740 Drug class Drug No. of Change in systolic BP Change in diastolic BP patients mm Hg 95% CI mm Hg 95% CI Diuretics 732 –19.2 –20.3, –18.0 –11.1 –11.7, –10.5 Cicletanine ND Furosemide ND Hydrochlorothiazide 467 –17.3 –18.8, –15.7 –10.7 –11.4, –10.0 Indapamide SR 265 –22.2 –23.9, –20.6 –11.7 –12.8, –10.7 Spironolactone ND β-Blockers 804 –14.8 –15.9, –13.7 –11.4 –12.0, –10.9 Atenolol 804 –14.8 –15.9, –13.7 –11.4 –12.0, –10.9 Calcium channel 2087 –16.4 –17.0, –15.8 –11.4 –11.8, –11.1 © 2007 Adis Data Information BV. All rights reserved. antagonists Amlodipine 1815 –16.4 –17.1, –15.8 –11.2 –11.5, –10.8 Lercanidipine 89 –14.2 –16.8, –11.6 –12.2 –13.4, –11.0 Manidipine 183 –17.5 –19.5, –15.6 –13.7 –14.8, –12.6 ACE inhibitors 184 –15.6 –17.6, –13.6 –10.8 –11.9, –9.7 Enalapril 137 –15.0 –17.3, –12.6 –10.5 –11.7, –9.2 Ramipril 17 –15.0 –22.4, –7.6 –9.0 –12.1, –5.9 Trandolapril 30 –18.6 –30.7, –6.5 –13.4 –21.9, –4.9 ARBsa 6027b –13.2 –13.6, –12.9 –10.3 –10.5, –10.1 Candesartan cilexetil 1044 –14.2 –15.0, –13.4 –11.0 –11.4, –10.5 Irbesartan 990 –14.1 –15.0, –13.2 –10.6 –11.1, –10.1 Losartan 3041 –12.7 –13.3, –12.2 –10.0 –10.3, –9.7 d d Olmesartan medoxomilc 436 (20mg) –15.1 –12.2 d d 195 (40mg) –17.6 –13.1 Telmisartan 408 –15.5 –16.6, –14.4 –11.3 –11.9, –10.7 Valsartan 544 –12.5 –13.6, –11.4 –10.0 –10.5, –9.4 Renin inhibitor 353 –13.5 –14.2, –12.9 –11.3 –11.7, –10.9 Aliskiren 353 –13.5 –14.2, –12.9 –11.3 –11.7, –10.9 b All drugs (total) 10 186 –14.5 –14.8, –14.2 –10.7 –10.8, –10.5 a Weighted reductions for angiotensin II type 1 receptor antagonists exclude olmesartan medoxomil, since CIs could not be calculated from the available data for this drug. b Data for the total exclude olmesartan medoxomil. c The results presented for olmesartan medoxomil are those of Giles and Robinson as this is the best available evidence. However, CIs could not be calculated for this study, which prevented results for two other trials being included (because there was no statistical means of combining the data). d No information on variability was provided, preventing the use of an approximation for CI estimation. ACE = angiotensin-converting enzyme; ARBs = angiotensin II type 1 receptor antagonists; β-Blockers = β-adrenoceptor antagonists; CIs = confidence intervals; ND = no study satisfied the inclusion criteria, or the data reported were insufficient to allow incorporation into the meta-analysis; SR = sustained-release. Clin Drug Invest 2007; 27 (11) Baguet et al.  Table IV. Weighted average reductions of systolic and diastolic BP by drug and by daily dosage Drug class Drug Dosage No. of Change in systolic BP Change in diastolic BP (mg/day) patientsa mm Hg 95% CI mm Hg 95% CI Diuretics Cicletanine ND Furosemide ND Hydrochlorothiazide ≤25 317 –18.9 –20.8, –16.9 –11.0 –11.9, –10.1 12.5–50 94 –10.8 –14.3, –7.3 –7.9 –9.5, –6.3 50 56 –19.3 –22.6, –16.0 –14.0 –16.0, –12.0 Indapamide SR 1.5 265 –22.2 –23.9, –20.6 –11.7 –12.8, –10.7 Spironolactone ND β-Blockers Atenolol 50 321 –14.2 –15.9, –12.6 –10.4 –11.3, –9.5 50–100 483 –15.2 –16.7, –13.8 –12.1 –12.9, –11.4 Calcium channel Amlodipine 5 316 –19.9 –22.5, –17.3 –11.5 –14.1, –10.0 © 2007 Adis Data Information BV. All rights reserved. antagonists 5–10 1400 –15.7 –16.4, –15.0 –11.2 –11.6, –10.9 10 75 –13.9 –21.3, –6.5 –7.0 –11.0, –3.1 Lercanidipine 10–20 89 –14.2 –16.8, –11.6 –12.2 –13.4, –11.0 Updated Meta-Analysis on Antihypertensive Drugs Manidipine 10 183 –17.5 –19.5, –15.6 –13.7 –14.8, –12.6 ACE inhibitors Enalapril 20 116 –13.9 –16.2, –11.6 –9.8 –11.1, –8.6 20–40 21 –21.0 –30.0, –12.0 –14.0 –18.5, –9.5 Ramipril 2.5–5 17 –15.0 –22.4, –7.6 –9.0 –12.1, –5.9 Trandolapril 2 30 –18.6 –30.7, –6.5 –13.4 –21.9, –4.9 ARBs Candesartan cilexetil 8 151 –12.2 –14.7, –9.8 –8.9 –10.2, –7.5 8–16 749 –14.6 –15.5, –13.7 –11.7 –12.2, –11.2 16 144 –13.7 –16.4, –10.9 –9.0 –10.4, –7.6 Irbesartan 150 287 –11.5 –13.1, –9.9 –9.8 –10.7, –8.9 150–300 563 –14.7 –16.0, –13.5 –10.7 –11.4, –10.0 300 140 –16.4 –18.6, –14.2 –11.7 –13.0, –10.5 Losartan 50 569 –14.5 –15.7, –13.2 –10.7 –11.3, –10.0 50–100 2310 –12.3 –12.9, –11.7 –9.9 –10.3, –9.6 100 162 –13.1 –15.3, –11.0 –8.6 –9.9, –7.3 c c Olmesartan 20 436 –15.1 –12.2 medoxomilb c c 40 195 –17.6 –13.1 Telmisartan 40–80 164 –12.5 –26.8, +1.8 –10.9 –18.8, –3.0 80 244 –14.0 –14.9, –13.1 –9.0 –9.5, –8.5 Continued next page 741 Clin Drug Invest 2007; 27 (11) 742 Baguet et al. ACE = angiotensin-converting enzyme; ARBs = angiotensin II type 1 receptor antagonists; β-Blockers = β-adrenoceptor antagonists; CIs = confidence intervals; ND = no study variability of relevant outcomes of the meta-analysis, no calculation of the CIs was possible and therefore the studies by Chrysant et al. and Oparil et al. could not be extended meta-analysis was not possible. As Giles and Robinson did not provide information on either the individual studies contained within their meta-analysis or the Of all the drugs analysed, indapamide SR showed the greatest reduction in SBP (–22.2mm Hg) from Olmesartan data are based on the meta-analysis of Giles and Robinson; although two other studies were available for this drug, combination of their data into an baseline values. –12.9, –11.7 –10.5, –9.4 –10.9, –9.7 95% CI Discussion Change in diastolic BP This update of the previous analysis evaluating the efficacy of antihypertensive drugs in reducing SBP and DBP in patients with grade 1 or 2 hyperten- mm Hg sion over periods of 8–12 weeks has both confirmed –10.0 –10.3 –12.3 satisfied the inclusion criteria, or the data reported were insufficient to allow incorporation into the meta-analysis; SR = sustained-release. and extended the earlier findings. The previous combined with these data. Thus, the results presented are those of Giles and Robinson since this is the best available evidence. analysis, which included 72 trials and involved the use of 11 antihypertensive drugs in a total of 9094 patients, was extended to 80 trials involving the use –13.6, –11.4 –13.1, –11.2 –16.0, –14.0 of 16 drugs in 10 818 patients in the present analy- sis. As with the previous analysis, the reductions in 95% CI SBP over 8–12 weeks of treatment were most Change in systolic BP marked with diuretics, followed by CCAs and ACE inhibitors, while reductions in DBP were of similar No information on variability was provided, preventing the use of an approximation for CI estimation. magnitude with all classes but were most marked with the β-blocker atenolol, CCAs and diuretics. mm Hg –12.5 –12.1 –15.0 The updated analysis again confirmed that in- dapamide SR was the most effective drug in reduc- ing SBP over 8–12 weeks (mean reduction from baseline of –22.2mm Hg). Generalisation of these results is limited by the patientsa No. of drug selection criteria adopted, the inclusion/exclu- 544 178 175 sion criteria applied, and the analysis methods used. Numbers of patients included in the various studies of each drug. In terms of the selection process, the analysis was entirely confined to published trials identified via the PubMed database, and the possible impact of (mg/day) Dosage publication bias must therefore be taken into ac- 150 300 count. Although PubMed is the most widely used 80 database in the biomedical field, it is not the only one available, and the use of others such as EM- BASE®, BIOSIS® and PASCAL® could have re- sulted in a lower level of selection bias that might Valsartan Aliskiren have lessened the potential impact of this limitation Drug on our findings. However, the procedure that we adopted is widely used and is consistent with that of other analyses of antihypertensive drug efficacy. An important feature of the selection process is that Table IV. Contd Renin inhibitor the analysis was confined to monotherapy with anti- Drug class hypertensive drugs, which made it possible to com- pare the results obtained with drugs of different classes and exclude potential limitations introduced a b c © 2007 Adis Data Information BV. All rights reserved. Clin Drug Invest 2007; 27 (11) Updated Meta-Analysis on Antihypertensive Drugs 743 by the use of drug combinations. However, these present the results by way of weighted average sums limitations should be less pre-eminent for diuretics of BP reductions over 8–12 weeks, a period consis- because of their well demonstrated synergistic effect tent with current clinical recommendations (e.g. the when combined with inhibitors of the renin-angio- HAS [Haute Autorité de Santé] guidelines) for tensin system and CCAs. In addition, our analysis assessing the clinical efficacy and tolerability of was limited to the use of fixed-dose monotherapy or antihypertensive therapies following their initiation. trials where a dose increase during the evaluation The weighted means method, which has been used period was allowed, which permitted evaluation of in other meta-analyses, takes into account the the efficacy of different dosages for some of the different sizes of trials and provides results that are drugs selected. The dose effect efficacy on BP re- easy to interpret clinically. Other approaches such as duction of some drug classes should interfere only the standardised effects method (which utilises the slightly with our observations because the mean difference between standard means over the stan- result of the effect of several dosages was analysed dard deviation of the first measurement time) could for each class. Confining the analysis to monother- have been used; however, the principal limitation of apy trials does place some limitations on the appli- the standardised effects method lies in the difficulty cability of the results to routine clinical practice, inherent in its clinical interpretation. where many patients receive treatment with more According to the latest North American and Eu- than one antihypertensive agent. Another potential ropean guidelines, SBP is considered a better car- limitation of the analysis is the relatively small diovascular risk prediction factor than DBP.[3,6] In- number of patients treated with some antihyperten- deed, high SBP leads to a greater increase in cardio- sive drugs, notably ramipril (n = 17) and trando- vascular events than high DBP. In this regard, the lapril (n = 30), which carries with it the need for cautious interpretation of data relating to these results of our analysis showing that diuretics are the drugs. most effective therapeutic class in reducing SBP suggest that these drugs may be of particular value Among the studies selected for analysis, some in initial antihypertensive drug regimens. Although heterogeneity was evident when considering factors the reductions in SBP varied from one diuretic regi- such as the characteristics of study populations (e.g. men to another (table IV), indapamide SR 1.5 mg/ mean patient age) and the use of non-pharmacologi- day provided the greatest mean reduction in SBP cal (lifestyle) measures, for which recommendations (–22.2mm Hg), and this change was greater than can differ from one clinical setting to another. Age that recorded with any other antihypertensive drug has not been taken into account in other recent meta- in the analysis. A possible explanation for this find- analyses of different antihypertensive drugs, and ing lies in the direct, non-diuretic-dependent effect in the absence of analyses that have evaluated its of indapamide on arterial function and structure that influence, age cannot be taken as a moderator varia- has been demonstrated in experimental studies. ble. The mean age (≈50 years for most of the stud- Though the present analysis was not designed to ies) and the fact that no study included in the analy- detect statistical differences between individual sis was solely dedicated to systolic hypertension drugs or drug classes, the observation of a greater should not have favoured drug classes usually con- magnitude of reduction in SBP with indapamide SR sidered more efficient for treating isolated systolic than was seen in trials of hydrochlorothiazide ad- hypertension. The same is true with respect to the ministered in a fixed dosage is in agreement with the lack of drug-placebo comparisons, which could not findings of Emeriau et al., who reported that be performed as part of this analysis because of the indapamide SR 1.5 mg/day was more effective in differing designs of the trials selected. lowering SBP than hydrochlorothiazide 25 mg/day Rather than grouping the data to permit head-to- in a randomised, double-blind study. After diuretics, head comparisons of the various drugs, we chose to the CCAs and ACE inhibitors were the next most © 2007 Adis Data Information BV. All rights reserved. Clin Drug Invest 2007; 27 (11) 744 Baguet et al. effective drug classes in reducing SBP, while ARBs low-dose diuretics are the most effective drugs for appeared to be the least effective. With respect to preventing the occurrence of cardiovascular disease DBP, the greatest reductions with the various drug morbidity and mortality. Together, these findings classes were observed with β-blockers (atenolol) suggest that prompt and clinically relevant BP re- and CCAs followed by diuretics, while the ARBs ductions by diuretics are associated with important were again the least effective agents. Our findings benefits in preventing cardiovascular morbidity and with ARBs are in agreement with those of the meta- mortality. Although our findings with indapamide analysis of Conlin et al., who reported similar or SR support a greater magnitude of BP reduction smaller reductions in SBP and DBP for monother- with this agent, whether this will be reflected in apy with ARBs (SBP –10.4 to –11.8mm Hg; DBP greater longer term benefits in terms of reducing –8.2 to –8.9mm Hg) compared with those recorded cardiovascular events in hypertensive patients re- in our analysis. Despite the relatively good DBP- mains to be proven in further research. lowering efficacy of atenolol seen in this analysis, it is important to note that this agent has been found to Conclusions perform poorly in cardiovascular outcome studies and appears to have limited efficacy in reducing This updated meta-analytical approach of 80 cardiovascular morbidity and mortality. randomised, controlled trials of commonly used an- tihypertensive drugs involving 10 818 patients with As not all of the trials selected for our analysis grade 1 or 2 essential hypertension has confirmed included tolerability data, we were unable to per- and extended the findings of the earlier analysis. form a parallel comparison of the safety of the Over a period of 8–12 weeks, the average weighted various drugs evaluated. In addition, because we reductions in SBP appeared most marked with di- monitored BP reductions over 8–12 weeks, we can- uretics, and in particular indapamide SR 1.5 mg/day not extrapolate our results to the longer term bene- (mean change from baseline of –22.2mm Hg), fits of the treatments on cardiovascular morbidity which reduced SBP to a greater extent than any of and mortality. However, in this regard, the findings the other drugs evaluated, at any dosage. In compar- of some recent studies are pertinent. For example, ison, average weighted reductions in SBP were low- the VALUE (Valsartan Antihypertensive Long-term er with other drug classes: ARBs (–13.2mm Hg), β- Use Evaluation) study, which compared valsartan blockers (–14.8mm Hg), ACE inhibitors (–15.6mm and amlodipine in patients at high cardiovascular Hg), CCAs (–16.4mm Hg), and the renin inhibitor risk, emphasised the importance of prompt BP con- aliskiren (–13.5mm Hg). Average weighted reduc- trol (within 3 months) for optimising the prevention tions in DBP over the evaluation period were gener- of cardiac events, while a meta-analysis of the ally similar with all classes of drugs and ranged from effects of different BP-lowering regimens on major –11.4mm Hg with the β-blocker atenolol and CCAs cardiovascular outcomes by the Blood Pressure to –10.3mm Hg with the ARBs. Lowering Treatment Trialists’ Collaboration con- The most important finding of this analysis was cluded that larger reductions in BP (especially SBP that, within the period of 2–3 months, indapamide reduction) are associated with larger reductions in SR 1.5mg seemed to be most efficacious in reducing cardiovascular risk. This is reflected in the 2007 SBP. SBP reduction in particular is considered an European Society of Hypertension (ESH)/European important aspect of cardiovascular event prevention Society of Cardiology (ESC) guidelines, which state in patients with hypertension. that the size of BP reduction is more important than the class used for cardiovascular event reduction. Appendix 1 (Table V) Furthermore, a review of health outcomes associat- ed with various antihypertensive therapies used as first-line agents by Psaty et al. concluded that Appendix 2 (Table VI) © 2007 Adis Data Information BV. All rights reserved. Clin Drug Invest 2007; 27 (11)  Table V. Appendix 1: Characteristics of the studies analysed for potential inclusion in the meta-analysis Drug class Drug Dosage No. of Age Sex ratio Measurement References (mg/day) patients [y (mean ± SD)] (m/f)a interval (wk) Diuretics Cicletanine ND Furosemide ND Hydrochlorothiazide ≤25 40 55.1 NA 8 24 171 72.7 ± 5.8 59/112 12 19 85 56.4 ± 10.8 48/37 8 25 21 69 ± 1 13/8 8 26 12.5–50 18 66 ± 5 16/2 8 27 76 51 ± 10 41/35 12 28 50 56 20–70b 8 29 Indapamide SR 1.5 178 72.2 ± 5.9 68/110 12 19 © 2007 Adis Data Information BV. All rights reserved. 30 59.8 ± 8.7 30/34 12 30 57 55.2 ± 11.3 25/32 8 31 Spironolactone ND Updated Meta-Analysis on Antihypertensive Drugs β-Blockers Atenolol 50 55 40–49b 55/0 8 32 16 55.6 ± 8.36 8/8 12 33 62 60.4 30/32 12 34 188 51.6 90/98 12 35 50–100 14 45 ± 8 6/8 8 36 17 53 ± 8 11/6 12 37 18 46.7 17/19 12 38 69 55 ± 14 38/31 8 39 39 57.4 ± 2.3 17/26 8 40 22 57 8 41 12 33–68b 24/12 12 42 121 55.9 ± 9.4 67/54 12 43 18 51.6 ± 10.1 9/9 10 44 66 53.9 46/22 12 45 17 58 ± 2.2 1/16 12 46 43 54 ± 9 12 47 18 21–75b 12 48 9 57 ± 15 4/30 10 49 Continued next page 745 Clin Drug Invest 2007; 27 (11)  Table V. Contd Drug class Drug Dosage No. of Age Sex ratio Measurement References 746 (mg/day) patients [y (mean ± SD)] (m/f)a interval (wk) Calcium channel Amlodipine 5 175 72.4 ± 6.1 68/107 12 19 antagonists 84 52.9 ± 8.9 48/36 8 50 81 55.1 ± 11.4 12 51 5–10 10 51 ± 9 6/4 12 52 101 54.1 ± 10.1 50/50 8 53 21 69 ± 1 12/9 8 26 244 54.0 ± 9.2 154/90 8 54 29 49.4 ± 9.7 8 55 298 57.8 155/153 12 56 © 2007 Adis Data Information BV. All rights reserved.