Clinical Trial: ADVANCE Trial

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1 Effects of Combination of Perindopril, Indapamide, and Calcium Channel Blockers in Patients With Type 2 Diabetes Mellitus Results From the Action in Diabetes and Vascular Disease: Preterax and Diamicron Controlled Evaluation (ADVANCE) Trial John Chalmers, Hisatomi Arima, Mark Woodward, Giuseppe Mancia, Neil Poulter, Yoichiro Hirakawa, Sophia Zoungas, Anushka Patel, Bryan Williams, Stephen Harrap See Editorial Commentary, pp Clinical Trial: ADVANCE Trial Abstract The objective of the present analysis was to determine the effects of a fixed combination of perindopril and indapamide in combination with calcium channel blockers (CCBs) in patients with type 2 diabetes mellitus. The Action in Diabetes and Vascular Disease: Preterax and Diamicron Controlled Evaluation (ADVANCE) trial was a factorial randomized controlled trial. A total of patients with type 2 diabetes mellitus were randomly assigned to fixed combination of perindopril indapamide (4/1.25 mg) or placebo. Effects of randomized treatment on mortality and major cardiovascular outcomes were examined in subgroups defined by baseline use of CCBs. Patients on CCB at baseline (n=3427) constituted a higher risk group compared with those not on CCB (n=7713), with more extensive use of antihypertensive and other protective therapies. Active treatment reduced the relative risk of death by 28% (95% confidence interval, 10% 43%) among patients with CCB at baseline compared with 5% ( 12% to 20%) among those without CCB (P homogeneity=0.02) and 14% (2% 25%) for the whole population. Similarly, the relative risk reduction for major cardiovascular events was 12% ( 8% to 28%) versus 6% ( 10% to 19%) for those with and without CCB at baseline although the difference was not statistically significant (P homogeneity=0.38). There was no detectable increase in adverse effects in those receiving CCB. The combination of perindopril and indapamide with CCBs seems to provide further protection against mortality in patients with type 2 diabetes mellitus. (Hypertension. 2014;63: ) Online Data Supplement Key Words: angiotensin-converting enzyme inhibitors blood pressure calcium channel blockers diabetes mellitus diuretics drug therapy, combination randomized controlled trial It is a sad reflection of our collective failure to deal effectively with the growing burden of blood pressure related diseases 1 that control rates among patients known to be hypertensive remain poor in most regions of the world. 2 7 Thus, national, regional, and international guidelines uniformly stress the importance and the frequent need of combination therapy for effective control of hypertension and of suboptimal blood pressure in highrisk groups Despite this, control rates remain poor with <15% well controlled in 17 countries participating in the Prospective Urban Rural Epidemiology (PURE) study. 4 This is partly attributable to the continuing reliance on monotherapy and partly to the inadequacy of control rates achieved with combinations of 2 drugs. 4,14,15 There is also a considerable resistance on the part of community doctors to the use of fixed-dose (single-pill) combinations, 16,17 although there is considerable evidence to support their effectiveness in improving adherence to therapy and achievement of effective blood pressure control. 2 11,13,18 21 Among several possible combinations recommended by current guidelines, 8 13 some of the most favored combinations supported by evidence from randomized trials include angiotensin-converting enzyme (ACE) inhibitors and diuretics, as in the Perindopril Protection Against Recurrent Stroke Study (PROGRESS), 22 Action in Diabetes and Vascular Disease: Preterax and Diamicron Controlled Evaluation (ADVANCE), 19 and Hypertension in the Very Elderly Received August 16, 2013; first decision August 28, 2013; revision accepted October 28, From The George Institute for Global Health, Sydney, Australia (J.C., H.A., M.W., Y.H., S.Z., A.P.); The University of Sydney, Sydney, Australia (J.C., H.A., M.W., Y.H., A.P.); Royal Prince Alfred Hospital, Sydney, Australia (J.C., H.A., M.W., Y.H., A.P.); IRCCS Istituto Auxologico Italiano and University of Milan-Bicocca, Milan, Italy (G.M.); Imperial College London, London, United Kingdom (N.P.); School of Public Health, Monash University, Clayton, Australia (S.Z.); University College London and The National Institute for Health Research University College London Hospitals Biomedical Research Centre, London, United Kingdom (B.W.); and Department of Physiology, University of Melbourne, Melbourne, Victoria, Australia (S.H.). This paper was sent to Takayoshi Ohkubo, Guest editor, for review by expert referees, editorial decision, and final disposition. The online-only Data Supplement is available with this article at /-/DC1. Correspondence to John Chalmers, The George Institute for Global Health, PO Box M201, Camperdown, NSW 2050, Australia. chalmers@ georgeinstitute.org.au 2013 American Heart Association, Inc. Hypertension is available at DOI: /HYPERTENSIONAHA

2 260 Hypertension February 2014 Trial (HYVET) trials, 23 and ACE inhibitors and calcium channel blockers (CCBs), as in the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) 24 and Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) 20 trial. In this context, the ADVANCE trial provides us with an opportunity to examine the possible advantages of a triple combination for which there are as yet no randomized data from cardiovascular outcome trials. In this trial, the study drugs were the ACE inhibitor perindopril and the diuretic indapamide, used in fixed combination. 19 In this article, we compare the effects of randomized treatment with the combination of perindopril and indapamide in subgroups defined by use of CCBs at baseline. Specifically, we examine the effects on major cardiovascular events (the primary outcome), cardiovascular death, and all-cause mortality. We also report observational analyses comparing the effects of randomized treatment, with the fixed combination of perindopril and indapamide, in subgroups defined by use of CCBs at any time, whether before or after randomization. Methods ADVANCE trial was a factorial randomized controlled trial of blood pressure lowering and intensive blood glucose control in patients with type 2 diabetes mellitus. Details of the design and procedures have been described previously. 19,25 Patients were potentially eligible if they had been diagnosed with type 2 diabetes mellitus at the age of 30 years and were aged 55 years at entry to the study. Potentially eligible patients also needed to have 1 of the following: a history of major cardiovascular disease (stroke, myocardial infarction, hospital admission for transient ischemic attack, hospital admission for unstable angina, coronary revascularization, peripheral revascularization, or amputation secondary to vascular disease) or 1 other risk factor for cardiovascular disease. There were no blood pressure criteria for entry. Prior blood pressure lowering medications were not required to be stopped at the start of the run-in period. Approval for the trial was obtained from each center s institutional review board, and all participants provided written informed consent. Participants who tolerated 6 weeks of run-in therapy with fixed combination tablet consisting of perindopril (2 mg) and indapamide (0.625 mg) were randomly assigned, in a double-blind fashion, to fixed combination of perindopril and indapamide (2/0.625 mg for the first 3 months and 4/1.25 mg thereafter) or matching placebo. Information on use of CCBs (any dihydropyridine or nondihydropyridine) was collected at baseline and follow-up visits. The outcomes for the present analysis were major cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death), cardiovascular death, and death from any cause. Statistical Analysis The effects of randomized treatment on events were calculated using univariate Cox proportional hazards models, according to the principle of intention-to-treat. The effects of randomized treatment on blood pressure were estimated using linear mixed models. Comparisons of treatment effects between subgroups were examined by adding an interaction term to the statistical models. Drug effects were also estimated from observational analyses that used Cox proportional hazards models after adjustment for wide variety of covariates as described in the legends of Figures and Tables. Percentage risk reductions were calculated as ([1 hazard ratio] 100). All P values were calculated from 2-tailed tests of statistical significance. Results Analyses of Randomized Data A total of patients with type 2 diabetes mellitus were randomized into the blood pressure arm of ADVANCE trial, with 5569 assigned to active treatment with the fixed combination of perindopril and indapamide and 5571 to matching placebo. 19 Of these, 3427 (1669 in active group and 1758 in placebo group) were taking a CCB and 7713 (3900 in active group and 3813 in placebo group) were not at baseline. The mean duration of follow-up was 4.3 years. The characteristics of these patients at baseline are shown in Table 1. Those on CCB represent a higher risk group with longer duration of diabetes mellitus, higher systolic and diastolic blood pressures despite higher rates of treatment with antihypertensive drugs, and higher rates of previous cardiovascular disease. The mean difference in systolic blood pressure between those on active treatment and those on placebo, across the whole period of randomized treatment, was 4.7 mm Hg (95% confidence interval, ) in those on CCB and 6.2 mm Hg ( ) in those Table 1. Characteristic Baseline Characteristics by Baseline Use of CCBs No Baseline CCB (n=7713) Baseline CCB (n=3427) Demographic Age, y (SD) 66 (6) 66 (6) Women, % Asian,* % Medical history Duration of diabetes mellitus, y (IQR) 6 (3 11) 7 (3 12) History of macrovascular disease, % History of microvascular disease, % 9 12 Current smoking, % Blood pressure Systolic blood pressure, mm Hg (SD) 144 (22) 148 (21) Diastolic blood pressure, mm Hg (SD) 80 (11) 81 (11) Blood test HbA1c, % (SD) 7.5 (1.5) 7.5 (1.6) LDL cholesterol, mmol/l (SD) 3.1 (1.0) 3.1 (1.0) HDL cholesterol, mmol/l (SD) 1.3 (0.4) 1.3 (0.4) Medication, % Antihypertensive therapy Angiotensin-converting enzyme inhibitor Angiotensin receptor blocker 5 6 β-blocker Diuretic Others Glucose-lowering therapy Gliclazide (modified release) 7 8 Other sulfonylurea Metformin Other oral drugs Insulin 1 2 Antiplatelet therapy Oral anticoagulants 3 4 Lipid-lowering therapy CCB indicates calcium channel blocker; HbA1c, hemoglobin A1c; HDL, highdensity lipoprotein; IQR, interquartile range; and LDL, low-density lipoprotein. *Participants recruited from People s Republic of China. Currently treated hypertension.

3 Chalmers et al Combination Therapy in ADVANCE Trial 261 Table 2. Effects of Baseline CCB (Nonstudy Drug) on Major Cardiovascular Events and Death, in the Whole Cohort, Independent of Randomized Treatment Outcome No. of Events (Annual Rate) No CCB (n=7713) CCB (n=3427) Hazard Ratio (95% CI) P Value Major cardiovascular 628 (1.9) 372 (2.6) 1.24 ( ) event Cardiovascular death 286 (0.9) 182 (1.3) 1.22 ( ) 0.04 Total death 573 (1.7) 306 (2.1) 1.07 ( ) 0.40 Hazard ratios and P values were adjusted for age, sex, duration of diabetes mellitus, systolic blood pressure, hemoglobin A1c, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, log-transformed triglyceride, estimated glomerular filtration rate, urinary albumin creatinine ratio, body mass index, smoking, ECG abnormalities, and randomized treatments. 95% CI indicates 95% confidence interval; and CCB, calcium channel blocker. not on CCB, reflecting the greater difficulty of lowering blood pressure in a higher risk group of patients that was receiving more extensive antihypertensive therapy (Tables 1 and 2). Figure 1 shows the effects of randomized treatment in subgroups defined by use of CCBs at baseline. Active treatment with the fixed combination of perindopril and indapamide reduced the relative risk of death by 28% (10% 43%) among patients with CCB compared with 5% ( 12% to 20%) among those without CCB (P homogeneity=0.02) and 14% (2% 25%) for the whole population (Figure 1). There were also trends, although not significant, for greater reductions in major cardiovascular events and cardiovascular mortality (Figure 1). Analyses of Observational Data We compared the effects of blood pressure lowering in the group assigned to randomized treatment with the fixed combination of perindopril and indapamide who received CCBs at any time point (whether at baseline or during follow-up) with effects in the group assigned to placebo who did not receive CCBs at any time, whether before or after randomization. The baseline characteristics of those 2 groups are shown in Table S1 in the online-only Data Supplement. Once again, the group receiving CCBs was a higher risk group. As can be seen in Figure 2, after adjustment, those receiving active treatment plus CCBs had substantial and significant reductions in both all-cause mortality and cardiovascular death. We also compared the effects of blood pressure lowering in the group assigned to randomized treatment with the fixed combination of perindopril and indapamide who also received CCBs at baseline with effects in the group assigned to placebo who also received open-label perindopril and a CCB. The baseline characteristics of those 2 groups are shown in Table S2. As can be seen in Figure 3, after adjustment, the group receiving the triple therapy with ACE inhibitor, diuretic, and CCB had a significant reduction in all-cause mortality compared with the patients on dual therapy with CCB and ACE inhibitor. There was a nonsignificant trend to greater reduction in major cardiovascular events and cardiovascular death (Figure 3). Permanent Discontinuation and Adverse Effects of Study Treatment The frequency of permanent discontinuation and key adverse effects among patients assigned active treatment and those assigned placebo are reported by baseline use of CCBs in Table S3. Compared with participants who did not receive CCBs at baseline, there was no clear increase in the frequency of total permanent discontinuation or of discontinuation attributable to adverse effects such as hypotension and cough among those on CCBs at baseline for both active and placebo groups. Discussion The present analyses in patients with type 2 diabetes mellitus indicate that adding a CCB to the combination of an ACE inhibitor and a diuretic produces additional tangible benefits. Thus, being on a CCB as well as the fixed combination of perindopril and indapamide in patients participating in ADVANCE trial led to significantly greater reductions in all-cause mortality, with nonsignificant trends to greater reduction in cardiovascular mortality and major cardiovascular events, than being on the fixed combination alone. Furthermore, these benefits seemed to be independent of the degree of blood pressure reduction and were observed despite the greater risk profile of the patients receiving CCB, either at baseline or during follow-up. The best combinations of blood pressure lowering drugs combine different primary actions so as to achieve fully Figure 1. Effects of randomized treatment with the fixed combination of perindopril and indapamide on major cardiovascular (CV) events and death by baseline use of calcium channel blockers (CCBs). Solid boxes represent estimates of treatment effect on the risk of clinical outcomes. Centers of the boxes are placed at the estimates of effect; areas of the boxes are proportional to the reciprocal of the variance of the estimates. Horizontal lines represent 95% confidence interval (CI). Diamonds represent estimates and 95% CI for overall effects in both groups. The P value for homogeneity tested the consistency of the treatment effect between subgroups.

4 262 Hypertension February 2014 Figure 2. Effects of the combination of perindopril and indapamide (randomized study drugs) with calcium channel blockers (CCBs) at any visit (nonstudy drug) on major cardiovascular (CV) events and death compared with participants on placebo who never received CCBs. Solid boxes represent estimates of treatment effect on the risk of clinical outcomes. Centers of the boxes are placed at the estimates of effect; areas of the boxes are proportional to the reciprocal of the variance of the estimates. Horizontal lines represent 95% confidence interval (CI). Hazard ratios and P values were adjusted for age, sex, duration of diabetes mellitus, systolic blood pressure, hemoglobin A1c, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, log-transformed triglyceride, estimated glomerular filtration rate, urinary albumin creatinine ratio, body mass index, smoking, ECG abnormalities, and randomized glucoselowering treatment. additive effects on blood pressure reduction. At the same time, the combination of 2 drugs enables the use of each drug either in standard dose or even in low dose, thus reducing the frequency of side effects and enhancing acceptability and adherence to therapy. 8 11,13,26 Two of the most favored combinations in the modern era are the use of ACE inhibitors with diuretics and the use of ACE inhibitors with CCBs. The former has the advantage of opposing effects on potassium secretion by the kidneys, thus minimizing the risks of hyper- or hypokalemia. This combination has been shown to have outstanding effects on mortality and hard cardiovascular outcomes in the PROGRESS, 22 ADVANCE, 19 and HYVET trials 23 in which the ACE inhibitor was perindopril and the diuretic was indapamide. The combination of ACE inhibitors with CCBs also has additive effects on blood pressure lowering and has been amply vindicated by the ASCOT which achieved excellent results on hard outcomes, using perindopril and amlodipine 24 and the ACCOMPLISH trial using benazepril and amlodipine, on a range of cardiovascular outcomes. 20 The present analyses indicate that when a third drug is necessary, the combination of an ACE inhibitor, a diuretic, and a CCB provides an excellent 3-fold option to reduce the risk of death and major cardiovascular events with low rates of adverse events. Furthermore, the triple combination of perindopril, indapamide, and a CCB seems superior to the double combination of either perindopril and indapamide alone (Figure 1) or perindopril and a CCB (Figure 3). Many guidelines for management of hypertension recommend combination antihypertensive therapy for patients with hypertension and also for patients with high cardiovascular risk, whether hypertensive or not. 8 11,13 However, one of the biggest dilemmas in our field continues to be the great gap between evidence and practice, with low levels of achievement of recommended blood pressure targets worldwide. 2 7 One possible reason for the resistance of both patients and community physicians against combination therapy is likely to be the increase in the number of antihypertensive agents. There is considerable evidence that use of fixed-dose (singlepill) combinations of 2, 3, or even more blood pressure lowering agents may result in better adherence to medications and subsequent better blood pressure control ,18,21,27 In the present analysis, the effects of active treatment with the fixed combination of perindopril and indapamide on total mortality were larger among patients with CCB compared with those without CCB, with nonsignificant trend for the outcome of cardiovascular death. It is difficult to explain the reasons for this finding clearly, but it should be noted that the main results of ADVANCE trial reported major reductions in allcause mortality (14%) and cardiovascular mortality (18%). 19 In addition, possible imbalance in unknown confounding factors may have contributed to these findings. The analyses reported here have the advantage of being based on a large-scale clinical trial with sufficient power to examine the effects of randomized treatment in a variety of subgroups Figure 3. Effects of the combination of perindopril and indapamide (randomized study drugs) with calcium channel blockers (CCBs) at baseline (nonstudy drug) on major cardiovascular (CV) events and death compared with participants on placebo who received nonrandomized perindopril and CCBs at baseline (nonstudy drugs). Solid boxes represent estimates of treatment effect on the risk of clinical outcomes. Centers of the boxes are placed at the estimates of effect; areas of the boxes are proportional to the reciprocal of the variance of the estimates. Horizontal lines represent 95% confidence interval (CI). Hazard ratios and P values were adjusted for age, sex, duration of diabetes mellitus, systolic blood pressure, hemoglobin A1c, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, log-transformed triglyceride, estimated glomerular filtration rate, urinary albumin creatinine ratio, body mass index, smoking, ECG abnormalities, and randomized glucose-lowering treatment.

5 Chalmers et al Combination Therapy in ADVANCE Trial 263 defined by baseline characteristics, in this instance the use of CCBs or not. The analyses also have several limitations. They are all post hoc, and none were prespecified at the time the ADVANCE trial was designed. Because the use of CCB was not randomly assigned, there was significant heterogeneity in baseline characteristics and in the risks of cardiovascular events and deaths between patients with and without CCB. Furthermore, some analyses are based on observational data and lose the advantage of unbiased randomized comparison. Perspectives The addition of CCBs to the combination of the ACE inhibitor perindopril with the diuretic indapamide seems to enhance the reduction of all-cause mortality and hard cardiovascular outcomes in patients with type 2 diabetes mellitus in ADVANCE trial. These potential benefits were seen without any detectable increase in adverse events. Sources of Funding The ADVANCE trial was funded by grants from the National Health and Medical Research Council (NHMRC) of Australia and Servier International. Disclosures J. Chalmers and N. Poulter have received research grants and lecture fees from Servier International. H. Arima holds Future Fellowship from Australian Research Council (ARC). M. Woodward, G. Mancia, and S. Zoungas have received lecture fees from Servier International. M. Woodward holds a Senior Research Fellowship from the NHMRC. Y. Hirakawa holds a fellowship from the Uehara Memorial Foundation. B. Williams has received lecture fees from Servier, Novartis, and Boehringer Ingelheim and is a National Institutes for Health Research (NIHR) Senior Investigator. The other authors report no conflicts. References 1. Lozano R, Naghavi M, Foreman K, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study Lancet. 2012;380: Egan BM, Zhao Y, Axon RN. US trends in prevalence, awareness, treatment, and control of hypertension, JAMA. 2010;303: Heeley EL, Peiris DP, Patel AA, Cass A, Weekes A, Morgan C, Anderson CS, Chalmers JP. Cardiovascular risk perception and evidence practice gaps in Australian general practice (the AusHEART study). Med J Aust. 2010;192: Yusuf S, Islam S, Chow CK, et al; Prospective Urban Rural Epidemiology (PURE) Study Investigators. Use of secondary prevention drugs for cardiovascular disease in the community in high-income, middle-income, and low-income countries (the PURE Study): a prospective epidemiological survey. Lancet. 2011;378: Prugger C, Keil U, Wellmann J, de Bacquer D, de Backer G, Ambrosio GB, Reiner Z, Gaita D, Wood D, Kotseva K, Heidrich J; EUROASPIRE III Study Group. Blood pressure control and knowledge of target blood pressure in coronary patients across Europe: results from the EUROASPIRE III survey. J Hypertens. 2011;29: Meng XJ, Dong GH, Wang D, Liu MM, Lin Q, Tian S, Xu LX, Hou H, Ren YF, Lee YL. Prevalence, awareness, treatment, control, and risk factors associated with hypertension in urban adults from 33 communities of China: the CHPSNE study. J Hypertens. 2011;29: Prince MJ, Ebrahim S, Acosta D, Ferri CP, Guerra M, Huang Y, Jacob KS, Jimenez-Velazquez IZ, Rodriguez JL, Salas A, Sosa AL, Williams JD, Gonzalez-Viruet M, Jotheeswaran AT, Liu Z. Hypertension prevalence, awareness, treatment and control among older people in Latin America, India and China: a 10/66 cross-sectional population-based survey. J Hypertens. 2012;30: World Health Organization International Society of Hypertension Writing Group World Health Organization (WHO)/International Society of Hypertension (ISH) statement on management of hypertension. J Hypertens. 2003;21: Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, Roccella EJ; Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. National Heart, Lung, and Blood Institute; National High Blood Pressure Education Program Coordinating Committee. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003;42: Mancia G, De Backer G, Dominiczak A, et al; Management of Arterial Hypertension of the European Society of Hypertension; European Society of Cardiology Guidelines for the Management of Arterial Hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens. 2007;25: Ogihara T, Kikuchi K, Matsuoka H, et al; Japanese Society of Hypertension Committee. The Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH 2009). Hypertens Res. 2009;32: National Institute for Health and Clinical Excellence. Hypertension: Clinical Management of Primary Hypertension in Adults. NICE Clinical Guideline 127. London, UK: National Institute for Health and Clinical Excellence; Mancia G, Fagard R, Narkiewicz K, et al; Task Force Members ESH/ESC Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens. 2013;31: Thoenes M, Neuberger HR, Volpe M, Khan BV, Kirch W, Böhm M. Antihypertensive drug therapy and blood pressure control in men and women: an international perspective. J Hum Hypertens. 2010;24: Campbell DJ, McGrady M, Prior DL, Coller JM, Boffa U, Shiel L, Liew D, Wolfe R, Stewart S, Reid CM, Krum H. Most individuals with treated blood pressures above target receive only one or two antihypertensive drug classes. Intern Med J. 2013;43: Chalmers J, Arima H, Harrap S, Touyz RM, Park JB. Global survey of current practice in management of hypertension as reported by societies affiliated with the International Society of Hypertension. J Hypertens. 2013;31: Chalmers J, Harrap S, Narkiewicz K, Poulter N, Redon J, Zanchetti A, Mancia G. Issues in the development of new combinations of blood pressure lowering drugs. J Hypertens. 2010;28: Bangalore S, Kamalakkannan G, Parkar S, Messerli FH. Fixed-dose combinations improve medication compliance: a meta-analysis. Am J Med. 2007;120: ADVANCE Collaborative Group. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet. 2007;370: Jamerson K, Weber MA, Bakris GL, Dahlöf B, Pitt B, Shi V, Hester A, Gupte J, Gatlin M, Velazquez EJ; ACCOMPLISH Trial Investigators. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med. 2008;359: Gupta AK, Arshad S, Poulter NR. Compliance, safety, and effectiveness of fixed-dose combinations of antihypertensive agents: a meta-analysis. Hypertension. 2010;55: PROGRESS Collaborative Group. Randomised trial of a perindoprilbased blood pressure lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack. Lancet. 2001;358: Beckett NS, Peters R, Fletcher AE, et al; HYVET Study Group. Treatment of hypertension in patients 80 years of age or older. N Engl J Med. 2008;358: Dahlöf B, Sever PS, Poulter NR, Wedel H, Beevers DG, Caulfield M, Collins R, Kjeldsen SE, Kristinsson A, McInnes GT, Mehlsen J, Nieminen M, O Brien E, Ostergren J; ASCOT Investigators. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet. 2005;366: The ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358:

6 264 Hypertension February Law MR, Wald NJ, Morris JK, Jordan RE. Value of low dose combination treatment with blood pressure lowering drugs: analysis of 354 randomised trials. BMJ. 2003;326: The Indian Polycap Study (TIPS). Effects of a polypill (Polycap) on risk factors in middle-aged individuals without cardiovascular disease (TIPS): a phase II, double-blind, randomised trial. Lancet. 2009;373: Novelty and Significance What Is New? These analyses present the first evidence from randomized data that the use of a triple combination of antihypertensive agents (angiotensinconverting enzyme inhibitor+diuretic+calcium channel blocker) is more effective than a double combination (angiotensin-converting enzyme inhibitor+diuretic) in reducing mortality. What Is Relevant? Combination therapy is recommended by most guidelines to improve control of hypertension worldwide, but there is so far little evidence of the benefits of triple combinations on hard end points. Summary The combination of perindopril and indapamide with calcium channel blockers seems to provide further protection against mortality in patients with type 2 diabetes mellitus. This article provides the first report of improvement in hard end points in patients receiving the combination of 3 antihypertensive drugs compared with those on 2 drugs.