Just Accepted by Current Medical Research & Opinion Commentary Combination Therapy In Hypertension: An Asia-Pacific Consensus Viewpoint Abdul Rashid Abdul Rahman, Eugenio B Reyes, Piyamitr Sritara, Arvind Pancholia, Phuoc Van Dang, Brian Tomlinson doi: 10.1185/03007995.2015.1020368 Curr Med Res Opin Downloaded from informahealthcare.com by McMaster University on 02/27/15 For personal use only Abstract Hypertension incurs a significant healthcare burden in Asia-Pacific countries, which have suboptimal rates of blood pressure (BP) treatment and control A consensus meeting of hypertension experts from the AsiaPacific region convened in Hanoi, Vietnam, in April 2013 The principal objectives were to discuss the growing problem of hypertension in the Asia-Pacific region, and to develop consensus recommendations to promote standards of care across the region A particular focus was recommendations for combination therapy, since it is known that most patients with hypertension will require two or more antihypertensive drugs to achieve BP control, and also that combinations of drugs with complementary mechanisms of action achieve BP targets more effectively than monotherapy The expert panel reviewed guidelines for hypertension management from the USA and Europe, as well as individual AsiaPacific countries, and devised a treatment matrix/guide, in which they propose the preferred combination therapy regimens for patients with hypertension, both with and without compelling indications This report summarises key recommendations from the group, including recommended antihypertensive combinations for specific patient populations These strategies generally entail initiating therapy with free drug combinations, starting with the lowest available dosage, followed by treatment with single-pill combinations once the BP target has been achieved A single reference for the whole Asia-Pacific region may contribute to increased consistency of treatment and greater proportions of patients achieving BP control, and hence reducing hypertension-related morbidity and mortality © 2014 Informa UK Ltd This provisional PDF corresponds to the article as it appeared upon acceptance Fully formatted PDF and full text (HTML) versions will be made available soon DISCLAIMER: The ideas and opinions expressed in the journal’s Just Accepted articles not necessarily reflect those of Informa Healthcare (the Publisher), the Editors or the journal The Publisher does not assume any responsibility for any injury and/or damage to persons or property arising from or related to any use of the material contained in these articles The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosages, the method and duration of administration, and contraindications It is the responsibility of the treating physician or other health care professional, relying on his or her independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient Just Accepted articles have undergone full scientific review but none of the additional editorial preparation, such as copyediting, typesetting, and proofreading, as have articles published in the traditional manner There may, therefore, be errors in Just Accepted articles that will be corrected in the final print and final online version of the article Any use of the Just Accepted articles is subject to the express understanding that the papers have not yet gone through the full quality control process prior to publication COMMENTARY COMBINATION THERAPY IN HYPERTENSION: AN ASIA-PACIFIC CONSENSUS VIEWPOINT Abdul Rashid Abdul Rahmana, Eugenio B Reyesb, Piyamitr Sritarac, Arvind Pancholiad, Phuoc Curr Med Res Opin Downloaded from informahealthcare.com by McMaster University on 02/27/15 For personal use only Van Dange, Brian Tomlinsonf a Cyberjaya University College of Medical Sciences, Selangor, Malaysia b University of the Philippines, College of Medicine, Department of Medicine, Manila, Malate, Philippines c Mahidol University, Department of Medicine, Ramathibodi Hospital, Bangkok, Thailand d Arihant Hospital and Research Center and Gokuldas Heart Center, Department of Medicine and Preventive Cardiology, Madhya Pradesh, India e Vietnam National University, Ho Chi Minh City, School of Medicine, Ho Chi Minh City, Vietnam f The Chinese University of Hong Kong, Department of Medicine and Therapeutics, Prince of Wales Hospital, Hong Kong SAR, China Address for correspondence: Brian Tomlinson, MBBS, MD, FRCP, Professor of Medicine and Therapeutics, The Chinese University of Hong Kong, Department of Medicine and Therapeutics, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China Tel/Fax: (852) 26323139; btomlinson@cuhk.edu.hk [Short title: Asia-Pacific Consensus on Combination Antihypertensives] Key words: hypertension, antihypertensive combination therapy, fixed-dose combinations, , Asia-Pacific consensus, guidelines Curr Med Res Opin Downloaded from informahealthcare.com by McMaster University on 02/27/15 For personal use only ABSTRACT Hypertension incurs a significant healthcare burden in Asia-Pacific countries, which have suboptimal rates of blood pressure (BP) treatment and control A consensus meeting of hypertension experts from the Asia-Pacific region convened in Hanoi, Vietnam, in April 2013 The principal objectives were to discuss the growing problem of hypertension in the Asia-Pacific region, and to develop consensus recommendations to promote standards of care across the region A particular focus was recommendations for combination therapy, since it is known that most patients with hypertension will require two or more antihypertensive drugs to achieve BP control, and also that combinations of drugs with complementary mechanisms of action achieve BP targets more effectively than monotherapy The expert panel reviewed guidelines for hypertension management from the USA and Europe, as well as individual Asia-Pacific countries, and devised a treatment matrix/guide, in which they propose the preferred combination therapy regimens for patients with hypertension, both with and without compelling indications This report summarises key recommendations from the group, including recommended antihypertensive combinations for specific patient populations These strategies generally entail initiating therapy with free drug combinations, starting with the lowest available dosage, followed by treatment with single-pill combinations once the BP target has been achieved A single reference for the whole Asia-Pacific region may contribute to increased consistency of treatment and greater proportions of patients achieving BP control, and hence reducing hypertension-related morbidity and mortality INTRODUCTION Curr Med Res Opin Downloaded from informahealthcare.com by McMaster University on 02/27/15 For personal use only HYPERTENSION IN THE ASIA-PACIFIC REGION Hypertension is a significant global health problem, outranking smoking, elevated blood glucose, obesity, and physical inactivity as a leading cause of morbidity and mortality1 Hypertension is a major independent risk factor for stroke, myocardial infarction (MI) and heart failure, sudden death, end-stage renal failure, and peripheral vascular disease; this relationship is evident at all ages and irrespective of ethnicity, and holds from relatively low to high blood pressure (BP) values2 In Asian countries, approximately two-thirds of all cardiovascular (CV) disease is attributable to hypertension, and although the correlation between increased systolic blood pressure (SBP) and coronary heart disease (CHD) is similar in Asians and Caucasians, there is an even stronger association with stroke in Asians3 More than a quarter of adults worldwide have hypertension Kearney and colleagues have predicted that the global prevalence of hypertension will rise from 26.4% of the adult population (972 million people) in 2000 to 29.2% (1.56 billion people) by 2025, with increases in all regions, including Asia-Pacific4 Due to the size and growth of their populations, China and India alone are expected to account for 500 million cases of hypertension by 20254 The increasing prevalence of hypertension in the Asia-Pacific region is due to multiple factors, which include population ageing, increasing urbanisation, reduced physical activity, increasing obesity, and adoption of a more “Western” diet (increased consumption of meat, dairy products and sugar)3 Despite increasing prevalence of hypertension in Asia-Pacific countries, levels of public awareness remain low5 As a consequence, treatment rates across the region are suboptimal and BP control rates are lower still (160/100 mmHg, and for those whose BP remains uncontrolled on monotherapy2,27-29 Most guidelines favour single-pill combinations and antihypertensive agents suited to once-daily administration Table summarises recommendations for combination therapy in European and United States (US) guidelines International treatment guidelines generally recommend all of the five major antihypertensive classes (ACEIs, ARBs, beta-blockers [BBs], CCBs, and diuretics), as they have similar BPlowering effects and reductions in CV events are largely thought to be due to BP lowering per se30,31 This is based on results from clinical trials, including a meta-analysis that showed similar benefits in terms of reducing CV events and strokes for all five drug classes30 This meta-analysis also found CCBs to be associated with a possible additional benefit for stroke prevention, and that BBs had a significant additional protective effect post-MI beyond BP-lowering alone30 Some guidelines give a weaker recommendation for BBs or not recommend their use for firstline therapy in the absence of compelling indications This stance is due to concerns that BBs have lower efficacy than drugs from other antihypertensive classes, and also that there is a risk of Curr Med Res Opin Downloaded from informahealthcare.com by McMaster University on 02/27/15 For personal use only new-onset diabetes when BBs are combined with thiazide diuretics28,29 Likewise, the recently published eighth report of the US Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC8) 2014, has downgraded BBs to a fourth-line medication option in the management algorithm27 It should be noted that this evidence applies primarily to less selective BBs such as atenolol, whereas highly selective BBs, such as bisoprolol, are less likely to be associated with adverse metabolic effects5,31 When BBs are used in combination with CCBs, a dihydropyridine such as amlodipine should be used to avoid the risk of bradycardia or heart block2,18 This was in contrast to the previous Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC7) 2003, which recommended that combination regimens involve primarily a thiazide diuretic in addition to an ACEI, ARB, BB or CCB While thiazide diuretics were the preferred initial therapy, JNC7 recommended other antihypertensive classes in patients with compelling indications, such as heart failure, post-MI, high CHD risk, diabetes, chronic kidney disease (CKD), and prior stroke32 The Cambridge AB/CD rule for optimising antihypertensive treatment, which the British Hypertension Society (BHS) adapted into their 2004 guidelines for hypertension management (BHS-IV)28, selects appropriate antihypertensive therapy based on predicted levels of plasma renin activity (Figure 1).28 For initial therapy, non-Black patients and those aged 160/100 mmHg or high cardiovascular risk, and following initial monotherapy for other patients whose BP remains uncontrolled2,31 The ESC/ESH favour the use of combinations http://www.thefilipinodoctor.com/cpm_pdf/CPM15th%20HYPERTENSION%20%28PSH%29.p df2011 44 New Zealand Guidelines Group New Zealand Primary Care Handbook 2012 (3rd Edition) 2012; http://www.health.govt.nz/publication/new-zealand-primary-care-handbook-2012 Accessed 14 March, 2013 Curr Med Res Opin Downloaded from informahealthcare.com by McMaster University on 02/27/15 For personal use only 45 Ogihara T, Kikuchi K, Matsuoka H, et al The Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH 2009) Hypertens Res 2009;32:3-107 46 Park JB 2004 Korean Hypertension Treatment Guideline and Its Perspective Korean Circulation J 2006;36:405-410 47 Singapore MoH MOH Clinical Practice Guidelines: Hypertension 2/2005 2005; http://www.moh.gov.sg/content/dam/moh_web/HPP/Doctors/cpg_medical/withdrawn/cpg_Hype rtension-Jun%202005.pdf Accessed 12 June, 2013 48 Thai Hypertension Society Thai Guidelines on the Treatment of Hypertension Update 2012 2012; http://www.thaihypertension.org/guideline.html Accessed 16 March, 2013 49 Vietnamese Society of Hypertension, Vietnam Heart Association Guidelines for Diagnosis, Treatment, Prevention of Hypertension 2014 Paper presented at: 1st Vietnam Congress of Hypertension; May 17-18, 2014; Hue City, Vietnam 50 Perhimpunan Dokter Hipertensi Indonesia Consensus Management of Hypertension 2014.[Konsensus penatalaksanaan hipertensi 2014] Jakarta: Perhimpunan Dokter Hipertensi Indonesia (InaSH); 2014 51 PROGRESS Collaborative Group Randomised trial of a perindopril-based blood-pressurelowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack Lancet 2001;358:1033-1041 22 52 Beckett NS, Peters R, Fletcher AE, et al Treatment of hypertension in patients 80 years of age or older N Engl J Med 2008;358:1887-1898 53 Dahlof B, Devereux RB, Kjeldsen SE, et al Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol Lancet 2002;359:995-1003 Curr Med Res Opin Downloaded from informahealthcare.com by McMaster University on 02/27/15 For personal use only 54 Dahlof B, Sever PS, Poulter NR, et al 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;366:895-906 55 Julius S, Kjeldsen SE, Weber M, et al Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial Lancet 2004;363:2022-2031 56 Patel A, MacMahon S, Chalmers J, et al Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type diabetes mellitus (the ADVANCE trial): a randomised controlled trial Lancet 2007;370:829-840 57 Pepine CJ, Handberg EM, Cooper-DeHoff RM, et al A calcium antagonist vs a non-calcium antagonist hypertension treatment strategy for patients with coronary artery disease The International Verapamil-Trandolapril Study (INVEST): a randomized controlled trial JAMA 2003;290:2805-2816 58 Jamerson K, Weber MA, Bakris GL, et al Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients N Engl J Med 2008;359:2417-2428 23 59 Quan A Fetopathy associated with exposure to angiotensin converting enzyme inhibitors and angiotensin receptor antagonists Early Hum Dev 2006;82:23-28 60 Tomlinson B Pharmacokinetic and pharmacodynamic responses to cardiovascular drugs in Asians Acta Pharmacological Sinica 1998;19:12-13 61 Burroughs VJ, Maxey RW, Levy RA Racial and ethnic differences in response to medicines: Curr Med Res Opin Downloaded from informahealthcare.com by McMaster University on 02/27/15 For personal use only towards individualized pharmaceutical treatment J Natl Med Assoc 2002;94:1-26 62 Rasool AH, Rahman AR, Ismail R, et al Ethnic differences in response to non-selective betablockade among racial groups in Malaysia Int J Clin Pharmacol Ther 2000;38:260-269 63 Sulaiman MN, Rahman AR, Noor AR Effectiveness of combination therapy with or without diuretics in the treatment of essential hypertension Asia Pacific Journal of Pharmacology 2001;15:17-24 64 Brown MJ, Cruickshank JK, Dominiczak AF, et al Better blood pressure control: how to combine drugs J Hum Hypertens 2003;17:81-86 24 FIGURES AND TABLES Figure AB/CD algorithm for management of hypertension Adapted from Brown et al, 2003 ,64 Curr Med Res Opin Downloaded from informahealthcare.com by McMaster University on 02/27/15 For personal use only with permission 25 Table Guideline recommendations for combination therapy in international guidelines and guidelines from individual Asia-Pacific countries Curr Med Res Opin Downloaded from informahealthcare.com by McMaster University on 02/27/15 For personal use only Guideline Recommendations INTERNATIONAL GUIDELINES British Society of Hypertension Second-line in patients not achieving BP control with monotherapy; AB/CD algorithm 200428 Recommended combinations: ACEI or ARB plus CCB; BB plus CCB; ACEI or ARB plus diuretic; BB plus diuretic UK NICE 201129 Second-line for patients not achieving BP control with monotherapy Preferred combination: CCB plus ACEI or ARB (ARB preferred for black patients) If a CCB is not suitable: ACEI or ARB plus thiazide diuretic Patients receiving a BB as initial therapy should receive a CCB rather than a thiazide diuretic if combination therapy is required European Society of Hypertension First-line for patients with BP >160/100 mmHg or high/very high CV risk and European Society of Second line for patients not achieving BP control with monotherapy Cardiology 20132 Recommended combinations: thiazide diuretic plus ACEI, ARB, or CCB; CCB plus ARB, or ACEI JNC8 201427 First-line for patients with SBP >160 and/or DBP >100 mmHg (or exceeding BP goals by >20/10 mmHg) Second-line for patients not achieving BP control with monotherapy 26 Recommended combinations usually include a thiazide diuretic: diuretic plus ACEI, ARB, or CCB Curr Med Res Opin Downloaded from informahealthcare.com by McMaster University on 02/27/15 For personal use only ASIA-PACIFIC GUIDELINES Australia Second-line in patients not achieving BP control with monotherapy National Heart Foundation 201042 Preferred combination: ACEI or ARB plus CCB Other combinations: ACEI or ARB plus thiazide diuretic (particularly post-stroke or patients with heart failure); BB plus CCB (particularly patients with CHD); thiazide diuretic plus CCB: thiazide diuretic plus BB (not recommended for patients with impaired glucose tolerance, metabolic syndrome or diabetes) China 201140 First-line for patients with SBP >160 and/or DBP >100 mmHg (or exceeding BP goals by ≥20/10 mmHg) or high CV risk; second-line in patients not achieving BP control with monotherapy Two-drug combination: ARB or ACEI plus CCB; ARB or ACEI plus diuretic; BB plus CCB; CCB plus diuretic Three-drug combinations: ARB or ACEI plus CCB plus diuretic; ARB or ACEI plus CCB plus BB; ARB or ACEI plus diuretic plus alpha-blocker India First-line for patients with SBP >160 and/or DBP >100 mmHg; second-line in patients not achieving BP control National Rural Health Mission with monotherapy37,38 (NRHM) 200737 NRHM does not recommend specific combinations, but recommends that one drug be a diuretic37 Association of Physicians of India Association of Physicians follows the AB/CD algorithm from British Society of Hypertension guidelines38 200738 27 Curr Med Res Opin Downloaded from informahealthcare.com by McMaster University on 02/27/15 For personal use only Indonesia First-line for patients with BP >160/100 mmHg or high CV risk; second-line for patients not achieving BP Indonesian Society of control with monotherapy Hypertension (Perhimpunan Closely follows the 2013 ESC/ESH guidelines in terms of recommended specific combinations Hipertensi Indonesia) 201450 Japan First-line for SBP >160 and/or DBP >100 mmHg (as an alternative to monotherapy) and other patients with high Japanese Society of Hypertension CV risk or compelling indications for a particular drug class; second-line in patients not achieving BP goals after 200945 initial monotherapy Recommended combinations: ACEI or ARB plus CCB; ACEI or ARB plus diuretic; BB plus CCB, CCB plus diuretic Low-dose diuretic recommended for 3-drug regimens if not already included in two-drug combination Malaysia First-line for SBP >160 and/or DBP >100 mmHg; second-line if BP is not controlled after ~6 weeks of Ministry of Health 200841 monotherapy Recommended combinations: ACEI or ARB plus diuretic; ACEI or ARB plus CCB; BB plus CCB; BB plus diuretic New Zealand Second-line if BP control is not achieved with initial monotherapy NZ Guidelines Group 201244 No specific combinations recommended Philippines First-line for patients with comorbidities and/or target organ damage; second-line if BP control not achieved with 28 Multisectoral Task Force monotherapy Consensus on the Detection and No specific combinations recommended Curr Med Res Opin Downloaded from informahealthcare.com by McMaster University on 02/27/15 For personal use only Management of Hypertension in the Philippines 201143 Singapore First-line for SBP >160 and/or DBP >100 mmHg (especially patients with BP ≥180/100 mmHg); second-line if Ministry of Health 200547 BP goals not reached with monotherapy Recommended combinations: BB plus CCB; ACEI or ARB plus diuretic; ACEI or ARB plus CCB; BB plus diuretic; CCB plus diuretic South Korea Second-line after initial monotherapy Korean Society of Hypertension No specific combinations recommended; follows AB/CD algorithm from British Hypertension Society guidelines 200646 Taiwan Second-line after initial monotherapy; acknowledges that combination therapy is frequently required for patients Taiwan Society of Cardiology with SBP >160 and/or DBP >100 mmHg 201039 Follows AB/CD algorithm from British Hypertension Society guidelines BBs are only recommended for patients with heart failure, a history of CHD, and hyperadrenergic state; BBs can be used in combination with CCBs in patients with CHD Thailand Second-line after initial therapy 29 Thai Hypertension Society 201248 Follows an A/CD algorithm (as per British Hypertension Society guidelines, excluding BBs) BBs are only Curr Med Res Opin Downloaded from informahealthcare.com by McMaster University on 02/27/15 For personal use only recommended for patients with compelling indications Vietnam First-line for patients with SBP >20 mmHg above goal and/or DBP >10 mmHg above goal Vietnam Association of Second-line for patients not achieving BP control with monotherapy Cardiology 201449 Recommended combinations: thiazide diuretic plus ACEI, ARB or CCB; ACEI or ARB plus CCB BBs are only recommended for patients with compelling indications ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BB, beta-blocker; BP, blood pressure; CCB, calcium channel blocker; CHD, coronary heart disease; CV, cardiovascular; DBP; diastolic blood pressure; JNC7, The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (USA); NICE, National Institute for Health and Care Excellence; NZ, New Zealand; SBP, systolic blood pressure 30 Table Key studies of combination antihypertensive therapy E FFECTIVE Curr Med Res Opin Downloaded from informahealthcare.com by McMaster University on 02/27/15 For personal use only STUDY C OMBINATI COMPARATOR PATIENT POPULATION STUDIED OUTCOME ON Patients aged 50–80 years with Less intensive HOT36 hypertension and diastolic BP ≥100 BB + CCB Low rate of CV events with intensive BP lowering treatment mmHg and ≤115 mmHg PROGRESS5 ACEI + Placebo Placebo diuretic 34% reduction in CV events (p100 mmHg) mmHg) First choice Alternative First choice choice Curr Med Res Opin Downloaded from informahealthcare.com by McMaster University on 02/27/15 For personal use only Heart failure Alternative choice ACEI ARB – Stable: ACEI or BB candesartan or BB or diuretic valsartan Decompensated: ACEI-intolerant: ACEI + diuretic – aldosterone antagonist Post-MI ACEI ARB ACEI + BB (add Any BB (without – on CCB) ISA) High CHD ACEI or ARB – risk ACEI + CCB Add on diuretic or ARB + CCB BB (depending on HR, BP) Obesity Young: highly – ACEI + selective selective BB BB Elderly: ARB ACEI + CCB BB + CCB Diabetes ACEI ARB ACEI + CCB – CKD Any – ACEI + CCB – ACEI + diuretic Albuminuria ACEI (stage CKD) ARB – ACEI + CCB ACEI + loop 35 – diuretic Recurrent ACEI (add-on stroke diuretic) – ACEI + diuretic – ACEI + CCB prevention COPD CCB or ARB – Any combination – except BB Curr Med Res Opin Downloaded from informahealthcare.com by McMaster University on 02/27/15 For personal use only ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BB, betablocker; BP, blood pressure; CCB, calcium channel blocker; CHD, coronary heart disease; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; DBP, diastolic blood pressure; HR, heart rate; ISA, intrinsic sympathomimetic activity; MI, myocardial infarction; SBP, systolic blood pressure 36 ... recommendations from the group, including recommended antihypertensive combinations for specific patient populations These strategies generally entail initiating therapy with free drug combinations,... they attained a unanimous consensus INTERNATIONAL GUIDELINES ON COMBINATION THERAPY International guidelines for the management of hypertension emphasise the importance of lifestyle modification... combinations and antihypertensive agents suited to once-daily administration Table summarises recommendations for combination therapy in European and United States (US) guidelines International treatment