Essential hypertension ICD11 code: BA00.Z
Telmisartan + amlodipine
Oral > Solid: 40 mg + 5 mg ; 80 mg + 5 mg ; 80 mg + 10 mg
EML status history
Adolescents and adults
The recommendation is for this specific medicine
Expert Committee recommendation
The Committee recommended the addition of four two-drug FDCs, each with multiple strength formulations to the core list of the EML for use in the treatment of hypertension. Each component of the combinations should be listed with a square box, indicating that other medicines within the respective pharmacological classes represent therapeutically equivalent alternatives. For the calcium channel blocker component, the square box should be limited to dihydropyridine class of calcium channel blockers. The Committee accepted the efficacy of FDC antihypertensives compared to placebo or monotherapy for reducing blood pressure and cardiovascular events, but expressed concern that the application did not provide strong evidence of the claimed advantages of FDC therapy versus dual component monotherapy. However, the Committee accepted that many patients require multiple antihypertensive treatment to achieve blood pressure targets and recognized that FDCs may confer advantages for patients over single medicines given concomitantly in terms of better adherence and reduced pill burden. The Committee considered that the ongoing availability of single agent antihypertensive medicines is critical to allow treatment modification where necessary, and that FDCs should not displace single components at country level. The Committee also noted that the availability of multiple FDCs in varying strengths may be associated with significant supply chain and affordability issues for LMICs. The Committee noted that the cost of FDCs versus the sum of the cost of component monotherapies varies in different settings and is not always the same (or lower) than the sum of component monotherapies. The Committee stressed that the cost of FDCs should not be significantly higher than the sum of the cost of their component monotherapies. In particular, in resource-constrained settings where access is limited, the opportunity costs associated with treating patients with FDCs must be considered.
The application proposed the addition of four two-drug fixed-dose combinations (FDC) to the core list of the EML for use in the treatment of hypertension. The pharmacological classes of angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, calcium channel blockers and thiazide diuretics are all represented on the EML with square box listings. The individual components of the proposed FDCs are included on the EML either specifically (amlodipine, hydrochlorothiazide) or as members of pharmacological classes represented by square box listings (lisinopril (represented by enalapril), telmisartan (represented by losartan)). In 2017, an application for inclusion of an FDC of lisinopril + hydrochlorothiazide on the EML was not recommended by the Committee. The Committee considered that listing a single FDC of medicines for treatment of hypertension would limit choice from the variety of combinations, component medicines and dosages available that would be necessary to tailor therapy for individual patients. However, the Committee acknowledged that appropriate FDCs for hypertension may have advantages over the single medicines given concomitantly, including increased adherence and reduced pill burden. An explanatory note to this effect was included in Section 12 of the EML (1). To address the concerns of the 2017 Committee, the current application proposed four different combinations, with each component qualified with a square box, and with multiple dose options.
Public health relevance
Cardiovascular diseases are the leading cause of death globally, responsible for 31% of total deaths in 2016. Hypertension is the leading modifiable risk factor for cardiovascular disease. The global prevalence of hypertension (defined as systolic and/or diastolic blood pressure more than or equal to 140/90 mmHg) in adults was 24.1% in men and 20.1% in women in 2015. The number of adults with hypertension has increased by over half a billion to 1.13 billion in the 40 years to 2015, with the increase seen largely in low- and middle-income countries (LMICs) (2). In LMICs, nearly three quarters of patients treated for hypertension in 2010 did not have adequate blood pressure control (3). Data from the ALLHAT trial (4) suggest that two or more antihypertensive medicines are required by the majority of patients in order to achieve blood pressure targets below 140/90 mmHg. A meta-analysis of 42 trials involving almost 11 000 participants found that combination therapy using medicines from any two pharmacological classes of thiazide diuretics, beta-blockers, ACE-inhibitors and calcium channel blockers produces a greater blood pressure lowering effect than doubling the dose of monotherapy (5). Greater blood pressure lowering effects have been associated with greater reductions in cardiovascular events such as myocardial infarction and stroke (6–9).
Dual versus monotherapy for initial treatment of hypertension: A systematic review conducted for the application of dual versus monotherapy as initial treatment identified 33 randomized trials involving over 10 000 participants. Compared to patients receiving monotherapy, there was a 27% increase in the rate of achieving blood pressure control among patients receiving dual combination therapy. The application also described the results of three studies that compared initial combination antihypertensive treatment with alternative initial treatment regimens including monotherapy, sequential monotherapy and stepped-care (10–12). In all comparisons, combination therapy was associated with greater improvements in blood pressure control, without an increase in adverse events. Effects of combination therapy versus placebo on cardiovascular events: As in the 2017 application, the current application presented the same findings of a review of 11 randomized controlled trials (RCTs) involving 35 208 patients comparing combination antihypertensive treatment with placebo/no treatment on cardiovascular outcomes and mortality (13–23). Combination therapy was found to significantly reduce the risk of cardiovascular outcomes and mortality for all studies combined, and to a greater extent when only the studies demonstrating a reduction in systolic pressure of more than 6 mmHg were considered. Lisinopril + hydrochlorothiazide: Two trials reported data for either the comparison of lisinopril + HCTZ versus placebo or versus component monotherapy (24, 25). In both studies, combination therapy was associated with a significant reduction in both systolic and/or diastolic blood pressure. Two trials reported data for the comparison of lisinopril + HCTZ with alternative dual combination therapy (sustained release verapamil + trandolapril, atenolol + chlorthalidone (25); and candesartan + HCTZ (26)). There were no significant differences in the adjusted mean change from baseline in sitting systolic or diastolic blood pressure between treatment groups. Telmisartan + amlodipine: One trial reported data for various strength combinations of telmisartan (20–80 mg) + amlodipine (2.5–10 mg) versus placebo (27). Six trials reported data for various strengths of the combination compared with single component monotherapy at the same or higher dose (28–33). All studied comparisons favoured dual combination therapy for differences in mean systolic and diastolic blood pressure. One trial compared telmisartan 80 mg + amlodipine 5 mg with olmesartan 40 mg + HCTZ 12.5 mg (34). At six months, both combinations were associated with significant reductions in mean systolic and diastolic blood pressure. There was no significant difference between treatment groups. Telmisartan + hydrochlorothiazide: Two trials reported data for the comparison of telmisartan + HCTZ versus placebo (35, 36). In both studies, there were significant differences in both systolic and diastolic blood pressure favouring combination therapy. Three trials reported data for the comparison of telmisartan + HCTZ versus telmisartan monotherapy (37–39). Combination therapy was significantly more effective than the corresponding strength of telmisartan monotherapy in reducing mean systolic and diastolic blood pressure. Four trials reported data for the comparison of telmisartan + HCTZ with the same combination at different doses of HCTZ (40), or different dual combinations (36, 41, 42). Both doses of telmisartan + HCTZ (12.5 mg and 25 mg) produced reductions from baseline in adjusted mean seated systolic and diastolic blood pressure, with the 25 mg HCTZ combination producing a greater blood pressure lowering effect (40). Comparisons of telmisartan + HCTZ with dual combination therapy with valsartan + HCTZ, showed that compared with placebo, both combinations produced substantial reductions in blood pressure. Patients treated with telmisartan + HCTZ had significantly greater reductions in systolic and diastolic blood pressure than patients treated with valsartan + HCTZ (36, 41). In the comparison of telmisartan + HCTZ versus dual combination therapy with barnidipine (a calcium channel blocker) + losartan, blood pressure was reduced in both treatment arms, however, the blood pressure-lowering effect was greater in the barnidipine + losartan group (42). Lisinopril + amlodipine: One small (n=15) cross-over trial compared lisinopril + amlodipine with single component monotherapy (43). After one month, combination therapy demonstrated a significant additional blood pressure-lowering effect compared with each component as monotherapy.
The adverse event profiles of ACE inhibitors, angiotensin receptor blockers, thiazide diuretics, and dihydropyridine calcium channel blockers are well known. Safety data from the studies of the dual combination therapies presented with the application are consistent with the known adverse event profiles of these medicines. An analysis of 33 placebo-controlled trials of antihypertensive therapy as monotherapy or dual combination therapy found that dual therapy was associated with adverse events at less than double the rate observed for monotherapy (7.5% vs 5.2%) (44), suggesting that there is not an additive effect of dual therapy in relation to adverse events.
Cost / cost effectiveness
The application presented a review of private sector prices in India of the proposed FDCs versus their component monotherapies, which showed the FDC prices to be similar or slightly lower than component monotherapies. However, the Committee noted that this may not be the case in every jurisdiction. For example, a review of the MSH International Medical Products Price Guide (2015) reports the mean buyer prices to be US$ 0.1977, US$ 0.0233 and US$ 0.0077 for lisinopril + HCTZ 20 mg/12.5 mg, lisinopril 20 mg, and HCTZ 12.5mg, respectively. The Committee agreed that medicine prices should be considered with regard to the potential cost-savings from improved hypertension control due to improved compliance (52–54), reduced need for repeat visits to achieve blood pressure control and with the use of FDC in settings where individuals requiring more than one blood pressure-lowering drug may have limited access to multiple drug classes (55, 56). A price advantage of an FDC over its component monotherapies may be justified by a demonstrated advantage in clinical outcome or compliance. FDC therapy may also be associated with reduced health system costs and out-of-pocket costs for patients. In a meta-analysis published in 2011 (57), the annual total health care costs from 44 336 patients in all included observational studies (n = 7) were lower for patients treated with FDC compared to individual monotherapy for hypertension (mean pooled difference US$ 1357; 95%CI US$ 778 to US$ 1935). An analysis using data from the 2004 Medical Expenditure Panel Survey in the United States (58) demonstrated that total monthly prescription expenditures were lower for 23 of 27 FDC medications examined compared to the separate individual drugs (mean decrease in monthly total costs US$ 20.89, 95%CI US$ 20.10 to US$ 21.68). Using pharmacy claims data in Japan, a study demonstrated transitioning to FDC therapy from separate drugs was associated with an annual saving of US$ 112 for patients (59). The cost savings of FDC therapy for patients also translate to the larger health system. In Canada, 60–100% of patients receiving two separate drugs transitioning to FDC therapy has been estimated to lead to a yearly cost-saving of US$ 27 million to US$ 45 million (60).
The HEARTS technical package for cardiovascular disease management in primary care includes recommended treatment protocols for dual combination antihypertensive treatment as both first- and second-line interventions for hypertension (45, 46). Dual combination antihypertensive therapy is recommended for use in patients not controlled on monotherapy, and in selected patients as initial therapy in multiple international guidelines including Europe (47), the United States (48), India (49), Thailand (50) and China (51). Single pill FDCs are recommended in most guidelines as an alternative to separate pills to improve patient adherence. The 2018 European guidelines also recommended FDC therapy as initial therapy in most patients (47).
The proposed FDCs are available globally, either in the stated combinations, or alternatives within pharmacological classes.
Comments on the application were received from the WHO Department for Management of Noncommunicable Diseases, Disability, Violence and Injury Prevention. The technical unit advised that it supported the inclusion of dual FDC antihypertensives to the EML, stating that most people with hypertension require more than one antihypertensive agent to achieve control and that FDCs are likely to improve adherence to treatment.
Square box listings as representative of the following pharmacological class combinations: – ACE inhibitor + dihydropyridine calcium channel blocker – ACE inhibitor + thiazide or thiazide-like diuretic – Angiotensin receptor blocker + dihydropyridine calcium channel blocker – Angiotensin receptor blocker + thiazide or thiazide-like diuretic Square box listings of the components of the FDCs should be interpreted by countries as limited to: – Lisinopril > any ACE inhibitor (ATC code C09AA--) – Telmisartan > any angiotensin receptor blocker (ATC code C09CA--) – Amlodipine > any once-daily dihydropyridine calcium channel blocker (intrinsically long-acting e.g. amlodipine, lercanidipine, lacidipine; or modified-release e.g. nifedipine, felodipine) – HCTZ > chlortalidone or indapamide.
1. The selection and use of essential medicines. Report of the WHO Expert Committee, 2017 (including the 20th WHO Model List of Essential Medicines and the 6th WHO Model List of Essential Medicines for Children) (WHO Technical Report Series, No. 1006). Geneva: World Health Organization; 2017. Available from https://apps.who.int/iris/bitstream/handle/10665/259481/9789241210157-eng.pdf, accessed 30 October 2019. 2. Zhou B, Bentham J, Di Cesare M, Bixby H, Goodarz D, Cowan MJ et al. Worldwide trends in blood pressure from 1975 to 2015: a pooled analysis of 1479 population-based measurement studies with 19.1 million participants. Lancet. 2017;389(10064):37–55. 3. Mills KT, Bundy JD, Kelly TN, Reed JE, Kearney PM, Reynolds K et al. Global Disparities of Hypertension Prevalence and Control: A Systematic Analysis of Population-Based Studies From 90 Countries. Circulation. 2016;134(6):441–50. 4. Cushman WC, Ford CE, Cutler JA, Margolis KL, Davis BR, Grimm RH et al. Success and predictors of blood pressure control in diverse North American settings: the antihypertensive and lipid lowering treatment to prevent heart attack trial (ALLHAT). J Clin Hypertens (Greenwich). 2002;4(6):393–404. 5. Wald DS, Law M, Morris JK, Bestwick JP, Wald NJ. Combination therapy versus monotherapy in reducing blood pressure: meta-analysis on 11,000 participants from 42 trials. Am J Med. 2009;122(3):290–300. 6. Turnbull F. Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomised trials. Lancet. 2003;362(9395):1527–35. 7. Ettehad D, Emdin CA, Kiran A, Anderson SG, Callender T, Emberson J et al. Blood pressure lowering for prevention of cardiovascular disease and death: a systematic review and meta-analysis. Lancet. 2016;387(10022):957–67. 8. Law MR, Morris JK, Wald NJ. Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies. BMJ. 2009;338:b1665. 9. Xie X, Atkins E, Lv J, Bennett A, Neal B, Ninomiya T et al. Effects of intensive blood pressure lowering on cardiovascular and renal outcomes: updated systematic review and meta-analysis. Lancet. 2016;387(10017):435–43. 10. Feldman RD, Zou GY, Vandervoort MK, Wong CJ, Nelson SA, Feagan BG. A simplified approach to the treatment of uncomplicated hypertension: a cluster randomized, controlled trial. Hypertension. 2009;53(4):646–53. 11. Mourad JJ, Waeber B, Zannad F, Laville M, Duru G, Andrejak M. Comparison of different therapeutic strategies in hypertension: a low-dose combination of perindopril/indapamide versus a sequential monotherapy or a stepped-care approach. J Hypertens. 2004;22(12):2379–86. 12. MacDonald TM, Williams B, Webb DJ, Morant S, Caulfield M, Cruickshank JK, et al. Combination Therapy Is Superior to Sequential Monotherapy for the Initial Treatment of Hypertension: A Double-Blind Randomized Controlled Trial. J Am Heart Assoc. 2017;6(11). 13. Lonn EM, Bosch J, Lopez-Jaramillo P, Zhu J, Liu L, Pais P et al. Blood-Pressure Lowering in Intermediate-Risk Persons without Cardiovascular Disease. N Engl J Med. 2016;374(21):2009–20. 14. Patel A, MacMahon S, Chalmers J, Neal B, Billot L, Woodward M et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358(24):2560–72. 15. PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack. Lancet. 2001;358(9287):1033–41. 16. Hypertension-Stroke Cooperative Study Group. Effect of antihypertensive treatment on stroke recurrence. JAMA. 1974;229(4):409–18. 17. Carter AB. Hypotensive therapy in stroke survivors. Lancet. 1970;1(7645):485-9. 18. Dahlof B, Lindholm LH, Hansson L, Schersten B, Ekbom T, Wester PO. Morbidity and mortality in the Swedish Trial in Old Patients with Hypertension (STOP-Hypertension). Lancet. 1991; 338(8778):1281–5. 19. Coope J, Warrender TS. Randomised trial of treatment of hypertension in elderly patients in primary care. Br Med J (Clin Res Ed). 1986;293(6555):1145–51. 20. Bulpitt CJ, Beckett NS, Peters R, Leonetti G, Gergova V, Fagard R et al. Blood pressure control in the Hypertension in the Very Elderly Trial (HYVET). J Hum Hypertens. 2012;26(3):157–63. 21. Smith WM. Treatment of mild hypertension: results of a ten-year intervention trial. Circ Res. 1977;40(5 Suppl 1):I98–105. 22. Effects of treatment on morbidity in hypertension. Results in patients with diastolic blood pressures averaging 115 through 129 mm Hg. JAMA. 1967;202(11):1028–34. 23. Effects of treatment on morbidity in hypertension. II. Results in patients with diastolic blood pressure averaging 90 through 114 mm Hg. JAMA. 1970;213(7):1143–52. 24. Chrysant SG. Antihypertensive effectiveness of low-dose lisinopril-hydrochlorothiazide combination. A large multicenter study. Lisinopril-Hydrochlorothiazide Group. Arch Intern Med. 1994;154(7):737–43. 25. de Leeuw PW, Notter T, Zilles P. Comparison of different fixed antihypertensive combination drugs: a double-blind, placebo-controlled parallel group study. J Hypertens. 1997;15(1):87–91. 26. McInnes GT, O’Kane KP, Istad H, Keinanen-Kiukaanniemi S, Van Mierlo HF. Comparison of the AT1- receptor blocker, candesartan cilexetil, and the ACE inhibitor, lisinopril, in fixed combination with low dose hydrochlorothiazide in hypertensive patients. J Hum Hypertens. 2000;14(4):263–9. 27. Littlejohn TW, 3rd, Majul CR, Olvera R, Seeber M, Kobe M, Guthrie R et al. Results of treatment with telmisartan-amlodipine in hypertensive patients. J Clin Hypertens (Greenwich). 2009;11(4): 207–13. 28. Zhu D, Gao P, Holtbruegge W, Huang C. A randomized, double-blind study to evaluate the efficacy and safety of a single-pill combination of telmisartan 80 mg/amlodipine 5 mg versus amlodipine 5 mg in hypertensive Asian patients. J Int Med Res. 2014;42(1):52–66. 29. Neutel JM, Mancia G, Black HR, Dahlof B, Defeo H, Ley L et al. Single-pill combination of telmisartan/ amlodipine in patients with severe hypertension: results from the TEAMSTA severe HTN study. J Clin Hypertens (Greenwich). 2012;14(4):206–15. 30. Sharma AM, Bakris G, Neutel JM, Littlejohn TW, Kobe M, Ting N et al. Single-pill combination of telmisartan/amlodipine versus amlodipine monotherapy in diabetic hypertensive patients: an 8-week randomized, parallel-group, double-blind trial. Clin Ther. 2012;34(3):537–51. 31. Neldam S, Edwards C, Jones R. Switching patients with uncontrolled hypertension on amlodipine 10 mg to single-pill combinations of telmisartan and amlodipine: results of the TEAMSTA-10 study. Curr Med Res Opin. 2011;27(11):2145–53. 32. Neldam S, Lang M, Jones R. Telmisartan and amlodipine single-pill combinations vs amlodipine monotherapy for superior blood pressure lowering and improved tolerability in patients with uncontrolled hypertension: results of the TEAMSTA-5 study. J Clin Hypertens (Greenwich). 2011;13(7):459–66. 33. Sharma A, Bagchi A, Kinagi SB, Sharma YK, Baliga VP, Bollmall C. Results of a comparative, phase III, 12-week, multicenter, prospective, randomized, double-blind assessment of the efficacy and tolerability of a fixed-dose combination of telmisartan and amlodipine versus amlodipine monotherapy in Indian adults with stage II hypertension. Clin Ther. 2007;29(12):2667–76. 34. Jagodzinski A, Neumann JT, Ojeda F, Sorensen NA, Wild P, Munzel T et al. Cardiovascular Biomarkers in Hypertensive Patients with Medical Treatment-Results from the Randomized TEAMSTA Protect I Trial. Clin Chem. 2017;63(12):1877–85. 35. McGill JB, Reilly PA. Telmisartan plus hydrochlorothiazide versus telmisartan or hydrochlorothiazide monotherapy in patients with mild to moderate hypertension: a multicenter, randomized, doubleblind, placebo-controlled, parallel-group trial. Clin Ther. 2001;23(6):833–50. 36. White WB, Punzi HA, Murwin D, Koval SE, Davidai G, Neutel JM. Effects of the angiotensin II receptor blockers telmisartan vs valsartan in combination with hydrochlorothiazide 25 mg once daily for the treatment of hypertension. J Clin Hypertens (Greenwich). 2006;8(9):626–33. 37. Lacourciere Y, Tytus R, O’Keefe D, Lenis J, Orchard R, Martin K. Efficacy and tolerability of a fixed-dose combination of telmisartan plus hydrochlorothiazide in patients uncontrolled with telmisartan monotherapy. J Hum Hypertens. 2001;15(11):763–70. 38. Lacourciere Y, Martin K. Comparison of a fixed-dose combination of 40 mg telmisartan plus 12.5 mg hydrochlorothiazide with 40 mg telmisartan in the control of mild to moderate hypertension. Am J Ther. 2002;9(2):111–7. 39. Zhu DL, Bays H, Gao P, Mattheus M, Voelker B, Ruilope LM. Efficacy and tolerability of initial therapy with single-pill combination telmisartan/hydrochlorothiazide 80/25 mg in patients with grade 2 or 3 hypertension: a multinational, randomized, double-blind, active-controlled trial. Clin Ther. 2012;34(7):1613–24. 40. Neldam S, Edwards C. Results of increasing doses of hydrochlorothiazide in combination with an angiotensin receptor blocker in patients with uncontrolled hypertension. J Clin Hypertens (Greenwich). 2008;10(8):612–8. 41. White WB, Murwin D, Chrysant SG, Koval SE, Davidai G, Guthrie R. Effects of the angiotensin II receptor blockers telmisartan versus valsartan in combination with hydrochlorothiazide: a large, confirmatory trial. Blood Press Monit. 2008;13(1):21–7. 42. Derosa G, Querci F, Franzetti I, Dario Ragonesi P, D’Angelo A, Maffioli P. Comparison of the effects of barnidipine+losartan compared with telmisartan+hydrochlorothiazide on several parameters of insulin sensitivity in patients with hypertension and type 2 diabetes mellitus. Hypertens Res. 2015;38(10):690–4. 43. Cappuccio FP, Markandu ND, Singer DR, MacGregor GA. Amlodipine and lisinopril in combination for the treatment of essential hypertension: efficacy and predictors of response. J Hypertens. 1993;11(8):839–47. 44. 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(7404):1427. 45. HEARTS Technical Package for Cardiovascular Disease Management in Primary Health Care. Geneva: World Health Organization; 2016. Available from https://www.who.int/cardiovascular_ diseases/hearts/Hearts_package.pdf, accessed 4 February 2019, accessed 29 September 2019. 46. HEARTS Technical package for cardiovascular disease management in primary health care: evidence-based treatment protocols. Geneva: World Health Organization; 2018. Available from https://apps.who.int/iris/bitstream/handle/10665/260421/WHO-NMH-NVI-18.2-eng.pdf;jsession id=F7BBBE11E93C7AF4FB5799C127724A7B?sequence=1, accessed 29 September 2019. 47. Williams B, Mancia G, Spiering W, Agabiti Rosei E, Azizi M, Burnier M et al. 2018 ESC/ESH Guidelines for the management of arterial hypertension. Eur Heart J. 2018;39(33):3021–104. 48. Whelton PK, Carey RM, Aronow WS, Casey DE, Jr., Collins KJ, Dennison Himmelfarb C et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2018;138(17):e426–e83. 49. Indian guidelines on hypertension (I.G.H.) - III. 2013. J Assoc Physicians India. 2013;61(2 Suppl):6–36. 50. Buranakitjaroen P, Sitthisook S, Wataganara T, Ophascharoensuk V, Bunnag P, Roubsanthisuk W et al. 2015 Thai Hypertension Guideline. Available from http://www.thaihypertension.org/ files/2015%20Thai%20Hypertension%20Guideline.pdf, accessed 29 September 2019. 51. Liu LS. [2010 Chinese guidelines for the management of hypertension]. Zhonghua xin xue guan bing za zhi. 2011;39(7):579–615. 52. Mallat SG, Tanios BY, Itani HS, Lotfi T, Akl EA. Free versus Fixed Combination Antihypertensive Therapy for Essential Arterial Hypertension: A Systematic Review and Meta-Analysis. PLoS One. 2016;11(8):e0161285. 53. Gupta AK, Arshad S, Poulter NR. Compliance, safety, and effectiveness of fixed-dose combinations of antihypertensive agents: a meta-analysis. Hypertension. 2010;55(2):399–407. 54. Bangalore S, Kamalakkannan G, Parkar S, Messerli FH. Fixed-dose combinations improve medication compliance: a meta-analysis. Am J Med. 2007;120(8):713-9. 55. Attaei MW, Khatib R, McKee M, Lear S, Dagenais G, Igumbor EU et al. Availability and affordability of blood pressure-lowering medicines and the effect on blood pressure control in high-income, middle-income, and low-income countries: an analysis of the PURE study data. Lancet Public Health. 2017;2(9):e411–e9. 56. Khatib R, McKee M, Shannon H, Chow C, Rangarajan S, Teo K et al. Availability and affordability of cardiovascular disease medicines and their effect on use in high-income, middle-income, and low-income countries: an analysis of the PURE study data. Lancet. 2016;387(10013):61–9. 57. Sherrill B, Halpern M, Khan S, Zhang J, Panjabi S. Single-pill vs free-equivalent combination therapies for hypertension: a meta-analysis of health care costs and adherence. J Clin Hypertens (Greenwich). 2011;13(12):898–909. 58. Rabbani A, Alexander GC. Out-of-pocket and total costs of fixed-dose combination antihypertensives and their components. Am J Hypertens. 2008;21(5):509–13. 59. Akazawa M, Fukuoka K. Economic impact of switching to fixed-dose combination therapy for Japanese hypertensive patients: a retrospective cost analysis. BMC Health Serv Res. 2013;13:124. 60. Stankus V, Hemmelgarn B, Campbell NR, Chen G, McAlister FA, Tsuyuki RT. Reducing costs and improving hypertension management. Can J Clin Pharmacol. 2009;16(1):e151–5.