[Skip to Content]
[Skip to Content Landing]

Fixed Low-Dose Triple Combination Antihypertensive Medication vs Usual Care for Blood Pressure Control in Patients With Mild to Moderate Hypertension in Sri LankaA Randomized Clinical Trial

Educational Objective
To learn whether a low-dose triple combination antihypertensive pill improves blood pressure control.
1 Credit CME
Key Points

Question  Does the use of a pill containing low doses of 3 antihypertensive medications provide improved blood pressure control compared with usual care among patients with mild or moderate hypertension?

Findings  In this randomized clinical trial of 700 patients with hypertension who were untreated or receiving monotherapy, 70% of patients in the triple combination pill therapy group achieved a systolic/diastolic blood pressure of less than 140/90 mm Hg (or <130/80 mm Hg in patients with diabetes or chronic kidney disease) at 6 months compared with 55% of patients in the usual care group (a significant difference).

Meaning  Use of a low-dose triple combination blood pressure–lowering pill for initiation of treatment or escalation from monotherapy increased the proportion of patients with hypertension reaching their blood pressure targets.


Importance  Poorly controlled hypertension is a leading global public health problem requiring new treatment strategies.

Objective  To assess whether a low-dose triple combination antihypertensive medication would achieve better blood pressure (BP) control vs usual care.

Design, Setting, and Participants  Randomized, open-label trial of a low-dose triple BP therapy vs usual care for adults with hypertension (systolic BP >140 mm Hg and/or diastolic BP >90 mm Hg; or in patients with diabetes or chronic kidney disease: >130 mm Hg and/or >80 mm Hg) requiring initiation (untreated patients) or escalation (patients receiving monotherapy) of antihypertensive therapy. Patients were enrolled from 11 urban hospital clinics in Sri Lanka from February 2016 to May 2017; follow-up ended in October 2017.

Interventions  A once-daily fixed-dose triple combination pill (20 mg of telmisartan, 2.5 mg of amlodipine, and 12.5 mg of chlorthalidone) therapy (n = 349) or usual care (n = 351).

Main Outcomes and Measures  The primary outcome was the proportion achieving target systolic/diastolic BP (<140/90 mm Hg or <130/80 mm Hg in patients with diabetes or chronic kidney disease) at 6 months. Secondary outcomes included mean systolic/diastolic BP difference during follow-up and withdrawal of BP medications due to an adverse event.

Results  Among 700 randomized patients (mean age, 56 years; 58% women; 29% had diabetes; mean baseline systolic/diastolic BP, 154/90 mm Hg), 675 (96%) completed the trial. The triple combination pill increased the proportion achieving target BP vs usual care at 6 months (70% vs 55%, respectively; risk difference, 12.7% [95% CI, 3.2% to 22.0%]; P < .001). Mean systolic/diastolic BP at 6 months was 125/76 mm Hg for the triple combination pill vs 134/81 mm Hg for usual care (adjusted difference in postrandomization BP over the entire follow-up: systolic BP, −9.8 [95% CI, −7.9 to −11.6] mm Hg; diastolic BP, −5.0 [95% CI, −3.9 to −6.1] mm Hg; P < .001 for both comparisons). Overall, 419 adverse events were reported in 255 patients (38.1% for triple combination pill vs 34.8% for usual care) with the most common being musculoskeletal pain (6.0% and 8.0%, respectively) and dizziness, presyncope, or syncope (5.2% and 2.8%). There were no significant between-group differences in the proportion of patient withdrawal from BP-lowering therapy due to adverse events (6.6% for triple combination pill vs 6.8% for usual care).

Conclusions and Relevance  Among patients with mild to moderate hypertension, treatment with a pill containing low doses of 3 antihypertensive drugs led to an increased proportion of patients achieving their target BP goal vs usual care. Use of such medication as initial therapy or to replace monotherapy may be an effective way to improve BP control.

Trial Registration  anzctr.org.au Identifier: ACTRN12612001120864; slctr.lk Identifier: SLCTR/2015/020

Sign in to take quiz and track your certificates

Buy This Activity

JN Learning™ is the home for CME and MOC from the JAMA Network. Search by specialty or US state and earn AMA PRA Category 1 CME Credit™ from articles, audio, Clinical Challenges and more. Learn more about CME/MOC

Article Information

Corresponding Author: Ruth Webster, PhD, The George Institute for Global Health, PO Box M201, Missenden Road, Camperdown, NSW 2050, Australia (rwebster@georgeinstitute.org.au).

Accepted for Publication: June 27, 2018.

Correction: This article was corrected on November 13, 2018, to fix 2 minor errors to the power calculation information in the first 2 sentences of the Statistical Analysis section.

Author Contributions: Drs Webster and Patel had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Webster, Salam, H. de Silva, Rajapakse, Guggilla, Jan, Maulik, Naik, Prabhakaran, Thom, Senaratne, Rodgers, Patel.

Acquisition, analysis, or interpretation of data: Webster, Salam, H. de Silva, Selak, Stepien, Rajapakse, Amarasekara, Amarasena, Billot, A. de Silva, Fernanado, Guggilla, Jayawardena, Maulik, Sepalika Mendis, Suresh Mendis, Munasinghe, Prabhakaran, Ranasinghe, Tissera, Wijekoon, Wijeyasingam, Rodgers, Patel.

Drafting of the manuscript: Webster, Salam, Rodgers, Patel.

Critical revision of the manuscript for important intellectual content: Webster, Salam, H. de Silva, Selak, Stepien, Rajapakse, Amarasekara, Amarasena, Billot, A. de Silva, Fernanado, Guggilla, Jan, Jayawardena, Maulik, Sepalika Mendis, Suresh Mendis, Munasinghe, Naik, Prabhakaran, Ranasinghe, Thom, Tissera, Senaratne, Wijekoon, Wijeyasingam, Patel.

Statistical analysis: Webster, Stepien, Billot, Rodgers.

Obtained funding: Webster, Guggilla, Jan, Maulik, Rodgers, Patel.

Administrative, technical, or material support: Webster, Salam, H. de Silva, Selak, Rajapakse, Amarasena, A. de Silva, Guggilla, Jan, Jayawardena, Maulik, Sepalika Mendis, Suresh Mendis, Munasinghe, Naik, Prabhakaran, Thom, Tissera, Wijekoon.

Supervision: Webster, Salam, H. de Silva, Rajapakse, Amarasekara, Amarasena, Billot, A. de Silva, Fernanado, Jayawardena, Sepalika Mendis, Suresh Mendis, Munasinghe, Prabhakaran, Ranasinghe, Thom, Tissera, Senaratne, Wijekoon, Wijeyasingam, Rodgers, Patel.

Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Drs Webster and Patel reported receiving a salary from George Health Enterprises, which is the social enterprise arm of The George Institute for Global Health. George Health Enterprises has received investment funds to develop fixed-dose combination products containing aspirin, statin, and blood pressure–lowering drugs and has submitted a patent for the treatment of hypertension. Dr Rodgers is listed as an inventor on this patent; however, he does not have a financial interest in it. No other disclosures were reported.

Funding/Support: The study was funded by grants APP1041052 and APP1052555 from the Australian National Health and Medical Research Council (NHMRC) Global Alliance for Chronic Disease. RemediumOne (site management organization contracted to conduct the study) received payment from NHMRC project grant APP1041052. All TRIUMPH Study Group members were either salaried study coordinators or received investigator payments for their role in the study from RemediumOne. Dr Webster is funded by NHMRC early career fellowship No. APP1125044. Dr Jan is funded by NHMRC principal research fellowship No. APP1119443. Dr Maulik is a Wellcome Trust/DBT India Alliance intermediate career fellow and The George Institute for Global Health provided grant support for his work. Dr Thom received support from the NIHR Biomedical Research Centre at Imperial College Healthcare NHS Trust and Imperial College London. Dr Rodgers is funded by NHMRC principal research fellowship No. APP1066280. Dr Patel is funded by NHMRC principal research fellowship No. APP1136898.

Role of the Funder/Sponsor: The funding sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Group Information: The TRIUMPH Study Group members are Keshinie Samarasekara, Chiranthi Kongala Liyanage, Verni Sopan, Wasantha Kumara, Hansika Pathirana, Lumbini Perera, Manisha Somasiri, Aruna Wijesinghe, Jayamini Jayantha, Sonali Liyanagamage,Muditha de Silva, Chandika Jayawardena, Dilini Karunarathna, Mitrakrishnan Rayno Navinan, Zumra Shukri, Charitha Herath, Nadeeja Seneviratne, Amila Isurangana, Zulaiha Liyakath, Thamal Dasitha, Gerald Rajakulenthiran, Aaisha Azam, Chandika Jayawardena, Manori Jayawardena, Vinodhan Sunderalingam, Milinda Withana, Anushiya Annaraja, Keshini Soza, Dulani Dasanayake, Keshini Soza, Dhanushka de Silva, and Shakoor Niyasdeen (National Hospital, Colombo, Sri Lanka); Uthpala Chandradeva, Safiya Fathima, and Aruna Jayawardana (Colombo South Teaching Hospital, Colombo, Sri Lanka); Ranasinghe Chathurika, Manik de Mel, Tharini Mendis, Saumya Withanage, Kandula Pieris, Manik de Mel, Gayathri Fernando, Chamila Mettanda, Saumya Withanage, and Kandula Pieris (Colombo North Teaching Hospital, Colombo, Sri Lanka); Eshani de Silva and Imali Wijerathna (Sri Jayawardenapura General Hospital); Jeevaraj Thanushanthan, Devaki Dharmawardena, Shehan Gnanapragasam, Shalomi Weerawardena, Matheesha Suduwelikandage, Ingrid de Silva, Sachini Wathsala, Ruchiranga Ekanayaka, Anuradha Dahanayaka, Vindhya Fernando, Lakmal Jayaweera, and Namal Wijesinghe (RemediumOne); and Murali Dhakshinamurthy, MBA, Ullas Arabhavi, MPharm, Harish Sankarankutty, MSc, Mohammed Muddaseer, BPharm, Sarath Gudivada, MSc, Aditi Moitra, Ayesha Tazeen, MSc, Karuna Acharya, MSc, Prakash Velappan, BSc, Ambika Yoganathan, BTech, Vipin Jose, MPharm (George Clinical, Bangalore, India).

Additional Contributions: The data and safety monitoring committee chair was Neil Poulter, FRCP (Imperial College, London, England). The other members of the committee were Chris Reid, PhD (Curtin University, Perth, Australia), and Nikhil Tandon, FRCP (All India Institute of Medical Sciences, New Delhi). The data and safety monitoring committee was not compensated for its work. Jayanthi Mysore and Severine Bompoint provided statistical support and were compensated as part of their salaries (The George Institute for Global Health). Site management was provided by RemediumOne, which coordinated project execution and data collection. George Clinical (Bangalore, India) provided project management, monitoring, and data management services. The statistical analyses were conducted by The George Institute for Global Health (Sydney, Australia).

Gakidou  E, Afshin  A, Abajobir  AA,  et al.  Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2016.  Lancet. 2017;390(10100):1345-1422.PubMedGoogle ScholarCrossref
Turnbull  F; Blood Pressure Lowering Treatment Trialists’ Collaboration.  Effects of different blood-pressure-lowering regimens on major cardiovascular events.  Lancet. 2003;362(9395):1527-1535. doi:10.1016/S0140-6736(03)14739-3PubMedGoogle ScholarCrossref
Mills  KT, Bundy  JD, Kelly  TN,  et al.  Global disparities of hypertension prevalence and control.  Circulation. 2016;134(6):441-450.PubMedGoogle ScholarCrossref
Khatib  R, McKee  M, Shannon  H,  et al.  Availability and affordability of cardiovascular disease medicines and their effect on use in high-income, middle-income, and low-income countries.  Lancet. 2016;387(10013):61-69.PubMedGoogle ScholarCrossref
Law  MR, Wald  NJ, Morris  JK, Jordan  RE.  Value of low dose combination treatment with blood pressure lowering drugs.  BMJ. 2003;326(7404):1427-1431. doi:10.1136/bmj.326.7404.1427PubMedGoogle ScholarCrossref
Leung  AA, Nerenberg  K, Daskalopoulou  SS,  et al.  Hypertension Canada’s 2016 Canadian hypertension education program guidelines for blood pressure measurement, diagnosis, assessment of risk, prevention, and treatment of hypertension.  Can J Cardiol. 2016;32(5):569-588.PubMedGoogle ScholarCrossref
Gabb  GM, Mangoni  AA, Anderson  CS,  et al.  Guideline for the diagnosis and management of hypertension in adults—2016.  Med J Aust. 2016;205(2):85-89. doi:10.5694/mja16.00526PubMedGoogle ScholarCrossref
Whelton  PK, Carey  RM, Aronow  WS,  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  [published correction appears in J Am Coll Cardiol. 2018;71(19):2275-2279].  J Am Coll Cardiol. 2018;71(19):e127-e248.PubMedGoogle ScholarCrossref
Wald  DS, Morris  JK, Wald  NJ.  Randomized polypill crossover trial in people aged 50 and over.  PLoS One. 2012;7(7):e41297.PubMedGoogle ScholarCrossref
Chow  CK, Thakkar  J, Bennett  A,  et al.  Quarter-dose quadruple combination therapy for initial treatment of hypertension.  Lancet. 2017;389(10073):1035-1042.PubMedGoogle ScholarCrossref
Gupta  AK, Arshad  S, Poulter  NR.  Compliance, safety, and effectiveness of fixed-dose combinations of antihypertensive agents.  Hypertension. 2010;55(2):399-407.PubMedGoogle ScholarCrossref
Webster  R, Patel  A, Selak  V,  et al.  Effectiveness of fixed dose combination medication (‘polypills’) compared with usual care in patients with cardiovascular disease or at high risk.  Int J Cardiol. 2016;205:147-156. doi:10.1016/j.ijcard.2015.12.015PubMedGoogle ScholarCrossref
Okonofua  EC, Simpson  KN, Jesri  A,  et al.  Therapeutic inertia is an impediment to achieving the Healthy People 2010 blood pressure control goals.  Hypertension. 2006;47(3):345-351.PubMedGoogle ScholarCrossref
Kizilirmak  P, Berktas  M, Uresin  Y, Yildiz  OB.  The efficacy and safety of triple vs dual combination of angiotensin II receptor blocker and calcium channel blocker and diuretic.  J Clin Hypertens (Greenwich). 2013;15(3):193-200.PubMedGoogle ScholarCrossref
Ford  I, Norrie  J.  Pragmatic trials.  N Engl J Med. 2016;375(5):454-463. doi:10.1056/NEJMra1510059PubMedGoogle ScholarCrossref
Salam  A, Webster  R, Singh  K,  et al.  TRIple pill vs Usual care Management for Patients with mild-to-moderate Hypertension (TRIUMPH).  Am Heart J. 2014;167(2):127-132.PubMedGoogle ScholarCrossref
Webster  R.  Protocol changes to the TRIUMPH study.  Am Heart J. 2017;191:e1.PubMedGoogle ScholarCrossref
EuroQol Group.  EuroQol—a new facility for the measurement of health-related quality of life.  Health Policy. 1990;16(3):199-208.PubMedGoogle ScholarCrossref
Bennett  A, Chow  CK, Chou  M,  et al.  Efficacy and safety of quarter-dose blood pressure-lowering agents.  Hypertension. 2017;70(1):85-93.PubMedGoogle ScholarCrossref
Feldman  RD, Zou  GY, Vandervoort  MK,  et al.  A simplified approach to the treatment of uncomplicated hypertension.  Hypertension. 2009;53(4):646-653.PubMedGoogle ScholarCrossref
Calhoun  DA, Lacourcière  Y, Chiang  YT, Glazer  RD.  Triple antihypertensive therapy with amlodipine, valsartan, and hydrochlorothiazide.  Hypertension. 2009;54(1):32-39.PubMedGoogle ScholarCrossref
van Buuren  S.  Multiple imputation of discrete and continuous data by fully conditional specification.  Stat Methods Med Res. 2007;16(3):219-242. doi:10.1177/0962280206074463PubMedGoogle ScholarCrossref
Abdi  H. Holm’s sequential Bonferroni procedure. In:  Encyclopedia of Research Design. Thousand Oaks, CA: SAGE Publications; 2010:1-8.
Wald  DS, Law  M, Morris  JK, Bestwick  JP, Wald  NJ.  Combination therapy versus monotherapy in reducing blood pressure.  Am J Med. 2009;122(3):290-300. doi:10.1016/j.amjmed.2008.09.038PubMedGoogle ScholarCrossref
Mahmud  A, Feely  J.  Low-dose quadruple antihypertensive combination.  Hypertension. 2007;49(2):272-275.PubMedGoogle ScholarCrossref
MacDonald  TM, Williams  B, Webb  DJ,  et al.  Combination therapy is superior to sequential monotherapy for the initial treatment of hypertension.  J Am Heart Assoc. 2017;6(11):6.PubMedGoogle ScholarCrossref
Mourad  JJ, Waeber  B, Zannad  F,  et al.  Comparison of different therapeutic strategies in hypertension.  J Hypertens. 2004;22(12):2379-2386.PubMedGoogle ScholarCrossref
Wang  YR, Alexander  GC, Stafford  RS.  Outpatient hypertension treatment, treatment intensification, and control in Western Europe and the United States.  Arch Intern Med. 2007;167(2):141-147. doi:10.1001/archinte.167.2.141PubMedGoogle ScholarCrossref
Ferrari  P; National Coordinators for the Reasons for not Intensifying Antihypertensive Treatment (RIAT) trial12.  Reasons for therapeutic inertia when managing hypertension in clinical practice in non-Western countries.  J Hum Hypertens. 2009;23(3):151-159. doi:10.1038/jhh.2008.117PubMedGoogle ScholarCrossref
Egan  BM, Zhao  Y, Axon  RN,  et al.  Uncontrolled and apparent treatment resistant hypertension in the United States, 1988 to 2008.  Circulation. 2011;124(9):1046-1058.PubMedGoogle ScholarCrossref
Redón  J, Coca  A, Lázaro  P,  et al.  Factors associated with therapeutic inertia in hypertension.  J Hypertens. 2010;28(8):1770-1777.PubMedGoogle ScholarCrossref
Katulanda  P, Ranasinghe  P, Jayawardena  R,  et al.  The prevalence, predictors and associations of hypertension in Sri Lanka.  Clin Exp Hypertens. 2014;36(7):484-491.PubMedGoogle ScholarCrossref
Volpe  M, Gallo  G, Tocci  G.  Is early and fast blood pressure control important in hypertension management?  Int J Cardiol. 2018;254:328-332.PubMedGoogle ScholarCrossref
Goldman  AI, Steele  BW, Schnaper  HW,  et al.  Serum lipoprotein levels during chlorthalidone therapy.  JAMA. 1980;244(15):1691-1695.PubMedGoogle ScholarCrossref
Olde Engberink  RH, Frenkel  WJ, van den Bogaard  B,  et al.  Effects of thiazide-type and thiazide-like diuretics on cardiovascular events and mortality.  Hypertension. 2015;65(5):1033-1040. PubMedGoogle ScholarCrossref
Beddhu  S, Rocco  MV, Toto  R,  et al.  Effects of intensive systolic blood pressure control on kidney and cardiovascular outcomes in persons without kidney disease.  Ann Intern Med. 2017;167(6):375-383. PubMedGoogle ScholarCrossref
Attaei  MW, Khatib  R, McKee  M,  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.  Lancet Public Health. 2017;2(9):e411-e419.PubMedGoogle ScholarCrossref
Muntner  P, Carey  RM, Gidding  S,  et al.  Potential US population impact of the 2017 ACC/AHA high blood pressure guideline.  Circulation. 2018;137(2):109-118.PubMedGoogle ScholarCrossref
Jaffe  MG, Lee  GA, Young  JD, Sidney  S, Go  AS.  Improved blood pressure control associated with a large-scale hypertension program.  JAMA. 2013;310(7):699-705. doi:10.1001/jama.2013.108769PubMedGoogle ScholarCrossref
If you are not a JN Learning subscriber, you can either:
Subscribe to JN Learning for one year
Buy this activity
If you are not a JN Learning subscriber, you can either:
Subscribe to JN Learning for one year
Buy this activity
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right

Name Your Search

Save Search
With a personal account, you can:
  • Track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience

Lookup An Activity


My Saved Searches

You currently have no searches saved.

With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right
State Requirements