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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?
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).
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.
Poorly controlled hypertension is a leading global public health problem requiring new treatment strategies.
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.
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.
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.
anzctr.org.au Identifier: ACTRN12612001120864; slctr.lk Identifier: SLCTR/2015/020
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Corresponding Author: Ruth Webster, PhD, The George Institute for Global Health, PO Box M201, Missenden Road, Camperdown, NSW 2050, Australia (email@example.com).
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).
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