Optimising TRIUMPH with 6·25 mg chlorthalidone – Authors' reply
Authors: Thomas Lung, Anthony Rodgers, Tracey-Lea Laba, Ruth Webster, Anushka Patel
Journal: The Lancet Global Health (2020)

We thank Anil Pareek and colleagues for their suggestion that lower doses of chlorthalidone could reduce metabolic side-effects and improve the cost-effectiveness of a low-dose triple-pill strategy.1Lung T Jan S de Silva HA et al.Fixed-combination, low-dose, triple-pill antihypertensive medication versus usual care in patients with mild-to-moderate hypertension in Sri Lanka: a within-trial and modelled economic evaluation of the TRIUMPH trial.Lancet Glob Health. 2019; 7: e1359-e1366Summary Full Text Full Text PDF PubMed Scopus (11) Google Scholar Although moderate-to-high doses of thiazide-like diuretics have provided large reductions in cardiovascular events in previous trials,2Olde Engberink RH Frenkel WJ van den Bogaard B Brewster LM Vogt L van den Born BJ Effects of thiazide-type and thiazide-like diuretics on cardiovascular events and mortality: systematic review and meta-analysis.Hypertension. 2015; 65: 1033-1040Crossref PubMed Scopus (72) Google Scholar we agree there would be considerable clinical value in regimens with greater blood pressure lowering efficacy and fewer side-effects. We would like to make four main points in reply. First, a half-standard dose of chlorthalidone was used instead of hydrochlorothiazide in TRIUMPH because of proven effectiveness in large-scale clinical outcome trials of blood pressure lowering2Olde Engberink RH Frenkel WJ van den Bogaard B Brewster LM Vogt L van den Born BJ Effects of thiazide-type and thiazide-like diuretics on cardiovascular events and mortality: systematic review and meta-analysis.Hypertension. 2015; 65: 1033-1040Crossref PubMed Scopus (72) Google Scholar and to maximise the probable blood pressure reductions. Second, over a 6-month period in TRIUMPH, only 3·4% of the intervention group received the higher dose of the triple pill (containing 25 mg chlorthalidone);3Webster R Salam A de Silva HA et al.Fixed low-dose triple combination antihypertensive medication vs usual care for blood pressure control in patients with mild to moderate hypertension in Sri Lanka: a randomized clinical trial.JAMA. 2018; 320: 566-579Crossref PubMed Scopus (68) Google Scholar hence, any supplementary observational analyses on adverse events could not be done with such a small sample. Third, drug-specific side-effects can be substantially reduced with combination therapy; randomised trials show that adding an angiotensin-receptor blocker to chlorthalidone substantially reduces hypokalaemia4Sica D Bakris GL White WB et al.Blood pressure-lowering efficacy of the fixed-dose combination of azilsartan medoxomil and chlorthalidone: a factorial study.J Clin Hypertens (Greenwich). 2012; 14: 284-292Crossref PubMed Scopus (37) Google Scholar and adding an angiotensin-receptor blocker, angiotensin-converting-enzyme inhibitor, or diuretic reduces the incidence of leg oedema with amlodipine.5Makani H Bangalore S Romero J Wever-Pinzon O Messerli FH Effect of renin-angiotensin system blockade on calcium channel blocker-associated peripheral edema.Am J Med. 2011; 124: 128-135Summary Full Text Full Text PDF PubMed Scopus (97) Google Scholar Finally, our economic evaluation did not consider the costs associated with laboratory examinations as these data were not collected during the trial period; however, we agree that further research is required to properly assess and include these costs for future economic evaluations. As there was no difference in withdrawals of blood pressure medication use because of adverse events between the two groups and a small number of individuals receiving the higher dose of the triple pill,4Sica D Bakris GL White WB et al.Blood pressure-lowering efficacy of the fixed-dose combination of azilsartan medoxomil and chlorthalidone: a factorial study.J Clin Hypertens (Greenwich). 2012; 14: 284-292Crossref PubMed Scopus (37) Google Scholar we expect that in this study there would be minimal differences in laboratory examination costs between the triple pill and monotherapy group. Hence, we suspect that incorporating laboratory examination costs into this economic evaluation is unlikely to change our conclusion that the triple-pill strategy is cost-effective as a first-line treatment option when compared with monotherapy. RW and AP report 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. AR is listed as an inventor on this patent; however, he does not have a financial interest in it. All other authors declare no competing interests. Fixed-combination, low-dose, triple-pill antihypertensive medication versus usual care in patients with mild-to-moderate hypertension in Sri Lanka: a within-trial and modelled economic evaluation of the TRIUMPH trialCompared with usual care, the triple-pill strategy is cost-effective for patients with mild-to-moderate hypertension. Scaled up investment in the triple pill for hypertension management in Sri Lanka should be supported to address the high population burden of cardiovascular disease. Full-Text PDF Open AccessOptimising TRIUMPH with 6·25 mg chlorthalidoneThe TRIUMPH trial found that use of the low-dose fixed-combination triple pill as initial therapy provided better blood pressure control than usual care. In their modelled economic evaluation of TRIUMPH,1 Thomas Lung and colleagues reported that this triple-pill strategy is cost-effective as a first-line treatment option, especially for older individuals. For their analysis, the authors referred to WHO-CHOICE, which includes health system costs associated with clinic visits, medications, and inpatient hospital admissions, but excludes those associated with laboratory examinations. Full-Text PDF Open Access