Optimising TRIUMPH with 6·25 mg chlorthalidone
Authors: Anil Pareek, C Venkata S Ram, Ravi T Mehta, Shruti Dharmadhikari
Journal: The Lancet Global Health (2020)

The 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,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 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. This is important because the higher-dose triple pill includes 25 mg chlorthalidone, and the following points must be considered. Electrolyte and metabolic adverse effects associated with thiazides are dose-related and 12·5 mg of chlorthalidone should not be exceeded in combination therapies to retain efficacy and tolerability. In the SHEP study,2Franse LV Pahor M Di Bari M Somes GW Cushman WC Applegate WB Hypokalemia associated with diuretic use and cardiovascular events in the Systolic Hypertension in the Elderly Program.Hypertension. 2000; 35: 1025-1030Crossref PubMed Scopus (256) Google Scholar 25 mg chlorthalidone was associated with higher incidence of electrolyte disturbances compared with 12·5 mg and 6·25 mg. Previously, when chlorthalidone was used in doses greater than 25 mg per day, biochemical adverse effects led to decreased use. This decreased use might have contributed to worsening of hypertension and cardiovascular disease. Similarly, use of 25 mg chlorthalidone in a fixed triple pill will necessitate more frequent monitoring of electrolyte and metabolic variables, thereby adding to cost of therapy, which was not considered in the present analysis. Chlorthalidone is twice as potent as the more commonly prescribed thiazide diuretic hydrochlorothiazide (25 mg chlorthalidone corresponds to 50 mg hydrochlorothiazide). The most frequently prescribed dose of hydrochlorothiazide in combination therapy is 12·5 mg, which therapeutically translates to 6·25 mg chlorthalidone. The ceiling dose of chlorthalidone should be 12·5 mg in any combination. A reason that these low doses are preferred in the Indian subcontinent could be the hot and humid climate, meaning that 25 mg chlorthalidone is not tolerated by many patients, especially older people. On this basis, a series of comparative trials using 6·25 mg chlorthalidone in monotherapy3Pareek AK Messerli FH Chandurkar NB et al.Efficacy of low-dose chlorthalidone and hydrochlorothiazide as assessed by 24-h ambulatory blood pressure monitoring.J Am Coll Cardiol. 2016; 67: 379-389Crossref PubMed Scopus (42) Google Scholar and combination therapy4Pareek A Zawar SD Salagre SB Chandurkar NB Karnik ND Antihypertensive efficacy of metoprolol XL/low dose chlorthalidone (6·25 mg) combination: a randomized, comparative study in Indian patients with mild-to-moderate essential hypertension.Eur J Med Res. 2009; 14: 297-303Crossref PubMed Google Scholar, 5Pareek A Basavanagowdappa H Zawar S Kumar A Chandurkar N A randomized, comparative study evaluating the efficacy and tolerability of losartan-low dose chlorthalidone (6·25 mg) combination with losartan-hydrochlorothiazide (12·5 mg) combination in Indian patients with mild-to-moderate essential hypertension.Expert Opin Pharmacother. 2009; 10: 1529-1536Crossref PubMed Scopus (14) Google Scholar have shown this lower dose to be superior to 12·5 mg hydrochlorothiazide in blood pressure control. A similar health economic model extrapolating these trial-based findings of reduced blood pressure will translate to lower long-term health-care costs. Although the cost of the triple pill may be high, a huge number of lives could be saved through prevention of the complications of uncontrolled hypertension. To conclude, we feel that the two versions of this triple pill should contain 6·25 mg and 12·5 mg chlorthalidone to further optimise the cost effectiveness of this mass strategy. AP, RTM, and SD report personal fees from Ipca Laboratories, outside the submitted work. CVSR reports that he is the editor in chief of the Hypertension Journal, which receives advertisements from companies, including Ipca. 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 chlorthalidone – Authors' replyWe 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.1 Although moderate-to-high doses of thiazide-like diuretics have provided large reductions in cardiovascular events in previous trials,2 we agree there would be considerable clinical value in regimens with greater blood pressure lowering efficacy and fewer side-effects. Full-Text PDF Open Access