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

Abstract

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.

Figure 1.. Flow of Patients Through the Triple Pill vs Usual Care Management for Patients With Mild-to-Moderate Hypertension Study

Figure 2.. Mean Blood Pressure in the 2 Treatment Groups During the Course of the Trial

The SD at each visit is shown. Longitudinal linear models were used to estimate the differences in blood pressure during all 3 visits combined and included treatment group, trial visit as a categorical variable, a treatment × visit interaction, the baseline value (ie, baseline systolic or diastolic blood pressure), and use of blood pressure–lowering therapy at baseline as fixed effects along with trial center as a random effect. ^aRefers to drug classes (eg, angiotensin-converting enzyme inhibitor, β-blocker, diuretic) the patient was taking. The mean No. of classes of blood pressure–lowering drugs was less than 3 during follow-up in the triple combination pill group because some patients were discontinued from this treatment. ^bRefers to the No. of physical tablets or pills that the participant was taking each day. Some patients took more than 1 pill of the same drug to achieve the prescribed dose. The standard dose in milligrams of each medication was defined with reference to usual maintenance doses recorded by major formularies as described by Bennett et al and Law et al (detailed standard dose listing appears in eTable 1 in Supplement 2). ^cThe No. of standard doses in the triple combination pill was 1.5 (calculated as the sum of 0.5 of a standard dose for each of the 3 components).

Figure 3.. Blood Pressure–Lowering Medication Classes by Randomized Group

Subsequent to randomization, 5 patients (3 in the triple combination pill group and 2 in the usual care group) were identified as taking more than 1 blood pressure–lowering medication at baseline and these were reported as protocol violations. Patients taking less than 3 blood pressure–lowering classes during follow-up visits had stopped the triple combination pill and commenced an alternate therapy.

Figure 4.. Primary Outcome by Subgroups

The dashed vertical line represents the relative risk (1.23) of the primary outcome for the overall study population. The proportion of participants achieving target blood pressure control at 6 months was analyzed using log-binomial regression (binomial distribution with a log link) with the treatment group and use of blood pressure–lowering therapy at baseline as fixed effects and trial center as a random effect. Homogeneity of treatment effects across subgroups for the primary outcome was tested by adding interaction terms to the log-binomial model. Subgroups only contain patients for whom blood pressure readings were available at 6 months. BP indicates blood pressure. ^aLow education indicates none or primary school completion; high education indicates secondary school, university, or vocational education. ^bExpressed as Sri Lankan rupee.