eFigure 1. Time at target calculation
eFigure 2. TITRE achieved in triple pill and usual care groups (n=700)
eTable. Subgroup analyses by different patient groups (n=700)
eFigure 3. Scatter plot of blood pressure variability vs time at target
The TRIUMPH Study Group members
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Gnanenthiran SR, Wang N, Di Tanna GL, et al. Association of Low-Dose Triple Combination Therapy vs Usual Care With Time at Target Blood Pressure: A Secondary Analysis of the TRIUMPH Randomized Clinical Trial. JAMA Cardiol. 2022;7(6):645–650. doi:10.1001/jamacardio.2022.0471
Is low-dose triple combination antihypertensive therapy associated with greater time at target blood pressure compared with usual care?
In this secondary analysis of a randomized clinical trial including patients with mild to moderate hypertension, treatment with a low-dose triple combination pill was associated with an increase in time at target compared with usual care.
Time at target, a novel longitudinal measurement of blood pressure control, may have the capacity to augment current cross-sectional measures by being less susceptible to variability and providing more reliable and consistent measurements.
Cumulative exposure to high blood pressure (BP) is an adverse prognostic marker. Assessments of BP control over time, such as time at target, have been developed but assessments of the effects of BP-lowering interventions on such measures are lacking.
To evaluate whether low-dose triple combination antihypertensive therapy was associated with greater rates of time at target compared with usual care.
Design, Setting, and Participants
The Triple Pill vs Usual Care Management for Patients With Mild-to-Moderate Hypertension (TRIUMPH) trial was a open-label randomized clinical trial of low-dose triple BP therapy vs usual care conducted in urban hospital clinics in Sri Lanka from February 2016 to May 2017. Adults with hypertension (systolic BP >140 mm Hg and/or diastolic BP >90 mm Hg or in patients with diabetes or chronic kidney disease, systolic BP >130 mm Hg and/or diastolic BP >80 mm Hg) requiring initiation (untreated patients) or escalation (patients receiving monotherapy) of antihypertensive therapy were included. Patients were excluded if they were currently taking 2 or more blood pressure–lowering drugs or had severe or uncontrolled blood pressure, accelerated hypertension or physician-determined need for slower titration of treatment, a contraindication to the triple combination pill therapy, an unstable medical condition, or clinically significant laboratory values deemed by researchers to be unsuitable for the study. All 700 individuals in the original trial were included in the secondary analysis. This post hoc analysis was conducted from December 2020 to December 2021.
Once-daily fixed-dose triple combination pill (telmisartan 20 mg, amlodipine 2.5 mg, and chlorthalidone 12.5 mg) therapy vs usual care.
Main Outcomes and Measures
Between-group differences in time at target were compared over 24 weeks of follow-up, with time at target defined as percentage of time at target BP.
There were a total of 700 randomized patients (mean [SD] age, 56  years; 403 [57.6%] women). Patients allocated to the triple pill group (n = 349) had higher time at target compared with those in the usual care group (n = 351) over 24 weeks’ follow-up (64% vs 43%; risk difference, 21%; 95% CI, 16-26; P < .001). Almost twice as many patients receiving triple pill therapy achieved more than 50% time at target during follow-up (64% vs 37%; P < .001). The association of the triple pill with an increase in time at target was seen early, with most patients achieving more than 50% time at target by 12 weeks. Those receiving the triple pill achieved a consistently higher time at target at all follow-up periods compared with those receiving usual care (mean [SD]: 0-6 weeks, 36.3% [30.9%] vs 21.7% [28.9%]; P < .001; 6-12 weeks, 55.2% [31.9%] vs 33.7% [33.0%]; P < .001; 12-24 weeks, 66.0% [31.1%] vs 43.5% [34.3%]; P < .001).
Conclusions and Relevance
To our knowledge, this analysis provides the first estimate of time at target as an outcome assessing longitudinal BP control in a randomized clinical trial. Among patients with mild to moderate hypertension, treatment with a low-dose triple combination pill was associated with substantially higher time at target compared with usual care.
To date, hypertension guidelines have focused on cross-sectional blood pressure (BP) targets based on 1-time measurements without consideration of the proportion of time that individuals are at target BP.1,2 Longitudinal assessments of BP control, such as time spent at target, have historically received little attention in practice. Clinical trials typically report BP control according to singular time points (often at the end of follow-up); hence there is little information on the effects of different strategies on time at target BP. Because of the high variability of BP, many people with a measure below target could have many or even most future readings above target. Observational data suggest that cumulative exposure to hypertension is an adverse prognostic marker3-7 associated with end organ damage, cardiovascular disease, and mortality.3,8
This recognition led to the concept of time at target as a new outcome for evaluating the effectiveness of BP control.3 Time at target is the percentage of time spent at target systolic and diastolic BP.3 Time at target incorporates systolic and diastolic BP, multiple time points, and BP targets in a single metric that is readily understandable; as such, it has advantages over other metrics, such as cumulative systolic BP (measured in mm HG years) or BP control rates at each visit, with multiple values per person. Chung et al3 demonstrated that higher time at target had a stronger association with a reduction in cardiovascular events than BP variability and cross-sectional BP values. A similar analysis in the Systolic Blood Pressure Intervention Trial8 also demonstrated that increased time in target systolic BP was associated with reduced cardiovascular events, but diastolic BP was not evaluated.
The strategy of initial or early use of single pill combination antihypertensive therapy may facilitate more rapid and effective BP control compared with gradual multistep titration pathways.9 However, the effect of any intervention, including single pill combinations, on time at target has not, to our knowledge, been examined, nor has this been used as an outcome in randomized clinical trials. We therefore conducted a post hoc analysis of the Triple Pill vs Usual Care Management for Patients With Mild-to-Moderate Hypertension (TRIUMPH) randomized clinical trial to evaluate whether low-dose triple combination antihypertensive pill therapy was associated with an increase time at target compared with usual care.
The details of the TRIUMPH trial9 have been reported elsewhere. In brief, the trial was conducted at 11 urban hospital outpatient departments in Sri Lanka and recruited patients with mild to moderate hypertension. Participants were randomized to a once-daily single pill combination of 3 BP lowering drugs (triple pill) at half the standard dose (telmisartan 20 mg, amlodipine 2.5 mg, and chlorthalidone 12.5 mg) or to usual care. Participants were monitored for 24 weeks. This study complied with the Declaration of Helsinki. The locally appointed ethics committee approved the research protocol and written informed consent was obtained from all participants. The study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline.
The primary outcome was time at target, with target BP defined as per the TRIUMPH9 protocol: systolic BP less than 140 mm Hg and/or diastolic BP less than 90 mm Hg or systolic BP less than 130 mm Hg and/or diastolic BP less than 80 mm Hg in patients with diabetes or chronic kidney disease.
Descriptive statistics are presented as frequencies and percentages for categorical variables (eg, comorbidities and proportion of patients achieving time at target), while means and SDs are reported for continuous variables (eg, age and time at target). For each individual, time at target was calculated as the percentage of time at target systolic and diastolic BP over the follow-up period as calculated by the extrapolation method used by Chung et al3 (eFigure 1 in Supplement 1) and using BP readings at weeks 0, 6, 12, and 24. The number of days at target BP for systolic and diastolic readings were subsequently averaged. There were few missing values at each time point (<5%). An intention-to-treat analysis was used, with time at target calculated with available values. Time at target was not calculated if more than 2 BP readings were missing (n = 13).
Subgroup analyses were performed to determine mean time at target, stratified by age, sex, comorbidities, and treatment group. More than 50% time at target was chosen to identify participants achieving the majority of time at target BP. BP variability was also measured by the mean intraindividual standard deviation of follow-up systolic and diastolic BP measures in each patient (week 6, 12, and 24).10 Pearson coefficients were used to correlate BP variability and time at target. All analyses were performed using SPSS version 24.0 (IBM). All tests were 2-sided and significance was set at P < .05.
Baseline patient characteristics have been described previously.9 In summary, 700 participants in the TRIUMPH trial9 were monitored for 24 weeks. The mean (SD) age was 56.2 (11.0) years, and 403 participants (57.6%) were women. A total of 220 patients (31.4%) had diabetes, 110 (15.7%) had a history of smoking, and 10 (1.4%) had a history of chronic kidney disease. Mean baseline BP was 154/90 mm Hg and 287 participants (41.0%) were receiving antihypertensive therapy prerandomization.
Table 1 shows the mean time at target and proportion of patients achieving time at target by treatment group. Participants in the triple pill group achieved a higher time at target compared with the usual care group (64.2% vs 43.4%). Patients in the triple pill group were more likely to achieve more than 50% time at target of the total follow-up time compared with the usual care group (time at target >50%-75%, 29.2% vs 21.4%; χ2, 5.38; P = .02; time at target >75%, 34.8% vs 15.1%; χ2, 35.58; P < .001) (Table 1; eFigure 2A in Supplement 1). Patients who achieved more than 50% time at target were more likely to achieve target systolic and diastolic BP at final 24-week follow-up (Table 2). One-fourth of patients spent less than 25% of time at target during follow-up, with fewer from the triple pill group compared with the usual care group (15.2% vs 34.5%; P < .001) (Table 1).
eFigure 2B in Supplement 1 demonstrates how the proportion of time spent at target changed over the course of the trial in the 0- to 6-week interval, 6- to 12-week interval, and 12- to 24-week interval. The association of time at target with triple pill therapy was seen early, with most participants achieving more than 50% time at target by 12-week study visit. Those in the triple pill group achieved a consistently higher time at target at all follow-up periods compared with those in the usual care group (mean [SD]: 0-6 weeks, 36.3% [30.9%] vs 21.7% [28.9%]; P < .001; 6-12 weeks, 55.2% [31.9%] vs 33.7% [33.0%]; P < .001; 12-24 weeks, 66.0% [31.1%] vs 43.5% [34.3%]; P < .001). Among the 300 patients who did not reach BP targets at week 6, 95 (31.7%) achieved more than 50% time at target by end of study. Among 269 patients who did not reach BP targets at week 12, 23 (8.6%) achieved more than 50% time at target by end of study.
The association between triple pill and greater time at target was consistent across subgroups, with patients in the triple pill group achieving a higher mean time at target across all subgroups over the 24-week follow-up (eTable in Supplement 1). People receiving triple pill therapy were also more likely to achieve more than 50% time at target across subgroups (Figure).
There was no significant difference in mean intraindividual systolic and diastolic BP variability between the triple pill and usual care groups during follow-up (systolic BP mean [SD]: 9.9 [7.2] mm Hg vs 10.7 [7.0] mm Hg, respectively; P = .13; diastolic BP mean [SD]: 6.2 [4.2] vs 6.3 [3.8], respectively; P = .65). However, time at target was correlated between systolic BP variability (r, −0.25; 95% CI, −0.33 to −0.18; P < .001) and diastolic BP variability (r, −0.14; 95% CI, −0.22 to −0.07; P < .001) (eFigure 3 in Supplement 1).
In this post hoc analysis, low-dose triple combination pill therapy was associated with greater time at target compared with usual care over 24-week follow-up in patients with mild to moderate hypertension. To our knowledge, this is the first analysis of a randomized clinical trial to examine time at target as an outcome and also the first to assess the association of combination BP-lowering therapy with time at target. Treatment effects appeared to be larger than those suggested by the main trial primary outcome at 24 weeks, as time at target captured the benefits of both reduced time to BP control and more sustained BP control with low-dose triple pill therapy.
Time at target, a longitudinal measurement of BP control, may have the capacity to augment current cross-sectional measures. Current hypertension guidelines focus on cross-sectional BP targets, and BP targets are not currently expressed with a time dimension or an acceptable minimum proportion of BP measures at target.1,2 Single BP measures taken a few days or weeks apart that are often part of real-world practice are subject to poor reliability because they vary considerably by time of day11 and season.12 Whereas time at target integrating both systolic and diastolic BP at multiple time points is likely to be much less susceptible to variability and may provide more sensitive, consistent measurements compared with cross-sectional measures. Such longitudinal outcomes also provide clinically meaningful ways to detect a larger magnitude of between-group differences than identified by standard cross-sectional definitions.9
Compared with single BP measures, long-term BP load is more closely associated with hypertension-mediated organ damage and cardiovascular outcomes, as supported by 24-hour ambulatory BP monitoring and observational evidence13,14 demonstrating increased left ventricular mass index,4 incipient left ventricular dysfunction,6 and higher albuminuria.7 Compared with people with 0% time at target, patients with 25% or more time at target had one-fourth the rates of cardiovascular death, myocardial infarction, and risk of stroke.3 Even longitudinal measurements of improved time in target systolic BP are associated with reduced CV events.8 Additionally, the ability to capture reduced time to BP control may have prognostic value as a shorter time to control has been associated with lower cardiovascular risk.15 In light of this evidence, reevaluation of the current paradigm of BP targets to incorporate longitudinal targets may need to be considered.3 New BP devices, including wearable cuffless devices, may facilitate the capture of longitudinal-control at-home BP measurement and remote monitoring systems.
Our study had several limitations. First, long-term cardiovascular outcomes were not examined, and thus the degree to which improvements in time at target translate to reduced cardiovascular events need further assessment. The trial protocol only included 4 time points for calculation of time at target. Nevertheless, this low number of visits may represent real clinical practice. The original article by Chung et al3 calculated time at target using only 1.6 BP measures per year, with time at target still correlating better with cardiovascular end points than cross-sectional end points and BP variability. Current calculations of time at target assume a linear time course of BP reduction, when in fact BP lowering effect is seen within a few weeks. Further research is needed to explore the optimal frequency of BP measurements required for time at target calculations and whether longitudinal BP assessment provides superior prediction of clinical outcomes compared with current cross-sectional definitions. Despite these limitations, this is the first trial to our knowledge to use time at target as an outcome in a randomized setting in post hoc analysis and to examine the association of a triple combination antihypertensive pill with time at target.
The findings suggest that among patients with mild to moderate hypertension, treatment with a triple pill containing low doses of 3 antihypertensive medications was associated with an increase in time at target compared with usual care. This study not only provides evidence that low-dose triple pill therapy may be an effective way to improve longitudinal BP control, but also introduces time at target as a novel outcome in randomized clinical trials.
Accepted for Publication: February 17, 2022.
Published Online: April 13, 2022. doi:10.1001/jamacardio.2022.0471
Correction: This article was corrected on June 1, 2022, to fix a typographical error in the Abstract Results section.
Corresponding Author: Anthony Rodgers, PhD, The George Institute for Global Health, University of New South Wales, Level 10, King George V Building, PO Box M201, Camperdown NSW 2050, Australia (email@example.com).
Author Contributions: Drs Gnanenthiran and Rodgers 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: Gnanenthiran, Wang, Salam, Jan, Thom, Prabhakaran, Patel, Rodgers.
Acquisition, analysis, or interpretation of data: Gnanenthiran, Wang, Di Tanna, Webster, De Silva, Guggilla, Jan, Maulik, Naik, Selak, Prabhakaran, Schutte, Rodgers.
Drafting of the manuscript: Gnanenthiran, Wang, Salam, Rodgers.
Critical revision of the manuscript for important intellectual content: Gnanenthiran, Wang, Di Tanna, Webster, De Silva, Guggilla, Jan, Maulik, Naik, Selak, Thom, Prabhakaran, Schutte, Patel, Rodgers.
Statistical analysis: Gnanenthiran, Wang, Di Tanna.
Obtained funding: Webster, Guggilla, Jan, Maulik, Prabhakaran, Patel, Rodgers.
Administrative, technical, or material support: Salam, Webster, De Silva, Guggilla, Maulik, Prabhakaran.
Supervision: De Silva, Naik, Thom, Prabhakaran, Schutte, Rodgers.
Conflict of Interest Disclosures: Dr Di Tanna was previously an employee of Amgen. Dr Webster reports grants from National Health and Medical Research Council during the conduct of the study. Dr Guggilla is a shareholder of Ajanta Pharma, Asensus Surgical US, Bayer, Cellectis, Cocrystal Pharma, Divi’s Laboratories, Editas Medicine, Intercept Pharmaceuticals, Jaguar Health, Natco Pharma, Roche, and Zynerba Pharmaceuticals. Dr Maulik reports grants from National Health and Medical Research Council and the UK Research and Innovation Medical Research Council outside the submitted work. Dr Schutte reports personal fees from Servier, Novartis, Takeda, Sun Pharmaceuticals, and Abbott outside the submitted work. Dr Patel reports grants from National Health and Medical Research Council during the conduct of the study and is employed by the George Institute for Global Health, which has submitted patent applications in respect of low fixed-dose combination products for the treatment of cardiovascular or cardiometabolic disease; George Health Enterprises and its subsidiary, George Medicines, have received investment funds to develop fixed-dose combination products, including combinations of blood pressure–lowering drugs; George Health Enterprise is the social enterprise arm of the George Institute for Global Health; Dr Patel does not have a direct financial interest in these patent applications or investments. Dr Rodgers is employed by the George Institute for Global Health and Imperial College London and is seconded part-time to George Medicines, which is partly owned by George Health Enterprises, the social enterprise arm of the George Institute for Global Health; the George Institute for Global Health holds patents for ultra–low-dose fixed-dose combination products for the treatment of hypertension and diabetes, and Dr Rodgers is listed as one of the inventors (US 10,369,15; US 10,799,487; US 10,322,117; US 11,033,544); George Health Enterprises and George Medicines have received funding from public and private investors to conduct the research required for regulatory approval of cardiovascular combination products; Dr Rodgers does not have a financial interest in these patent applications or investments. No other disclosures were reported.
Funding/Support: The study was funded by grants from the Australian National Health and Medical Research Council Global Alliance for Chronic Disease (APP1041052) and the National Health and Medical Research Council (APP1052555).
Role of the Funder/Sponsor: The funders 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.
The TRIUMPH Study Group members: The members of the TRIUMPH Study Group are in Supplement 2.