Browsing by Author "Gnanenthiran, S.R."

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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
(American Medical Association, 2022) Gnanenthiran, S.R.; Wang, N.; Luca Di Tanna, G.; Salam, A.; Webster, R.; de Silva, H.A.; Guggilla, R.; Jan, S.; Maulik, P.K.; Naik, N.; Selak, V.; Thom, S.; Prabhakaran, D.; Schutte, A.E.; Patel, A.; Rodgers, A.; TRIUMPH Study Group
Importance: 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. Objective: 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. Intervention: 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. Results: There were a total of 700 randomized patients (mean [SD] age, 56 [11] 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, 5.2% [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.
Efficacy and safety of a novel low-dose triple single-pill combination of telmisartan, amlodipine and indapamide, compared with dual combinations for treatment of hypertension: a randomised, double-blind, active-controlled, international clinical trial
(Elsevier, 2024-10) Rodgers, A.; Salam, A.; Schutte, A.E.; Cushman, W.C.; De Silva, H.A.; Tanna, G.L.D.; Grobbee, D.E.; Narkiewicz, K.; Ojji, D.B.; Poulter, N.R.; Schlaich, M.P.; Oparil, S.; Spiering, W.; Williams, B.; Jr, J.T.W.; Lakshman, P.; Uluwattage, W.; Hay, P.; Pereira, T.; Amarasena, N.; Ranasinghe, G.; Gianacas, C.; Shanthakumar, M.; Liu, X.; Wang, N.; Gnanenthiran, S.R.; Whelton, P.K.; GMRx2 Investigators
BACKGROUND Single-pill combinations (SPCs) of three low-dose antihypertensive drugs can improve hypertension control but are not widely available. A key issue for any combination product is the contribution of each component to efficacy and tolerability. This trial compared a new triple SPC called GMRx2, containing telmisartan, amlodipine, and indapamide, with dual combinations of components for efficacy and safety.METHODS In this international, randomised, double-blind, active-controlled trial, we enrolled adults with hypertension receiving between zero and three antihypertensive drugs, with a screening systolic blood pressure (SBP) ranging from 140-179 mm Hg (on no drugs) to 110-150 mm Hg (on three drugs). Participants were recruited from Australia, the Czech Republic, New Zealand, Poland, Sri Lanka, the UK, and the USA. In a 4-week active run-in, existing medications were switched to GMRx2 half dose (telmisartan 20 mg, amlodipine 2·5 mg, and indapamide 1·25 mg). Participants were then randomly allocated (2:1:1:1) to continued GMRx2 half dose or to each possible dual combination of components at half doses (telmisartan 20 mg with amlodipine 2·5 mg, telmisartan 20 mg with indapamide 1·25 mg, or amlodipine 2·5 mg with indapamide 1·25 mg). At week 6, doses were doubled in all groups, unless there was a clinical contraindication. The primary efficacy outcome was mean change in home SBP from baseline to week 12, and the primary safety outcome was withdrawal of treatment due to an adverse event from baseline to week 12. Secondary efficacy outcomes included differences in clinic and home blood pressure levels and control rates. This study is registered with ClinicalTrials.gov, NCT04518293, and is completed.FINDINGS The trial was conducted between July 9, 2021 and Sept 1, 2023. We randomly allocated 1385 participants to four groups: 551 to GMRx2, 276 to telmisartan-indapamide, 282 to telmisartan-amlodipine, and 276 to amlodipine-indapamide groups. The mean age was 59 years (SD 11), 712 (51%) participants self-reported as female and 673 (48·6%) male, and the mean clinic blood pressure at the screening visit was 142/85 mm Hg when taking an average of 1·6 blood pressure medications. Following the run-in on GMRx2 half dose, the mean clinic blood pressure level at randomisation was 133/81 mm Hg and the mean home blood pressure level was 129/78 mm Hg. At week 12, the mean home SBP was 126 mm Hg in the GMRx2 group, which was lower than for each of the dual combinations: -2·5 (95% CI -3·7 to -1·3, p<0·0001) versus telmisartan-indapamide, -5·4 (-6·8 to -4·1, p<0·0001) versus telmisartan-amlodipine, and -4·4 (-5·8 to -3·1, p<0·0001) versus amlodipine-indapamide. For the same comparisons, differences in clinic blood pressure at week 12 were 4·3/3·5 mm Hg, 5·6/3·7 mm Hg, and 6·3/4·5 mm Hg (all p<0·001). Clinic blood pressure control rate below 140/90 mm Hg at week 12 was superior with GMRx2 (74%) to with each dual combination (range 53-61%). Withdrawal of treatment due to adverse events occurred in 11 (2%) participants in the GMRx2 group, four (1%) in telmisartan-indapamide, three (1%) in telmisartan-amlodipine, and four (1%) in amlodipine-indapamide, with none of the differences being statistically significant.INTERPRETATION A novel low-dose SPC product of telmisartan, amlodipine, and indapamide provided clinically meaningful improvements in blood pressure reduction compared with dual combinations and was well tolerated. This SPC provides a new therapeutic option for the management of hypertension and its use could result in a substantial improvement in blood pressure control in clinical practice.
Rationale for a new low-dose triple single pill combination for the treatment of hypertension
(Elsevier, 2024) Rodgers, A.; Salam, A.; Cushman, W.; de Silva, A.; Tanna, G.L.D.; Gnanenthiran, S.R.; Grobbee, D.; Narkiewicz, K.; Ojji, D.; Oparil, S.; Poulter, N.; Schlaich, M.P.; Schutte, A.E.; Spiering, W.; Williams, B.; Wright, J.T.Jr.; Whelton, P.
Two recent large trials showed the potential of single pill combinations (SPCs) with ≥3 low-dose components among people with hypertension who were untreated or receiving monotherapy. In both trials, these 'hypertension polypills' were superior to usual care, achieving >80% BP control without increasing withdrawal due to side effects. However, there are no such products available for prescribers. To address this unmet need, George Medicines developed GMRx2 with telmisartan/amlodipine/indapamide in three strengths (mg): 10/1.25/0.625, 20/2.5/1.25; 40/5/2.5. Two pivotal trials are ongoing to support FDA submission for the treatment of hypertension, including initial treatment. These assess efficacy and safety of GMRx2 compared to: placebo, and each of the three possible dual combinations. Regulatory submissions are planned for 2024, with the aim of providing access to GMRx2 in developed and developing regions. Wider implementation of GMRx2-based treatment strategies will be guided by further research to inform access and appropriate scale up.
Reduced efficacy of blood pressure lowering drugs in the presence of diabetes mellitus-results from the TRIUMPH randomised controlled trial
(Nature Publishing Group, 2023) Gnanenthiran, S.R.; Webster, R.; de Silva, A.; Maulik, P.K.; Salam, A.; Selak, V.; Guggilla, R.K.; Schutte, A.E.; Patel, A.; Rodgers, A.; TRIUMPH Study Group
We investigated whether diabetes mellitus (DM) affects the efficacy of a low-dose triple combination pill and usual care among people with mild-moderate hypertension. TRIUMPH (TRIple pill vs Usual care Management for Patients with mild-to-moderate Hypertension) was a randomised controlled open-label trial of patients requiring initiation or escalation of antihypertensive therapy. Patients were randomised to a once-daily low-dose triple combination polypill (telmisartan-20mg/amlodipine-2.5 mg/chlorthalidone-12.5 mg) or usual care. This analysis compared BP reduction in people with and without DM, both in the intervention and control groups over 24-week follow-up. Predicted efficacy of prescribed therapy was calculated (estimation methods of Law et al.). The trial randomised 700 patients (56 ± 11 yrs, 31% DM). There was no difference in the number of drugs prescribed or predicted efficacy of therapy between people with DM and without DM. However, the observed BP reduction from baseline to week 24 was lower in those with DM compared to non-diabetics in both the triple pill (25/11 vs 31/15 mmHg, p ≤ 0.01) and usual care (17/7 vs 22/11 mmHg, p ≤ 0.01) groups, and these differences remained after multivariable adjustment. DM was a negative predictor of change in BP (β-coefficient -0.08, p = 0.02). In conclusion, patients with DM experienced reduced efficacy of BP lowering therapies as compared to patients without DM, irrespective of the type of BP lowering therapy received.