Medicine
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This repository contains the published and unpublished research of the Faculty of Medicine by the staff members of the faculty
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Item Efficacy and safety of a novel low-dose triple single-pill combination compared with placebo for initial treatment of hypertension(Elsevier Biomedical, 2024) Rodgers, A.; Salam, A.; Schutte, A.E.; Cushman, W.C.; De Silva, H.A.; Tanna, G.L.D.; Grobbee, D.; Narkiewicz, K.; Ojji, D.B.; Poulter, N.R.; Schlaich, M.P.; Oparil, S.; Spiering, W.; Williams, B.; Jr, J.T.W.; Gutierez, A.; Sanni, A.; Lakshman, P.; McMullen, D.; Ranasinghe, G.; Gianacas, C.; Shanthakumar, M.; Liu, X.; Wang, N.; Whelton, P.BACKGROUND Single-pill combinations of 3 or more low-dose blood pressure (BP)-lowering drugs hold promise for initial or early treatment of hypertension.OBJECTIVES We conducted a placebo-controlled trial of a new single-pill combination containing low doses of telmisartan, amlodipine, and indapamide in 2 dose options to assess efficacy and safety.METHODS This international, randomized, double-blind, placebo-controlled, parallel-group trial enrolled adults with hypertension receiving 0 to 1 BP-lowering drugs. After a 2-week placebo run-in during which any BP-lowering medication was stopped, participants were eligible if home systolic BP (SBP) was 130 to 154 mm Hg. Participants were randomized in a 2:2:1 ratio to GMRx2 ¼ dose (telmisartan 10 mg/amlodipine 1.25 mg/indapamide 0.625 mg), GMRx2 ½ dose (telmisartan 20 mg/amlodipine 2.5 mg/indapamide 1.25 mg), or placebo. The primary efficacy outcome was difference in change in home SBP from randomization to week 4, and primary safety outcome was treatment discontinuation due to an adverse event.RESULTS From June 14, 2021 to October 18, 2023, a total of 295 participants (mean age: 51 years; 56% female) were randomized and 96% completed the trial. Baseline mean home BP was 139/86 mm Hg and clinic BP was 138/86 mm Hg after placebo run-in. The placebo-corrected least square mean differences in home SBP at Week 4 were -7.3 mm Hg (95% CI: -4.5 to -10.2) for GMRx2 ¼ dose and -8.2 mm Hg (95% CI: -5.2 to -11.3) for GMRx2 ½ dose; reductions for clinic BP were 8.0/4.0 and 9.5/4.9 mm Hg. At Week 4, clinic BP control (<140/90 mm Hg) was 37%, 65%, and 70% for placebo, GMRx2 ¼ dose, and GMRx2 ½ dose, respectively (both doses P < 0.001 vs placebo). Placebo, GMRx2-triple ¼, and GMRx2 ½ treatment discontinuation due to an adverse event occurred in 1 (1.6%), 0, and 6 (5.1%), respectively; out of normal range serum sodium or potassium was observed in 4 (6.3%), 12 (10.6%), and 12 (10.1%), respectively, but no participant had a serum sodium <130/>150 mmol/L or potassium <3.0/>6.0 mmol/L. Serious adverse events were reported by 2 participants in the placebo and GMRx2 ½ groups and none in the GMRx2 ¼ group.CONCLUSIONS In a population with mild-to-moderate BP elevation, both dose versions of the novel low-dose triple single-pill combination showed good tolerability and clinically relevant BP reductions compared with placebo. (Efficacy and Safety of GRMx2 Compared to Placebo for the Treatment of Hypertension: NCT04518306).Item Efficacy and safety of low-dose triple and quadruple combination pills vs monotherapy, usual care, or placebo for the initial management of hypertension: A systematic review and meta-analysis(American Medical Association, 2023) Wang, N.; Rueter, P.; Atkins, E.; Webster, R.; Huffman, M.; de Silva, A.; Chow, C.; Patel, A.; Rodgers, A.IMPORTANCE: Low-dose combination (LDC) antihypertensives consisting of 3 or 4 blood pressure (BP)-lowering drugs have emerged as a potentially important therapy for the initial management of hypertension. OBJECTIVE: To assess the efficacy and safety of LDC therapies for the management of hypertension. DATA SOURCES: PubMed and Medline were searched from date of inception until September 2022. STUDY SELECTION: Randomized clinical trials comparing LDC consisting of 3 or 4 BP-lowering drugs compared to either monotherapy, usual care, or placebo. DATA EXTRACTION AND SYNTHESIS: Data were extracted by 2 independent authors and synthesized using both random and fixed-effects models using risk ratios (RR) for binary outcomes and mean differences for continuous outcomes. MAIN OUTCOMES AND MEASURES: The primary outcome was mean reduction in systolic BP (SBP) between LDC and monotherapy, usual care, or placebo. Other outcomes of interest included the proportion of patients achieving BP less than 140/90 mm Hg, rates of adverse effects, and treatment withdrawal. RESULTS: Seven trials with a total of 1918 patients (mean [mean range] age, 59 [50-70] years; 739 [38%] female) were included. Four trials involved triple-component LDC and 3 involved quadruple-component LDC. At 4 to 12 weeks follow-up, LDC was associated with a greater mean reduction in SBP than initial monotherapy or usual care (mean reduction, 7.4 mm Hg; 95% CI, 4.3-10.5) and placebo (mean reduction, 18.0 mm Hg; 95% CI, 15.1-20.8). LDC was associated with a higher proportion of participants achieving BP less than 140/90 mm Hg at 4 to 12 weeks compared to both monotherapy or usual care (66% vs 46%; RR, 1.40; 95% CI, 1.27-1.52) and placebo (54% vs 18%; RR, 3.03; 95% CI, 1.93-4.77). There was no significant heterogeneity between trials enrolling patients with and without baseline BP-lowering therapy. Results from 2 trials indicated LDC remained superior to monotherapy or usual care at 6 to 12 months. LDC was associated with more dizziness (14% vs 11%; RR 1.28, 95% CI 1.00-1.63) but no other adverse effects nor treatment withdrawal. CONCLUSIONS AND RELEVANCE: The findings in the study showed that LDCs with 3 or 4 antihypertensives were an effective and well-tolerated BP-lowering treatment option for the initial or early management of hypertension.Item 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 GroupWe 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.Item Triple therapy prevention of recurrent intracerebral disease events trial: rationale, design and progress(Blackwell Publishing, 2022) Anderson, C.S.; Rodgers, A.; de Silva, H.A.; Martins, S.O.; Klijn, C.J.; Senanayake, B.; Freed, R.; Billot, L.; Arima, H.; Thang, N.H.; Zaidi, W.A.W.; Kherkheulidze, T.; Wahab, K.; Fisher, U.; Lee, T.H.; Chen, C.; Pontes-Neto, O.; Robinson, T.; Wang, J.; Naismith, S.; Song, L.; Schreuder, F.H.; Lindley, R.I.; Woodward, M.; MacMahon, S.; Salman, R.A.; Chow, C.K.; Chalmers, J.Background: Patients who suffer intracerebral hemorrhage (ICH) are at very high risk of recurrent ICH and other serious cardiovascular events. A single-pill combination (SPC) of blood pressure (BP) lowering drugs offers a potentially powerful but simple strategy to optimize secondary prevention. Objectives: The Triple Therapy Prevention of Recurrent Intracerebral Disease Events Trial (TRIDENT) aims to determine the effects of a novel SPC "Triple Pill," three generic antihypertensive drugs with demonstrated efficacy and complementary mechanisms of action at half standard dose (telmisartan 20 mg, amlodipine 2.5 mg, and indapamide 1.25 mg), with placebo for the prevention of recurrent stroke, cardiovascular events, and cognitive impairment after ICH. Design: An international, double-blind, placebo-controlled, randomized trial in adults with ICH and mild-moderate hypertension (systolic BP: 130-160 mmHg), who are not taking any Triple Pill component drug at greater than half-dose. A total of 1500 randomized patients provide 90% power to detect a hazard ratio of 0.5, over an average follow-up of 3 years, according to a total primary event rate (any stroke) of 12% in the control arm and other assumptions. Secondary outcomes include recurrent ICH, cardiovascular events, and safety. Results: Recruitment started 28 September 2017. Up to 31 October 2021, 821 patients were randomized at 54 active sites in 10 countries. Triple Pill adherence after 30 months is 86%. The required sample size should be achieved by 2024.Item Association of low-dose triple combination therapy with therapeutic inertia and prescribing patterns in patients with hypertension: A Secondary analysis of the TRIUMPH trial(American Medical Association., 2020) Wang, N.; Salam, A.; Webster, R.; de Silva, A.; Guggilla, R.; Stepien, S.; Mysore, J.; Billot, L.; Jan, S.; Maulik, P. K.; Naik, N.; Selak, V.; Thom, S.; Prabhakaran, D.; Patel, A.; Rodgers, A.; TRIUMPH Study GroupIMPORTANCE: Fixed-dose combination (FDC) therapies are being increasingly recommended for initial or early management of patients with hypertension, as they reduce treatment complexity and potentially reduce therapeutic inertia. OBJECTIVE: To investigate the association of antihypertensive triple drug FDC therapy with therapeutic inertia and prescribing patterns compared with usual care. DESIGN, SETTING, AND PARTICIPANTS: A post hoc analysis of the Triple Pill vs Usual Care Management for Patients With Mild-to-Moderate Hypertension (TRIUMPH) study, a randomized clinical trial of 700 patients with hypertension, was conducted. Patients were enrolled from 11 urban hospital clinics in Sri Lanka from February 2016 to May 2017; follow-up ended in October 2017. Data were analyzed from September to November 2019. INTERVENTIONS: Once-daily FDC antihypertensive pill (telmisartan, 20 mg; amlodipine, 2.5 mg; and chlorthalidone, 12.5 mg) or usual care. MAIN OUTCOMES AND MEASURES: Therapeutic inertia, defined as not intensifying therapy in those with blood pressure (BP) above target, was assessed at baseline and during follow-up visits. Prescribing patterns were characterized by BP-lowering drug class and treatment regimen potency. Predictors of therapeutic inertia were assessed with binomial logistic regression. RESULTS: Of the 700 included patients, 403 (57.6%) were female, and the mean (SD) age was 56 (11) years. Among patients who did not reach the BP target, therapeutic inertia was more common in the triple pill group compared with the usual care group at the week 6 visit (92 of 106 [86.8%] vs 124 of 194 [63.9%]; P < .001) and week 12 visit (81 of 90 [90%] vs 116 of 179 [64.8%]; P < .001). At the end of the study, 221 of 318 patients in the triple pill group (69.5%) and 182 of 329 patients in the usual care group (55.3%) reached BP targets. Among those who received treatment intensification, the increase in estimated regimen potency was greater in the triple pill group compared with the usual care group at baseline (predicted mean [SD] increase in regimen potency: triple pill, 15 [6] mm Hg; usual care, 10 [5] mm Hg; P < .001), whereas there were no significant differences at the week 6 or at week 12 visit. Clinic systolic BP level was the only consistent predictor of treatment intensification during follow-up. During follow-up, there were 23 vs 54 unique treatment regimens per 100 treated patients in the triple pill vs usual care groups, respectively (P < .001). CONCLUSIONS AND RELEVANCE: Triple pill FDC therapy was associated with greater rates of therapeutic inertia compared with usual care. Despite this, triple pill FDC therapy substantially simplified prescribing patterns and improved 6-month BP control rates compared with usual care. Further improvements in hypertension control could be achieved by addressing therapeutic inertia among the minority of patients who do not achieve BP control after initial FDC therapy.Item Determinants of uncontrolled hypertension in rural communities in South Asia - Bangladesh, Pakistan, and Sri Lanka(Oxford University Press, 2018) Jafar, T.H.; Gandhi, M.; Jehan, I.; Naheed, A.; de Silva, H.A.; Shahab, H.; Alam, D.; Luke, N.; Lim, C.W.; COBRA-BPS Study GroupBACKGROUND: Uncontrolled blood pressure (BP) is a leading risk factor for death and disability in South Asia. We aimed to determine the cross-country variation, and the factors associated with uncontrolled BP among adults treated for hypertension in rural South Asia. METHODS: We enrolled 1718 individuals aged ≥40 years treated for hypertension in a cross-sectional study from rural communities in Bangladesh, Pakistan, and Sri Lanka. Multivariable logistic regression model was used to determine the factors associated with uncontrolled BP (systolic BP ≥140 mmHg or diastolic BP ≥90 mmHg). RESULTS: Among hypertensive individuals, 58.0% (95% confidence interval 55.7, 60.4) had uncontrolled BP: 52.8% (49.0, 56.6) in Bangladesh, 70.6% (65.7, 75.1) in Pakistan, and 56.5% (52.7, 60.1) in Sri Lanka. The odds (odds ratio (95% confidence interval)) of uncontrolled BP were significantly higher in individuals with lower wealth index (1.17 (1.02, 1.35)); single vs married (1.46 (1.10, 1.93)); higher log urine albumin-to-creatinine ratio (1.41 (1.24, 1.60)); lower estimated glomerular filtration rate (1.23 (1.01, 1.49)); low vs high adherence to antihypertensive medication (1.50 (1.16, 1.94)); and Pakistan (2.91 (1.60, 5.28)) vs Sri Lanka. However, the odds were lower in those with vs without self-reported kidney disease (0.51 (0.28, 0.91)); and receiving vs not receiving statins (0.62 (0.44, 0.87)). CONCLUSIONS: The majority of individuals with treated hypertension have uncontrolled BP in rural Bangladesh, Pakistan, and Sri Lanka with significant disparities among and within countries. Urgent public health efforts are needed to improve access and adherence to antihypertensive medications in disadvantaged populations in rural South Asia.Item Prevalence of hypertension in a rural district of Sri Lanka(Sri Lanka Medical Association, 2017) Luke, W.A.N.V.; Ediriweera, D.S.; de Silva, K.C.; Balasooriya, E.R.; Perera, K.M.N.; Ranasinha, C.D.; Kasturiratne, A.; de Silva, H.A.INTRODUCTION & OBJECTIVES: Hypertension is a leading cause of cardiovascular morbidity and mortality. Data on prevalence of hypertension in rural settings of Sri Lanka is limited. We conducted a study to determine the prevalence of hypertension among adults over 40 years of age in the Puttalam district.METHODS: A community-based prevalence study was conducted in selected Grama Niladhari divisions in ten Medical Officer of Health areas in the Puttalam district. Adults over 40 years of age living in consecutive households were screened by trained research assistants using digital blood pressure (BP) meters. Basic demographic data were obtained using an intervieweradministered questionnaire. Previously undiagnosed adults with persistent elevation of BP (SBP > 140 and /or DBP > 90 mmHg on two readings) and those already on treatment for hypertension were identified. RESULTS: A total of 2289 were screened. The mean (SD) of SBP and DBP were 134.5(21.3) and 82.1 (13.5) mmHg respectively. The overall hypertension prevalence was 458.5 (95% CI 438.1– 478.8) per 1000 population. 16.3% were newly diagnosed. Prevalence of uncontrolled hypertension among those on treatment was 516.2 (95% CI 479.4–552.9) per 1000. 98.7 (95% CI 86.6–110.9) per 1000 had blood pressure >160/110 mmHg. There was an increasing trend in blood pressure with increasing age (OR=1.07, 95% CI 1.06–1.08, p<0.01) but not with the male sex. CONCLUSION: Prevalence of hypertension is high in this rural adult cohort. Previously undetected hypertension and uncontrolled hypertension among those already on treatment are common. Community-based approaches targeting screening and BP control are essential to reduce adverse outcomes of hypertension.Item Prevalence of hypertension and its risk factors among estate workers in the Medical Officer of Health area, panvila, in the district of Kandy(Sri Lanka Medical Association, 2017) Aththaragama, A.S.I.; Kasturiratne, A.INTRODUCTION & OBJECTIVES: Hypertension is the leading modifiable risk factor of cardiovascular diseases. The prevalence of hypertension differs across countries, geographical areas and social strata. The objective was to determine the prevalence of hypertension and its associated factors among estate workers in the Panvila MOH area in the Kandy district. METHODS: A cross-sectional analytical study was conducted among randomly selected 411 estate workers between 30-59 years of age from eight estates within the Panvila MOH area. Screening was done in collaboration with the Office of the Medical Officer of Health, Panvila. After informed consent, blood pressure and anthropometric measurements were obtained. An interviewer-administered questionnaire was used to obtain data on risk factors. RESULTS: Of the sample, 36.2% were males and 95% were Tamils. The crude prevalence of hypertension was 24.6% and age-adjusted prevalence rates were 272 and 245 per 1000 population for males and females, respectively. More than 80% of the hypertensives were previously undiagnosed. Only 23% of diagnosed hypertensives were on treatment. About 27% of the participants had a BMI ≥23 kg/m2. 99% were highly physically active. The daily salt consumption was higher than the recommended amount in 90%. Dysglycaemia was present in 3.5%. Age, ethnicity, dysglycaemia and high salt consumption were associated significantly with hypertension in the bi-variate analysis. Advancing age group was the only independent predictor of hypertension in the multivariate analysis. CONCLUSION: Nearly 25% of the estate workers are hypertensive. Undetected hypertension is common and compliance with treatment is poor. These findings will be important for planning and implementing targeted interventions.