Medicine
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Item Alirocumab and cardiovascular outcomes according to sex and lipoprotein(a) after acute coronary syndrome: a report from the ODYSSEY OUTCOMES study(Elservier, 2024) Schwartz, G.G.; Bhatt, D.L.; Chua, T; de Silva, H.A.; Diaz, R.; Goodman, S.G.; Harrington, R.A.; Jukema, J.W.; McGinniss, J.; Pordy, R.; Garon, G.; Scemama, M.; White, H.D.; Steg, P.G.; Szarek, M.; ODYSSEY OUTCOMES Investigators; Bittner, V. A.Background: The ODYSSEY OUTCOMES trial (NCT01663402) compared the effects of the pro- protein convertase subtilisin/kexin type 9 inhibitor alirocumab with placebo on major adverse cardiovas- cular events (MACE) in patients with recent acute coronary syndrome (ACS). Objective: We assessed efficacy and safety of alirocumab versus placebo according to sex and lipoprotein(a) level. Methods: This prespecified analysis compared the effects of alirocumab versus placebo on lipopro- teins, MACE (coronary heart disease death, non-fatal myocardial infarction, fatal/non-fatal ischemic stroke, unstable angina requiring hospitalization), death, total cardiovascular events, and adverse events in 4762 women and 14,162 men followed for a median of 2.8 years. In post-hoc analysis, we evaluated total cardiovascular events according to sex, baseline lipoprotein(a), and treatment. Results: Women were older, had higher baseline LDL-C levels (89.6 vs 85.3 mg/dL) and lipopro- tein(a) (28.0 vs 19.3 mg/dL) and had more co-morbidities than men. At 4 months, alirocumab lowered LDL-C by 49.4 mg/dL in women and 54.0 mg/dL in men and lipoprotein(a) by 9.7 and 8.1 mg/dL, respectively (both p < 0.0001). Alirocumab reduced MACE, death, and total cardiovascular events sim- ilarly in both sexes. In the placebo group, lipoprotein(a) was a risk factor for total cardiovascular events in women and men. In both sexes, reduction of total cardiovascular events was greater at higher base- line lipoprotein(a), but this effect was more evident in women than men (pinteraction = 0.08). Medication adherence and adverse event rates were similar in both sexes. Conclusions: Alirocumab improves cardiovascular outcomes after ACS irrespective of sex. Reduc- tion of total cardiovascular events was greater at higher baseline lipoprotein(a). ©2024 National Lipid Association. Published by Elsevier Inc. This is an open access article under the CC BY license ( http://creativecommons.org/licenses/by/4.0/ )Item Post-intervention acceptability of multicomponent intervention for management of hypertension in rural Bangladesh, Pakistan, and Sri Lanka- a qualitative study(Public Library of Science, 2023) Jafar, T.H.; Tavajoh, S.; de Silva, H.A.; Naheed, A.; Jehan, I.; de Silva, C.K.; Chakma, N.; Huda, M.; Legido-Quigley, H.; COBRA-BPS Study Group.BACKGROUND: COBRA-BPS (Control of Blood Pressure and Risk Attenuation-Bangladesh, Pakistan, Sri Lanka), a multicomponent, community health-worker (CHW)-led hypertension management program, has been shown to be effective in rural communities in South Asia. This paper presents the acceptability of COBRA-BPS multicomponent intervention among the key stakeholders. METHODS: We conducted post-implementation interviews of 87 stakeholder including 23 community health workers (CHWs), 19 physicians and 45 patients in 15 rural communities randomized to COBRA-BPS multicomponent intervention in in Bangladesh, Pakistan, and Sri Lanka. We used Theoretical Framework for Acceptability framework (TFA) with a focus on affective attitude, burden, ethicality, intervention coherence, opportunity cost, perceived effectiveness and self-efficacy. RESULTS: COBRA-BPS multicomponent intervention was acceptable to most stakeholders. Despite some concerns about workload, most CHWs were enthusiastic and felt empowered. Physicians appreciated the training sessions and felt trusted by their patients. Patients were grateful to receive the intervention and valued it. However, patients in Pakistan and Bangladesh expressed the need for supplies of free medicines from the primary health facilities, while those in Sri Lanka were concerned about supplies' irregularities. All stakeholders favoured scaling-up COBRA-BPS at a national level. CONCLUSIONS: COBRA-BPS multicomponent intervention is acceptable to the key stakeholders in Bangladesh, Pakistan and Sri Lanka. Community engagement for national scale-up of COBRA-BPS is likely to be successful in all three countries.Item Budget impact and cost-effectiveness analyses of the COBRA-BPS multicomponent hypertension management programme in rural communities in Bangladesh, Pakistan, and Sri Lanka(Elsevier, 2021) Finkelstein, E.A.; Krishnan, A.; Naheed, A.; Jehan, I.; de Silva, H.A.; Gandhi, M.; Lim, C.W.; Chakma, N.; Ediriweera, D.S.; Khan, J.; Kasturiratne, A.; Hirani, S.; Solayman, A.K.M.; Jafar, T.H.; COBRA-BPS study group.BACKGROUND: COBRA-BPS (Control of Blood Pressure and Risk Attenuation-Bangladesh, Pakistan, Sri Lanka), a multi-component hypertension management programme that is led by community health workers, has been shown to be efficacious at reducing systolic blood pressure in rural communities in Bangladesh, Pakistan, and Sri Lanka. In this study, we aimed to assess the budget required to scale up the programme and the incremental cost-effectiveness ratios. METHODS: In a cluster-randomised trial of COBRA-BPS, individuals aged 40 years or older with hypertension who lived in 30 rural communities in Bangladesh, Pakistan, and Sri Lanka were deemed eligible for inclusion. Costs were quantified prospectively at baseline and during 2 years of the trial. All costs, including labour, rental, materials and supplies, and contracted services were recorded, stratified by programme activity. Incremental costs of scaling up COBRA-BPS to all eligible adults in areas covered by community health workers were estimated from the health ministry (public payer) perspective. FINDINGS: Between April 1, 2016, and Feb 28, 2017, 11 510 individuals were screened and 2645 were enrolled and included in the study. Participants were examined between May 8, 2016, and March 31, 2019. The first-year per-participant costs for COBRA-BPS were US$10•65 for Bangladesh, $10•25 for Pakistan, and $6•42 for Sri Lanka. Per-capita costs were $0•63 for Bangladesh, $0•29 for Pakistan, and $1•03 for Sri Lanka. Incremental cost-effectiveness ratios were $3430 for Bangladesh, $2270 for Pakistan, and $4080 for Sri Lanka, per cardiovascular disability-adjusted life year averted, which showed COBRA-BPS to be cost-effective in all three countries relative to the WHO-CHOICE threshold of three times gross domestic product per capita in each country. Using this threshold, the cost-effectiveness acceptability curves predicted that the probability of COBRA-BPS being cost-effective is 79•3% in Bangladesh, 85•2% in Pakistan, and 99•8% in Sri Lanka. INTERPRETATION: The low cost of scale-up and the cost-effectiveness of COBRA-BPS suggest that this programme is a viable strategy for responding to the growing cardiovascular disease epidemic in rural communities in low-income and middle-income countries where community health workers are present, and that it should qualify as a priority intervention across rural settings in south Asia and in other countries with similar demographics and health systems to those examined in this study. FUNDING: The UK Department of Health and Social Care, the UK Department for International Development, the Global Challenges Research Fund, the UK Medical Research Council, Wellcome Trust.Item Multicomponent intervention versus usual care for management of hypertension in rural Bangladesh, Pakistan and Sri Lanka: study protocol for a cluster randomized controlled trial(BioMed Central, 2017) Jafar, T.H.; Jehan, I.; de Silva, H.A.; Naheed, A.; Gandhi, M.; Assam, P.; Finkelstein, E.A.; Quigley, H.L.; Bilger, M.; Khan, A.H.; Clemens, J.D.; Ebrahim, S.; Turner, E.L.; Kasturiratne, A.; for COBRA-BPS Study GroupBACKGROUND: High blood pressure (BP) is the leading attributable risk for cardiovascular disease (CVD). In rural South Asia, hypertension continues to be a significant public health issue with sub-optimal BP control rates. The goal of the trial is to compare a multicomponent intervention (MCI) to usual care to evaluate the effectiveness and cost-effectiveness of the MCI for lowering BP among adults with hypertension in rural communities in Bangladesh, Pakistan and Sri Lanka. METHODS/DESIGN: This study is a stratified, cluster randomized controlled trial with a qualitative component for evaluation of processes and stakeholder feedback. The MCI has five components: (1) home health education by government community health workers (CHWs), (2) BP monitoring and stepped-up referral to a trained general practitioner using a checklist, (3) training public and private providers in management of hypertension and using a checklist, (4) designating hypertension triage counter and hypertension care coordinators in government clinics and (5) a financing model to compensate for additional health services and provide subsidies to low income individuals with poorly controlled hypertension. Usual care will comprise existing services in the community without any additional training. The trial will be conducted on 2550 individuals aged ≥40 years with hypertension (with systolic BP ≥140 mm Hg or diastolic BP ≥90 mm Hg, based on the mean of the last two of three measurements from two separate days, or on antihypertensive therapy) in 30 rural communities in Bangladesh, Pakistan and Sri Lanka. The primary outcome is change in systolic BP from baseline to follow-up at 24 months post-randomization. The incremental cost of MCI per CVD disability-adjusted life years averted will be computed. Stakeholders including policy makers, provincial- and district-level coordinators of relevant programmes, physicians, CHWs, key community leaders, hypertensive individuals and family members in the identified clusters will be interviewed. DISCUSSION: The study will provide evidence of the effectiveness and cost-effectiveness of MCI strategies for BP control compared to usual care in the rural public health infrastructure in South Asian countries. If shown to be successful, MCI may be a long-term sustainable strategy for tackling the rising rates of CVD in low resourced countries.Item Comparison of one and two weeks of triple therapy for eradication of H. pylori: a randomized, controlled study in a tropical country(Wiley Blackwell Scientific Publications, 2004) de Silva, H.A.; Hewavisenthi, J.; Pathmeswaran, A.; Navarathne, N.M.M; Peiris, R.; Dassanayake, A.S.; de Silva, H.J.INTRODUCTION: Resistance of H. pylori to antibiotics may be particularly high in parts of the tropics. Infection may prove difficult to eradicate in such situations, and there is some evidence of benefit in increasing duration of treatment (triple therapy) from one week to two or three weeks. AIM : To assess the efficacy and tolerability of one-week versus two weeks triple therapy for eradication of H. pylori in a Sri Lankan population. METHODS: 82 consecutive patients aged 18–70 years with peptic ulcer disease testing positive for H. pylori infection (histology and rapid urease test on gastric antral biopsies) were randomly allocated to two treatment groups. The baseline characteristics of the two groups were similar. Both groups received omeprazole 20mg, clarithromycin 250mg, and tinidazole 500mg. Group A (n = 42) received the trial medication twice daily for one week and the Group B (n = 40) twice daily for two weeks. H. pylori eradication was defined as a negative 14C labeled urea breath test at two weeks after completion of therapy. The assessors were blind to randomization and other patient information. RESULTS; All patients presented for follow up after completion of therapy. H. pylori infection was eradicated in 36 (85.7%) patients in group A and 36 (90%) patients in group B (p = 0.9; 95% CI: -19.1 to 10.8). 23 (55%) patients in group A and 17 (43%) in group B reported adverse effects attributable to trial medication (p = 0.387); none were serious. 3 (7.5%) patients in group B discontinued treatment due to adverse events that developed on days 7, 9 and 10. CONCLUSION: Twice daily treatment with clarithromycin, tinidazole, and omeprazole for one-week is well tolerated and provides as good a rate of H. pylori eradication as two weeks therapy in Sri Lankan patients.Item Low-dose adrenaline, promethazine, and hydrocortisone in the prevention of acute adverse reactions to antivenom following snakebite: a randomised, double-blind, placebo-controlled trial(Public Library of Science, 2011) de Silva, H.A.; Pathmeswaran, A.; Ranasinha, C.D.; Jayamanne, S.; Samarakoon, S.B.; Hittarage, A.; Kalupahana, R.; Ratnatilaka, G.A.; Uluwatthage, W.; Aronson, J.K.; Armitage, J.M.; Lalloo, D.G.; de Silva, H.J.BACKGROUND: Envenoming from snakebites is most effectively treated by antivenom. However, the antivenom available in South Asian countries commonly causes acute allergic reactions, anaphylactic reactions being particularly serious. We investigated whether adrenaline, promethazine, and hydrocortisone prevent such reactions in secondary referral hospitals in Sri Lanka by conducting a randomised, double-blind placebo-controlled trial. METHODS AND FINDINGS: In total, 1,007 patients were randomized, using a 2 × 2 × 2 factorial design, in a double-blind, placebo-controlled trial of adrenaline (0.25 ml of a 1∶1,000 solution subcutaneously), promethazine (25 mg intravenously), and hydrocortisone (200 mg intravenously), each alone and in all possible combinations. The interventions, or matching placebo, were given immediately before infusion of antivenom. Patients were monitored for mild, moderate, or severe adverse reactions for at least 96 h. The prespecified primary end point was the effect of the interventions on the incidence of severe reactions up to and including 48 h after antivenom administration. In total, 752 (75%) patients had acute reactions to antivenom: 9% mild, 48% moderate, and 43% severe; 89% of the reactions occurred within 1 h; and 40% of all patients were given rescue medication (adrenaline, promethazine, and hydrocortisone) during the first hour. Compared with placebo, adrenaline significantly reduced severe reactions to antivenom by 43% (95% CI 25-67) at 1 h and by 38% (95% CI 26-49) up to and including 48 h after antivenom administration; hydrocortisone and promethazine did not. Adding hydrocortisone negated the benefit of adrenaline. CONCLUSIONS: Pretreatment with low-dose adrenaline was safe and reduced the risk of acute severe reactions to snake antivenom. This may be of particular importance in countries where adverse reactions to antivenom are common, although the need to improve the quality of available antivenom cannot be overemphasized.Item Comparison of one week and two weeks of triple therapy for the eradication of Helicobacter pylori in a Sri Lankan population: a randomised, controlled study(Sri Lanka Medical Association, 2004) de Silva, H.A.; Hewavisenthi, J.; Pathmeswaran, A.; Dassanayake, A.S.; Navarathne, N.M.M.; Peiris, R.; de Silva, H.J.INTRODUCTION: Resistance of Helicobacter pylori to antibiotics may be particularly high in parts of the tropics. Infection may prove difficult to eradicate in such situations, and there is some evidence of benefit in increasing the duration of treatment (triple therapy) from 1 week to 2 or 3 weeks. AIM: To assess the efficacy and tolerability of 1 week versus 2 weeks of triple therapy for eradication of H. pylori in a Sri Lankan population. METHODS: Eighty two patients aged 18-70 years with gastritis or peptic ulcer and testing positive for H. pylori infection were randomly allocated totwo treatment groups. Both groups received omeprazole 20 mg, clarithromycin 250 mg, and tinidazole 500 mg. Group A (n = 42) received the trial medication twice daily for 1 week and the Group B (n = 40) twice daily for 2 weeks. H. pylori eradication was defined as a negative 14C labelled urea breath test at 2 weeks after completion of the therapy. RESULTS: H. pylori infection was eradicated in 36 (85.7%) patients in Group A and 36 (90%) patients in Group B (p = 0.9). Twenty three (55%) patients in Group A and 17 (43%) in Group B reported adverse effects attributable to trial medication (p = 0.387); none were serious. Three (7.5%) patients in Group B discontinued treatment due to adverse events that developed on days 7, 9 and 10. CONCLUSION: Twice daily treatment with clarithromycin, tinidazole, and omeprazole for 1 week is well tolerated and provides as good a rate of H.pylori eradication as 2-week therapy in Sri Lankan patients.Item Liv. 52 in alcoholic liver disease: a prospective controlled trial(Elsevier, 2003) de Silva, H.A.; Saparamadu, P.A.M.; Thabrew, M.I.; Pathmeswaran, A.; Fonseka, M.M.D.; de Silva, H.J.Liv.52, a hepatoprotective agent of herbal origin, is used empirically for the treatment of alcoholic liver disease in Sri Lanka. We conducted acontrolled trial to assess the efficacy of Liv.52 in patients with alcoholic liver disease. Patients with evidence of alcoholic liver disease attending outpatient clinics were included in a prospective, double blind, randomized, placebo controlled trial. During the trial period, 80 patients who fulfilled inclusion criteria were randomly assigned Liv.52 (cases; n = 40) or placebo (controls) the recommended dose of three capsules twice daily for 6 months. All patients underwent clinical examination (for which a clinical score was computed), and laboratory investigations for routine blood chemistry and liver function before commencement of therapy (baseline). Thereafter, clinical assessments were done monthly for 6 months, while laboratory investigations were done after 1 and 6 months of therapy. There was no significant difference in the age composition, alcohol intake and baseline liver function between the two groups. The two-sample t-test was used to analyze data obtained after 1 and 6 months of therapy against baseline values. There was no significant difference in clinical outcome and liver chemistry between the two groups at any time point. There were no reports of adverse effects attributable to the drug. Our results suggest that Liv.52 may not be useful in the management of patients with alcohol induced liver disease.Item Multiple-dose activated charcoal for treatment of yellow oleander poisoning : a single-blind randomized placebo controlled trial(Lancet Publishing Group, 2003) de Silva, H.A.; Fonseka, M.M.D.; Pathmeswaran, A.; Alahakoon, D.G.S.; Ratnatilaka, G.A.; Gunatilake, S.B.; Ranasinha, C.D.; Lalloo, D.G.; Aronson, J.K.; de Silva, H.J.BACKGROUND: Deliberate self-poisoning with yellow oleander seeds is common in Sri Lanka and is associated with severe cardiac toxicity and a mortality rate of about 10%. Specialised treatment with antidigoxin Fab fragments and temporary cardiac pacing is expensive and not widely available. Multiple-dose activated charcoal binds cardiac glycosides in the gut lumen and promotes their elimination. We aimed to assess the efficacy of multiple-dose activated charcoal in the treatment of patients with yellow-oleander poisoning. METHODS: On admission, participants received one dose of activated charcoal and were then randomly assigned either 50 g of activated charcoal every 6 h for 3 days or sterile water as placebo. A standard treatment protocol was used in all patients. We monitored cardiac rhythm and did 12-lead electocardiographs as needed. Death was the primary endpoint, and secondary endpoints were life-threatening cardiac arrhythmias, dose of atropine used, need for cardiac pacing, admission to intensive care, and number of days in hospital. Analysis was by intention to treat. FINDINGS: 201 patients received multiple-dose activated charcoal and 200 placebo. There were fewer deaths in the treatment group (five [2.5%] vs 16 [8%]; percentage difference 5.5%; 95% CI 0.6-10.3; p=0.025), and we noted difference in favour of the treatment group for all secondary endpoints, apart from number of days in hospital. The drug was safe and well tolerated. INTERPRETATION: Multiple-dose activated charcoal is effective in reducing deaths and life-threatening cardiac arrhythmias after yellow oleander poisoning and should be considered in all patients. Use of activated charcoal could reduce the cost of treatment.