Cost-Effectiveness of Serum Galactomannan Surveillance during Mould-Active Antifungal Prophylaxis.

Serial galactomannan (GM) monitoring can aid the diagnosis of invasive aspergillosis (IA) and optimise treatment decisions. However, widespread adoption of mould-active prophylaxis has reduced the incidence of IA and challenged its use. We evaluated the cost-effectiveness of prophylaxis-biomarker strategies. A Markov model simulating high-risk patients undergoing routine GM surveillance with mould-active versus non-mould-active prophylaxis was constructed. The incremental cost for each additional quality-adjusted life-year (QALY) gained over a lifetime horizon was calculated. In 40- and 60-year-old patients receiving mould-active prophylaxis coupled with routine GM surveillance, the total cost accrued was the lowest at SGD 11,227 (USD 8255) and SGD 9234 (USD 6790), respectively, along with higher QALYs gained (5.3272 and 1.1693). This strategy, being less costly and more effective, dominated mould-active prophylaxis with no GM monitoring or GM surveillance during non-mould-active prophylaxis. The prescription of empiric antifungal treatment was influential in the cost-effectiveness. When the GM test sensitivity was reduced from 80% to 30%, as might be anticipated with the use of mould-active prophylactic agents, the conclusion remained unchanged. The likelihood of GM surveillance with concurrent mould-active prophylaxis being cost-effective was 77%. Routine GM surveillance remained cost-effective during mould-active prophylaxis despite lower IA breakthroughs. Cost-saving from reduced empirical antifungal treatment was an important contributing factor.

Neurostimulation therapies in major depressive disorder: A decision-analytic model.

AIM: Neurostimulation techniques are effective treatments for major depressive disorders (MDD). However, the optimal sequence of electroconvulsive therapy (ECT) and transcranial magnetic stimulation (TMS) as part of antidepressant treatment algorithm is unclear. We examined the cost-effectiveness of ECT and TMS in MDD. METHODS: A decision-analytic model was developed to determine total costs, quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICERs) for 10 strategies. Each strategy comprised four treatment lines with ECT and TMS incorporated as second, third, or fourth line. A scenario analysis that explored the cost-effectiveness of maintenance approach by continuing ECT and TMS after acute treatment was performed. RESULTS: In the base case, fourth-line TMS after three preceding trials of antidepressants was least costly at US$ 5523 yielding 1.424 QALYs. Compared with this strategy, fourth-line ECT and third-line TMS followed by ECT were cost-effective with ICERs of US$ 7601 per QALY gained and US$ 11 388 per QALY gained, respectively. In the scenario analysis where continuation treatments of ECT and TMS were provided, third-line TMS followed by ECT was cost-effective, with an ICER of US$ 17 198 per QALY gained. Effectiveness of ECT and cost of managing severe depression were influential parameters affecting the cost-effectiveness results. CONCLUSIONS: In acute treatment of MDD, fourth-line ECT was the most cost-effective strategy. In maintenance treatment, the strategy that incorporated third-line TMS and fourth-line ECT was cost-effective. The overall findings confirmed the value of neurostimulation therapies which should be offered early in the process of managing depression.

The costs of an expanded screening criteria for COVID-19: A modelling study.

OBJECTIVES: Nosocomial infection is an ongoing concern in the COVID-19 outbreak. The effective screening of suspected cases in the healthcare setting is therefore necessary, enabling the early identification and prompt isolation of cases for epidemic containment. We aimed to assess the cost and health outcomes of an extended screening strategy, implemented in Singapore on 07 February 2020, which maximizes case identification in the public healthcare system. METHODS: We explored the effects of the expanded screening criteria which allow clinicians to isolate and investigate patients presenting with undifferentiated fever or respiratory symptoms or chest x-ray abnormalities. We formulated a cost appraisal framework which evaluated the treatment costs averted from the prevention of secondary transmission in the hospital setting, as determined by a branching process infection model, and compared these to the costs of the additional testing required to meet the criteria. RESULTS: In the base case analysis, an R0 of 2.5 and incubation period of 4 days, an estimated 239 (95% CI: 201-287) cases could be averted over 150 days within the hospital setting through ESC. A corresponding $2.36 (2-2.85) million USD in costs could be averted with net cost savings of $124,000 (95% CI: -334,000 to 516,000). In the sensitivity analyses, when positive identification rates (PIR) were above 7%, regardless of R0 and incubation period, all scenarios were cost-saving. CONCLUSION: The expanded screening criteria can help to identify and promptly isolate positive COVID cases in a cost-saving manner or within acceptable cost margins where the costs incurred from the testing of negative patients could be negated by the averted costs. Outbreak control must be sustainable and effective; the proposed screening criteria should be considered to mitigate nosocomial transmission risk within healthcare facilities.

Impact of coconut oil consumption on cardiovascular health: a systematic review and meta-analysis.

CONTEXT: Coconut oil is rich in medium-chain fatty acids and has been claimed to have numerous health benefits. OBJECTIVE: This review aimed to examine the evidence surrounding coconut oil consumption and its impact on cardiovascular health. DATA SOURCES: A systematic literature search of the PubMed, Embase, the Cochrane Library, and CINAHL databases, up to May 2019, was performed. DATA EXTRACTION: Study characteristics including study design, population, intervention, comparator, outcome, and source of funding were summarized. DATA ANALYSIS: Meta-analyses included 12 studies to provide estimates of effects. Subgroup analyses were performed to account for any differences in the study-level characteristics. When compared with plant oils and animal oils, coconut oil was found to significantly increase high-density lipoprotein cholesterol (HDL-C) by 0.57 mg/dL (95%CI, 0.40-0.74 mg/dL; I2 = 6.7%) and 0.33 mg/dL (0.01-0.65 mg/dL; I2 = 0%), respectively. Coconut oil significantly raised low-density lipoprotein cholesterol (LDL-C) by 0.26 mg/dL (0.09-0.43 mg/dL; I2 = 59.7%) compared with plant oils and lowered LDL-C (-0.37 mg/dL; -0.69 to -0.05 mg/dL; I2 = 48.1%) compared with animal oils. No significant effects on triglyceride were observed. Better lipid profiles were demonstrated with the virgin form of coconut oil. CONCLUSION: Compared with animal oils, coconut oil demonstrated a better lipid profile n comparison with plant oils, coconut oil significantly increased HDL-C and LDL-C.

Distinguishing Zika and Dengue Viruses through Simple Clinical Assessment, Singapore.

Dengue virus and Zika virus coexist in tropical regions in Asia where healthcare resources are limited; differentiating the 2 viruses is challenging. We showed in a case-control discovery cohort, and replicated in a validation cohort, that the diagnostic indices of conjunctivitis, platelet count, and monocyte count reliably distinguished between these viruses.

Cost-effectiveness analysis of biodegradable polymer versus durable polymer drug-eluting stents incorporating real-world evidence.

AIM: Compared with second-generation durable polymer drug-eluting stents (DP-DES), the cost-effectiveness of biodegradable polymer drug-eluting stents (BP-DES) remains unclear in the real-world setting. We assessed the cost-effectiveness of BP-DES in patients with coronary artery disease undergoing percutaneous coronary intervention (PCI). METHODS: We developed a decision-analytic model to compare the cost-effectiveness of BP-DES to DP-DES over 1 year and 5 years from healthcare payer perspective. Relative treatment effects during the first year post-PCI were obtained from a real-world population analysis while clinical event risks in the subsequent 4 years were derived from a meta-analysis of published studies. RESULTS: At 1 year, based on the clinical data analysis of 497 propensity-score matched pairs of patients, BP-DES were associated with an incremental cost-effectiveness ratio (ICER) of USD20 503 per quality-adjusted life-year (QALY) gained. At 5 years, BP-DES yielded an ICER of USD4062 per QALY gained. At the willingness-to-pay threshold of USD50 400 (one gross domestic product per capita in Singapore in 2015), BP-DES were cost-effective. Sensitivity analysis showed that the cost of stents had a significant impact on the cost-effectiveness of BP-DES. Threshold analysis demonstrated that if the cost difference between BP-DES and DP-DES exceeded USD493, BP-DES would not be cost-effective in patients with 1 year of follow-up. CONCLUSIONS: Biodegradable polymer drug-eluting stents were cost-effective compared with DP-DES in patients with coronary artery disease at 1 year and 5 years after PCI. It is worth noting that the cost of stents had a significant impact on the findings.

Evaluation of a risk-guided strategy for empirical carbapenem use in febrile neutropenia.

Febrile neutropenia (FN) is associated with substantial morbidity and necessitates empirical broad-spectrum antimicrobial treatment. In this prospective cohort study, a risk-guided management strategy for FN using empirical piperacillin/tazobactam (TZP) or a carbapenem was evaluated. The analysis involved 723 FN episodes in hospitalised adult patients, including those with severe sepsis or prior infection/colonisation with extended-spectrum ß-lactamase (ESBL)-producing Enterobacteriaceae. Propensity score matching analysis was used to adjust for baseline differences between treatment groups and produced 267 matched pairs. The primary outcome was all-cause mortality. Secondary outcomes were the incidences of drug-resistant Gram-negative (including ESBL-producing) and Gram-positive bacterial isolates and of invasive pulmonary aspergillosis (IPA) and their associated mortality. There was no difference in mortality between empirical carbapenem and TZP [18/267 (6.7%) vs. 14/267 (5.2%); P = 0.466]. Higher incidences of drug-resistant Gram-negative isolates [77/267 (28.8%) vs. 26/267 (9.7%); P < 0.001], including ESBL-producing bacteria [57/267 (21.3%) vs. 16/267 (6.0%); P < 0.001], were observed in carbapenem-treated episodes where its use lowered mortality. Mortality rates for ESBL-positive infections were 5.3% (3/57) and 25.0% (4/16) (P = 0.037) and for drug-resistant Gram-negative infections were 6.5% (5/77) and 23.1% (6/26) (P = 0.018) in carbapenem- and TZP-treated episodes, respectively. More IPA was observed with carbapenem use [16/267 (6.0%) vs. 6/267 (2.2%); P = 0.029]. Antifungal prophylaxis reduced the risk of death (odds ratio = 0.39, 95% confidence interval 0.17-0.87; P = 0.017). Risk-guided carbapenem prescribing in FN correctly identified cases prone to drug-resistant Gram-negative infections and reduced the mortality in these episodes.

A propensity score-matched comparison of biodegradable polymer vs second-generation durable polymer drug-eluting stents in a real-world population.

AIMS: The safety and efficacy of BP-DES compared to second-generation DP-DES remain unclear in the real-world setting. We compared the clinical outcomes of biodegradable polymer drug-eluting stents (BP-DES) with second-generation durable polymer drug-eluting stents (DP-DES) in an all-comer percutaneous coronary intervention (PCI) registry. METHODS/RESULTS: The study included a cohort of 1065 patients treated with either BP-DES or DP-DES from January 2009 through October 2015. Propensity score matching was performed to account for potential confounders and produced 497 matched pairs of patients. The primary endpoint was target lesion failure (TLF) at one-year follow-up. The rates of TLF were comparable between BP-DES and DP-DES (8.7% vs 9.1%, P = .823) at 1 year. The rates of stent thrombosis at 30 days (0.4% vs 0.4%, P = 1.00) and 1 year (0.8% vs 0.8%, P = 1.00) did not differ between BP-DES and DP-DES. There were no significant differences in other clinical outcomes including target vessel failure (8.9% vs 9.5%, P = .741), in-stent restenosis (1.8% vs 1.0%, P = .282), and cardiac death (6.4% vs 7.4%, P = .533) at 1 year. Multivariate cox regression analysis showed that the risk of TLF at one-year did not differ significantly between BP-DES and DP-DES (hazard ratio 0.94, P = .763). CONCLUSIONS: Efficacy and safety of BP-DES were not better than DP-DES at one-year follow-up.

Cost-Effectiveness Modeling of Repetitive Transcranial Magnetic Stimulation Compared to Electroconvulsive Therapy for Treatment-Resistant Depression in Singapore.

BACKGROUND: Compared to electroconvulsive therapy (ECT), the cost-effectiveness of repetitive transcranial magnetic stimulation (rTMS) in the management of treatment-resistant depression (TRD) remains unclear. OBJECTIVE/HYPOTHESIS: This study evaluated the cost-effectiveness of rTMS vs. ECT for TRD from Singapore societal perspective. METHODS: We constructed a Markov model to project the cost and benefit of rTMS compared with ECT over one year in patients with TRD. The relative treatment effects between rTMS and ECT were obtained from meta-analyses of published trials. The effectiveness and quality of life data for patients using ECT, resource use for TRD and their associated costs were derived from the national tertiary mental institution in Singapore. RESULTS: At one year, rTMS was cost-effective relative to ECT. The incremental cost-effectiveness ratio (ICER) associated with ECT was Singapore dollars (SGD) 311,024 per quality-adjusted life-year (QALY) gained. This exceeded the willingness-to-pay threshold of SGD 70,000 per QALY gained. A similar trend was observed for ICER per remission achieved (i.e., SGD 143,811 per remission achieved with ECT). In the subgroup analysis, rTMS was found to be less costly and more effective than ECT in nonpsychotic depressive patients. In the scenario analysis, ECT employed as an ambulatory service yielded a much smaller ICER (i.e., SGD 78,819 per QALY gained) compared to the standard inpatient setting. CONCLUSIONS: rTMS was a cost-effective treatment compared to ECT in TRD over one year. The cost-effectiveness of rTMS was attenuated when ECT was used in the outpatient setting.

Cost-Effectiveness Analysis of Ticagrelor and Prasugrel for the Treatment of Acute Coronary Syndrome.

BACKGROUND: In the management of Asian patients with acute coronary syndrome (ACS), the comparative cost-effectiveness of ticagrelor and prasugrel, referenced to generic clopidogrel, is unknown. OBJECTIVE: To assess the cost-effectiveness of ticagrelor and prasugrel as compared with generic clopidogrel in patients with ACS in Singapore. METHODS: A Markov model simulating a typical cohort of 62-year-old patients with ACS was constructed from a patient's perspective over a lifetime horizon. Treatment effects and adverse events, including nonfatal myocardial infarction, major bleeding related to non-coronary artery bypass grafting, dyspnea, or death, were estimated from pivotal trials comparing clopidogrel with ticagrelor and prasugrel, respectively. Costs were estimated from a tertiary hospital with more than 1500 admissions for ACS per year. RESULTS: The incremental cost-effectiveness ratio (ICER) per life-year gained for ticagrelor was about three times more favorable than for prasugrel (Singapore dollar [SGD] 13,276 vs. SGD 38,809). The ICER per quality-adjusted life-year (QALY) for prasugrel and ticagrelor, however, was comparable at SGD 18,921 and SGD 18,647, respectively. Deterministic sensitivity analysis revealed that the ICER per QALY gained for prasugrel and ticagrelor was most sensitive to the hazard ratio of all-cause mortality and utility for dyspnea, respectively. Probabilistic sensitivity analysis demonstrated that compared with clopidogrel, the probabilities of prasugrel and ticagrelor being cost-effective are 87.1% and 88.3% based on the willingness-to-pay value of SGD 65,000 (one time the gross domestic product per capita in Singapore). CONCLUSIONS: Ticagrelor is more cost-effective than prasugrel in reducing all-cause mortality in patients with ACS. The cost-effectiveness of ticagrelor and prasugrel become similar, however, when accounting for the impact of dyspnea on QALY.

Long-term antipsychotic treatment in schizophrenia: systematic review and network meta-analysis of randomised controlled trials.

BACKGROUND: For treatment of patients diagnosed with schizophrenia, comparative long-term effectiveness of antipsychotic drugs to reduce relapses when minimising adverse effects is of clinical interest, hence prompting this review. AIMS: To evaluate the comparative long-term effectiveness of antipsychotic drugs. METHOD: We systematically searched electronic databases for reports of randomised controlled trials (RCTs) of antipsychotic monotherapy aimed at reducing relapse risks in schizophrenia. We conducted network meta-analysis of 18 antipsychotics and placebo. RESULTS: Studies of 10 177 patients in 56 reports were included; treatment duration averaged 48 weeks (range 4-156). Olanzapine was significantly more effective than chlorpromazine (odds ratio (OR) 0.35, 95% CI 0.14-0.88) or haloperidol (OR=0.50, 95% CI 0.30-0.82); and fluphenazine decanoate was more effective than chlorpromazine (OR=0.31, 95% CI 0.11-0.88) in relapse reduction. Fluphenazine decanoate, haloperidol, haloperidol decanoate and trifluoperazine produced more extrapyramidal adverse effects than olanzapine or quetiapine; and olanzapine was associated with more weight gain than other agents. CONCLUSIONS: Except for apparent superiority of olanzapine and fluphenazine decanoate over chlorpromazine, most agents showed intermediate efficacy for relapse prevention and differences among them were minor. Typical antipsychotics yielded adverse neurological effects, and olanzapine was associated with weight gain. The findings may contribute to evidence-based treatment selection for patients with chronic psychotic disorders. DECLARATION OF INTEREST: R.J.B. received grants from the Bruce J. Anderson Foundation and the McLean Private Donors Psychopharmacology Research Fund. COPYRIGHT AND USAGE: © The Royal College of Psychiatrists 2016. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) licence.

Cost-effectiveness of strategy-based approach to treatment of genotype 1 chronic hepatitis C.

BACKGROUND AND AIM: The high cost of chronic hepatitis C (HCV) direct-acting antivirals (DAAs) poses significant financial challenges for health payers, especially in Asia. A personalized treatment strategy based on individualized probability of virological response using oral DAAs as second-line therapy would seem practical but has not been studied. METHODS: We performed a Markov model to project health outcomes and costs for patients with genotype 1 HCV through 10 treatment strategies over a lifetime period. The implication of retreatment was also incorporated to reflect real-life situation. RESULTS: Using boceprevir and peginterferon/ribavirin (BOC/PR, the least costly treatment) as a base case, the all-oral therapies such as ombitasvir/paritaprevir/ritonavir-dasabuvir are cost-effective with an incremental cost-effective ratio of $US50 828. However, the all-oral DAAs would no longer be cost-effective compared with conventional therapies if retreatment were taken into account. A road map strategy using rapid virological response to guide use of BOC/PR and sofosbuvir/PR had the most favorable incremental cost-effective ratio ($US27 782) relative to BOC/PR. Nevertheless, the trade-off with the cost-effectiveness of the road map strategy is an increased number of liver-related deaths compared with all-oral DAAs (52 vs 10-20 per 10 000 patients) by incorporating retreatment. CONCLUSIONS: The 12-week all-oral DAAs were cost-effective options using conventional drug-to-drug comparison. However, they cease to be cost-effective when treatment strategies incorporating DAA retreatment for interferon failures are incorporated. HCV management can be optimized by adopting individualized treatment algorithm providing a practical solution to health payers to make oral DAAs accessible to those who need them most.

INTEGRATING HEALTH TECHNOLOGY ASSESSMENT PRINCIPLES IN FORMULARY MANAGEMENT.

OBJECTIVES: Effective formulary management in healthcare institutions safeguards rational drug use and optimizes health outcomes. We implemented a formulary management program integrating the principles of health technology assessment (HTA) to improve the safe, appropriate, and cost-effective use of medicine in Singapore. METHODS: A 3-year formulary management program was initiated in 2011 in five public healthcare institutions. This program was managed by a project team comprising HTA researchers. The project team worked with institutional pharmacy and therapeutics (P&T) committees to: (i) develop tools for formulary drug review and decision making; (ii) enhance the HTA knowledge and skills of formulary pharmacists and members of P&T committees; (iii) devise a prioritization framework to overcome resource constraints and time pressure; and (iv) conceptualize and implement a framework to review existing formulary. RESULTS: Tools that facilitate drug request submission, drug review, and decision making were developed for formulary drug inclusion. A systematic framework to review existing formulary was also developed and tested in selected institutions. A competency development plan was rolled out over 2 years to enhance formulary pharmacists' proficiency in systematic literature search and review, meta-analysis, and pharmacoeconomic evaluation. The plan comprised training workshops and on-the-job knowledge transfer between the project team and institutional formulary pharmacists through collaborating on selected drug reviews. A resource guide that consolidated the tools and templates was published to encourage the adoption of best practices in formulary management. CONCLUSIONS: Based on the concepts of HTA, we implemented an evidence-based approach to optimize formulary management.

Network Meta-analysis and Pharmacoeconomic Evaluation of Fluconazole, Itraconazole, Posaconazole, and Voriconazole in Invasive Fungal Infection Prophylaxis.

Invasive fungal infections (IFIs) are associated with high mortality rates and large economic burdens. Triazole prophylaxis is used for at-risk patients with hematological malignancies or stem cell transplants. We evaluated both the efficacy and the cost-effectiveness of triazole prophylaxis. A network meta-analysis (NMA) of randomized controlled trials (RCTs) evaluating fluconazole, itraconazole capsule and solution, posaconazole, and voriconazole was conducted. The outcomes of interest included the incidences of IFIs and deaths. This was coupled with a cost-effectiveness analysis from patient perspective over a lifetime horizon. Probabilities of transitions between health states were derived from the NMA. Resource use and costs were obtained from the Singapore health care institution. Data on 5,505 participants in 21 RCTs were included. Other than itraconazole capsule, all triazole antifungals were effective in reducing IFIs. Posaconazole was better than fluconazole (odds ratio [OR], 0.35 [95% confidence interval [CI], 0.16 to 0.73]) and itraconazole capsule (OR, 0.25 [95% CI, 0.06 to 0.97]), but not voriconazole (OR, 1.31 [95% CI, 0.43 to 4.01]), in preventing IFIs. Posaconazole significantly reduced all-cause deaths, compared to placebo, fluconazole, and itraconazole solution (OR, 0.49 to 0.54 [95% CI, 0.28 to 0.88]). The incremental cost-effectiveness ratio for itraconazole solution was lower than that for posaconazole (Singapore dollars [SGD] 12,546 versus SGD 26,817 per IFI avoided and SGD 5,844 versus SGD 12,423 per LY saved) for transplant patients. For leukemia patients, itraconazole solution was the dominant strategy. Voriconazole was dominated by posaconazole. All triazole antifungals except itraconazole capsule were effective in preventing IFIs. Posaconazole was more efficacious in reducing IFIs and all-cause deaths than were fluconazole and itraconazole. Both itraconazole solution and posaconazole were cost-effective in the Singapore health care setting.

Clinical and Safety Outcomes of Oral Antithrombotics for Stroke Prevention in Atrial Fibrillation: A Systematic Review and Network Meta-analysis.

INTRODUCTION: Novel oral anticoagulants (NOACs) expanded the options for stroke prevention in atrial fibrillation (AF). Earlier studies comparing their relative effectiveness and safety typically do not incorporate age-related differences or postmarketing studies. This study aimed to summarize and compare clinical and safety outcomes of oral antithrombotics for stroke prevention in AF in younger (65-74 years) and older (≥75 years) elderly. METHODS: We searched PubMed, Embase, and The Cochrane Library from inception through May 1, 2015, for randomized and nonrandomized studies comparing NOACs, warfarin, and aspirin in elderly with AF. Stroke and systemic embolism (SSE) and major bleeding (MB) are the main outcomes. We also studied secondary outcomes of ischemic stroke, all-cause mortality, intracranial bleeding, and gastrointestinal bleeding. RESULTS: Of 5255 publications identified, 25 randomized controlled trials and 24 nonrandomized studies of 897,748 patients were included. NOACs reduced the risk of SSE compared with warfarin (rate ratios [RRs] range from 0.78-0.82). Relative to SSE, NOACs demonstrated a smaller benefit for ischemic stroke (dabigatran 110 mg, RR 1.08; edoxaban, 1.00; apixaban, 0.99). On the contrary, aspirin was associated with a significantly higher risk of SSE, ischemic stroke, and mortality than warfarin or NOACs (RR > 1), particularly in older elderly. Regarding safety, medium-dose aspirin (100-300 mg daily) and aspirin/clopidogrel combination showed an increased risk of MB compared with warfarin (RR 1.17 and 1.15, respectively), as per dabigatran 150 mg and rivaroxaban in older elderly (RR 1.17 and 1.12, respectively). Among the NOACs, dabigatran 150 mg conferred greater gastrointestinal bleeding risk compared with warfarin (RR 1.51), whereas rivaroxaban (RR 0.73) demonstrated less benefit of reduced intracranial bleeding than other NOACs (RRs range 0.39-0.46). CONCLUSIONS: Lower rates of SSE and intracranial bleeding were observed with the NOACs compared with warfarin. Dabigatran 150 mg and rivaroxaban were associated with higher rates of MB in older elderly.

Statins for Primary Prevention of Cardiovascular Disease in Elderly Patients: Systematic Review and Meta-Analysis.

BACKGROUND: Statins have been shown to be beneficial in primary and secondary prevention settings; however, their role in the elderly remains a clinical conundrum, given that age-related factors could alter the risk-benefit ratio of statin treatment. This study aimed to critically evaluate the efficacy and safety of statins for primary prevention of cardiovascular disease (CVD) in the elderly. METHODS: We systematically reviewed randomized controlled trials comparing any statins with placebo or usual care for primary prevention of CVD in subjects aged ≥65 years. Relative risks (RRs) using a random effects model were calculated and sensitivity analyses were performed to assess the robustness of findings. RESULTS: Eight studies (n = 25,952) were included in the meta-analysis. Statins significantly reduced the risks of composite major adverse cardiovascular events (RR 0.82, 95% CI 0.74-0.92), nonfatal myocardial infarction [MI] (0.75, 0.59-0.94) and total MI (0.74, 0.61-0.90). Treatment effects of statins were statistically insignificant in fatal MI (0.43, 0.09-2.01), stroke (fatal: 0.76, 0.24-2.45; nonfatal: 0.76, 0.53-1.11; total: 0.85, 0.68-1.06) and all-cause mortality (0.96, 0.88-1.04). Significant differences were not observed in myalgia (0.88, 0.69-1.13), elevation of hepatic transaminases (0.98, 0.71-1.34), new-onset diabetes (1.07, 0.77-1.48), serious adverse events (1.00, 0.97-1.04) and discontinuation due to adverse events (1.10, 0.85-1.42). The occurrence of myopathy, rhabdomyolysis and cognitive impairment was largely unreported in the included trials. CONCLUSIONS: From a risk-benefit perspective, there is a role of statins for the primary prevention of major adverse cardiovascular events in elderly patients. Further studies are needed to ascertain the benefits of statins on fatal MI, stroke and all-cause mortality.

Network Meta-Analysis and Cost-Effectiveness Analysis of New Generation Antidepressants.

BACKGROUND: Major depressive disorder (MDD) impacts health, quality of life and workplace productivity. Antidepressant treatment is the primary therapeutic intervention. This study assessed the efficacy and tolerability of new generation antidepressants and their cost-effectiveness in the Singapore healthcare system. METHODS: We conducted a systematic search for head-to-head randomised controlled trials on ten antidepressants (agomelatine, duloxetine, escitalopram, fluvoxamine, fluoxetine, mirtazapine, paroxetine, sertraline, trazodone and venlafaxine) employed as monotherapy in acute MDD management. We performed a network meta-analysis to compare their relative efficacy. The outcome measures for efficacy were response and remission rate, and mean change in Hamilton Depression Rating Scale (HDRS) score; and for tolerability, study withdrawal rates due to adverse events. To evaluate their relative cost effectiveness, a decision tree simulating a cohort of MDD patients using antidepressant as monotherapy was constructed from a societal perspective over 6 months. We used effectiveness data from our network meta-analysis and local data on resource use for depression in Singapore. The incremental cost expected for each additional quality-adjusted life-year (QALY) gained was calculated and presented as the incremental cost-effectiveness ratio (ICER). RESULTS: We identified 76 relevant articles for the network meta-analysis. Of the ten agents included in the analysis, mirtazapine and agomelatine were most efficacious in achieving response and remission, respectively. Mirtazapine and duloxetine resulted in the greatest magnitude of change in the HDRS score. Agomelatine, escitalopram and sertraline were the best tolerated of the drugs analysed, while duloxetine was the least well tolerated drug. Using a composite outcome of efficacy (response and remission rates) and tolerability, agomelatine, escitalopram and mirtazapine were the favoured treatments. In the cost-effectiveness analysis, apart from agomelatine, all the treatments were dominated by mirtazapine. Against mirtazapine, agomelatine was not cost effective given that its ICER exceeded the threshold value. CONCLUSION: Agomelatine, escitalopram and mirtazapine had favourable balance between efficacy and tolerability. In addition, mirtazapine was a cost-effective option in the Singapore healthcare system.

Long-term Cost-effectiveness of Statin Treatment for Primary Prevention of Cardiovascular Disease in the Elderly.

PURPOSE: This study aimed to evaluate the cost-effectiveness of statins for primary prevention of stroke and myocardial infarction (MI) in the elderly in Singapore. METHODS: A Markov model was developed to investigate the lifetime costs, quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs) of statin treatment in those aged 65 years and older without a history of stroke or MI from the perspective of Singapore's healthcare system, using elderly-specific clinical data and local costs from hospital databases. A lifetime horizon was used and all costs and health outcomes were discounted at 3% annually. RESULTS: In the base-case analysis, statin treatment prevented an additional four strokes and eight MIs among 1,000 "healthy" elderly individuals compared with no treatment. Statin treatment resulted in a QALY gain of 0.26 and additional costs of SGD 11,314 per person, yielding an ICER of SGD 43,925 (USD 33,495) per QALY gained. The results were sensitive to statin effectiveness, particularly statins' effect on all-cause mortality, and cost of statin medication. Probabilistic sensitivity analysis demonstrated that the probability of statin treatment being cost-effective was 72% at a willingness-to-pay threshold of SGD 65,000 (USD 49,546) per QALY gained. Shortening the time horizon from lifetime to 10 years (simulating limited life expectancy) considerably increased the ICER to SGD 291,313 (USD 167,171) per QALY. Female gender and younger age were also associated with higher ICERs owing to a lower baseline risk of cardiovascular disease (CVD) and higher costs to manage events in these subgroups. CONCLUSIONS: Statin treatment for the primary prevention of CVD in the elderly was cost-effective. However, treatment warrants re-evaluation when the prognosis of the individual is considered less than ten years; other goals may take precedence over CVD prevention.

Bimodal Influence of Vitamin D in Host Response to Systemic Candida Infection-Vitamin D Dose Matters.

Vitamin D level is linked to susceptibility to infections, but its relevance in candidemia is unknown. We aimed to investigate the in vivo sequelae of vitamin D3 supplementation in systemic Candida infection. Implicating the role of vitamin D in Candida infections, we showed that candidemic patients had significantly lower 25-OHD concentrations. Candida-infected mice treated with low-dose 1,25(OH)2D3 had reduced fungal burden and better survival relative to untreated mice. Conversely, higher 1,25(OH)2D3 doses led to poor outcomes. Mechanistically, low-dose 1,25(OH)2D3 induced proinflammatory immune responses. This was mediated through suppression of SOCS3 and induction of vitamin D receptor binding with the vitamin D-response elements in the promoter of the gene encoding interferon γ. These beneficial effects were negated with higher vitamin D3 doses. While the antiinflammatory effects of vitamin D3 are well described, we found that, conversely, lower doses conferred proinflammatory benefits in Candida infection. Our study highlights caution against extreme deviations of vitamin D levels during infections.