Boon Peng Lim

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.

Comparative Efficacy and Tolerability of Topical Prostaglandin Analogues for Primary Open-Angle Glaucoma and Ocular Hypertension

Objective: To systematically review the efficacy and tolerability of 4 prostaglandin analogues (PGAs) as first-line monotherapies for intraocular pressure (IOP) lowering in adult patients with primary open-angle glaucoma or ocular hypertension. Data Sources: A literature search was performed in PubMed (1965-June 2013) and the Cochrane Library (1980-June 2013) using the search terms ocular hypertension, open-angle glaucoma, prostaglandin analogues, bimatoprost, latanoprost, tafluprost, and travoprost. Additional studies were searched from the reference lists of identified publications. Study Selection and Data Extraction: In all, 32 randomized controlled trials comparing between PGAs (bimatoprost 0.03%, latanoprost 0.005%, tafluprost 0.0015%, and travoprost 0.004%) or PGA with timolol were selected. Data Synthesis: A network meta-analysis was conducted. Using timolol as reference, the relative risks (RRs) of achieving treatment success, defined as the proportion of patients achieving at least 30% IOP reduction, with 95% CIs, were as follows: bimatoprost, 1.59 (1.28-1.98); latanoprost, 1.32 (1.00-1.74); travoprost, 1.33 (1.03-1.72); and tafluprost, 1.10 (0.85-1.42). The mean IOP reductions after 1 month were 1.98 (1.50-2.47), 1.01 (0.55-1.46), 1.08 (0.59-1.57), and 0.46 (−0.41 to 1.33) mm Hg, respectively, and the results were sustained at 3 months. Bimatoprost was associated with the highest risk of developing hyperemia, whereas latanoprost had the lowest risk, with RRs (95% CI) of 4.66 (3.49-6.23) and 2.30 (1.76-3.00), respectively. Conclusions: Bimatoprost achieved the highest efficacy in terms of IOP reduction, whereas latanoprost had the most favorable tolerability profile. This review serves to guide selection of the optimal PGA agent for individual patient care in clinical practice.

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

ABSTRACT 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.

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

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

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.

Comparative cost-effectiveness of 11 oral antipsychotics for relapse prevention in schizophrenia within Singapore using effectiveness estimates from a network meta-analysis.

This study modelled the cost-effectiveness of 11 oral antipsychotics for relapse prevention among patients with remitted schizophrenia in Singapore. A network meta-analysis determined the relative efficacy and tolerability of 11 oral antipsychotics (amisulpride, aripiprazole, chlorpromazine, haloperidol, olanzapine, paliperidone, quetiapine, risperidone, sulpiride, trifluoperazine and ziprasidone). The clinical estimates were applied in a Markov model to estimate lifetime costs and quality-adjusted life-years gained. Quality-of-life data were obtained from published literature. Resource utilization and cost data were retrieved from local hospital databases. The annual direct cost of healthcare services for a patient experiencing a relapse episode was three-fold that of a patient not in relapse of schizophrenia. The most favourable pharmacological treatment for relapse prevention was olanzapine with an annual probability of relapse of 0.24 (0.13–0.38) with placebo as a reference of 0.75 (0.73–0.78). Olanzapine emerged as the dominant treatment with the highest quality-adjusted life-years gained and lowest lifetime costs. Ziprasidone, aripiprazole and paliperidone incurred higher lifetime costs compared with no treatment. Probability and cost of relapse were key drivers of cost-effectiveness in sensitivity analyses. The data can help prescribers in choosing appropriate treatment and payers in allocating resources for the clinical management of this serious psychiatric disorder.

A multicenter, multidisciplinary, high-alert medication collaborative to improve patient safety: the Singapore experience.

BACKGROUND High-alert medications can cause significant patient harm when used in error. A multicenter, multidisciplinary, high-alert medication collaborative was established in Singapore in 2009 to identify and maintain a current list of high-alert medications and to create systematic approaches for preventing and reducing the risk of medication errors and adverse drug events (ADEs) for high-alert medications. METHODS The collaborative was led by a core multidisciplinary team consisting of pharmacists, nurses, and physicians, as well as clinical services and quality personnel, from six primary and acute care institutions. Multidisciplinary work groups were formed to drive the improvement efforts using the Plan-Do-Study-Act (PDSA) cycles. Tracking of improvement work was conducted with an adaptation of the Institute for Healthcare Improvement Trigger Tool method. RESULTS A localized high-alert medication list was developed through local ADE reports, literature review, an online survey of health care professionals, and expert opinion. Some 130 interventions were proposed to prevent, detect, and mitigate harm from the use of high-alert medications for 10 drug classes/drugs. A significant number of these interventions were tested and revised during the PDSA cycles before implementation throughout the institution and subsequent spread to other institutions. Outcome audits identified areas for improvement. The interventions, which were subsequently incorporated into the change packages, led to a 50% and 67% decline in the ADE rates for radiocontrast agents and heparin, respectively. CONCLUSION The collaborative has provided a sound framework for ongoing development and refinement of high-alert medication change packages and for sharing of ADE data and best practices across the participating institutions.

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 patients 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.

Cost-effectiveness modelling of novel oral anticoagulants incorporating real-world elderly patients with atrial fibrillation

BACKGROUND Novel oral anticoagulants (NOACs) expand the treatment options for patients with atrial fibrillation (AF). Their benefits need to be weighed against the risk-benefit ratio in real-world elderly patients, prompting this cost-effectiveness study of NOACs (apixaban, dabigatran, edoxaban and rivaroxaban), warfarin and aspirin for stroke prevention in AF. METHODS Applying effectiveness estimates from a network meta-analysis involving over 800,000 patients from randomised controlled trials and observation studies, our Markov model projected cost and health outcomes for a cohort of 65-year-old AF patients over a life-time. We performed subgroup analysis stratified by age (65-74 and ≥75years), with further analysis limited to observational studies involving dabigatran and rivaroxaban. RESULTS Compared to warfarin, NOACs (except dabigatran 110) were associated with incremental cost-effectiveness ratios ranging from USD 24,476 to USD 41,448 that were within cost-effectiveness threshold of USD 49,700 (one gross domestic product per capita in Singapore in 2015). Aspirin regimens were dominated. In elderly aged ≥75years, cost effectiveness of NOACs (except apixaban) decreased, owing to worsened performance in safety profile. Analysis limited to observational studies revealed that dabigatran 150 and rivaroxaban were not cost-effective, reflecting increased bleeding risks in non-controlled settings. Threshold analyses revealed that apixaban was no longer cost-effective at two to three times higher bleeding risk. CONCLUSIONS Whilst NOACs are cost-effective in the younger elderly compared to warfarin, their benefits appear to be offset by worsened risk profile in older elderly, especially in non-controlled settings. Decisions on appropriate AF treatment should balance treatment-related benefits, risks, and patient preference.

Cost-Effectiveness Modeling of Repetitive Transcranial Magnetic Stimulation Compared to Electroconvulsive Therapy for Treatment-Resistant Depression in Singapore: COST-EFFECTIVENESS OF ECT VS. RTMS IN DEPRESSION

Compared to electroconvulsive therapy (ECT), the cost‐effectiveness of repetitive transcranial magnetic stimulation (rTMS) in the management of treatment‐resistant depression (TRD) remains unclear.