Metabolic events associated with the use of antipsychotics in children, adolescents and young adults: a multinational sequence symmetry study.

It is known that younger patients treated with antipsychotics are at increased risk of metabolic events; however, it is unknown how this risk varies according to ethnicity, the class of antipsychotic and the specific product used, and by age group. We conducted a multinational sequence symmetry study in Asian populations (Hong Kong, Japan, Korea, Taiwan and Thailand) and non-Asian populations (Australia and Denmark) to evaluate the metabolic events associated with antipsychotics in both Asian and non-Asian populations, for typical and atypical antipsychotics, and by the subgroups of children and adolescents, and young adults. Patients aged 6-30 years newly initiating oral antipsychotic drugs were included. We defined a composite outcome for metabolic events which included dyslipidemia, hypertension and hyperglycemia. We calculated the sequence ratio (SR) by dividing the number of people for whom a medicine for one of the outcome events was initiated within a 12-month period after antipsychotic initiation by the number before antipsychotic initiation. This study included 346,904 antipsychotic initiators across seven countries. Antipsychotic use was associated with an increased risk of composite metabolic events with a pooled adjusted SR (ASR) of 1.22 (95% CI 1.00-1.50). Pooled ASRs were similar between Asian (ASR, 1.22; 95% CI 0.88-1.70) and non-Asian populations (ASR, 1.22; 95% CI 1.04-1.43). The pooled ASR for typical and atypical antipsychotics was 0.98 (95% CI 0.85-1.12) and 1.24 (95% CI 0.97-1.59), respectively. No difference was observed in the relative effect in children and adolescents compared to young adults. The risk of metabolic events associated with antipsychotics use was similar in magnitude in Asian and non-Asian populations despite the marked difference in drug utilization patterns.

The cost-effectiveness analysis of laparoscopic hepatectomy compared with open liver resection in the early stage of hepatocellular carcinoma: a decision-analysis model in Thailand.

BACKGROUND: Laparoscopic liver resection is increasing operate. In the early stage of hepatocellular carcinoma (HCC), many studies supported that laparoscopic liver resection was a safe procedure and showed some clinical benefits. However, the full economic evaluation has not been fully investigated. METHODS: A hybrid model of decision tree and Markov state transition model was constructed. Health outcomes were life-year gained (LYs), and quality-adjusted life years (QALYs). A deterministic sensitivity analysis was performed and a probabilistic sensitivity analysis was conducted by 1,000 micro-simulation. The incremental cost-effectiveness ratio (ICER) was reported and the willingness to pay (WTP) was defined at 160,000 THB per QALY gained. RESULTS: Laparoscopic liver resection in the early stage of HCC was not cost-effective. In the base-case analysis, the total lifetime cost of laparoscopic approach was an average of 413,377 THB (US$13,214) higher than open approach by 55,474 THB (US$1,773) with a small QALY gained. The resulting ICER was 1,356,521 THB (US$43,362) per QALY gained. CONCLUSION: Laparoscopic liver resection is not considered as a cost-effective alternative to open liver surgery in the early stage of HCC. In the Thai healthcare perspective, the results from this study may inform policymakers for the future policy implementation and healthcare resource allocation.

Systemic treatments for eczema: a network meta-analysis.

BACKGROUND: Eczema is a common and chronic, relapsing, inflammatory skin disorder. It seriously impacts quality of life and economic outcomes, especially for those with moderate to severe eczema. Various treatments allow sustained control of the disease; however, their relative benefit remains unclear due to the limited number of trials directly comparing treatments. OBJECTIVES: To assess the comparative efficacy and safety of different types of systemic immunosuppressive treatments for moderate to severe eczema using NMA and to generate rankings of available systemic immunosuppressive treatments for eczema according to their efficacy and safety. SEARCH METHODS: We searched the following databases up to August 2019: the Cochrane Skin Specialised Register, CENTRAL, MEDLINE, and Embase. SELECTION CRITERIA: All randomised controlled trials (RCTs) of systemic immunosuppressive agents for moderate to severe atopic eczema when compared against placebo or any other eligible eczema treatment. DATA COLLECTION AND ANALYSIS: We synthesised data using pair-wise analysis and NMA to compare treatments and rank them according to their effectiveness. Effectiveness was assessed primarily by determining the proportion of participants who achieved at least 75% improvement in the Eczema Area and Severity Index (EASI75) and improvement in the Patient-Oriented Eczema Measure (POEM). Safety was evaluated primarily by considering the proportion of participants with serious adverse events (SAEs) and infection. We deemed short-term follow-up as ≤ 16 weeks and long-term follow-up as > 16 weeks. We assessed the certainty of the body of evidence from the NMA for these primary outcomes using six domains of CiNEMA grading. MAIN RESULTS: We included a total of 74 studies, with 8177 randomised participants. Approximately 55% of participants were male, with average age of 32 years (range 2 to 84 years), although age and gender were unreported for 419 and 902 participants, respectively. Most of the included trials were placebo controlled (65%), 34% were head-to-head studies (15% assessed the effects of different doses of the same drug), and 1% were multi-armed studies with both an active comparator and a placebo. All trials included participants with moderate to severe eczema, but 62% of studies did not separate data by severity; 38% of studies assessed only severe eczema. The total duration of included trials ranged from 2 weeks to 60 months, whereas treatment duration varied from a single dose (CIM331, KPL-716) to 60 months (methotrexate (MTX)). Seventy studies were available for quantitative synthesis; this review assessed 29 immunosuppressive agents from three classes of interventions. These included (1) conventional treatments, with ciclosporin assessed most commonly; (2) small molecule treatments, including phosphodiesterase (PDE)-4 inhibitors, tyrosine kinase inhibitors, and Janus kinase (JAK) inhibitors; and (3) biological treatments, including anti-CD31 receptors, anti-interleukin (IL)-22, anti-IL-31, anti-IL-13, anti-IL-12/23p40, anti-OX40, anti-TSLP, anti-CRTH2, and anti-immunoglobulin E (IgE) monoclonal antibodies, but most commonly dupilumab. Most trials (73) assessed outcomes at a short-term duration ranging from 2 to 16 weeks, whereas 33 trials assessed long-term outcomes, with duration ranging from 5 to 60 months. All participants were from a hospital setting. Fifty-two studies declared a source of funding, and of these, pharmaceutical companies funded 88%. We rated 37 studies as high risk; 21, unclear risk, and 16, low risk of bias, with studies most commonly at high risk of attrition bias. Network meta-analysis suggests that dupilumab ranks first for effectiveness when compared with other biological treatments. Dupilumab is more effective than placebo in achieving EASI75 (risk ratio (RR) 3.04, 95% confidence interval (CI) 2.51 to 3.69) and improvement in POEM score (mean difference 7.30, 95% CI 6.61 to 8.00) at short-term follow-up (high-certainty evidence). Very low-certainty evidence means we are uncertain of the effects of dupilumab when compared with placebo, in terms of the proportion of participants who achieve EASI75 (RR 2.59, 95% CI 1.87 to 3.60) at longer-term follow-up. Low-certainty evidence indicates that tralokinumab may be more effective than placebo in achieving short-term EASI75 (RR 2.54, 95% CI 1.21 to 5.34), but there was no evidence for tralokinumab to allow us to assess short-term follow-up of POEM or long-term follow-up of EASI75. We are uncertain of the effect of ustekinumab compared with placebo in achieving EASI75 (long-term follow-up: RR 1.17, 95% CI 0.40 to 3.45; short-term follow-up: RR 0.91, 95% CI 0.28 to 2.97; both very low certainty). We found no evidence on ustekinumab for the POEM outcome. We are uncertain whether other immunosuppressive agents that targeted our key outcomes influence the achievement of short-term EASI75 compared with placebo due to low- or very low-certainty evidence. Dupilumab and ustekinumab were the only immunosuppressive agents evaluated for longer-term EASI75. Dupilumab was the only agent evaluated for improvement in POEM during short-term follow-up. Low- to moderate-certainty evidence indicates a lower proportion of participants with SAEs after treatment with QAW039 and dupilumab compared to placebo during short-term follow-up, but low- to very low-certainty evidence suggests no difference in SAEs during short-term follow-up of other immunosuppressive agents compared to placebo. Evidence for effects of immunosuppressive agents on risk of any infection during short-term follow-up and SAEs during long-term follow-up compared with placebo was of low or very low certainty but did not indicate a difference. We did not identify differences in other adverse events (AEs), but dupilumab is associated with specific AEs, including eye inflammation and eosinophilia. AUTHORS' CONCLUSIONS: Our findings indicate that dupilumab is the most effective biological treatment for eczema. Compared to placebo, dupilumab reduces eczema signs and symptoms in the short term for people with moderate to severe atopic eczema. Short-term safety outcomes from clinical trials did not reveal new safety concerns with dupilumab. Overall, evidence for the efficacy of most other immunosuppressive treatments for moderate to severe atopic eczema is of low or very low certainty. Given the lack of data comparing conventional with newer biological treatments for the primary outcomes, there remains high uncertainty for ranking the efficacy and safety of conventional treatments such as ciclosporin and biological treatments such as dupilumab. Most studies were placebo-controlled and assessed only short-term efficacy of immunosuppressive agents. Further adequately powered head-to-head RCTs should evaluate comparative long-term efficacy and safety of available treatments for moderate to severe eczema.

Clinical burden associated with postsurgical complications in major cardiac surgeries in Asia-Oceania countries: A systematic review and meta-analysis.

BACKGROUND: Evidence on the burden of postsurgical complications is mainly from studies in western countries, and little is highlighted in the Asia-Oceania region. This study aimed to identify and compare the burden of postsurgical complications in major cardiac surgeries in Asia-Oceania countries. METHODS: A systematic search was performed in PubMed, Embase, and CENTRAL between January 2000 and July 2018. Inclusion criteria were: (a) observational studies or randomized control trials; (b) studied in coronary artery bypass graft (CABG) and/or heart valve procedures; (c) measured postsurgical clinical outcomes; and (d) conducted in Asia-Oceania countries. Pooled effects were calculated using a random-effects model. RESULTS: Of the 6032 articles screened, 472 studies with a total of 614 161 patients met the inclusion criteria. The pooled incidences (95% confidence interval) of hospital mortality and 30-day mortality were similar at 2.38% (2.16%-2.59%) and 2.33% (2.16%-2.50%), respectively. Length of stay (LOS) was 14.07 days (13.44-14.71 days). The incidence for atrial fibrillation (AF) and stroke/cerebrovascular accident (CVA) was 17.49% (15.99%-18.99%) and 1.64% (1.51%-1.78%), respectively. Below outcomes tended to be better in studies on CABG compared to heart valve procedures, including the incidence of hospital mortality (1.97%[1.75%-2.18%] vs 3.97% [3.29%-4.65%]), AF (16.47% [14.85%-18.10%] vs 21.98% [17.41%-26.54%]), stoke/CVA (1.51% [1n 37%-1.65%] vs 2.55% [2.07%-3.04%]), and mean LOS (days) (13.08 [12.51-13.65] vs 19.58 [16.72-22.45]). Similarly, all postsurgical complications tended to be higher in studies involving high-risk patients vs non-high-risk patients. CONCLUSIONS: There are opportunities to improve clinical outcomes of patients with high surgical risks and those undertaking heart valve procedures, as they tend to have poorer survival and higher risk in developing postsurgical complications.

Association between adherence and severe asthma exacerbation: A systematic review and meta-analysis.

OBJECTIVE: To assess the association between adherence levels and severe asthma exacerbation. DESIGN: A systematic search was performed from inception to November 2018 on the following databases: PubMed, CENTRAL, EMBASE, and ClinicalTrials.gov. SETTING AND PARTICIPANTS: Randomized-controlled trials (RCTs) and cohort and case-control studies that investigated the impact of adherence to controller medications on severe asthma exacerbation were included in the analysis. Data extraction was undertaken by 2 reviewers, and all studies were assessed for their qualities using the Cochrane risk of bias tool for RCT and the Newcastle-Ottawa scale for cohort and case-control studies. Random-effects model meta-analyses were performed. OUTCOME MEASURES: Severe asthma exacerbation. RESULTS: From 8061 articles, 8 studies were included in quantitative synthesis. The meta-analyses revealed that the odds of exacerbation among the patients with 80% or more adherence were lowered by 47% (odds ratio 0.53 [95% CI 0.42-0.66], P < 0.001) compared with less than 80%. When compared with less than 20% adherence, a 33% reduction in the odds (0.67 [0.53-0.86], P = 0.001) was associated with the patients achieving 50% or more, whereas a decrease in exacerbation was not associated with 20% to 49% adherence (0.94 [0.85-1.04], P = 0.22). In addition, a 2.4-fold increase in the odds (2.4 [2.1-2.7], P < 0.001) was associated with discontinuation of therapy. CONCLUSION: The highest reduction in the odds of exacerbation was associated with patients achieving 80% or more adherence, and the odds also reduced among those with 50% or more adherence, whereas a substantial increase in exacerbation was associated with discontinuation of therapy.

Comparative effects of telemedicine and face-to-face warfarin management: A systematic review and network meta-analysis.

OBJECTIVE: To determine the comparative effects of different types of telemedicine on anticoagulation control and adverse outcomes in patients taking warfarin. DATA SOURCES: A systematic search was conducted in PubMed, the Cochrane library, EMBASE, CINAHL, OpenGrey, and DART-Europe from inception to September 2019. STUDY SELECTION: Randomized controlled trials, quasi-experimental and cohort studies were included if they evaluated the effect of telemedicine in patients using warfarin for 3 months or more. METHODS: Two reviewers extracted and assessed the quality of studies by means of the Cochrane Effective Practice and Organization of Care Group. Network meta-analyses were performed using a random-effects model. Surface under the cumulative ranking curve (SUCRA) methods were used to rank different telemedicine types. RESULTS: Of the 14,673 articles retrieved, 12 studies involving 11,478 patients met the inclusion criteria. The 5 types of telemedicine categorized were 1) laboratory draw with individual telephonic follow-up by health care (HC) providers (Lab/Tel/HC); 2) laboratory draw with individual telephonic follow-up with periodic, routine routine face-to-face (F2F) visit (Lab/Tel+F2F/HC); 3) laboratory draw with individual and group follow-up via online access (Lab/Online/HC); 4) patient self-test (PST) with telephonic or Web-based follow-up by automated management system (PST/Tel-Online/Auto); and 5) PST with telephonic follow-up by HC provider (PST/Tel/HC). PST/Tel-Online/Auto appears to be superior to F2F for TTR (mean difference 8.78%; 95% CI 0.06%-17.50%) and Lab/Online/HC for in-range INR (odds ratio 2.59; 95% CI 1.04-6.46). The SUCRAs suggested that PST/Tel-Online/Auto was preferred for both TTR and INR, at 84.2% and 93.9%, respectively, whereas Lab/Tel/HC was preferred to prevent major bleeding (74.1%) or thromboembolic event (70.7%). CONCLUSION: According to the current evidence of uncertain quality, the best effects on anticoagulation control and adverse outcomes were achieved from different types of telemedicine. Variations in the effects of telemedicine on diverse outcomes should be considered before implementing telemedicine interventions in patients taking warfarin.

The effects of cannabis, cannabinoids, and their administration routes on pain control efficacy and safety: A systematic review and network meta-analysis.

OBJECTIVES: To determine the effects of cannabis, cannabinoids, and their administration routes on pain and adverse euphoria events. DATA SOURCES: A systematic search was performed in PubMed, ScienceDirect, ClincalTrials.gov, Scopus, Cochrane Library, and Embase from inception until June 2017. STUDY SELECTION: Randomized controlled trials investigating the effects of cannabis or cannabinoids on pain reduction. DATA EXTRACTION: Two reviewers extracted and assessed the quality of studies by means of Cochrane risk of bias. Standardized mean difference (SMD) was calculated. Random-effects model was undertaken to pool the treatment effects. RESULTS: A total of 25 studies involving 2270 patients were included. We found that delta-9-tetrahydrocannabinol/cannabidiol (THC/CBD) (oromucosal route), THC (oromucosal route), and standardized dried cannabis (with THC; SCT; inhalation route) could reduce neuropathic pain score (SMD -0.41, 95% CI -0.7 to -0.1; -0.61, 95% CI -1.2 to -0.02; and -0.77, 95% CI -1.4 to -0.2; respectively). For nociceptive pain, only standardized cannabis extract (with THC; SCET) via oral route could reduce pain score (SMD -1.8, 95% C; -2.4 to -1.2). In cancer pain, THC/CBD via oromucosal route and THC via oral or oromucosal route could reduce pain score (SMD -0.7, 95% CI -1.2 to -0.2; and -2.1, 95% CI -2.8 to -1.4; respectively). No study was observed for THC/CBD via oral route or inhalation or THC via inhalation for cancer and nociceptive pain, SCET via oromucosal route or inhalation for neuropathic and cancer pain, THC via oromucosal route for nociceptive pain, and SCT via oromucosal or oral route for neuropathic, cancer, and nociceptive pain. Statistically significant increased risks of euphoria were observed in THC/CBD (oromucosal), THC (oromucosal), and SCT (inhalation). CONCLUSION: The use of cannabis and cannabinoids via certain administration routes could reduce different types of pain. Product developers could consider our findings as part of their product design so that the effective route of cannabis and cannabinoids for pain control can be achieved.

Clinical Outcomes of Telephone Service for Patients on Warfarin: A Systematic Review and Meta-Analysis.

Objective: To evaluate clinical outcomes of telephone-based service for patients on warfarin. Methods: Five bibliographic databases and gray literature were searched for articles that reported the effects of telephone interventions provided to patients using warfarin compared with those receiving usual clinic-based care. Mean difference (MD) and relative risk (RR) were used to calculate the effects of telephone intervention on time in therapeutic range (TTR) and visit in range (VIR), respectively. Adverse events (AEs) were pooled and reported as incidence rate ratios. Results: A total of 1,840 articles were examined. Eight articles involving 8,087 subjects were included in the quantitative synthesis. The pooled estimates from seven studies showed no difference on TTR between the telephone service group and the usual care group (MD 2.30; 95% confidence interval [CI] -3.56 to 8.16). In addition, VIR in the telephone service group was not different from the usual care group (RR 1.22, 95% CI 0.87-1.71). Moreover, patients in telephone service groups appeared to have a lower incidence of AEs compared with usual care groups. Discussion: Telephone-based service could be considered as an alternative anticoagulant management. However, owing to a lack of evidence from well-designed studies, further high-quality randomized control trials are warranted.

Cost-Effectiveness Analysis of Non-Vitamin K Antagonist Oral Anticoagulants Versus Warfarin in Thai Patients With Non-Valvular Atrial Fibrillation.

BACKGROUND: Non-vitamin K antagonist oral anticoagulants (NOACs) have been recommended as preferred options for stroke prevention in patients with atrial fibrillation (AF) versus warfarin by guidelines worldwide. AIM: This study aimed to evaluate the cost-effectiveness of each NOAC in a Thai health care environment, a country with upper middle-income economies based on the World Bank's classification. METHOD: A lifetime Markov model was created from a Thai societal perspective. The model consisted of 19 health states separated into two cycles: event cycle and consequence cycle. The consequences of AF included in the model were ischaemic stroke, intracranial haemorrhage, extracranial haemorrhage, and myocardial infarction. All NOACs available in Thailand (dabigatran 150 mg and 110 mg twice daily; rivaroxaban 20 mg once daily; apixaban 5 mg twice daily; edoxaban 60 mg and 30 mg once daily) were assessed using warfarin with an international normalised ratio of 2-3 as the reference. Inputs were a combination of published literature and local data when available. A willingness-to-pay of 160,000 Thai baht (THB)/quality-adjusted life year (QALY) was used as the threshold of being cost-effective. Incremental cost-effectiveness ratios and cost-effectiveness acceptability curves were estimated. RESULTS: All NOACs were not cost-effective strategies for the Thai AF population. The ranking of incremental cost-effectiveness ratios from lowest to highest were apixaban 5 mg twice daily (THB 692,136 or US$21,862) followed by edoxaban 60 mg once daily (THB 911,772 or US$28,799), edoxaban 30 mg once daily (THB 913,749 or US$28,861), dabigatran 150 mg twice daily (THB 1,102,106 or US$34,811), dabigatran 110 mg twice daily (THB 1,195,347 or US$37,756), and rivaroxaban 20 mg once daily (THB 1,347,650 or US$42,566). Cost-effectiveness acceptability curve indicated that apixaban had the highest potential to be a cost-effective strategy versus other NOACs. CONCLUSIONS: Our findings indicated that all NOACs were not cost-effective in the Thai AF population. Of the NOACs, apixaban may be the most likely to be cost-effective. These data may be useful for policymakers to perform a comprehensive evaluation of these agents for formulary decision and pricing negotiation.

A Real-World Evidence Analysis of Associations Among Costs, Quality of Life, and Disease-Severity Indicators of Alzheimer's Disease in Thailand.

BACKGROUND: Although an increase in the burden of Alzheimer's disease (AD) is evident worldwide, knowledge of costs and health-related quality of life (HRQOL) associated with AD in low- and middle-income countries is still lacking. OBJECTIVES: This study aimed to collect real-world cost and HRQOL data, and investigate their associations with multiple disease-severity indicators among AD patients in Thailand. METHODS: We recruited AD patients aged ≥60 years accompanied by their caregivers at a university-affiliated tertiary hospital. A one-time structured interview was conducted to collect disease-severity indicators, HRQOL, and caregiving information using standardized tools. The hospital's database was used to retrieve healthcare resource utilization occurred over 6 months preceding the interview date. Costs were annualized and stratified based on cognitive status. Generalized linear models were employed to evaluate determinants of costs and HRQOL. RESULTS: Among 148 community-dwelling patients, average annual total societal costs of AD care were $8014 (95% confidence interval [CI]: $7295-$8844) per patient. Total costs of patients with severe stage ($9860; 95% CI: $8785-$11 328) were almost twice as high as those of mild stage ($5524; 95% CI: $4649-$6593). The major cost driver was direct medical costs, particularly those incurred by AD prescriptions. Functional status was the strongest determinant for both total costs and patient's HRQOL (P value <.001). CONCLUSION: Our real-world findings suggest the distinct major cost driver that results from expensive AD treatment, emphasizing the demand of country-specific cost evidence. Increases in cognitive and functional status are significantly associated with decreases in total costs of AD care and improvement in patient's HRQOL.

Treatment patterns and related clinical consequences in adults with asthma.

OBJECTIVE: A stepwise therapeutic management is recommended for asthma patients by the Global Initiative for Asthma (GINA). Little is known about the recommendations applied in real world settings. This study aims to associate Treatment step with clinical events in patients with mild or severe asthma. METHODS: A retrospective claims database analysis included adult patients with mild (GINA step 1) or severe asthma (GINA step 4). Maximum Treatment Step was measured within the first and second 90-day period after index date (the first date of asthma diagnosis during the inclusion period). Step-down was defined as a Treatment Step change from a higher to lower step, while Step-up was defined as a Treatment Step change from a lower to higher step. The primary outcome was a composite endpoint of asthma-related clinical events, measured at the third 90-day period. RESULTS AND CONCLUSIONS: A total of 6,354 mild-asthma patients and 5,695 severe-asthma patients were included. In mild-asthma, when compared with No Change in Treatment Step, Step-down was associated with a lower risk of future clinical events [adjusted odds ratio (OR) 0.80, 95% confidence interval (95% CI); 0.69-0.94], while Step-up was not associated with a change in clinical events [OR 0.98, 95% CI: 0.77-1.27]. In severe-asthma patients, Step-down was not associated with a change in clinical events [OR 0.94, 95% CI: 0.81-1.10], while Step-up was associated with a higher risk of future clinical events [OR 2.07, 95% CI: 1.29-3.33]. Our findings reassure the appropriateness of stepping-down treatment in mild-asthma patients. Clinicians should closely monitor and/or provide detailed asthma action plans for severe-asthma patients who are stepping-up treatment.

Cultural beliefs, utility values, and health technology assessment.

BACKGROUND: Health-care utilities differ considerably from country to country. Our objective was to examine the association of cultural values based on Hofstede's cultural dimensions' theory with utility values that were identified using the time trade off method. METHODS: We performed a literature search to determine preference-based value algorithms in the general population of a given country. We then fitted a second-order quadratic function to assess the utility function curve that links health status with health-care utilities. We ranked the countries according to the concavity and convexity properties of their utility functions and compared this ranking with that of the Hofstede index to check if there were any similarities. RESULTS: We identified 10 countries with an EQ-5D-5L-based value set and 7 countries with an EQ-5D-3L-based value set. Japan's degree of concavity was highest, while Germany's was lowest, based on the EQ-5D-3L and EQ-5D-5L value sets. Japan also ranked first in the Hofstede long-term orientation index, and rankings related to the degree of concavity, indicating a low time preference rate. CONCLUSIONS: This is the first evaluation to identify and report an association between different cultural beliefs and utility values. These findings underline the necessity to take local values into consideration when designing health technology assessment systems.

Prevention and Control of Multidrug-Resistant Gram-Negative Bacteria in Adult Intensive Care Units: A Systematic Review and Network Meta-analysis.

BACKGROUND: This study evaluated the relative efficacy of strategies for the prevention of multidrug-resistant gram-negative bacteria (MDR-GNB) in adult intensive care units (ICUs). METHODS: A systematic review and network meta-analysis was performed; searches of the Cochrane Library, PubMed, Embase, and CINAHL (Cumulative Index to Nursing and Allied Health Literature) included all randomized controlled trials and observational studies conducted in adult patients hospitalized in ICUs and evaluating standard care (STD), antimicrobial stewardship program (ASP), environmental cleaning (ENV), decolonization methods (DCL), or source control (SCT), simultaneously. The primary outcomes were MDR-GNB acquisition, colonization, and infection; secondary outcome was ICU mortality. RESULTS: Of 3805 publications retrieved, 42 met inclusion criteria (5 randomized controlled trials and 37 observational studies), involving 62068 patients (median age, 58.8 years; median APACHE [Acute Physiology and Chronic Health Evaluation] II score, 18.9). The majority of studies reported extended-spectrum ß-lactamase (ESBL)-producing Enterobacteriaceae and MDR Acinetobacter baumannii. Compared with STD, a 4-component strategy composed of STD, ASP, ENV, and SCT was the most effective intervention (rate ratio [RR], 0.05 [95% confidence interval {CI}, .01-.38]). When ENV was added to STD+ASP or SCT was added to STD+ENV, there was a significant reduction in the acquisition of MDR A. baumannii (RR, 0.28 [95% CI, .18-.43] and 0.48 [95% CI, .35-.66], respectively). Strategies with ASP as a core component showed a statistically significant reduction the acquisition of ESBL-producing Enterobacteriaceae (RR, 0.28 [95% CI, .11-.69] for STD+ASP+ENV and 0.23 [95% CI, .07-.80] for STD+ASP+DCL). CONCLUSIONS: A 4-component strategy was the most effective intervention to prevent MDR-GNB acquisition. As some strategies were differential for certain bacteria, our study highlighted the need for further evaluation of the most effective prevention strategies.

Forecasting the Long-Term Clinical and Economic Outcomes of Lumacaftor/Ivacaftor in Cystic Fibrosis Patients with Homozygous phe508del Mutation.

OBJECTIVES: To forecast lifetime outcomes and cost of lumacaftor/ivacaftor combination therapy in patients with cystic fibrosis (CF) with homozygous phe508del mutation from the US payer perspective. METHODS: A lifetime Markov model was developed from a US payer perspective. The model included five health states: 1) mild lung disease (percent predicted forced expiratory volume in 1 second [FEV1] >70%), 2) moderate lung disease (40% ≤ FEV1 ≤ 70%), 3) severe lung disease (FEV1 < 40%), 4) lung transplantation, and 5) death. All inputs were derived from published literature. We estimated lumacaftor/ivacaftor's improvement in outcomes compared with a non-CF referent population as well as CF-specific mortality estimates. RESULTS: Lumacaftor/ivacaftor was associated with additional 2.91 life-years (95% credible interval 2.55-3.56) and additional 2.42 quality-adjusted life-years (QALYs) (95% credible interval 2.10-2.98). Lumacaftor/ivacaftor was associated with improvements in survival and QALYs equivalent to 27.6% and 20.7%, respectively, for the survival and QALY gaps between CF usual care and their non-CF peers. The incremental lifetime cost was $2,632,249. CONCLUSIONS: Lumacaftor/ivacaftor increased life-years and QALYs in CF patients with the homozygous phe508del mutation and moved morbidity and mortality closer to that of their non-CF peers but it came with higher cost.

Does the use of efficacy or effectiveness evidence in cost-effectiveness analysis matter?

OBJECTIVE: To test the association of clinical evidence type, efficacy-based or effectiveness-based ("E"), versus whether or not asthma interventions' cost-effectiveness findings are favorable. DATA SOURCES: We conducted a systematic review of PubMed, EMBASE, Tufts CEA registry, Cochrane CENTRAL, and the UK National Health Services Economic Evaluation Database from 2009 to 2014. STUDY SELECTION: All cost-effectiveness studies evaluating asthma medication(s) were included. Clinical evidence type, "E," was classified as efficacy-based if the evidence was from an explanatory randomized controlled trial(s) or meta-analysis, while evidence from pragmatic trial(s) or observational study(s) was classified as effectiveness-based. We defined three times the World Health Organization cost-effectiveness willingness-to-pay (WTP) threshold or less as a favorable cost-effectiveness finding. Logistic regression tested the likelihood of favorable versus unfavorable cost-effectiveness findings against the type of "E." RESULTS AND CONCLUSIONS: 25 cost-effectiveness studies were included. Ten (40.0%) studies were effectiveness-based, yet 15 (60.0%) studies were efficacy-based. Of 17 studies using endpoints that could be compared to WTP threshold, 7 out of 8 (87.5%) effectiveness-based studies yielded favorable cost-effectiveness results, whereas 4 out of 9 (44.4%) efficacy-based studies yielded favorable cost-effectiveness results. The adjusted odds ratio was 15.12 (95% confidence interval; 0.59 to 388.75) for effectiveness-based versus efficacy-based achieving favorable cost-effectiveness findings. More asthma cost-effectiveness studies used efficacy-based evidence. Studies using effectiveness-based evidence trended toward being more likely to disseminate favorable cost-effective findings than those using efficacy. Health policy decision makers should pay attention to the type of clinical evidence used in cost-effectiveness studies for accurate interpretation and application.

Forecasting US ivacaftor outcomes and cost in cystic fibrosis patients with the G551D mutation.

Ivacaftor, a breakthrough treatment for cystic fibrosis (CF) patients with the G551D genetic mutation, lacks long-term clinical and cost projections. This study forecasted outcomes and cost by comparing ivacaftor plus usual care versus usual care alone.A lifetime Markov model was conducted from a US payer perspective. The model consisted of five health states: 1) forced expiratory volume in 1 s (FEV1) % pred ≥70%, 2) 40%≤ FEV1 % pred <70%, 3) FEV1 % pred <40%, 4) lung transplantation and 5) death. All inputs were extracted from published literature. Budget impact was also estimated. We estimated ivacaftor's improvement in outcomes compared with a non-CF referent population.Ivacaftor was associated with 18.25 (95% credible interval (CrI) 13.71-22.20) additional life-years and 15.03 (95% CrI 11.13-18.73) additional quality-adjusted life-years (QALYs). Ivacaftor was associated with improvements in survival and QALYs equivalent to 68% and 56%, respectively, for the survival and QALY gaps between CF usual care and their non-CF peers. The incremental lifetime cost was $3 374 584. The budget impact was $0.087 per member per month.Ivacaftor increased life-years and QALYs in CF patients with the G551D mutation, and moved morbidity and mortality closer to that of their non-CF peers. Ivacaftor costs much more than usual care, but comes at a relatively limited budget impact.

Brief Report: Databases in the Asia-Pacific Region: The Potential for a Distributed Network Approach.

BACKGROUND: This study describes the availability and characteristics of databases in Asian-Pacific countries and assesses the feasibility of a distributed network approach in the region. METHODS: A web-based survey was conducted among investigators using healthcare databases in the Asia-Pacific countries. Potential survey participants were identified through the Asian Pharmacoepidemiology Network. RESULTS: Investigators from a total of 11 databases participated in the survey. Database sources included four nationwide claims databases from Japan, South Korea, and Taiwan; two nationwide electronic health records from Hong Kong and Singapore; a regional electronic health record from western China; two electronic health records from Thailand; and cancer and stroke registries from Taiwan. CONCLUSIONS: We identified 11 databases with capabilities for distributed network approaches. Many country-specific coding systems and terminologies have been already converted to international coding systems. The harmonization of health expenditure data is a major obstacle for future investigations attempting to evaluate issues related to medical costs.

Renin angiotensin system blockers-associated angioedema in the Thai population: analysis from Thai National Pharmacovigilance Database.

BACKGROUND: Renin-angiotensin-aldosterone system (RAS) blockers are commonly used for cardiovascular diseases. Currently, little information exists for the Asian population on angioedema, a rare yet serious adverse event. OBJECTIVE: This study aimed to describe characteristics of RAS blockers-associated angioedema (RASBA) in Thai patients. METHODS: A retrospective study using the national pharmacovigilance database of Thailand was undertaken. Cases indicating the presence of angioedema with RAS blockers uses from 1984-2011 were identified. Patient demographics, co-morbidities, concomitant drugs, information for the RAS blockers and angioedema were obtained as well as causality assessment and quality of reports. RESULTS: A total of 895 cases were identified. Mean age was 59.9+12.8 years and 66.5% being female. Most angioedema events (48.6%) occurred during the first week of treatment. Angiotensin converting enzyme inhibitors (87.7%) were the most commonly implicated agents followed by angiotensin receptor blockers (10.5%), aldosterone antagonist (2.1%) and direct renin inhibitor (0.2%). Out of the 895 cases incorporated in this study, 165 (18.4%) were classified as serious events and resulted in hospitalization. The overall case fatality rate was 0.4%. Respiratory disturbance occurred in 46 cases (5.1%). Patients with respiratory complications tended to be younger (53.4+13.9 vs 60.3+12.7 years old; p=0.002) and with higher frequency of allergy history (26.1% vs 14.7%; p=0.032) compared to those without respiratory complications. Based on multivariate logistic regression, the adjusted OR for history of allergy was 2.23 (95%CI: 1.04 - 4.78, p = 0.041). CONCLUSIONS: RASBA in Thai population occurred mostly in elderly female patients and often led to hospitalization. Since large number of patients is regularly exposed to RAS-blockers, a nationwide attempt to raise awareness of clinicians when prescribing RAS-blockers is prudent.

Understanding medication oversupply and its predictors in the outpatient departments in Thailand.

BACKGROUND: Medication oversupply is an important problem in the healthcare systems. It causes unnecessary avoidable healthcare costs. Although some studies have determined the magnitude and financial loss due to medication oversupply in western countries, they may not be applicable to Asia-pacific countries. This study aims to determine the prevalence, financial loss, and patterns of medication oversupply and the factors associated with such oversupply in Thailand. METHODS: A retrospective database analysis was used from 3 public hospitals. Patients visiting the outpatient department of the hospitals in 2010 and receiving at least 2 prescriptions within 6 months were included. The modified medication possession ratio (MPRm) was used to determine the medication supply. Patients having MPRm > 1.20 were defined as receiving a medication oversupply. The measures were prevalence of medication oversupply, the number of oversupplied medications, and financial loss (2012 dollars) due to medication oversupply. Hierarchical logistic regression was used to determine the factors associated with the prevalence of medication oversupply. RESULTS: A total of 99,743 patients were included. Patients were on average 49.7 ± 21.2 years of age, and 42.8% were male. Most of them were adult (53.7%). Among those patients, 60.2% of the patients were under universal coverage schemes. Around 13.4% of all the patients received a medication oversupply, and the patients in regional hospitals had a higher prevalence of medication oversupply than patients in district hospitals (13.8% VS 8.2%). The patients under civil servant medical benefit schemes (CSMBS) (13.6%) had the most prevalence of medication oversupply. The total financial loss was $189,024 per year. The average financial loss was $1.9 ± 19.0 per patient/year. Patients under CSMBS experienced the highest average financial loss (2.6 ± 23.2 $/patient/year). Age, gender, health insurance schemes, and the number of medications that the patients received were the factors associated with medication oversupply. CONCLUSIONS: Medication oversupply is an important problem for the health system. Patients receiving care from regional hospitals had a higher likelihood of medication oversupply. Policymakers may consider developing policies for preventing medication oversupply. The policy should be implemented in regional hospitals and especially in children or patients with poly-pharmacy.

Systematic review and network meta-analysis in health technology assessment.

Conducting systematic review and meta-analysis (SR/MA) is a standard process for establishing evidences for health technology assessment. Quality assessment of studies included in SR/MA and SR/MA studies should be considered. This article provides recommendations on tools used for assessing the quality of studies included in each SR/MA and the quality of SR/MA. For assessing the quality of randomized controlled trial, we recommend a tool called "Risk of Bias", which focuses on random generation, allocation concealment, blinding and outcome reporting. For assessing the quality of observational study, the Newcastle Ottawa Scale (NOS) is recommended. The NOS consists of three different dimensions-selection, comparability and outcomes or exposure. Another tool which is recommended is the Down and Black scale. It focuses on the quality of reporting, validity, bias and confounding, and power of study. For assessing the quality of SR/MA, we recommend to use a checklist developed by Klassen et al, covering well-defined question, inclusion criteria, comprehensiveness, quality of included studies, reproducibility, and external validity. This article also provides a fundamental of network meta-analysis that should be considered where no direct evidence exists or when there is a need to compare multiple interventions at the same time.