Cost-effectiveness of tuberculosis evaluation and treatment of newly-arrived immigrants

BACKGROUND: Immigrants to the U.S. are required to undergo overseas screening for tuberculosis (TB), but the value of evaluation and treatment following entry to the U.S. is not well understood. We determined the cost-effectiveness of domestic follow-up of immigrants identified as tuberculosis suspects through overseas screening. METHODS: Using a stochastic simulation for tuberculosis reactivation, transmission, and follow-up for a hypothetical cohort of 1000 individuals, we calculated the incremental cost-effectiveness of follow-up and evaluation interventions. We utilized published literature, California Reports of Verified Cases of Tuberculosis (RVCTs), demographic estimates from the California Department of Finance, Medicare reimbursement, and Medi-Cal reimbursement rates. Our target population was legal immigrants to the United States, our time horizon is twenty years, and our perspective was that of all domestic health-care payers. We examined the intervention to offer latent tuberculosis therapy to infected individuals, to increase the yield of domestic evaluation, and to increase the starting and completion rates of LTBI therapy with INH (isoniazid). Our outcome measures were the number of cases averted, the number of deaths averted, the incremental dollar cost (year 2004), and the number of quality-adjusted life-years saved. RESULTS: Domestic follow-up of B-notification patients, including LTBI treatment for latently infected individuals, is highly cost-effective, and at times, cost-saving. B-notification follow-up in California would reduce the number of new tuberculosis cases by about 6–26 per year (out of a total of approximately 3000). Sensitivity analysis revealed that domestic follow-up remains cost-effective when the hepatitis rates due to INH therapy are over fifteen times our best estimates, when at least 0.4 percent of patients have active disease and when hospitalization of cases detected through domestic follow-up is no less likely than hospitalization of passively detected cases. CONCLUSION: While the current immigration screening program is unlikely to result in a large change in case rates, domestic follow-up of B-notification patients, including LTBI treatment, is highly cost-effective. If as many as three percent of screened individuals have active TB, and early detection reduces the rate of hospitalization, net savings may be expected

Potential Economic Viability of Two Proposed Rifapentine-Based Regimens for Treatment of Latent Tuberculosis Infection

Rationale: Rifapentine-based regimens for treating latent tuberculosis infection (LTBI) are being considered for future clinical trials, but even if they prove effective, high drug costs may limit their economic viability. Objectives: To inform clinical trial design by estimating the potential costs and effectiveness of rifapentine-based regimens for treatment of latent tuberculosis infection (LTBI). Methods: We used a Markov model to estimate cost and societal benefits for three regimens for treating LTBI: Isoniazid/ rifapentine daily for one month, isoniazid/rifapentine weekly for three months (self-administered and directly-observed), and isoniazid daily for nine months; a strategy of ‘‘no treatment’ ’ used for comparison. Costs, quality-adjusted life-years gained, and instances of active tuberculosis averted were calculated for all arms. Results: Both daily isoniazid/rifapentine for one month and weekly isoniazid/rifapentine for three months were less expensive and more effective than other strategies under a wide variety of clinically plausibly parameter estimates. Daily isoniazid/rifapentine for one month was the least expensive and most effective regimen. Conclusions: Daily isoniazid/rifapentine for one month and weekly isoniazid/rifapentine for three months should be studied in a large-scale clinical trial for efficacy. Because both regimens performed well even if their efficacy is somewhat reduced

Tolerance to bronchodilation during treatment with long-acting beta-agonists, a randomised controlled trial

BACKGROUND: Regular use of beta-agonists leads to tolerance to their bronchodilator effects. This can be demonstrated by measuring the response to beta-agonist following bronchoconstriction using methacholine. However most studies have demonstrated tolerance after a period of beta-agonist withdrawal, which is not typical of their use in clinical practice. This study assessed tolerance to the bronchodilator action of salbutamol during ongoing treatment with long-acting beta-agonist. METHODS: Random-order, double-blind, placebo-controlled, crossover trial. After 1 week without beta-agonists, 13 asthmatic subjects inhaled formoterol 12 μg twice daily or matching placebo for 1 week. Eight hours after the first and last doses subjects inhaled methacholine to produce a 20% fall in FEV(1). Salbutamol 100, 200 and 400 μg (cumulative dose) was then given at 5-minute intervals and FEV(1 )was measured 5 minutes after each dose. After a 1 week washout subjects crossed over to the other treatment. Unscheduled use of beta-agonists was not allowed during the study. The main outcome variable was the area under the salbutamol response curve. RESULTS: The analysis showed a significant time by treatment interaction indicating that the response to salbutamol fell during formoterol therapy compared to placebo. After 1 week of formoterol the area under the salbutamol response curve was 48% (95% confidence interval 28 to 68%) lower than placebo. This reduction in response remained significant when the analyses were adjusted for changes in the pre-challenge FEV(1 )and dose of methacholine given (p = 0.001). CONCLUSION: The bronchodilator response to salbutamol is significantly reduced in patients taking formoterol. Clinically relevant tolerance to rescue beta-agonist treatment is likely to occur in patients treated with long-acting beta-agonists

Selection of confounding variables should not be based on observed associations with exposure

In observational studies, selection of confounding variables for adjustment is often based on observed baseline incomparability. The aim of this study was to evaluate this selection strategy. We used clinical data on the effects of inhaled long-acting beta-agonist (LABA) use on the risk of mortality among patients with obstructive pulmonary disease to illustrate the impact of selection of confounding variables for adjustment based on baseline comparisons. Among 2,394 asthma and COPD patients included in the analyses, the LABA ever-users were considerably older than never-users, but cardiovascular co-morbidity was equally prevalent (19.9% vs. 19.9%). Adjustment for cardiovascular co-morbidity status did not affect the crude risk ratio (RR) for mortality: crude RR 1.19 (95% CI 0.93–1.51) versus RR 1.19 (95% CI 0.94–1.50) after adjustment for cardiovascular co-morbidity. However, after adjustment for age (RR 0.95, 95% CI 0.76–1.19), additional adjustment for cardiovascular co-morbidity status did affect the association between LABA use and mortality (RR 1.01, 95% CI 0.80–1.26). Confounding variables should not be discarded based on balanced distributions among exposure groups, because residual confounding due to the omission of confounding variables from the adjustment model can be relevant

Metformin-induced lactic acidosis: a case series

<p>Abstract</p> <p>Introduction</p> <p>Unlike other agents used in the treatment of type 2 diabetes mellitus, metformin has been shown to reduce mortality in obese patients. It is therefore being increasingly used in higher doses. The major concern of many physicians is a possible risk of lactic acidosis. The reported frequency of metformin related lactic acidosis is 0.05 per 1000 patient-years; some authors advocate that this rate is equal in those patients not taking metformin.</p> <p>Case presentation</p> <p>We present two case reports of metformin-associated lactic acidosis. The first case is a 77 year old female with a past medical history of hypertension and type 2 diabetes mellitus who had recently been prescribed metformin (3 g/day), perindopril and acetylsalicylic acid. She was admitted to the emergency department two weeks later with abdominal pain and psychomotor agitation. Physical examination revealed only signs of poor perfusion. Laboratory evaluation revealed hyperkalemia, elevated creatinine and blood urea nitrogen and mild leukocytosis. Arterial blood gases showed severe lactic acidemia. She was admitted to the intensive care unit. Vasopressor and ventilatory support was initiated and continuous venovenous hemodiafiltration was instituted. Twenty-four hours later, full clinical recovery was observed, with return to a normal serum lactate level. The patient was discharged from the intensive care unit on the sixth day. The second patient is a 69 year old male with a past medical history of hypertension, type 2 diabetes mellitus and ischemic heart disease who was on metformin (4 g/day), glycazide, acetylsalicylic acid and isosorbide dinitrate. He was admitted to the emergency department in shock with extreme bradycardia. Initial evaluation revealed severe lactic acidosis and elevated creatinine and urea. The patient was admitted to the Intensive Care Unit and commenced on continuous venovenous hemodiafiltration in addition to other supportive measures. A progressive recovery was observed and he was discharged from the intensive care unit on the seventh day.</p> <p>Conclusion</p> <p>We present two case reports of severe lactic acidosis most probably associated with high doses of metformin in patients with no known contraindications for metformin prescription. In both patients no other condition was identified to cause such severe lactic acidosis. Although controversial, lactic acidosis should be considered in patients taking metformin.</p

Early star-forming galaxies and the reionization of the Universe

Star forming galaxies represent a valuable tracer of cosmic history. Recent observational progress with Hubble Space Telescope has led to the discovery and study of the earliest-known galaxies corresponding to a period when the Universe was only ~800 million years old. Intense ultraviolet radiation from these early galaxies probably induced a major event in cosmic history: the reionization of intergalactic hydrogen. New techniques are being developed to understand the properties of these most distant galaxies and determine their influence on the evolution of the universe.Comment: Review article appearing in Nature. This posting reflects a submitted version of the review formatted by the authors, in accordance with Nature publication policies. For the official, published version of the review, please see http://www.nature.com/nature/archive/index.htm

Improved outcomes in patients with chronic obstructive pulmonary disease treated with salmeterol compared with placebo/usual therapy: results of a meta-analysis

BACKGROUND: Several studies have demonstrated that long-acting β(2)-agonists such as salmeterol are beneficial in chronic obstructive pulmonary disease (COPD). A meta-analysis was therefore conducted to review studies in COPD to provide pooled estimates of the effect of salmeterol 50 mcg taken twice daily in addition to usual therapy on several clinically relevant endpoints, when compared with placebo/usual therapy. METHODS: An extensive search of literature and clinical trial databases was conducted using the terms salmeterol, COPD, chronic, obstructive, bronchitis and emphysema. Nine randomized, double-blind, parallel-group, placebo-controlled trials of ≥12 week duration with salmeterol 50 mcg bid treatment in COPD were included (>3500 patients), with a further 14 trials excluded due to study design or reporting timelines. All patients were included, and a sub-group of subjects (84%) with poorly reversible COPD were considered separately. Statistical testing was carried out at the 5% level, except for interaction testing which was carried out at the 10% level. RESULTS: Patients treated with salmeterol over 12 months were less likely to withdraw early from the studies (19% patients compared with 25% on their current usual therapy, p < 0.001), less likely to suffer a moderate/severe exacerbation (34% compared with 39%, p < 0.0001) and had a greater increase in average FEV(1 )(73 mL difference vs placebo/usual therapy, p < 0.0001). Similar differences were found at 3 and 6 months. At all time points, more patients experienced an improvement in health status and also a greater change with salmeterol than with placebo/usual therapy (p < 0.002). There was no evidence of tachyphylaxis to salmeterol over 12 months. CONCLUSION: The meta-analysis confirmed clinically and statistically significant, sustained and consistent superiority of salmeterol 50 mcg bid over placebo/usual therapy on a broad range of outcome measures

Cardiac safety of indacaterol in healthy subjects: a randomized, multidose, placebo- and positive-controlled, parallel-group thorough QT study

<p>Abstract</p> <p>Background</p> <p>Indacaterol is a novel once-daily ultra long-acting β₂-agonist for the treatment of chronic obstructive pulmonary disease. It is known that β₂-agonists, like other adrenergic compounds, can prolong the QT-interval. This thorough QT/QTc study (as per ICH E14 guideline) evaluated the effect of indacaterol on the QT interval in healthy subjects.</p> <p>Methods</p> <p>In this randomized, double-blind, parallel-group, placebo- and positive-controlled (open-label moxifloxacin) study, non-smoking healthy subjects (18-55 years, body mass index: 18.5-32.0 kg/m²) were randomized (4:4:2:4:1) to 14-day treatment with once-daily indacaterol (150 μg, 300 μg, or 600 μg), placebo, or placebo/moxifloxacin (double-blind 14-day treatment with placebo and a single open-label dose of 400 mg moxifloxacin on Day 14). The primary endpoint was the change from baseline on Day 14 in QTcF (QT interval corrected for heart rate using Fridericia's formula).</p> <p>Results</p> <p>In total, 404 subjects were randomized to receive indacaterol (150 [n = 108], 300 [n = 108], 600 μg [n = 54]), placebo (n = 107), or placebo/moxifloxacin (n = 27); 388 subjects completed the study. Maximal time-matched mean (90% confidence intervals) treatment differences from placebo in QTcF change from baseline on Day 14 were 2.66 (0.55, 4.77), 2.98 (1.02, 4.93) and 3.34 (0.86, 5.82) ms for indacaterol 150 μg, 300 μg and 600 μg, respectively. Study sensitivity was confirmed with moxifloxacin demonstrating a significant maximal time-matched QTcF prolongation of 13.90 (10.58, 17.22) ms compared to placebo. All indacaterol doses were well tolerated.</p> <p>Conclusion</p> <p>Indacaterol, at doses up to 600 μg once daily (2-4 times the therapeutic dose) does not have any clinically relevant effect on the QT interval.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT01263808">NCT01263808</a></p

Insulin versus oral agents in the management of Cystic Fibrosis Related Diabetes: a case based study

BACKGROUND: Insulin is the recommend therapeutic agent of choice for the management of Cystic Fibrosis Related Diabetes (CFRD), despite only sub-optimal reductions in glycemic control and increased morbidity and mortality reported by centers using this agent. The newer insulin sensitizing agents demonstrated to have anti-inflammatory mechanisms may provide an alternative management option for CFRD. METHODS: A prospective case based therapeutic comparison between insulin, sulfonylurea, metformin and thiazolidinedione was observed over one decade with 20 CFRD patients diagnosed using American Diabetes Association guideline standards. Patients entering the study elected treatment based on risk and benefit information provided for treatment options. Patients receiving organ transplant or requiring combination diabetic medications were excluded from the study. RESULTS: No statistical advantage was achieved regarding overall glycemic control for oral agents over insulin. Additional outcome measures including changes in weight, liver function testing and FEV(1 )were not statistically significant. CONCLUSION: Insulin alone may not be the only therapeutic option in managing CFRD. Oral hypoglycemic agents were equally effective in treating CFRD and may provide an alternative class of agents for patients reluctant in using insulin

Metformin treatment in diabetes and heart failure: when academic equipoise meets clinical reality

<p>Abstract</p> <p>Objective</p> <p>Metformin has had a 'black box' contraindication in diabetic patients with heart failure (HF), but many believe it to be the treatment of choice in this setting. Therefore, we attempted to conduct a pilot study to evaluate the feasibility of undertaking a large randomized controlled trial with clinical endpoints.</p> <p>Study Design</p> <p>The pilot study was a randomized double blinded placebo controlled trial. Patients with HF and type 2 diabetes were screened in hospitals and HF clinics in Edmonton, Alberta, Canada (population ~1 million). Major exclusion criteria included the current use of insulin or high dose metformin, decreased renal function, or a glycosylated hemoglobin <7%. Patients were to be randomized to 1500 mg of metformin daily or matching placebo and followed for 6 months for a variety of functional outcomes, as well as clinical events.</p> <p>Results</p> <p>Fifty-eight patients were screened over a six month period and all were excluded. Because of futility with respect to enrollment, the pilot study was abandoned. The mean age of screened patients was 77 (SD 9) years and 57% were male. The main reasons for exclusion were: use of insulin therapy (n = 23; 40%), glycosylated hemoglobin <7% (n = 17; 29%) and current use of high dose metformin (n = 12; 21%). Overall, contraindicated metformin therapy was the most commonly prescribed oral antihyperglycemic agent (n = 27; 51%). On average, patients were receiving 1,706 mg (SD 488 mg) of metformin daily and 12 (44%) used only metformin.</p> <p>Conclusion</p> <p>Despite uncertainty in the scientific literature, there does not appear to be clinical uncertainty with regards to the safety or effectiveness of metformin in HF making a definitive randomized trial virtually impossible.</p> <p>Trial registration</p> <p>ClinicalTrials.gov Identifier: NCT00325910</p