Systematic review and meta-analysis to estimate the antibacterial treatment effect of nitrofurantoin for a non-inferiority trial in uncomplicated urinary tract infection.

OBJECTIVES: Active-comparator, non-inferiority study designs are used in uncomplicated urinary tract infection (uUTI) to establish the efficacy of a new antibacterial, given the availability of effective antibiotics. Here we estimated the treatment effect of a planned antimicrobial comparator (nitrofurantoin) from historical trial data to properly design an upcoming non-inferiority trial in uUTI. METHODS: A systematic literature review and meta-analysis was conducted in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, which incorporate recommendations for standardised data quality assessment, reporting of results, risk of bias assessment and sensitivity analyses. To account for interstudy variability, a weighted, non-iterative, random-effects model was fit using R software to obtain estimates of the microbiological response rate and corresponding 95% confidence interval (CI) for nitrofurantoin and placebo treatment. Interstudy heterogeneity was assessed with Cochran's χ2 test for interstudy heterogeneity; I2 statistic and P-values were computed and included in the forest plot of the meta-analysis. RESULTS: Twelve unique studies met the final eligibility criteria for meta-analysis inclusion; three trials assessed placebo efficacy, eight trials assessed nitrofurantoin efficacy, and one study assessed both nitrofurantoin and placebo efficacy in uUTI. The overall microbiological response (95% CI) was 0.766 (0.665-0.867) for nitrofurantoin and 0.342 (0.288-0.397) for placebo. CONCLUSION: The corresponding treatment effect estimate for nitrofurantoin was 26.8%, which supports a conservative non-inferiority margin of 12.5% and is consistent with the recently published draft FDA guidance. The findings from this systematic review and meta-analysis may inform future antibacterial trials by providing non-inferiority margin justification.

Quantifying the burden of steroid-related damage in SLE in the Hopkins Lupus Cohort.

OBJECTIVE: Corticosteroids are a mainstay of SLE treatment; however, cumulative steroid exposure may lead to organ damage. This study aimed to quantify the risk of new diabetes, hypertension, cataracts, osteoporosis and avascular necrosis that is attributable to cumulative corticosteroid exposure in SLE. METHODS: Using data from the Hopkins Lupus Cohort, a longitudinal study of lupus activity, organ damage and quality of life in patients with SLE, five matched case-control analyses nested within a prospectively enrolled SLE cohort were performed. Two randomly selected controls were matched to each case using incidence-density sampling from defined risk sets. Attributable risk was calculated for steroid exposure (dose and duration, separately). Cumulative steroid dose was modelled as a four-level categorical variable using clinically relevant thresholds: 0 g (no exposure); >0 and <3.65 g (<10 mg/day for a year); ≥3.65 g and <18.25 g (1-5 years at 10 mg/day); and ≥18.25 g (>5 years at 10 mg/day). RESULTS: Eligible cases were identified for diabetes (n=42), hypertension (n=79), cataract (n=132), osteoporosis (n=118) and avascular necrosis (n=38). The unadjusted OR for a one-category increase in cumulative steroid exposure ranged from 1.157 (cataract (0.889 to 1.506); p=0.2779) to 2.183 (avascular necrosis (1.162 to 4.103); p=0.0153). After adjusting for confounding variables, a one-category increase in the cumulative steroid dose was significantly associated with risk of cataract (OR (95% CI) 1.855 (1.190 to 2.892); p=0.0064) and osteoporosis (OR (95% CI) 1.604 (1.067 to 2.412); p=0.0232). ORs for avascular necrosis, diabetes and hypertension suggested a moderately increased risk (not significant). Duration of steroid exposure was not associated with any of the outcomes. The proportion of risk attributable to steroid exposure after adjustment for covariates was 0.711 for cataract and 0.540 for osteoporosis. CONCLUSIONS: Cumulative steroid exposure was associated with an increased risk of cataract and osteoporosis in patients with SLE. TRIAL REGISTRATION NUMBER: NCT01616472.

Renal Remission Status and Longterm Renal Survival in Patients with Lupus Nephritis: A Retrospective Cohort Analysis.

OBJECTIVE: This observational study was a retrospective analysis of prospectively collected Hopkins Lupus Cohort data to compare longterm renal survival in patients with lupus nephritis (LN) who achieved complete (CR), partial (PR), or no remission following standard-of-care LN induction therapy. METHODS: Eligible patients with biopsy-proven LN (revised American College of Rheumatology or Systemic Lupus Collaborating Clinics criteria) were identified and categorized into ordinal (CR, PR, or no remission) or binary (response or no response) renal remission categories at 24 months post-diagnosis [modified Aspreva Lupus Management Study (mALMS) and modified Belimumab International Lupus Nephritis Study (mBLISS-LN) criteria]. The primary endpoint was longterm renal survival [without endstage renal disease (ESRD) or death]. RESULTS: In total, 176 patients met the inclusion criteria. At Month 24 postbiopsy, more patients met mALMS remission criteria (CR = 59.1%, PR = 30.1%) than mBLISS-LN criteria (CR = 40.9%, PR = 16.5%). During subsequent followup, 18 patients developed ESRD or died. Kaplan-Meier plots suggested patients with no remission at Month 24 were more likely than those with PR or CR to develop the outcome using either mALMS (p = 0.0038) and mBLISS-LN (p = 0.0097) criteria for remission. Based on Cox regression models adjusted for key confounders, those in CR according to the mBLISS-LN (HR 0.254, 95% CI 0.082-0.787; p = 0.0176) and mALMS criteria (HR 0.228, 95% CI 0.063-0.828; p = 0.0246) were significantly less likely to experience ESRD/mortality than those not in remission. CONCLUSION: Renal remission status at 24 months following LN diagnosis is a significant predictor of longterm renal survival, and a clinically relevant endpoint.

Cost-utility analysis of genotype-guided antiplatelet therapy in patients with moderate-to-high risk acute coronary syndrome and planned percutaneous coronary intervention.

BACKGROUND: Prasugrel is recommended over clopidogrel in poor/intermediate CYP2C19 metabolizers with acute coronary syndrome (ACS) and planned percutaneous coronary intervention (PCI), reducing the risk of ischemic events. CYP2C19 genetic testing can guide antiplatelet therapy in ACS patients. OBJECTIVE: The purpose of this study was to evaluate the cost-utility of genotype-guided treatment, compared with prasugrel or generic clopidogrel treatment without genotyping, from the US healthcare provider's perspective. METHODS: A decision model was developed to project lifetime economic and humanistic burden associated with clinical outcomes (myocardial infarction [MI], stroke and major bleeding) for the three strategies in patients with ACS. Probabilities, costs and age-adjusted quality of life were identified through systematic literature review. Incremental cost-utility ratios (ICURs) were calculated for the treatment strategies, with quality-adjusted life years (QALYs) as the primary effectiveness outcome. Relative risk of developing myocardial infarction and stroke between patients with and without variant CYP2C19 when receiving clopidogrel were estimated to be 1.34 and 3.66, respectively. One-way and probabilistic sensitivity analyses were performed. RESULTS: Clopidogrel cost USD19,147 and provided 10.03 QALYs versus prasugrel (USD21,425, 10.04 QALYs) and genotype-guided therapy (USD19,231, 10.05 QALYs). The ICUR of genotype-guided therapy compared with clopidogrel was USD4,200. Genotype-guided therapy provided more QALYs at lower costs compared with prasugrel. Results were sensitive to the cost of clopidogrel and relative risk of myocardial infarction and stroke between CYP2C19 variant vs. non-variant. Net monetary benefit curves showed that genotype-guided therapy had at least 70% likelihood of being the most cost-effective alternative at a willingness-to-pay of USD100,000/QALY. In comparison with clopidogrel, prasugrel therapy was more cost-effective with <21% certainty at willingness-to-pay of >USD170,000/QALY. CONCLUSIONS: Our modeling analyses suggest that genotype-guided therapy is a cost-effective strategy in patients with acute coronary syndrome undergoing planned percutaneous coronary intervention.

Impact of early versus late systemic lupus erythematosus diagnosis on clinical and economic outcomes.

BACKGROUND AND OBJECTIVES: Systemic lupus erythematosus (SLE) is a multisystem complex autoimmune disease that often mimics symptoms of other illnesses, which complicates the ability of healthcare providers to make the diagnosis. The objective of this study was to assess clinical outcomes, resource utilization, and costs between patients with earlier versus later SLE diagnosis. METHODS: Patients aged 18-64 years were identified from a large US commercial claims database between January 2000 and June 2010. Confirmed SLE diagnosis with a claims-based algorithm required either three or more claims for a visit to a rheumatologist on separate dates with an SLE diagnosis (International Classification of Diseases [ICD-9] code 710.0x), two or more claims for visits to a rheumatologist at least 60 days apart with SLE diagnoses, or two or more claims for visits to rheumatologist less than 60 days apart with SLE diagnoses with at least one dispensing for a typical SLE medication. SLE probable onset date was identified during the 12-month baseline period by the second claim for antinuclear antibody tests or prodromal symptoms of SLE. Patients were stratified into early or late diagnosis groups based on time between probable SLE onset and diagnosis (<6 months or ≥6 months, respectively). Each patient observation period began on the date of the first medical claim, with a diagnosis code for SLE that satisfied the inclusion criteria, and ended on the earliest date between health plan disenrollment and 30 June 2010. Patients in each group were propensity-score matched on age, gender, diagnosis year, region, health plan type, and comorbidities. Flare rates and resource utilization were compared post-diagnosis between groups using rate ratios. All-cause and SLE-related costs (adjusted to 2010 US dollars) per patient per month (PPPM) were calculated. RESULTS: There were 4,166 matched patients per group. Post-SLE diagnosis, the early diagnosis group had lower rates of mild (rate ratio [RR] 0.95; 95 % CI 0.93-0.96), moderate (RR 0.96; 95 % CI 0.94-0.99), and severe (RR 0.87; 95 % CI 0.82-0.93) flares compared with the late diagnosis group. The rates of hospitalizations (RR 0.80; 95 % CI 0.75-0.85) were lower for the early diagnosis group than the late diagnosis group. Compared with late diagnosis patients, mean all-cause inpatient costs PPPM were lower for the early diagnosis patients (US$406 vs. US$486; p = 0.016). Corresponding SLE-related hospitalization costs were also lower for early compared with late diagnosis patients (US$71 vs. US$95; p = 0.013). Results were consistent for other resource use and cost categories. CONCLUSIONS: Patients diagnosed with SLE sooner may experience lower flare rates, less healthcare utilization, and lower costs from a commercially insured population perspective. This finding needs to be further explored within the context of background SLE disease activity.

Identification of and intervention to address therapeutic gaps in care.

OBJECTIVES: To determine if therapeutic gap identification, notification of community pharmacists, and intervention results in increased gap closure, reduced gap closure time, and fewer adherence gaps reopening. STUDY DESIGN: Prospective, controlled, clusterrandomized study. METHODS: State of Illinois employees and beneficiaries of State health plans filling prescriptions at independently owned community pharmacies were included. For selected chronic conditions and medications, gaps in medication adherence and omitted essential therapies were identified from prescription claims and sent as alerts for resolution with the patient and/or physician. Adherence and omission gap closure at 90 days were analyzed with Kaplan-Meier (KM) survival curve approach and Cox proportional hazards models including covariates. RESULTS: A total of 1433 intervention and 1181 control adherence gaps were identified, while 677 intervention and 534 control omission gaps were generated. Pharmacists intervened on 639 (44.6%) adherence and 506 (74.7%) omission gaps. Gaps were closed more often in intervention than control at 30 days (55.5% in intervention vs 50.6% in control), 45 days (61.1% vs 58.4%, respectively), 60 days (66.1% vs 65.2%, respectively), and 90 days (73.0% vs 72.9%, respectively; adjusted hazard ratio [HR] = 1.242; P = .022; 95% confidence interval [CI] 1.115-1.385). Adherence gaps reopened less frequently in the intervention group (HR = 0.863; P = .012; 95% CI 0.769-0.968). A total of 89 (13.1%) intervention and 29 (5.4%) control omission gaps closed within 90 days (adjusted HR = 1.770; P = .005; 95% CI 1.182-2.653). CONCLUSIONS: Independent community pharmacists reduced gaps in care and had fewer reopened adherence gaps, suggesting improvement in adherence. A continuation study will examine the impact of the program on long-term adherence.