Noninterventional studies in the COVID-19 era: methodological considerations for study design and analysis.

The global COVID-19 pandemic has generated enormous morbidity and mortality, as well as large health system disruptions including changes in use of prescription medications, outpatient encounters, emergency department admissions, and hospitalizations. These pandemic-related disruptions are reflected in real-world data derived from electronic medical records, administrative claims, disease or medication registries, and mobile devices. We discuss how pandemic-related disruptions in healthcare utilization may impact the conduct of noninterventional studies designed to characterize the utilization and estimate the effects of medical interventions on health-related outcomes. Using hypothetical studies, we highlight consequences that the pandemic may have on study design elements including participant selection and ascertainment of exposures, outcomes, and covariates. We discuss the implications of these pandemic-related disruptions on possible threats to external validity (participant selection) and internal validity (for example, confounding, selection bias, missing data bias). These concerns may be amplified in populations disproportionately impacted by COVID-19, such as racial/ethnic minorities, rural residents, or people experiencing poverty. We propose a general framework for researchers to carefully consider during the design and analysis of noninterventional studies that use real-world data from the COVID-19 era.

Incidence of catheter-related complications among Japanese patients with central venous catheters as well as patients with short bowel syndrome.

PURPOSE: Short bowel syndrome (SBS) is a serious rare disorder that is usually managed with parenteral nutrition. Central venous catheter (CVC)-related complications are known to occur, but their incidence rates (IRs) in Japan are unknown. The aim of this study was to estimate the incidence of complications in Japanese patients with CVCs, including patients with SBS using CVCs. PATIENTS AND METHODS: A retrospective cohort study in 64,817 patients with CVCs, including 81 patients with SBS, between April 2008 and October 2016 using a claims database in Japan was conducted. IRs of complications were calculated as total events divided by total catheter-days among all patients with CVCs and among patients with SBS. RESULTS: The majority (>90%) of patients in the CVC and SBS cohorts were ≥18 years old. Overall, IRs of any type of complication were numerically higher in patients with SBS compared with all patients with CVCs (2.68 vs 1.95 cases per 1,000 catheter-days, respectively). Among patients with SBS, septicemia, infection, and inflammatory reaction were the only complications observed. The complications with the highest incidence were catheter-related bloodstream infections (CRBSIs) in both the overall CVC cohort and the SBS cohort with IRs of 1.35 and 2.68 cases per 1,000 catheter-days, respectively. The IR of any CVC-related complication was numerically higher in patients with SBS with cancer vs without cancer (3.44 vs 1.86 cases per 1,000 catheter-days, respectively). CONCLUSION: Our study quantifies the incidence of complications in patients with CVCs, including those with SBS, in Japan.

Effect of Serum Triglycerides on Clinical Outcomes in Acute Pancreatitis: Findings From a Regional Integrated Health Care System.

OBJECTIVES: The aim of this study was to evaluate the effect of serum triglycerides on the development of multiple or persistent organ failure in patients with acute pancreatitis. METHODS: A retrospective cohort study was conducted among patients hospitalized for acute pancreatitis between 2006 and 2013. Triglyceride levels measured before and within 72 hours of admission were compared. In addition, the effect of triglyceride levels on the development of multiple or persistent organ failure during hospitalization for acute pancreatitis was assessed. RESULTS: Among 2519 patients, 267 patients (10.6%) developed organ failure, of which 75 patients developed multiple system organ failure and 82 patients developed persistent organ failure. Triglyceride levels in patients who developed organ failure were initially much higher than in patients who did not develop organ failure, but by 72 hours into admission, approached levels of patients who did not develop organ failure. Approximately 8% of patients had triglyceride levels greater than 500 mg/dL, the majority of which had similarly high levels before admission. CONCLUSIONS: Increased triglyceride levels were associated with the development of multiple or persistent organ failure among patients hospitalized with acute pancreatitis. Patients with high triglyceride levels at the time of admission were likely to have high triglyceride levels before admission.

A prospective observational study of oseltamivir safety and tolerability in infants and young children ≤24 months.

PURPOSE: Infants and young children are at elevated risk of influenza-associated complications, but information on the safety of antiviral therapies is limited in this age group. METHODS: In this prospective open-label observational safety study, children aged ≤24 months with a clinical diagnosis of influenza in routine practice received either no antiviral treatment ('unexposed' group) or oseltamivir treatment or prophylaxis ('exposed' group), according to the physician's judgment. Patients were followed up for 30 days after the baseline visit. RESULTS: Adverse events (AEs) were analysed in 1065 patients; they were reported in 390/711 (54.9%) in the unexposed group, 167/340 (49.1%) patients in the exposed group, and 6/14 prophylaxis patients. Cough and rhinitis were the most common events, reported more often in unexposed children (22.9 and 20.3% respectively) than in exposed children (13.2 and 10.0%; p < 0.001); pyrexia, diarrhoea and vomiting were less common, occurring at similar rates in exposed and unexposed patients. Nasal congestion (3.5%), bronchitis (5.6%) and upper respiratory tract infection (1.5%) were reported more frequently in exposed patients than in unexposed patients (0.7, 2.7 and 0.1% respectively; p < 0.05). In the exposed group, 11.2% of patients (n = 38) experienced 41 AEs considered at least possibly related to oseltamivir, none being assessed as serious. Overall, there were 79 serious AEs in 59 patients. Eleven discontinued treatment because of an AE. CONCLUSIONS: Oseltamivir has a good tolerability profile in infants and children aged ≤24 months. These findings contributed to the recent FDA approval of oseltamivir for treating infants aged 2-51 weeks.

Incidence of genitourinary conditions in women with a diagnosis of vulvar/vaginal atrophy.

OBJECTIVES: Vulvar/vaginal atrophy (VVA) is one genitourinary condition associated with a decline in estrogen. This may be bothersome for women following menopause. Although the clinical features of VVA and other conditions after menopause have been documented, few studies have quantified the magnitude of association between VVA and other genitourinary conditions. METHODS: A VVA cohort was identified from two United States administrative claims databases. A matched cohort of an equal number of controls was randomly selected from a pool of women 40-79 years of age without VVA. Baseline characteristics and medical history were tabulated for the VVA cohort and matched controls. Six genitourinary conditions ('urinary tract infections', 'other/unspecified genitourinary symptoms', 'other inflammatory diseases of female pelvic organs', 'menopausal disorders', 'female genital pain and other symptoms', and 'other/unspecified female genital disorders') were hypothesized a priori to be associated with VVA. Adjusted incidence rate ratios measured the strength of association of VVA with each condition. RESULTS: A total of 9080 women aged 40-79 years with newly diagnosed VVA during 2000-2010 were identified. The mean age of VVA patients and matched controls was 60.2 years. At baseline, a significantly (p < 0.001) higher proportion of women in the VVA cohort had a diagnosis of angina, osteoporosis, migraines, insomnia, or anxiety, or received estrogen supplementation or selective estrogen receptor modulators. VVA patients had a significantly (p < 0.001) higher incidence of each of the genitourinary conditions compared to controls. The condition most strongly associated with VVA with a relative risk of 6.2 was 'other inflammatory diseases of female pelvic organs'. CONCLUSIONS: Women with VVA have a greater risk of genitourinary conditions compared to those without. The overall prevalence of VVA and other genitourinary conditions may be underreported as claims data only captures information for patients under medical care and many women do not seek consultation for VVA symptoms.

Obesity in hospitalized type 2 diabetes patients: a descriptive study.

BACKGROUND: The association between obesity and type 2 diabetes has been well documented in epidemiological studies. Patients with type 2 diabetes have a higher body weight than control populations. Relatively few studies, however, have examined the prevalence of obesity in a cohort of hospitalized type 2 diabetes mellitus patients using an electronic health records database. This study measured the prevalence of obesity in hospitalized type 2 diabetes patients and described demographic and clinical characteristics using electronic health records from Convergence CT sites located in the southwestern United States. MATERIAL AND METHODS: Hospitalized patients with type 2 diabetes mellitus were identified in electronic health records from the Convergence Global Research Network. Demographic and clinical characteristics were examined for hospitalized patients with type 2 diabetes. Comparisons were made between males and females across different clinical characteristics as well as between obese patients (BMI ≥30 kg/m2) and patients with BMI <30 kg/m2. RESULTS: Approximately 26.8% of hospitalized type 2 diabetes patients were overweight (BMI=25-29.9 kg/m2) and 57.7% were obese (BMI ≥30 kg/m2). A higher percentage of females (61.3%) were obese compared to males (54.6%) (p=0.002). Obese patients with type 2 diabetes were younger, appeared to have inadequate glycemic control, exhibited higher blood pressure, and had worse lipid profiles compared to type 2 diabetes patients with BMI <30 kg/m2. CONCLUSIONS: Approximately 84.5% of the hospitalized type 2 diabetes patients identified in this study were overweight or obese (BMI ≥25 kg/m2), suggesting the need for effective weight loss intervention in this population.

Rheumatoid arthritis and the incidence of influenza and influenza-related complications: a retrospective cohort study.

BACKGROUND: Patients with rheumatoid arthritis (RA) are known to be at increased risk of infection, particularly if they are taking drugs with immunomodulatory effects. There is a need for more information on the risk of influenza in patients with RA. METHODS: A retrospective cohort study was carried out using data gathered from a large US commercial health insurance database (Thomson Reuters Medstat MarketScan) from 1 January 2000 to 31 December 2007. Patients were ≥18 years of age, with at least two RA claims diagnoses. The database was scanned for incidence of seasonal influenza and its complications on or up to 30 days after an influenza diagnosis in RA patients and matched controls. Other factors accounted for included medical conditions, use of disease-modifying anti-rheumatic drugs (DMARDs), use of biological agents, influenza vaccination and high- or low-dose corticosteroids. Incidence rate ratios (IRRs) were calculated for influenza and its complications in patients with RA. RESULTS: 46,030 patients with RA and a matching number of controls had a median age of 57 years. The incidence of influenza was higher in RA patients than in controls (409.33 vs 306.12 cases per 100,000 patient-years), and there was a 2.75-fold increase in incidence of complications in RA. Presence or absence of DMARDs or biologics had no significant effect. The adjusted IRR of influenza was statistically significant in patients aged 60-69 years, and especially among men. A significantly increased rate of influenza complications was observed in women and in both genders combined (but not in men only) when all age groups were combined. In general, the risk of influenza complications was similar in RA patients not receiving DMARDs or biologics to that in all RA patients. Pneumonia rates were significantly higher in women with RA. Rates of stroke/myocardial infarction (MI) were higher in men, although statistical significance was borderline. CONCLUSIONS: RA is associated with increased incidence of seasonal influenza and its complications. Gender- and age-specific subgroup data indicate that women generally have a greater rate of complications than men, but that men primarily have an increased rate of stroke and MI complications. Concomitant DMARD or biological use appears not to significantly affect the rate of influenza or its complications.

Pregnancy and fetal outcomes after exposure to mefloquine in the pre- and periconception period and during pregnancy.

BACKGROUND: Pregnant women who travel to malarious areas and their clinicians need data on the safety of malaria chemoprophylaxis. METHODS: The effect of exposure to mefloquine on pregnancy and offspring outcomes was evaluated using the F. Hoffmann-La Roche global drug safety database for the time frame 31 January 1986 through 26 October 2010. We investigated pregnancy and fetal outcomes in maternal, paternal, and both-parent exposure cases with a focus on congenital malformations and fetal loss. The main outcome measures were birth defect prevalence and types of malformations. RESULTS: A total of 2506 cases of mefloquine exposure during pregnancy or in the pre- and periconception period were evaluated. Most cases were maternal prospective (outcome of the pregnancy unknown at the time of reporting; n = 2246 [89.6%]) followed by maternal retrospective cases (outcome of the pregnancy known at the time of reporting; n = 227 [9.0%]), with small numbers of paternal and both-parent exposure cases. Of the total 2246 mefloquine maternal prospective exposures (95.2%), 2139 occurred before conception and/or during the first trimester. Of 1383 maternal prospective cases with known outcome, 978 (70.7%) resulted in delivery, 405 (29.3%) resulted in abortion (112 spontaneous, 293 therapeutic), and 43 resulted in birth defects, corresponding to a birth defect prevalence of 4.39% (43 of 978). Prospective cases overall showed no specific pattern of birth malformations. CONCLUSIONS: The drug safety database analysis of mefloquine exposure in pregnancy showed that the birth defect prevalence and fetal loss in maternal, prospectively monitored cases were comparable to background rates.

Body mass index and the incidence of influenza-associated pneumonia in a UK primary care cohort.

BACKGROUND: Accumulating data suggest an association between increased BMI/obesity and morbidity in patients with pandemic (H1N1) 2009 influenza. Information on metabolic status and prognosis in seasonal influenza is lacking, however. METHODS: A retrospective cohort study was carried out using the UK General Practice Research Database. Patients aged ≥18 with ≥1 recorded BMI in the 12-58 kg/m(2) range between January 1, 2000, and December 31, 2007, were observed for an influenza-associated pneumonia diagnosis after the date of baseline BMI, including 'influenza with pneumonia' or a diagnosis of 'pneumonia' up to 30 days after a diagnosis of 'influenza'. RESULTS: A total of 1,074,315 patients were included, of whom 73·2% were within the reference BMI range or overweight and 2·2% were underweight (<18·5 kg/m(2)). Pneumonia rates were 32·33-37·48/100,000 in all BMI categories except the underweight (98·29/100,000). Relative to patients with acceptable weight, those who were underweight had an increased pneumonia rate [adjusted IRR = 2·32 (95% CI 1·80-2·94)], while being overweight (BMI = 25·0-29·9 kg/m(2)) or obese (BMI ≥ 30·0 kg/m(2)) was associated with a decreased pneumonia rate [adjusted IRR = 0·77 (95% CI 0·68-0·86) and 0·85 (95% CI 0·73-1·00), respectively]. On the other hand, women and obese women with type 2 diabetes had increased pneumonia rates [adjusted IRR = 1·37 (95% CI 1·08-1·72) and 1·47 (95%CI 1·01-2·06), respectively]. CONCLUSIONS: In contrast to initial data from pandemic influenza, influenza pneumonia, and pneumonia following influenza were the most common in underweight persons, and an apparent decreased rate of pneumonia was noted with increasing BMI categories. Women with type 2 diabetes had increased rates of pneumonia.

Treatment persistence in and cost of therapy for patients with chronic hepatitis C: Peginterferon alfa-2a plus ribavirin versus peginterferon alfa-2b plus ribavirin.

PURPOSE: Treatment persistence and cost of therapy for patients with chronic hepatitis C (CHC) treated with peginterferon alfa-2a plus ribavirin and peginterferon alfa-2b plus ribavirin were evaluated. METHODS: This retrospective database analysis used eligibility, pharmacy, and medical claims data from a large U.S. health plan for patients with CHC treated with peginterferon alfa-2a plus ribavirin and peginterferon alfa-2b plus ribavirin from January 2002 through June 2006. For the purposes of this analysis, the study population included all hepatitis C virus (HCV) genotypes. Comparable groups for assessment of outcomes were constructed using propensity score matching to reduce the effect of known sources of bias. Outcome variables included treatment persistence and annualized overall and HCV-attributable health care costs. RESULTS: A total of 1783 matched pairs were analyzed. Compared with patients receiving peginterferon alfa-2a plus ribavirin, patients receiving peginterferon alfa-2b plus ribavirin were 18% less likely to be persistent with therapy at week 48 (p = 0.013). During the first six months of follow-up, mean all-cause costs (p = 0.0368) and HCV-attributable costs (p < 0.0001) were significantly lower for peginterferon alfa-2a plus ribavirin than for peginterferon alfa-2b plus ribavirin. Mean annualized all-cause costs (p = 0.0060) and HCV-attributable costs (p = 0.0167) over the entire follow-up period were significantly lower for patients treated with peginterferon alfa-2a plus ribavirin versus peginterferon alfa-2b plus ribavirin. CONCLUSION: Analysis of information from a health care claims database suggests that treating CHC with peginterferon alfa-2a plus ribavirin may improve treatment persistence and help reduce the health care costs imposed by CHC compared with treatment with peginterferon alfa-2b plus ribavirin.

Effects of oseltamivir on influenza-related complications in children with chronic medical conditions.

OBJECTIVE: This study investigated the influence of oseltamivir on influenza-related complications and hospitalizations for children and adolescents, 1 to 17 years of age, with chronic medical conditions or neurologic or neuromuscular disease. METHODS: In a retrospective study, outcomes for patients who were given oseltamivir within 1 day after influenza diagnosis were compared with those for patients who received no antiviral therapy. Anonymous data from MarketScan databases (Thomson Reuters, Cambridge, MA) were used to identify patients from 6 influenza seasons between 2000 and 2006. The study outcomes were frequencies of pneumonia, respiratory illnesses other than pneumonia, otitis media, and hospitalization. RESULTS: Oseltamivir was prescribed for 1634 patients according to the study criteria, and 3721 patients received no antiviral therapy for their influenza. After adjustment for demographic and medical history variables, oseltamivir was associated with significant reductions in the risks of respiratory illnesses other than pneumonia, otitis media and its complications, and all-cause hospitalization in the 14 days after influenza diagnosis. Analyses for 30 days after influenza diagnosis also showed significant risk reductions for respiratory illnesses other than pneumonia, otitis media and its complications, and all-cause hospitalization with oseltamivir. CONCLUSION: When it was prescribed at influenza diagnosis, oseltamivir was associated with reduced risks of influenza-related complications and hospitalizations for children and adolescents at high risk of influenza complications.

Risk of severe gastrointestinal events in women treated with monthly ibandronate or weekly alendronate and risedronate.

BACKGROUND: Bisphosphonate (BP)-related gastrointestinal (GI) adverse events can lead to discontinuation of osteoporosis treatment. Irritation of the GI tract related to BPs may be worsened by more frequent administration. OBJECTIVE: To compare the number of women who experienced severe GI events within 3 months of starting once-monthly oral ibandronate with those starting once-weekly oral BP (alendronate or risedronate). METHODS: In a retrospective database study design, eligible women with a new prescription for monthly ibandronate were propensity-matched to women with a new weekly BP prescription. Patients had continuous health plan enrollment for 6 months prior to the index date and for 3 months after the index date. Women with previous intravenous BP treatment, Paget's disease, or oral BP treatment within the 6-month preindex period were excluded. Severe GI events (including acute events involving perforation or bleeding/perforation) within 3 months of treatment initiation were identified by ICD-9 and Current Procedural Terminology codes. A post hoc analysis assessed treatment discontinuation after severe GI events. GI-related healthcare utilization rates and costs were also compared. RESULTS: Of the 8608 patients per group, 45 (0.52%) who were receiving monthly ibandronate and 70 (0.81%) of those receiving weekly BP treatment experienced a severe GI event. Ibandronate patients had a 36% reduction in the risk of severe GI events compared with weekly BP users (OR 0.64, 95% CI 0.44 to 0.93). Significantly more women receiving a weekly BP discontinued treatment after a severe GI event compared with those receiving ibandronate (100% vs 55.6%; p < 0.001). Most healthcare utilization outcomes were not significantly different between the 2 groups; outpatient visits were significantly higher for ibandronate (p = 0.02). Costs were not significantly different between the 2 groups. CONCLUSIONS: Patients receiving monthly ibandronate therapy had a significantly reduced risk of severe GI events compared with those receiving weekly BP treatment. In addition, patients receiving a weekly BP were more likely to discontinue treatment after a severe GI event.

Antiviral and antibiotic prescribing for influenza in primary care.

BACKGROUND: Anti-influenza antiviral medications reduce influenza-related morbidity, but may often be used inappropriately. OBJECTIVE: To measure the rate of antiviral and antibiotic prescribing, the appropriateness of antiviral prescribing, and evaluate independent predictors of antiviral and antibiotic prescribing for influenza in primary care. DESIGN AND PATIENTS: Retrospective analysis of 958 visits of clinician-diagnosed influenza in 21 primary care clinics in eastern Massachusetts from 1999 to 2007. We considered antiviral prescribing appropriate if patients had symptoms for 2 or fewer days, had fever, and any 2 of headache, sore throat, cough, or myalgias. MEASUREMENTS AND MAIN RESULTS: Clinicians prescribed antivirals in 557 (58%) visits and antibiotics in 104 visits (11%). Of antiviral prescriptions, 38% were not appropriate, most commonly because of symptoms for more than 2 days (24% of antiviral prescriptions). In multivariate modeling, selected independent predictors of antiviral prescribing were symptom duration of 2 or fewer days (odds ratio [OR], 12.4; 95% confidence interval [CI], 8.3 to 18.6), year (OR, 1.4 for each successive influenza season; 95% CI, 1.3 to 1.7), patient age (OR, 1.3 per decade; 95% CI, 1.2 to 1.5), and, compared to having no influenza testing, having a negative influenza test (OR, 5.5; 95% CI, 3.4 to 9.1) or a positive influenza test (OR, 11.4; 95% CI, 6.7 to 19.3). Independent predictors of antibiotic prescribing included otoscopic abnormalities (OR, 3.3; 95% CI, 1.8 to 6.0), abnormal lung examination (OR, 4.0; 95% CI, 2.1 to 6.2), and having a chest x-ray performed (OR, 2.2; 95% CI, 1.3 to 3.8). CONCLUSIONS: Primary care clinicians are much more likely to prescribe antivirals to patients with symptoms for 2 or fewer days, but also commonly prescribe antivirals inappropriately.

The influence of oseltamivir treatment on the risk of stroke after influenza infection.

OBJECTIVES: It was the aim of this study to examine the influence of the antiviral medication oseltamivir on stroke and transient ischemic attack (TIA) in adults diagnosed with influenza. METHODS: This retrospective cohort study used medical and pharmaceutical claims data from May 2000 to September 2006 from an administrative claims database. Episodes of stroke/TIA in the 6 months after influenza in adults (aged > or =18 years) prescribed oseltamivir within 1 day before or 2 days after influenza diagnosis (oseltamivir cohort), and adults prescribed no antivirals (comparison cohort) were compared using multivariate analyses adjusted for demographic and clinical risk factors. RESULTS: The oseltamivir cohort comprised 49,238 patients and the comparison cohort 102,692 patients. Oseltamivir was associated with a 28% reduction in risk of stroke/TIA in the 6 months after influenza [hazard ratio (HR) 0.72; 95% CI 0.62-0.82] and with significant reductions after 1 and 3 months. In patients <65 years of age, there was a 34% risk reduction with oseltamivir after 6 months (HR 0.66; 95% CI 0.56-0.77) and also significant reductions after 1 and 3 months. In those aged > or =65 years, there was a 51% reduction in risk after 1 month (HR 0.49; 95% CI 0.27-0.91). CONCLUSIONS: Prescription of oseltamivir for influenza is associated with a reduced risk of stroke/TIA.

Oseltamivir and influenza-related complications, hospitalization and healthcare expenditure in healthy adults and children.

OBJECTIVE: To assess influenza-related secondary complications and healthcare use and costs in patients prescribed oseltamivir for influenza. RESEARCH DESIGN AND METHODS: This study examined health insurance claims data for patients diagnosed with influenza during five influenza seasons. Patients prescribed oseltamivir were propensity matched with patients not prescribed antiviral therapy. MAIN OUTCOME MEASURES: Clinical outcomes were diagnosis with pneumonia, otitis media and hospitalizations, along with in-patient, out-patient and pharmacy use and costs. RESULTS: Each group included 45,751 patients. Patients prescribed oseltamivir had significant reductions in the risks of pneumonia (odds ratio [OR]: 0.89, 95% CI: 0.80, 1.00), otitis media (OR: 0.84, 95% CI: 0.77, 0.91) and hospitalization (OR: 0.71, 95% CI: 0.62, 0.83). The risks of pneumonia and otitis media were also lower in children and adolescents (< or = 17 years) prescribed oseltamivir (OR: 0.74, 95% CI: 0.60, 0.91 and OR: 0.77, 95% CI: 0.69, 0.85, respectively). Total healthcare costs were lower for patients prescribed oseltamivir versus no antiviral therapy (mean US$500 versus 510; p < 0.0001). Patients prescribed oseltamivir had fewer claims per patient for antibiotics (0.37 versus 0.45; p < 0.0001), fewer physician visits (1.72 versus 1.78; p < 0.0001), emergency room visits (0.11 versus 0.12; p < 0.0001), and spent fewer days in hospital (0.04 versus 0.05; p < 0.0001). CONCLUSION: The risks of influenza-related complications and hospitalization, as well as healthcare use and costs, were lower for patients prescribed oseltamivir than for those with no antiviral prescription.

Ibandronate and the risk of non-vertebral and clinical fractures in women with postmenopausal osteoporosis: results of a meta-analysis of phase III studies.

OBJECTIVE: The marketed doses of ibandronate, 150 mg once-monthly oral and 3 mg quarterly intravenous (IV) injection, produce greater increases in lumbar spine bone mineral density than treatment with the 2.5 mg oral daily dose. This meta-analysis assessed whether these doses also reduce fracture risk relative to placebo. STUDY DESIGN AND METHODS: Individual patient data from the intent-to-treat populations of the BONE, IV fracture prevention, MOBILE, and DIVA studies were grouped into three dose levels based on annual cumulative exposure (ACE), defined as the annual dose (mg) x bioavailability (0.6%, oral; 100%, IV) or placebo. Six key non-vertebral fractures (NVFs) (clavicle, humerus, wrist, pelvis, hip, and leg), all NVFs, and all clinical fractures were examined. RESULTS: This meta-analysis included 8710 patients. Cox proportional-hazards models estimated the adjusted relative risk (RR) for fracture with ibandronate versus placebo, and time to fracture was compared using log-rank tests. The high-dose group (ACE > or = 10.8 mg) showed significant reductions in the adjusted RR of key NVFs (34.4%, p = 0.032), all NVFs (29.9%, p = 0.041), and clinical fractures (28.8%, p = 0.010) relative to placebo. The high-dose group also had significantly longer time to fracture versus placebo for key NVFs (p = 0.031), all NVFs (p = 0.025), and clinical fractures (p = 0.002). Study limitations included: not all studies were placebo-controlled; a limited number of baseline characteristics were available for multivariate analyses. CONCLUSION: Ibandronate at dose levels of ACE > or = 10.8 mg, which includes the marketed 150 mg once-monthly oral and 3 mg quarterly IV injection regimens, may provide significant non-vertebral and clinical fracture efficacy.

Oseltamivir and the risk of influenza-related complications and hospitalizations in patients with diabetes.

OBJECTIVE: This subgroup analysis of a retrospective cohort study examined, from a managed care perspective, the risk of influenza-related complications and hospitalizations in patients with diabetes who were prescribed oseltamivir for the treatment of influenza and those who were not prescribed antiviral treatment. METHODS: Health insurance claims data from the Thomson Healthcare MarketScan Research Database for 6 influenza seasons (October 1-March 31) between 2000 and 2006 were used to identify patients aged >/=18 years with influenza and diabetes. Patients who received a prescription for oseltamivir within 1 day of a diagnosis of influenza were compared with those who received no antiviral treatment. Outcomes included the frequency of pneumonia, respiratory diagnoses, and otitis media and its complications, and rates of hospitalization within 14 days of the diagnosis of influenza. Cox proportional hazards regression was used to determine the relative risk (RR) of influenza-related complications and hospitalizations. RESULTS: A total of 9090 patients with diabetes and a diagnosis of influenza were identified who met all study criteria. Of these, 2919 (32%) received a prescription for oseltamivir and 6171 (68%) received no antiviral treatment. Patients receiving oseltamivir had a significant 17% reduction in the risk of respiratory illnesses (RR = 0.83; 95% CI, 0.73-0.93) and a 30% reduction in the risk of hospitalization for any reason (RR = 0.70; 95% CI, 0.52-0.94). There were no significant differences between the oseltamivir and control groups in terms of the risks for pneumonia (RR = 0.87; 95% CI, 0.64-1.18), otitis media and its complications (RR = 0.96; 95% CI, 0.48-1.91), or hospitalization for pneumonia (RR = 0.81; 95% CI, 0.41-1.58). CONCLUSION: In this retrospective study, the risk of influenza-associated respiratory illnesses and the number of hospitalizations for any reason were reduced in patients with diabetes who were prescribed oseltamivir compared with an unmatched group that was not prescribed antiviral therapy.

Impact of oseltamivir on the incidence of secondary complications of influenza in adolescent and adult patients: results from a retrospective population-based study.

OBJECTIVE: To assess the effectiveness of oseltamivir in reducing the risks of influenza-related secondary complications in otherwise healthy adolescent and adult patients aged > or = 13 years. RESEARCH DESIGN AND METHODS: Retrospective cohort analysis utilizing health insurance claims data in the USA (Thomson MarketScan Research Database) from six influenza seasons (October-March) between 2000 and 2006 to identify adults and adolescents (> or = 13 years) with influenza. Patients who received a prescription for oseltamivir within +/-1 day of diagnosis were compared with a propensity-matched control group receiving no antiviral treatment. The first claim evidence of influenza was used to establish the study index date. Differences in outcomes were determined using Cox proportional hazards regression and expressed in terms of hazard ratios (HR) with 95% confidence intervals (CI). MAIN OUTCOME MEASURES: Diagnosis of pneumonia, any respiratory condition, otitis media and its complications, hospitalizations due to pneumonia, and hospitalization for any reason within 14 days of the index date. Healthcare expenditure within 30 days of the index date was also analyzed. RESULTS: The oseltamivir and untreated control groups each included 36 751 eligible patients. Oseltamivir use reduced the risks of otitis media and its complications by 23% (HR=0.77; 95% CI: 0.65, 0.93), any respiratory disease by 18% (HR 0.82; 95% CI: 0.79, 0.86), and hospitalization for any reason by 22% (HR 0.78; 95% CI: 0.67, 0.91). There were no differences in any other clinical outcomes, including hospitalization for respiratory disease. Healthcare expenditure did not differ between the two groups. LIMITATIONS: The retrospective nature of the study meant that the findings may be susceptible to missing or lost data. The results obtained here represent individuals enrolled in private healthcare plans and may not, therefore, be representative of the entire US population. The lack of a virologic diagnosis of influenza, and an index date based on the first diagnosis of influenza rather than first exposure or symptom onset, may have resulted in a conservative estimate of treatment effect. CONCLUSIONS: Secondary complications of influenza, such as respiratory disease and otitis media, were reduced in patients treated with oseltamivir. The risk of hospitalization for respiratory diseases was not reduced, although there was a reduction in the risk of hospitalization for any reason. Clinical benefits observed with oseltamivir were not associated with a change in healthcare costs.

A review of the literature on osteonecrosis of the jaw in patients with osteoporosis treated with oral bisphosphonates: prevalence, risk factors, and clinical characteristics.

OBJECTIVE: This literature review was performed to elucidate the relationship between bisphosphonate use and development of osteonecrosis of the jaw (ONJ) in patients receiving oral bisphosphonates for the treatment of osteoporosis. METHODS: MEDLINE, the Cochrane Database of Systematic Reviews, the Cochrane Central Register of Controlled Trials, and EMBASE were searched for English-language articles published from 1966 to September 2006 whose titles included the term osteonecrosis of the jaw in conjunction with bisphosphonates, alendronate, risedronate, ibandronate, etidronate, clodronate, zoledronic acid, or pamidronate. Articles were included in the review if the population consisted of adults with ONJ; patients received bisphosphonates for the treatment of osteoporosis only; the reported data included baseline characteristics of the study population (age; sex; comorbidities; concomitant medications; history of dental surgery, trauma, or infection), characteristics of bisphosphonate treatment (specific bisphosphonate, dose, duration of treatment, mode of administration), clinical features of ONJ (signs, symptoms, site), the treatment protocol used to manage ONJ, or the prevalence of ONJ in patients with osteoporosis treated with bisphosphonates; and the publication involved a case report, case series, or observational study. RESULTS: After application of the search strategy and the inclusion/exclusion criteria, 11 publications reporting 26 cases of ONJ in patients receiving bisphosphonates for the treatment of osteoporosis were included in the review. The most commonly affected site was the mandible (16 patients), followed by the maxilla (6 patients). Among the 23 patients whose age was reported, 18 (78%) were aged >or=60 years. Among the 23 patients whose sex was reported, only 3 (13%) were men. Of 15 patients with a history of invasive dental treatment, 12 (80%) had undergone dental surgery or experienced dental trauma at the site of ONJ. Among the 10 patients for whom the duration of bisphosphonate treatment was reported, no clear relationship between the duration of bisphosphonate treatment and the development of ONJ was observed. CONCLUSIONS: Considering that millions of patients have been prescribed bisphosphonates for the treatment of osteoporosis, the relative prevalence of ONJ in these patients was low. Age >or=60 years, female sex, and previous invasive dental treatment were the most common characteristics of those who developed ONJ. However, it is not possible to draw further conclusions about the potential association between oral bisphosphonate use and ONJ in the identified studies because of incomplete reporting and the presence of confounding factors.

FluSTAR, a novel influenza surveillance system: outcomes from the 2005-2006 flu season.

BACKGROUND: The FluSTAR Surveillance System covers most of the United States, providing local and national information on influenza and influenza-like illness that is updated twice weekly. METHODS: Descriptive statistical analyses were performed to explore demographic characteristics, symptoms, vaccination status, and treatment of patients tested for influenza, using a rapid test kit, in the FluSTAR program during the 2005 to 2006 influenza season (October 1, 2005-April 11, 2006). RESULTS: Of 17,247 patients tested, the most common age groups were 35 to 49 (20%) or 19 to 34 years (18%). Overall, 22% of tests were positive. Patients testing positive were more likely to report influenza-associated symptoms such as cough and fever than those testing negative. Most patients testing positive were prescribed antiviral agents. CONCLUSIONS: Surveillance systems such as FluSTAR can provide timely data on the circulation of influenza and influenza-like illness. This information could assist with accurate diagnosis and aid treatment decisions.