The global aHUS registry: methodology and initial patient characteristics.

BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is a rare, genetically-mediated systemic disease most often caused by chronic, uncontrolled complement activation that leads to systemic thrombotic microangiopathy (TMA) and renal and other end-organ damage. METHODS: The global aHUS Registry, initiated in April 2012, is an observational, noninterventional, multicenter registry designed to collect demographic characteristics, medical and disease history, treatment effectiveness and safety outcomes data for aHUS patients. The global aHUS Registry will operate for a minimum of 5 years of follow-up. Enrollment is open to all patients with a clinical diagnosis of aHUS, with no requirement for identified complement gene mutations, polymorphisms or autoantibodies or particular type of therapy/management. RESULTS: As of September 30, 2014, 516 patients from 16 countries were enrolled. At enrollment, 315 (61.0 %) were adults (≥18 years) and 201 (39.0 %) were <18 years of age. Mean (standard deviation [SD]) age at diagnosis was 22.7 (20.5) years. Nineteen percent of patients had a family history of aHUS, 60.3 % had received plasma exchange/plasma infusion, 59.5 % had a history of dialysis, and 19.6 % had received ≥1 kidney transplant. Overall, 305 patients (59.1 %) have received eculizumab. CONCLUSIONS: As enrollment and follow-up proceed, the global aHUS Registry is expected to yield valuable baseline, natural history, medical outcomes, treatment effectiveness and safety data from a diverse population of patients with aHUS. TRIAL REGISTRATION: US National Institutes of Health www.ClinicalTrials.gov Identifier NCT01522183 . Registered January 18, 2012.

Analysis of left ventricular mass in untreated men and in men treated with agalsidase-ß: data from the Fabry Registry.

PURPOSE: The aim of this study was to evaluate the progression of left ventricular hypertrophy in untreated men with Fabry disease and to assess the effects of agalsidase-ß (recombinant human α-galactosidase A) on left ventricular hypertrophy. METHODS: Longitudinal Fabry Registry data were analyzed from 115 men treated with agalsidase-ß (1 mg/kg/2 weeks) and 48 untreated men. Measurements included baseline left-ventricular mass and at least one additional left-ventricular mass assessment over ≥ 2 years. Patients were grouped into quartiles, based on left-ventricular mass slopes. Multivariate logistic regression analyses identified factors associated with left ventricular hypertrophy progression. RESULTS: For men in whom treatment was initiated at the age of 18 to <30 years, mean left ventricular mass slope was -3.6 g/year (n = 31) compared with +9.5 g/year in untreated men of that age (n = 15) (P < 0.0001). Untreated men had a 3.4-fold higher risk of having faster increases in left-ventricular mass compared with treated men (odds ratio: 3.43; 95% confidence interval: 1.05-11.22; P = 0.0415). A baseline age of ≥ 40 years was also associated with left--ventricular hypertrophy progression (odds ratio: 5.03; 95% confidence interval: 1.03-24.49; P = 0.0457) compared with men younger than 30 years. CONCLUSION: Agalsidase-ß treatment for ≥2 years may improve or stabilize left-ventricular mass in men with Fabry disease. Further investigations may determine whether early intervention and stabilization of LVM are correlated with clinical outcomes.

Long-term clinical outcomes in type 1 Gaucher disease following 10 years of imiglucerase treatment.

OBJECTIVE: We studied the effect of long-term alglucerase/imiglucerase (Ceredase®/Cerezyme®, Genzyme, a Sanofi company, Cambridge, MA, USA) treatment on hematological, visceral, and bone manifestations of Gaucher disease type 1 (GD1). METHODS: The International Collaborative Gaucher Group (ICGG) Gaucher Registry identified GD1 patients treated with alglucerase/imiglucerase who had dose and clinical data at first infusion and after 10 years of follow-up. Data for hemoglobin, platelet count, organ volumes, bone pain, and bone crisis were analyzed. Tests of the null hypothesis (no change from first infusion to 10 years) were performed using t tests for within-patient absolute change in continuous measurements and McNemar/chi-square tests for change in distributions using categorical values. An alpha level of 0.05 designated statistical significance. RESULTS: As of October 2011, 557 nonsplenectomized and 200 splenectomized patients met the inclusion criteria. The majority of GD1 patients had at least one N370S allele. Compared with nonsplenectomized patients at first infusion, splenectomized patients had lower percentages of anemia (26.0 % vs. 42.8 %) and thrombocytopenia (14.2 % vs. 76.3 %), similar percentages of moderate or severe hepatomegaly (81.2 % vs. 80.0 %), and higher percentages of bone pain (88.9 % vs. 52.4 %) and bone crises (38.3 % vs. 16.0 %). After 10 years, both groups showed significant (p < 0.05) improvements in mean hemoglobin levels, platelet count, liver, and spleen (nonsplenectomized) volumes, and bone crises. Initial dosing in both groups ranged from <15 U/kg to ≤90 U/kg every 2 weeks. After 10 years, the majority was receiving 15 to ≤45 U/kg every 2 weeks. CONCLUSION: Ten years of imiglucerase treatment results in sustainable improvements in all GD1 parameters.

Characteristics of type I Gaucher disease associated with persistent thrombocytopenia after treatment with imiglucerase for 4-5 years.

The characteristics of Gaucher disease (GD) associated with persistent thrombocytopenia despite imiglucerase enzyme therapy in type 1 GD (GD1) were investigated by retrospective analysis of International Collaborative Gaucher Group (ICGG) Registry data. The study involved 1016 GD1 patients with an intact spleen for whom date of diagnosis, therapy initiation, and platelet counts were known, and who received continuous imiglucerase therapy for 4 to 5 years. These patients were stratified by last platelet count: ≥ 120 × 10(9) /l (n = 772); ≥ 100 to <120 × 10(9) /l (n = 94); ≥ 80 to <100 × 10(9) /l (n = 80); and <80 × 10(9) /l (n = 70; 20 with <60 × 10(9) /l) and characterized by initial and cumulative average imiglucerase dose, body mass index, platelet count, anaemia, hepatomegaly, splenomegaly, and skeletal assessments at baseline and after 4-5 years of therapy. Statistically significant associations were found between persistent thrombocytopenia and baseline platelet count (<80 × 10(9) /l), splenomegaly, and anaemia (all P < 0·0001). After 4-5 years, statistically significant associations were found with splenomegaly (P < 0·0001), anaemia (P < 0·0001), white blood cell count (P = 0·049), hepatomegaly (P = 0·004) and bone pain (P = 0·035). Exponential platelet decay in relation to splenomegaly suggests that platelets increase only when spleen volume decreases substantially.

Anti-α-galactosidase A antibody response to agalsidase beta treatment: data from the Fabry Registry.

Agalsidase beta, a form of recombinant human α-galactosidase A (αGAL), is approved for use as enzyme replacement therapy (ERT) for Fabry disease. An immunogenic response against a therapeutic protein could potentially impact its efficacy or safety. The development of anti-αGAL IgG antibodies was evaluated in 571 men and 251 women from the Fabry Registry who were treated with agalsidase beta. Most men developed antibodies (416 of 571, 73%), whereas most women did not (31 of 251, 12%). Women were also significantly more likely to tolerize than men; whereas 18 of 31 women tolerized (58%, 95%CI: 52%-64%), only 47 of 416 men tolerized during the observation period (11%, 95% CI: 8%-15%). Patients who eventually tolerized had lower median peak anti-αGAL IgG antibody titers than patients who remained seropositive at their most recent assessment (400 versus 3200 in men, 200 versus 400 in women, respectively). Patients with nonsense mutations in the GLA gene were more likely to develop anti-αGAL IgG antibodies than patients with missense mutations. Approximately 26% of men (151 of 571) reported infusion-associated reactions (IARs), compared to 11% of women (27 of 251). Men who developed anti-αGAL IgG antibodies were more likely to experience IARs compared to those who remained seronegative. Nine percent of seronegative men and women (34 of 375) reported IARs. The majority of IARs occurred during the first 6 to 12 months of agalsidase beta treatment and decreased over time, in both seroconverted and seronegative patients.

Renal outcomes of agalsidase beta treatment for Fabry disease: role of proteinuria and timing of treatment initiation.

BACKGROUND: The purpose of this study was to identify determinants of renal disease progression in adults with Fabry disease during treatment with agalsidase beta. METHODS: Renal function was evaluated in 151 men and 62 women from the Fabry Registry who received agalsidase beta at an average dose of 1 mg/kg/2 weeks for at least 2 years. Patients were categorized into quartiles based on slopes of estimated glomerular filtration rate (eGFR) during treatment. Multivariate logistic regression analyses were used to identify factors associated with renal disease progression. RESULTS: Men within the first quartile had a mean eGFR slope of -0.1 mL/min/1.73m(2)/year, whereas men with the most rapid renal disease progression (Quartile 4) had a mean eGFR slope of -6.7 mL/min/1.73m(2)/year. The risk factor most strongly associated with renal disease progression was averaged urinary protein:creatinine ratio (UP/Cr) ≥1 g/g (odds ratio 112, 95% confidence interval (95% CI) 4-3109, P = 0.0054). Longer time from symptom onset to treatment was also associated with renal disease progression (odds ratio 19, 95% CI 2-184, P = 0.0098). Women in Quartile 4 had the highest averaged UP/Cr (mean 1.8 g/g) and the most rapid renal disease progression: (mean slope -4.4 mL/min/1.73m(2)/year). CONCLUSIONS: Adults with Fabry disease are at risk for progressive loss of eGFR despite enzyme replacement therapy, particularly if proteinuria is ≥1 g/g. Men with little urinary protein excretion and those who began receiving agalsidase beta sooner after the onset of symptoms had stable renal function. These findings suggest that early intervention may lead to optimal renal outcomes.

Osteopenia in Gaucher disease develops early in life: response to imiglucerase enzyme therapy in children, adolescents and adults.

BACKGROUND: In Gaucher disease (GD), acid-ß-glucosidase (GBA1) gene mutations result in defective glucocerebrosidase and variable combinations of hematological, visceral, and diverse bone disease. Osteopenia is highly prevalent, but its age of onset during the natural course of GD is not known. It is also unclear if the degree of improvement in osteopenia, secondary to imiglucerase enzyme therapy, differs by the age of the patient. OBJECTIVE: We hypothesized that osteopenia develops early in life, during the natural course of type 1 Gaucher disease (GD1), and that its response to treatment is maximal during this period. METHODS: We examined data from the International Collaborative Gaucher Group (ICGG) Gaucher Registry of patients treated with imiglucerase between the ages of 5 and 50 years. Lumbar spine bone mineral density (BMD) (determined by dual-energy X-ray absorptiometry (DXA) and expressed as Z-scores) at baseline and for up to 10 years on imiglucerase were analyzed in children (ages ≥ 5 to <12 years), adolescents (≥ 12 to <20 years), young adults (≥ 20 to < 30 years), and older adults (≥ 30 to < 50 years). BMD was correlated with other disease characteristics. Pre-treatment, descriptive statistics were applied to 5-year age categories. Non-linear mixed effects regression models were used to analyze DXA Z-scores over time after treatment with imiglucerase. RESULTS: Pre-treatment, low BMD was prevalent in all age groups, most strikingly in adolescents. DXA Z-scores were at or below -1 in 44% of children (n=43), 76% of adolescents (n=41), 54% of young adults (n=56) and 52% of older adults (n=171). The most common GBA1 genotype was N370S heteroallelic. Baseline hematological and visceral manifestations in the 4 age groups were similar. In children with DXA Z-scores ≤-1 at baseline, imiglucerase therapy for 6 years resulted in improvement of mean DXA Z-scores from -1.38 (95% CI -1.73 to -1.03) to -0.73 (95% CI -1.25 to -0.21); in young adults DXA Z-scores improved from -1.95 (95% CI -2.26 to -1.64) to -0.67 (95% CI -1.09 to -0.26). BMD also improved in older adults, but the magnitude of the improvement was lower compared to younger patients. CONCLUSIONS: Low bone density is common in GD1 with the highest prevalence rate in adolescence, a developmental period critical to attainment of peak bone mass. Imiglucerase results in amelioration of osteopenia in all age groups, with the greatest improvements in younger patients.

The incidence of Parkinsonism in patients with type 1 Gaucher disease: data from the ICGG Gaucher Registry.

PURPOSE: Investigate the incidence of Parkinsonism among patients with Gaucher disease type 1 (GD1) and describe demographics, genotypes, and Gaucher disease (GD)-related characteristics for affected and non-affected patients. STUDY TYPE: Cohort study with age- and gender-matched nested case-control analysis. Calculation of event incidence, standardized morbidity ratio, and event-free survival (Kaplan-Meier). DATA SOURCE: The International Collaborative Gaucher Group (ICGG) Gaucher Registry data as of June 2010. Study cohort: GD1 patients with any report of Parkinsonism. Pre-matching control group: All GD1 patients with no report of Parkinsonism. RESULTS: The matched study cohort comprised of 68 patients with reports of Parkinsonism and 649 patients without Parkinsonism. Demographic and clinical characteristics suggest a milder GD phenotype in patients with Parkinsonism compared to the control group. The most prevalent GD1 genotype was N370S/N370S (39% for controls; 46% for patients with Parkinsonism). Patients with Parkinsonism were diagnosed with GD1 at a mean age of 37 years compared to 31 years in control patients. The standardized morbidity ratio for the development of Parkinsonism among all GD1 patients indicated an approximately 6 to 17 fold increase over that of 2 reference populations. The mean age of reported Parkinsonism onset was 57 years compared to 60 years in the general population (Lees, Hardy, and Revesz, 2009 [1]). The probability that a patient with GD1 will develop Parkinsonism before age 70 years is 5 to 7% and 9 to 12% before age 80 years. CONCLUSIONS: The incidence of Parkinsonism among GD1 patients is significantly increased compared to two reference populations. GD1 patients with Parkinsonism have a later median age at GD diagnosis, later age at the start of treatment, and later age at death than patients with GD1 alone. The Gaucher-related clinical profile of GD1 patients with Parkinsonism is similar to or milder than the GD1 alone group. Therefore, severity of the common GD1 clinical manifestations does not appear to be predictive for the onset of Parkinsonism.

Neuronopathic Gaucher disease: demographic and clinical features of 131 patients enrolled in the International Collaborative Gaucher Group Neurological Outcomes Subregistry.

OBJECTIVE: To describe demographic, genetic, and clinical characteristics of patients with neuronopathic Gaucher disease (NGD). METHODS: All patients enrolled in the Neurological Outcomes Subregistry of the International Collaborative Gaucher Group (ICGG) Gaucher Registry as of June 2007 were identified. RESULTS: The study cohort comprised 131 patients from 17 countries who were enrolled in the Neurological Outcomes Subregistry. The onset of neurological manifestations had occurred before 2 years of age in 47% (61 out of 131 patients), 2 years of age or older in 41% (54 out of 131), and could not be ascertained in the remaining 12% (16 out of 131). The most common manifestations were inability to look to the extreme up or down (45%, 55 out of 123), abnormally slow object tracking (43%, 53 out of 123), convergent squint (36%, 44 out of 121), and ataxia (15 to 20%, 18-27 out of 117). Seizures were reported in 19 out of 122 patients (16%), and myoclonic seizures were reported in 3 out of 121 patients (2%). The most common genotypes were L444P/L444P (76 out of 108, 70%), L444P/D409H (9 out of 108, 8%), D409H/D409H (8 out of 108, 7%), and L444P/rare allele (6 out of 108, 6%); full sequencing was not performed in all patients. CONCLUSIONS: Neurological manifestations of GD often begin to appear before the age of 2 years. The most common neurological signs and manifestations are brainstem abnormalities and fine motor dysfunction. The most common genotype is L444P/L444P.

Timing of initiation of enzyme replacement therapy after diagnosis of type 1 Gaucher disease: effect on incidence of avascular necrosis.

Data from the International Collaborative Gaucher Group Gaucher Registry were analysed to assess the relationship between enzyme replacement therapy with imiglucerase (ERT) and incidence of avascular necrosis (AVN) in type 1 Gaucher disease (GD1), and to determine whether the time interval between diagnosis and initiation of ERT influences the incidence rate of AVN. All patients with GD1 enrolled in the Gaucher Registry who received ERT and did not report AVN prior to starting therapy (n = 2700) were included. The incidence rate of AVN following initiation of ERT was determined. An incidence rate of AVN of 13.8 per 1000 person-years was observed in patients receiving ERT. Patients who initiated ERT within 2 years of diagnosis had an incidence rate of 8.1 per 1000 person-years; patients who started ERT >or=2 years after diagnosis had an incidence rate of 16.6 per 1000 person-years. The adjusted incidence rate ratio was 0.59 [95% confidence interval (CI) 0.36-0.96, P = 0.0343]. Splenectomy was an independent risk factor for AVN (adjusted incidence rate ratio 2.23, 95% CI 1.61-3.08, P < 0.0001). In conclusion, the risk of AVN was reduced among patients who initiated ERT within 2 years of diagnosis, compared to initiating treatment >or=2 years after diagnosis. A higher risk of AVN was observed among patients who had previously undergone splenectomy.

Dose-response relationships for enzyme replacement therapy with imiglucerase/alglucerase in patients with Gaucher disease type 1.

PURPOSE: To determine whether enzyme therapy with imiglucerase/alglucerase demonstrates dose-response relationships with doses and disease parameters used in routine clinical practice for Gaucher disease type 1 patients. METHODS: Analyses included all patients with Gaucher disease type 1 on enzyme therapy and with intact spleens in the large observational database of the International Collaborative Gaucher Group Gaucher Registry. Propensity scoring was used to match patients between enzyme therapy dose groups categorized as Group A (5 U to <29 U/kg/2 weeks), Group B (29 U to <48 U/kg/2 weeks), Group C (48 U to <75 U/kg/2 weeks). Hemoglobin concentration, platelet count, and hepatic and splenic volumes were assessed after initiation of enzyme therapy using nonlinear mixed effects models. The maximal effect (Emax) and half-time to Emax (T50) of enzyme therapy for each parameter were compared across dosing groups. RESULTS: Propensity score matching resulted in three comparable groups of 122 patients each (enzyme therapy in Groups A, B, and C). Dose-response relationships were found with regard to Emax and T50 over 96 months for each disease parameter. CONCLUSIONS: Enzyme therapy with imiglucerase/alglucerase displays a dose-dependent improvement in hematological and visceral parameters in Gaucher disease type 1 patients. Group C displayed greater treatment effects than Groups A or B. Propensity score matching and nonlinear mixed effects model analyses provide a prototype for assessment of treatment outcomes based on observational data from international rare disease registries.

Venous thromboembolism, myocardial infarction, and stroke among transdermal contraceptive system users.

OBJECTIVE: To estimate the incidence of venous thromboembolism, acute myocardial infarction, and ischemic stroke among transdermal contraceptive system users compared with users of norgestimate-containing oral contraceptives with 35 mcg ethinyl estradiol. METHODS: We began with insurance claims data from UnitedHealthcare. We identified women exposed to the transdermal contraceptive system or norgestimate-containing oral contraceptives from April 2002 through December 2004. Outcomes were confirmed from medical records. We calculated incidence rates and age-adjusted incidence rate ratios. In a nested case-control analysis, we investigated and controlled for confounding. RESULTS: There were 49,048 woman-years of transdermal contraceptive system exposure and 202,344 woman-years of norgestimate-containing oral contraceptives exposure. There was a more than two-fold increase in the venous thromboembolism rate (incidence rate ratio 2.2, 95% confidence interval [CI] 1.3-3.8) among transdermal contraceptive system users (20 cases, 40.8 per 100,000 woman-years) compared with norgestimate-containing oral contraceptives users (37 cases, 18.3 per 100,000 woman-years). Acute myocardial infarction occurred in three transdermal contraceptive system users compared with seven among norgestimate-containing oral contraceptives users (incidence rate ratio 1.8, 95% CI 0.5-6.8). No strokes occurred among transdermal contraceptive system users, whereas 10 occurred among norgestimate-containing oral contraceptives users. In the nested case-control analysis, after exclusions for high-risk factors, the odds ratio for venous thromboembolism was 2.4 (95% CI 1.1-5.5). CONCLUSION: There was a more than two-fold increase in the risk of venous thromboembolism associated with use of the transdermal contraceptive system. Acute myocardial infarction and stroke occurred too rarely to ascertain precise risk estimates. LEVEL OF EVIDENCE: II.

Drug copayment and adherence in chronic heart failure: effect on cost and outcomes.

STUDY OBJECTIVE: To measure the association among prescription copayment, drug adherence, and subsequent health outcomes among patients with chronic heart failure (CHF). DESIGN: Retrospective cohort study. DATA SOURCE: Database of a large, national health insurance plan. PATIENTS: Patients with CHF receiving commercial and Medicare supplemental benefits. MEASUREMENTS AND MAIN RESULTS: We estimated adherence to therapy with beta-blockers or angiotensin-converting enzyme (ACE) inhibitors in 2002 by using the medication possession ratio, an estimate of the proportion of days a patient was exposed to a drug while taking a drug regimen. For 2003, we measured the annualized total cost of health care and identified hospitalizations with a diagnostic code for CHF. We used a two-stage regression approach to model the association among copayment, adherence, and patient outcomes. For patients taking ACE inhibitors, a $10 increase in copayment was associated with a 2.6% decrease in the medication possession ratio (95% confidence interval [CI] 2.0-3.1%). This change in adherence was associated with a predicted 0.8% decrease in medical costs (95% CI -4.2-2.5%) but a predicted 6.1% increase in the risk of hospitalization for CHF (95% CI 0.5-12.0%). Among patients taking beta-blockers, a $10 increase in copayment was associated with a 1.8% decrease in the medication possession ratio (95% CI 1.4-2.2%). This change in adherence was associated with a predicted 2.8% decrease in medical costs (95% CI -5.9-0.1%) and a predicted 8.7% increase in the risk of hospitalization for CHF (95% CI 3.8-13.8%). CONCLUSION: Among patients with CHF, higher drug copayments were associated with poorer adherence. The change was relatively small and did not affect predicted total health care costs, but it was sufficient to increase the predicted risk of hospitalization for CHF.

Migraine, fibromyalgia, and depression among people with IBS: a prevalence study.

BACKGROUND: Case descriptions suggest IBS patients are more likely to have other disorders, including migraine, fibromyalgia, and depression. We sought to examine the prevalence of these conditions in cohorts of people with and without IBS. METHODS: The source of data was a large U.S. health plan from January 1, 1996 though June 30, 2002. We identified all people with a medical claim associated with an ICD-9 code for IBS. A non-IBS cohort was a random sample of people with an ICD-9 code for routine medical care. In the cohorts, we identified all claims for migraine, depression, and fibromyalgia. We estimated the prevalence odds ratios (PORs) of each of the three conditions using the Mantel-Haenszel method. We conducted quantitative sensitivity analyses to quantify the impact of residual confounding and in differential outcome identification. RESULTS: We identified 97,593 people in the IBS cohort, and a random sample of 27,402 people to compose the non-IBS comparison cohort. With adjustment, there was a 60% higher odds in the IBS cohort of having any one of the three disorders relative to the comparison cohort (POR 1.6, 95% CI 1.5 - 1.7). There was a 40% higher odds of depression in the IBS cohort (POR 1.4, 95% CI 1.3 - 1.4). The PORs for fibromyalgia and migraine were similar (POR for fibromyalgia 1.8, 95% CI 1.7 - 1.9; POR for migraine 1.6, 95% CI 1.4 - 1.7). Differential prevalence of an unmeasured confounder, or imperfect sensitivity or specificity of outcome detection would have impacted the observed results. CONCLUSION: People in the IBS cohort had a 40% to 80% higher prevalence odds of migraine, fibromyalgia, and depression.

Risk for respiratory events in a cohort of patients receiving inhaled zanamivir: a retrospective study.

BACKGROUND: Inhaled zanamivir is indicated for treatment of uncomplicated acute illness due to influenza A and B viruses in patients aged > or = 12 years who have been symptomatic for no more than 2 days. OBJECTIVE: The primary objective of this study was to estimate the incidence of adverse respiratory events among zanamivir-treated patients under conditions of usual care. METHODS: The Ingenix research database includes insurance claims for all dispensations, inpatient and outpatient services, and procedures including the associated diagnoses and costs for a subset of all enrolled UnitedHealthcare members. We identified all persons with a dispensation of zanamivir recorded between October 1, 1999, and April 30, 2000. We captured medical and pharmaceutical claims data for the 6 months before the dispensation to obtain information about comorbidities, overall health status, and respiratory events. Medical and hospital record abstraction and clinical review served to confirm inpatient/emergency department (ED) events. We also examined the records of an approximately 10% random sample of patients treated for a potential respiratory event in an outpatient/ physician office visit during the 10-day follow-up period. Respiratory events not sufficiently severe to result in medical care were not captured in this study. RESULTS: A total of 5498 eligible zanamivir dispensations contributed by 5450 patients (2911 females, 2539 males; mean age, 38.8 years), with 40 confirmed inpatient/ED respiratory events, were included in the study. Of these 40 events, 31 were pneumonia, bronchitis, or exacerbations of existing chronic respiratory disease; none required intubation or ventilation. No events occurred on the dispensation date. The overall risk for an inpatient/ ED respiratory event was 0.7 per 100 episodes (95% CI, 0.5-1.0). Seven events of wheezing or shortness of breath were not an obvious extension of the original influenza-like illness or of a complicating bronchitis (risk = 0.13 per 100 episodes; 95% CI, 0.06-0.26). CONCLUSIONS: No immediate or severe bronchoconstrictive responses occurred among 5498 zanamivir dispensations. The overall risk for any respiratory event was low, and none was sufficiently severe to suggest respiratory failure.

The effect of zanamivir treatment on influenza complications: a retrospective cohort study.

BACKGROUND: Complications of influenza are a major cause of morbidity and mortality during the influenza season. Clinical trials of zanamivir have reported a reduced incidence of influenza complications among high-risk patients. OBJECTIVES: This retrospective study sought to determine whether the use of zanamivir lowers the risk of acute influenza complications in a broader population, based on an analysis of claims data from a large managed care organization. METHODS: Medical and pharmacy health insurance claims data from October 1, 1999, through April 30, 2000, were compiled for UnitedHealthcare members in 19 states. All patients with a diagnosis of influenza (International Classification of Diseases, Ninth Revision, Clinical Modification diagnostic code 487.xx) associated with a physician visit were identified. From these, all patients were selected who had received zanamivir on the same day as the diagnosis of influenza. The propensity score matching technique was used to identify a comparison group with similar health service utilization and comorbidities who received a diagnosis of influenza but no antiviral therapy. Follow-up started the day after the influenza diagnosis and continued for 21 days. RESULTS: From the 43,741 patients originally identified, 2341 were selected who received a simultaneous diagnosis of influenza and a prescription for zanamivir. The untreated comparator group numbered 2337. Fewer zanamivir patients than untreated patients were hospitalized for complications, and the absolute risks were low (0.6% and 1.0%, respectively; risk ratio [RR], 0.58; 95% CI, 0.30-1.12). Zanamivir-treated patients had an excess of outpatient visits (16.9% vs 14.5%; RR, 1.16; 95% CI, 1.02-1.33) and antibiotic use (16.3% vs 14.8%; RR, 1.10; 95% CI, 0.97-1.26), although the RRs were modest. CONCLUSIONS: In the setting of a large managed care plan, patterns of influenza complications were similar in zanamivir-treated and untreated patients with a diagnosis of influenza. The results of this study are in contrast to those of published clinical trials reporting a reduction in the risk of influenza complications in zanamivir-treated patients.

Reducing selection bias in case-control studies from rare disease registries.

BACKGROUND: In clinical research of rare diseases, where small patient numbers and disease heterogeneity limit study design options, registries are a valuable resource for demographic and outcome information. However, in contrast to prospective, randomized clinical trials, the observational design of registries is prone to introduce selection bias and negatively impact the validity of data analyses. The objective of the study was to demonstrate the utility of case-control matching and the risk-set method in order to control bias in data from a rare disease registry. Data from the International Collaborative Gaucher Group (ICGG) Gaucher Registry were used as an example. METHODS: A case-control matching analysis using the risk-set method was conducted to identify two groups of patients with type 1 Gaucher disease in the ICGG Gaucher Registry: patients with avascular osteonecrosis (AVN) and those without AVN. The frequency distributions of gender, decade of birth, treatment status, and splenectomy status were presented for cases and controls before and after matching. Odds ratios (and 95% confidence intervals) were calculated for each variable before and after matching. RESULTS: The application of case-control matching methodology results in cohorts of cases (i.e., patients with AVN) and controls (i.e., patients without AVN) who have comparable distributions for four common parameters used in subject selection: gender, year of birth (age), treatment status, and splenectomy status. Matching resulted in odds ratios of approximately 1.00, indicating no bias. CONCLUSIONS: We demonstrated bias in case-control selection in subjects from a prototype rare disease registry and used case-control matching to minimize this bias. Therefore, this approach appears useful to study cohorts of heterogeneous patients in rare disease registries.

Incidence of IBS in a cohort of people with asthma.

We conducted a study to examine the relation of asthma and its treatment to irritable bowel syndrome (IBS). We identified cohorts of members with and without asthma from January 1996 though June 2002 and calculated rates of IBS in both cohorts. In a nested case-control study, we calculated odds ratios for oral steroid dispensing before IBS onset. To address differential IBS detection, we conducted a quantitative sensitivity analysis. We identified 91,237 people with asthma and sample of 24,518 people without asthma. There was a 20% increase in the incidence of IBS among people with asthma (standardized morbidity ratio = 1.2; 95% CI, 1.0-1.5), and no association between oral steroids and IBS among people with asthma (OR = 1.0; 95% CI, 0.9-1.1.) Misclassification of IBS would have biased the rate ratio toward the null. We observed a small increase in IBS among people with asthma, and no association between oral steroids and IBS onset among asthma patients.

Paroxetine in the first trimester and the prevalence of congenital malformations.

PURPOSE: To refine a preliminary analysis identifying a possibly increased prevalence of malformations among infants born to women exposed to paroxetine in the first trimester. METHODS: This study used data from UnitedHealthcare, a large U.S. insurer, using datasets originally for a study of bupropion in pregnancy. We identified women with a live-born delivery between January 1995 and September 2004. We classified women according to their first trimester mono- or mono/polytherapy exposure to paroxetine and other antidepressants. We confirmed malformation cases by medical record abstraction. We calculated the adjusted odds ratios (AORs) through logistic regression. RESULTS: For paroxetine, there were 815 infants among 791 women exposed as monotherapy, and 1020 infants among 989 women exposed as mono- or polytherapy. For other antidepressants, there were 4198 infants among 4072 women exposed as monotherapy, and 4936 infants among 4767 women exposed as mono- or polytherapy. AORs for all congenital malformations associated with paroxetine were 1.89 (95%CI 1.20-2.98) for monotherapy, and 1.76 (95%CI 1.18-2.64) for mono- or polytherapy. AORs for cardiovascular malformations associated with paroxetine were 1.46 (95%CI 0.74-2.88) for monotherapy, and 1.68 (95%CI 0.95-2.97) for mono- or polytherapy. CONCLUSIONS: These more detailed paroxetine findings confirm previous findings of analyses of these data among women exposed to all types of antidepressants. The present findings are consistent with other recent results suggesting the possibility of a modestly increased occurrence of congenital malformations following first trimester exposure to paroxetine compared to other antidepressants.