Supplementary data collection with case-cohort analysis to address potential confounding in a cohort study of thromboembolism in oral contraceptive initiators matched on claims-based propensity scores.

PURPOSE: Residual confounding is a potential limitation of pharmacoepidemiologic studies, and in particular, studies based on administrative claims data that do not capture lifestyle and clinical confounders. We describe an application of the case-cohort design to assess residual confounding by thromboembolic risk factors (e.g., smoking and obesity) not captured in claims data in a claims-based cohort study of thromboembolism among matched oral contraceptive (OC) initiators. METHODS: This study was conducted using the Ingenix Research Data Mart, a database containing medical claims for approximately 12 million members of a large health plan of the United States. We randomly sampled 701 OC initiators from cohorts of ethinyl estradiol/drospirenone (n = 22,429) and other OC initiators (n = 44,858) identified in the years 2001-2004 and matched by propensity score in a claims-based cohort study. Supplementary data on risk factors not measured in the cohort study were collected from medical records for the sample. We estimated the risk ratio of thromboembolism adjusted for the supplementary variables using Cox regression modified for a case-cohort design, and compared it to the rate ratio from the cohort study. RESULTS: The risk ratio adjusted for the supplementary variables was 0.90 (95 per cent (%) confidence interval (CI): 0.49, 1.68) which was similar to the rate ratio (0.92; 95%CI: 0.50, 1.63), indicating negligible confounding by the supplementary variables in the cohort study. CONCLUSIONS: Case-cohort methods were used to assess residual confounding in a claims-based cohort study. This approach adds to a growing number of methods to evaluate residual confounding in cohort studies.

Risk of hyperkalemia in women taking ethinylestradiol/drospirenone and other oral contraceptives.

BACKGROUND: The oral contraceptive ethinyl estradiol 0.03 mg/drospirenone 3 mg (EE/DRSP) contains a progestin component that possesses potassium-sparing diuretic activity similar to spironolactone. We sought to determine whether EE/DRSP use might lead to adverse effects possibly attributable to hyperkalemia. STUDY DESIGN: This was a matched cohort study in which we identified oral contraceptive (OC) initiators between July 2001 and June 2004 within a large, US health plan. We matched EE/DRSP initiators to other OC initiators in a 1:2 ratio on the basis of a prediction model (propensity score) of EE/DRSP initiation that incorporated dozens of characteristics. We identified insurance claims mentioning hyperkalemia, related clinical outcomes (electrolyte disturbances, arrhythmia, syncope, myocardial infarction) and verified the underlying condition through medical record review. RESULTS: There were 22,429 EE/DRSP initiators matched to 44,858 other OC initiators, with an average follow-up of 7.6 months. A composite clinical surrogate hyperkalemia end point occurred with equal frequency in the compared groups [118 cases in EE/DRSP and 260 in comparators; rate ratio (RR) 0.9, 95% confidence interval (CI) 0.7-1.1]. The individual hyperkalemia surrogate end points exhibited similar results. One EE/DRSP initiator and four comparators were diagnosed specifically with hyperkalemia (RR 0.5, 95% CI 0.0-4.9). The results were not different when we accounted for changes in OC use during follow-up. CONCLUSION: EE/DRSP initiators are no more likely than other OC initiators to experience hyperkalemia or related clinical outcomes which could be caused by hyperkalemia during follow-up.

Risk of thromboembolism in women taking ethinylestradiol/drospirenone and other oral contraceptives.

OBJECTIVE: The oral contraceptive ethinylestradiol 0.03 mg/drospirenone 3 mg contains a progestin component that differs from other oral contraceptives. Case reports and prescription event monitoring suggested that ethinylestradiol/drospirenone might be associated with an elevated risk of thromboembolism. We sought to estimate the association between ethinylestradiol/drospirenone and risk of thromboembolism relative to the association among other oral contraceptives. METHODS: We identified ethinylestradiol/drospirenone initiators and a twofold larger group of other oral contraceptive initiators between June 2001 and June 2004 within a U.S. health insurer database. The comparison group was selected to have demographic and health care characteristics preceding oral contraceptive initiation that were similar to ethinylestradiol/drospirenone initiators. Thromboembolism during the follow-up of the cohorts was identified through claims for medical services, and only medical record-confirmed cases were included in analyses. The primary (as-matched) analysis used proportional hazards regression, whereas a secondary (as-treated) analysis accounted for changes in oral contraceptives during follow-up using Poisson regression. RESULTS: The 22,429 ethinylestradiol/drospirenone initiators and 44,858 other oral contraceptive initiators were followed for an average of 7.6 months, and there were 18 cases of thromboembolism in ethinylestradiol/drospirenone initiators and 39 in the comparators (rate ratio 0.9, 95% confidence interval 0.5-1.6). More than 9,000 women would need to be prescribed oral contraceptives to observe a difference of one case of thromboembolism. Results of the as-treated analysis were similar to those of the as-matched analysis. CONCLUSION: Ethinylestradiol/drospirenone initiators and initiators of other oral contraceptives are similarly likely to experience thromboembolism. LEVEL OF EVIDENCE: II.

Serum potassium monitoring for users of ethinyl estradiol/drospirenone taking medications predisposing to hyperkalemia: physician compliance and survey of knowledge and attitudes.

PURPOSE: Yasmin-28 [ethinyl estradiol 0.03 mg/drospirenone 3 mg (EE/DRSP)] contains drospirenone, a progestin component that possesses antimineralocorticoid activity with a potassium-sparing diuretic effect similar to that in spironolactone. Product labeling recommends potassium monitoring in the first month of use for women concurrently receiving medication that may increase serum potassium. METHODS: We evaluated compliance with this recommendation by measuring monitoring around the date of oral contraceptive (OC) initiation in women who received EE/DRSP while being treated with medications predisposing to hyperkalemia and in similar women who received other OCs. Because preliminary analyses indicated incomplete compliance, we surveyed physicians who prescribed EE/DRSP to women receiving drugs predisposing to hyperkalemia on their knowledge and attitudes with regard to the recommendation. We conducted this study using data from the Ingenix Research Datamart, which includes insurance claims for reimbursement for medical services and prescription medications for approximately 8,000,000 members of a large nationally dispersed health plan. We used claims for pharmacy dispensings of prescription medications to identify all women aged 10-59 years old who initiated EE/DRSP or other OCs during the first 3 years of EE/DRSP availability (July 2001 to June 2004). The frequency of potassium monitoring was measured by identifying claims for serum potassium tests. We conducted a telephone survey of 58 physicians who had prescribed EE/DRSP up to June 2003 to women who received concomitant hyperkalemic drugs. RESULTS: Although potassium monitoring was generally more frequent among EE/DRSP initiators receiving concomitant hyperkalemic drugs than among other OC initiators receiving similar medications, only 40% of 466 EE/DRSP initiators with concurrent hyperkalemic treatment had potassium tests. More than 98% of surveyed physicians were aware of the potassium-sparing property of EE/DRSP. Compared with physicians whose patients had potassium tests, physicians of patients without such tests were more likely to disagree with the recommendation for users of angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists, heparin and nonsteroidal anti-inflammatory drugs. Patient barriers and health plan restrictions were other factors possibly contributing to noncompliance. CONCLUSION: This study demonstrates incomplete physician compliance with a labeling recommendation of potassium monitoring for initiators of EE/DRSP receiving concomitant therapy predisposing to hyperkalemia. The limited compliance was likely due to a combination of selective physician acceptance of the recommendations and specific patient and health plan barriers to testing.

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.

A study of influenza and influenza-related complications among children in a large US health insurance plan database.

BACKGROUND: Influenza places a substantial burden on the affected individual and society. While there are data available on the overall occurrence of influenza in children, less information is available on the differential impact of influenza on healthcare for previously healthy children and those at high risk of developing influenza-related complications. OBJECTIVE: To compare the frequency of influenza-related complications in healthy and 'at-risk' children, and quantify the associated use of medical resources and costs. DESIGN: Data were obtained from a large US-based health insurance plan database. MAIN OUTCOME MEASURES AND RESULTS: A total of 23 188 health insurance claims with an influenza diagnosis were identified over the 3-year period 1995-1997 (3 247 834 patient-years). Influenza-related complications were observed in approximately a quarter of the total diagnosed cases, with younger children (0-4 years of age) at substantially greater risk. 'At-risk' children were more likely to develop influenza-related complications than otherwise healthy children. The greatest difference in incidence rate in the 0-4 year age group was for asthma (incidence rate ratio 8.7, 95% CI 5.2-14.4), and in the 5-14 year age group for asthma (incidence rate ratio 8.5, 95% CI 5.2-13.7) and acute sinusitis (incidence rate ratio 2.7, 95% CI 1.2-5.4). The average direct medical costs of influenza in children under 15 years with complications were more than 3.5 times higher than those without. CONCLUSIONS: Measures to prevent and treat influenza-related complications are certainly warranted for at-risk children, although the elevated incidence rates for several common complications even among healthy children should prompt consideration of these measures for all children.

Effectiveness of an incomplete RotaTeq (RV5) vaccination regimen in preventing rotavirus gastroenteritis in the United States.

BACKGROUND: Effectiveness of the pentavalent rotavirus vaccine (RV5) after administration of the complete (3 dose) regimen has been demonstrated in a real-world setting. This study assessed the effectiveness of RV5 following partial completion of the 3-dose regimen. METHODS: Using a large national health insurance claims database, 2 cohorts of infants (those who received RV5 and a concurrent group who received diphtheria-tetanus-acellular pertussis, but not RV5) were followed through the 2007 and 2008 rotavirus seasons (January 1 to May 31) to identify cases of rotavirus gastroenteritis and all-cause gastroenteritis resulting in medical care encounters. Vaccine effectiveness following the first and the second RV5 doses was estimated by quantifying reductions in hospitalizations, emergency department (ED) and physician office visits. RESULTS: A first RV5 dose was received by 42,306 infants whereas 28,417 infants in the concurrent comparison group received a first diphtheria-tetanus-acellular pertussis dose; 43,704 infants received a second RV5 dose, and 31,810 infants received a second diphtheria-tetanus-acellular pertussis dose. One dose of RV5 was associated with 88% effectiveness against rotavirus gastroenteritis hospitalizations and ED visits and 44% effectiveness against all-cause gastroenteritis hospitalizations and ED visits. A 2-dose regimen of RV5 was associated with 94% effectiveness against rotavirus gastroenteritis hospitalizations and ED visits and 40% effectiveness against all-cause gastroenteritis hospitalizations and ED visits. CONCLUSION: The RV5 vaccine exhibits effectiveness against rotavirus gastroenteritis even before completing the full 3-dose regimen. These results are of particular relevance when considering the benefits of a partially completed rotavirus vaccine series.

Incidence of intussusception among infants in a large commercially insured population in the United States.

BACKGROUND: To estimate the incidence of intussusception among infants treated in inpatient and emergency department settings during the period preceding the US launch of second-generation rotavirus vaccines. METHODS: From a large US health insurance claims database, we sampled 100,000 infants aged 1 to 3 months at first diphtheria-tetanus-acellular pertussis vaccination between 2001 and 2005. Potential intussusception cases were identified on the basis of claims and were confirmed by medical record review. Incidence rates (IRs) and 95% confidence intervals (CIs) were estimated based on follow-up from first diphtheria-tetanus-acellular pertussis dose to up to 1 year of age, and within 21, 30, and 60 days after each dose. RESULTS: The IR of intussusception in the first year of life was 0.33/1000 person-years based on 22 confirmed cases (95% CI: 0.21-0.50/1000 person-years). The age-specific incidence peaked among infants aged 5 months (IR: 0.82/1000 person-years; 95% CI: 0.30-1.78/1000 person-years). During the 21, 30, and 60 days following any dose, the incidence per 1000 person-years was 0.27, 0.24, and 0.33, respectively. CONCLUSION: The rates described in this study can serve as a benchmark for comparison with incidences observed after the introduction of the second-generation rotavirus vaccines.

Postmarketing evaluation of the short-term safety of the pentavalent rotavirus vaccine.

BACKGROUND: A pentavalent rotavirus vaccine (RV5) demonstrated efficacy and safety in a large clinical trial before US licensure in 2006. The primary objective of this observational study was to assess the occurrence of intussusception (IS) among infants who received RV5 in routine use. Secondary objectives assessed the occurrence of Kawasaki disease (KD) and general safety. METHODS: We identified and followed infants with a health insurance claim for RV5 during the first 2 years of RV5 availability. Concurrent and historical cohorts receiving diphtheria-tetanus-acellular pertussis (DTaP) vaccine were used as comparators; the historical DTaP cohort informed sequential monitoring boundaries for IS and KD. Medical records from potential IS and KD cases were reviewed to confirm outcomes. General safety was evaluated across a wide range of outcomes using prespecified criteria. Incidence rates for outcomes along with relative risks and 95% confidence intervals (CIs) were estimated. RESULTS: The 85,397 RV5 and 62,820 DTaP recipients contributed 17,433 and 12,339 person-years, resulting in 6 and 5 confirmed cases of IS, respectively, within 30 days following any dose. The relative risk of IS was 0.8 (95% confidence interval: 0.22-3.52). The number of IS or KD cases did not cross the monitoring boundaries. The general safety evaluation did not identify any specific diagnoses or patterns of diagnoses that might suggest other safety concerns. CONCLUSION: RV5 was not associated with an increased risk of IS, KD, or any other recognized health outcome.

Extended case-control study results on thromboembolic outcomes among transdermal contraceptive users.

BACKGROUND: We extended an earlier study that found a twofold higher risk of venous thromboembolism (VTE) associated with the transdermal contraceptive system relative to norgestimate-containing oral contraceptives (NGM-OC). STUDY DESIGN: This case-control study identified potential cases of VTE, acute myocardial infarction (AMI) and stroke from 24 months of additional health care claims, with adjudication via medical records. Randomly selected controls were matched to cases on age (15-44 years) and characteristics of contraception use. Conditional logistic regression models provided odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: The transdermal contraceptive system was associated with a twofold higher risk of VTE (OR 2.0; 95% CI 1.2-3.3) compared with users of NGM-OC. The OR for stroke was 0.6 (95% CI 0.1-3.2) and for AMI 1.2 (95% CI 0.3-4.7). CONCLUSION: This extension was consistent with the earlier study, showing a twofold increased risk of VTE associated with use of the transdermal contraceptive system relative to NGM-OC.

Effectiveness of the pentavalent rotavirus vaccine in preventing gastroenteritis in the United States.

OBJECTIVE: In clinical trials, the pentavalent rotavirus vaccine (RV5) was efficacious in preventing severe rotavirus gastroenteritis (RGE) and related health care encounters. We assessed the vaccine effectiveness (VE) of RV5 among US infants during the first 2 rotavirus seasons after vaccine licensure. METHODS: Using a large, national, health insurance claim database, we monitored 2 cohorts of infants (infants who received 3 doses of RV5 and a concurrent group of infants who received 3 doses of diphtheria-tetanus-acellular pertussis vaccine but did not receive RV5) through the 2007 and 2008 rotavirus seasons (January 1 to May 31), to identify cases of RGE and all-cause acute gastroenteritis (AGE) resulting in medical care encounters. We estimated the VE in reducing hospitalizations, emergency department (ED) and physician office visits, and health care resource utilization, as measured by days and costs of hospitalizations and ED visits. RESULTS: A total of 33 140 RV5-vaccinated infants and 26 167 infants in the concurrent diphtheria-tetanus-acellular pertussis vaccine cohort were included in the analysis. The VE against RGE (hospitalization and ED) was 100% (95% confidence interval [CI]: 87%-100%), whereas the VE against AGE was 59% (95% CI: 47%-68%). In the outpatient setting, the VE against RGE and AGE was 96% (95% CI: 76%-100%) and 28% (95% CI: 22%-33%), respectively. There was a complete (100%) reduction in RGE hospitalization and ED visit days and a 100% reduction in costs. RV5 was associated with a 66% decrease in AGE-related hospitalization and ED visit days and a 74% reduction in costs. CONCLUSIONS: In this first nationwide study evaluating VE under conditions of routine use, RV5 was highly effective in preventing RGE and AGE and in reducing health care resource utilization. Further research is needed to assess VE with an incomplete rotavirus vaccination regimen.

Tegaserod and the risk of cardiovascular ischemic events: an observational cohort study.

OBJECTIVES: Tegaserod, a partial 5-HT(4) agonist previously approved for treatment of irritable bowel syndrome with constipation and chronic idiopathic constipation, was suspended from US marketing in 2007, based on pooled clinical trial results which contained a signal suggesting increased risk of cardiovascular ischemic events (CVIEs). We sought to evaluate whether there was an association between tegaserod and CVIE in a setting of routine clinical practice. METHODS: This was a matched cohort study conducted within a large US health insurance database, involving 52 229 patients who initiated tegaserod and 52 229 patients with similar characteristics who did not initiate tegaserod. Participants were followed for up to 6 months for the occurrence of CVIE (myocardial infarction, acute coronary syndrome, coronary revascularization, and stroke). Outcomes were identified using insurance claims and were confirmed by review of medical records. We conducted as-matched analyses providing hazard ratios (HRs) along with 95% confidence intervals (95% CI) and as-treated analyses accounting for changes in dispensed therapy. RESULTS: There was no increased risk of CVIE associated with tegaserod treatment. The as-matched association between tegaserod and ischemic cardiovascular outcomes (HR = 0.95, 95% CI 0.73-1.23) and stroke (HR = 0.90, 95% CI 0.46-1.77) did not change substantially in the as-treated analyses (cardiovascular relative risk [RR] = 1.14, 95% CI 0.83-1.56; stroke: RR = 1.09, 95% CI = 0.49-2.02). The results were largely unaffected by adjustment for characteristics or subgroup analyses. CONCLUSION: In this observational study of tegaserod use, we found no evidence for an increased risk of CVIE in tegaserod users.

Prevalence of serious eosinophilia and incidence of Churg-Strauss syndrome in a cohort of asthma patients.

BACKGROUND: Some leukotriene receptor antagonists, such as zafirlukast and montelukast, have been associated with systemic eosinophilia, with interest focused on Churg-Strauss syndrome (CSS). OBJECTIVE: To calculate the background incidence rate of CSS and prevalence of eosinophilia among people with asthma who have not used leukotriene receptor antagonists. METHODS: We conducted a cohort study in the setting of three geographically diverse UnitedHealthcare health plans. We identified 36,230 people who received a diagnosis of asthma during the period October 1994 through September 1997. We identified 241 potential cases from the claims data. Using a standardized hospital record abstract form, nurses abstracted relevant clinical data from the hospital charts of potential cases. We applied several a priori case definitions to the abstracted clinical data and computed incidence rates of CSS among patients with asthma. We additionally used these data to compute the prevalence of serious eosinophilia. RESULTS: Incidence rates of definite CSS among asthma patients ranged from zero (90% confidence interval 0.0 to 23.0) to 67 (90% confidence interval 22.5 to 160.6) cases per 1,000,000 person-years, depending on the definition used. All patients who met the criteria for CSS expressed symptoms consistent with mild asthma. CONCLUSIONS: This report is the first direct measurement of the incidence rate of CSS among asthma patients. We believe that the prevalence and incidence information that we report is a useful description of population rates in the United States for these conditions.

Comparison of resource utilization by patients treated with transdermal fentanyl and long-acting oral opioids for nonmalignant pain.

OBJECTIVE: To quantify resource utilization and costs incurred for patients who received transdermal fentanyl as their first long-acting analgesic for non-malignant pain, and to compare these with utilization and costs for similar patients dispensed other long-acting oral opioids. DESIGN: A retrospective matched cohort study using medical claims data from a large New England Insurer. PATIENTS: We identified 478 patients without cancer who received transdermal fentanyl during 1995-1998. We selected patients who had no previous long-acting opioid dispensings and were enrolled during the 180 days before and 30 days following the initial dispensing. We used propensity scores to identify a matched comparison group of 478 long-acting oral opioid users. RESULTS: Transdermal fentanyl and matched long-acting oral opioid users incurred identical median costs for outpatient medical services and prescriptions during 2 years of follow-up. A larger proportion of transdermal fentanyl patients were still taking their initial opioid analgesic at the end of the 2-year follow-up than were patients initially taking other long-acting opioids. Use of short-acting opioids tapered off more slowly among transdermal fentanyl patients than among long-acting opioid patients. In the first 6 months, the transdermal fentanyl patients had more hospital discharges than the long-acting oral opioid patients, but this difference appeared to reflect preexisting conditions. CONCLUSIONS: Users of fentanyl transdermal system and other long-acting opioids experienced essentially identical evolution of health services utilization and costs over a 2-year period. The choice of long-acting opioid analgesia does not appear to be a determinant of future medical costs.