Craig Cheetham

Risk of acute myocardial infarction and sudden cardiac death in patients treated with cyclo-oxygenase 2 selective and non-selective non-steroidal anti-inflammatory drugs: nested case-control study

BACKGROUND Controversy has surrounded the question about whether high-dose rofecoxib increases or naproxen decreases the risk of serious coronary heart disease. We sought to establish if risk was enhanced with rofecoxib at either high or standard doses compared with remote non-steroidal anti-inflammatory drug (NSAID) use or celecoxib use, because celecoxib was the most common alternative to rofecoxib. METHODS We used data from Kaiser Permanente in California to assemble a cohort of all patients age 18-84 years treated with a NSAID between Jan 1, 1999, and Dec 31, 2001, within which we did a nested case-control study. Cases of serious coronary heart disease (acute myocardial infarction and sudden cardiac death) were risk-set matched with four controls for age, sex, and health plan region. Current exposure to cyclo-oxygenase 2 selective and non-selective NSAIDs was compared with remote exposure to any NSAID, and rofecoxib was compared with celecoxib. FINDINGS During 2302029 person-years of follow-up, 8143 cases of serious coronary heart disease occurred, of which 2210 (27.1%) were fatal. Multivariate adjusted odds ratios versus celecoxib were: for rofecoxib (all doses), 1.59 (95% CI 1.10-2.32, p=0.015); for rofecoxib 25 mg/day or less, 1.47 (0.99-2.17, p=0.054); and for rofecoxib greater than 25 mg/day, 3.58 (1.27-10.11, p=0.016). For naproxen versus remote NSAID use the adjusted odds ratio was 1.14 (1.00-1.30, p=0.05). INTERPRETATION Rofecoxib use increases the risk of serious coronary heart disease compared with celecoxib use. Naproxen use does not protect against serious coronary heart disease.

Increasingly restrictive definitions of hyperkalemia outcomes in a database study: effect on incidence estimates.

To determine the incidence of hyperkalemia‐associated adverse outcomes among ambulatory patients with diabetes newly initiating renin‐angiotensin‐aldosterone system (RAAS) inhibitor therapy and to examine to what extent increasingly restrictive definitions of hyperkalemia‐associated outcomes influenced incidence estimates.

The Positive Predictive Value of a Hyperkalemia Diagnosis in Automated Health Care Data

Our objectives were to determine performance of coded hyperkalemia diagnosis at identifying (1) clinically evident hyperkalemia and (2) serum potassium>6 mmol/L.

PS1-17: H1N1 Flu and Pregnancy: The Kaiser Permanente Experience

Background/Aims It is known that seasonal influenza infection disproportionately impacts pregnancy. Based on preliminary information, the pandemic H1N1 virus that first surfaced in spring 2009 appears to cause disproportionate morbidity and mortality among pregnant women - possibly to an even greater degree than that seen from seasonal flu. While it is estimated that over 10% of the pandemic influenza-related deaths in the United States have been in pregnant women-there is little data on the total impact of H1N1 infection upon pregnant women and their developing infants. This study will present a population-based assessment of the impact of H1N1 flu upon pregnancy, maternal, and birth outcomes. Methods This is an open cohort study covering the seasonal (mid 2008–2009) and H1N1 (mid 2009–2010) influenza seasons, with follow-up for pregnancy and infant outcomes up to one month after delivery. All pregnant women in KPNC, KPSC, KPCO, KPMA and KPGA during this period (mid 2008–2010) will be categorized according to their infection status as defined via lab test and/ or ICD-9 code for influenza-like-illness. Descriptive and regression analyses will be conducted to examine neonatal and pregnancy outcomes. Results Due to time constraints in relation to availability of the most recent data within Kaiser Permanente, the final data extraction will not be completed until November 2010. Statistical analyses will be conducted on the following outcomes:: pregnancy (pre-eclampsia, eclampsia, premature labor, premature delivery, pregnancy-induced hypertension; maternal (hospitalization for respiratory-related conditions, other hospitalizations, death); infant (intra-uterine growth retardation; low birth weight, major congenital anomalies); vaccine use and effect (extent to which pregnant women received H1N1 and seasonal flu vaccine; impact of vaccination upon the risk for adverse pregnancy, maternal and infant outcomes); antiviral use and effect (extent to which pregnant women received antiviral medication for H1N1 or seasonal flu, and the impact of these therapeutics upon the risk for adverse pregnancy, maternal and infant outcomes). Conclusions This study will be both analytic and descriptive, showcase the abilities of CESR and inform the scientific and public health communities with a range of unique information related to H1N1 infection during pregnancy within the combined KP populations.Note: Final analyses and results will be presented at the HMORN Conference.

C-C3-02: Increasingly Restrictive Definitions of Hyperkalemia Outcomes in a Database Study: Effect on Incidence Estimates.

Background/Aims: Determination of hyperkalemia associated adverse outcomes incidence and risk assessment is complicated by lack of consistent hyperkalemia definitions across studies. Further, information about hyperkalemia from clinical trials, while reflecting the potential of renin-angiotensin-aldosterone system (RAAS) inhibitor treatment to increase serum potassium (K) concentration above a defined level, may not reflect risk or severity of outcomes. We sought to examine to what extent increasing levels of restriction influenced incidence estimates of hyperkalemia outcomes. Methods: The study cohort was drawn from a population of adult patients with diabetes at 3 HMORN sites. We identified all new users of a RAAS inhibitor between 01/01/2001 and 12/31/2006 and assessed hyperkalemia-associated outcomes within the first year of therapy. The initial definition of a hyperkalemia outcome to which other definitions were compared included any ambulatory (AV), emergency department (ED) or inpatient (IP) visit with a K level > 5.5 mmol/l or a coded hyperkalemia diagnosis within 7 days of the visit. The following restrictions were then applied: increasing minimum K concentration to > 6.0 mmol/l; reducing timeframe to 24 hours; and removing AV. Crude incidence rates of hyperkalemia-associated adverse outcomes were calculated using person years (p-y) determined as time from drug initiation to first outcome or other censoring event (e.g., drug discontinuation, end of study). Results: The cohort included 27,362 patients. Mean duration of initial therapy was 212 days. Hyperkalemia-associated outcome incidence estimates varied from 33.6 per 1000 p-y (defined as AV, ED or IP visit with K > 5.5 or a coded hyperkalemia diagnosis within 7 days) to 11.0 per 1000 p-y (defined as IP or ED visit with K > 6 or coded diagnosis within 24 hours). Removing AV had the greatest effect and reducing the timeframe to 24 hours had the least effect on incidence estimates. Conclusions: Modifying hyperkalemia definition criteria resulted in up to a 3-fold difference in by estimates of hyperkalemia-associated adverse outcomes. Further work linking these findings to adverse events is critical to decisions regarding appropriate definitions to answer specific study questions. We caution against comparing incidence estimates across published studies without considering the severity implications of differences in hyperkalemia outcomes definitions.

PS1-11: Feasibility of Prospective Surveillance for Adverse Drug Events – Lessons Learned from a 12-Month Pilot Study

Background/Aims When new medications are introduced, safety data are often sparse. Health plan data may be useful for active surveillance for adverse events. We conducted a 12-month pilot study to demonstrate the feasibility of prospective active surveillance using data from several large health insurers. This presentation will summarize logistical challenges and lessons learned. Methods We studied the safety of generic divalproex sodium, an antiepileptic drug introduced in July 2008, compared to the branded drug. We performed monthly surveillance using the maximized sequential probability ratio test, comparing observed outcomes in new users of the generic drug to expected counts based on new users of the branded drug from January 2002 – June 2008. Programmers at four HMO Research Network sites extracted data monthly, ran quality control (QC) programs, and returned summary tables to the lead site. Medication exposure was identified from outpatient pharmacy dispensings. Outcomes identified from health plan utilization data included potential adverse effects (e.g. pancreatitis and liver disease) and efficacy outcomes (e.g. hospital or emergency department visits for seizures.) Results We will discuss lessons learned related to data sharing and HIPAA compliance, timing and synchronization of data pulls, and QC activities. Obtaining IRB approval took 3.5 months, and protocol development took 7 months. Developing the analytic program required two rounds of corrections, one leading to meaningful changes in results. QC programs identified substantial differences in monthly extracts across sites. Some QC flags required only understanding differences across sites, but others revealed data problems requiring resolution at the site level. Overall, 14% (4/28) of monthly extracts across the four sites could not be used due to underlying data problems or lack of analyst availability for timely extracts. Conclusions Prospective drug safety surveillance is feasible, but future projects should anticipate the need for longer timelines and multiple revisions to data pulls and analytic programs. They should develop approaches to handling missing data, because some data pulls will not be usable. QC activities should continue throughout study implementation. A knowledgeable, engaged lead at each site is vital to ensure accuracy and appropriate interpretation of each site’s data.

PS2-07: Medication Use in Pregnancy and Birth Outcomes Program

Background/Aims: Our knowledge of safe medication use during pregnancy is limited, due primarily to the lack of rigorous studies evaluating birth outcomes associated with in utero exposure to medications. A collaborative research program, the Medication Use in Pregnancy and Birth Outcomes Program, between the Food and Drug Administration (FDA) and researchers at the HMO Research Network Center for Education and Research in Therapeutics (CERT), Kaiser Permanente Northern and Southern California, and Vanderbilt University, aims to develop common, necessary data linkages to enable the conduct of multiple studies of medication use and outcomes in pregnancy across participating sites. Methods: Specific components of the program include: maternal-infant record linkage of all women delivering an infant between 2001 and 2007, linkage to birth certificate data for infants delivered between 2001 and 2007, validation of data elements within the datasets through medical chart abstractions, and annual update of the datasets. Results: This collaboration will provide a large ethnically and geographically diverse population, with approximately 90,000 births per year. Data files on maternal and child enrollment, outpatient drug dispensing, and inpatient and outpatient diagnoses and procedures, in addition to data elements obtained from birth certificate data, will be developed and maintained at each of the program sites. The proposed poster will describe the program and the available standard file definitions and data elements. Conclusions: The program will be an important resource for the evaluation of birth outcomes (birth defects and other perinatal events) associated with medication use during pregnancy, patterns and trends in medication use during pregnancy, and studies of the risks and benefits of medication use for the pregnant women themselves.