Joan Landon

Aprotinin during Coronary-Artery Bypass Grafting and Risk of Death

BACKGROUND Aprotinin (Trasylol) is used to mitigate bleeding during coronary-artery bypass grafting (CABG). Accumulating evidence suggests that this practice increases mortality. METHODS Using electronic administrative records of the Premier Perspective Comparative Database, we studied hospitalized patients with operating-room charges for the use of aprotinin (33,517 patients) or aminocaproic acid (44,682 patients) on the day CABG was performed. We tabulated the numbers of patients with a hospital-discharge status of death and performed three types of analyses: a multivariable logistic-regression analysis (primary analysis); propensity-score matching in the highly selected subcohort of patients who received full amounts of the study drug, who underwent CABG by surgeons who performed 50 or more CABG surgeries during the study period, and for whom information on 10 additional covariates was available because the surgery occurred on hospital day 3 or later; and an instrumental-variable analysis of data from patients whose surgeons showed a strong preference for one of the two study drugs. RESULTS In all, 1512 of the 33,517 aprotinin recipients (4.5%) and 1101 of the 44,682 aminocaproic acid recipients (2.5%) died. After adjustment for 41 characteristics of patients and hospitals, the estimated risk of death was 64% higher in the aprotinin group than in the aminocaproic acid group (relative risk, 1.64; 95% confidence interval [CI], 1.50 to 1.78). In the first 7 days after surgery, the adjusted relative risk of in-hospital death in the aprotinin group was 1.78 (95% CI, 1.56 to 2.02). The relative risk in a propensity-score-matched analysis was 1.32 (95% CI, 1.08 to 1.63). In the instrumental-variable analysis, the use of aprotinin was found to be associated with an excess risk of death of 1.59 per 100 patients (95% CI, 0.14 to 3.04). Postoperative revascularization and dialysis were more frequent among recipients of aprotinin than among recipients of aminocaproic acid. CONCLUSIONS Patients who received aprotinin alone on the day of CABG surgery had a higher mortality than patients who received aminocaproic acid alone. Characteristics of neither the patients nor the surgeons explain the difference, which persisted through several approaches to control confounding.

Incidence of Hospitalized Rhabdomyolysis with Statin and Fibrate Use in an Insured US Population

Background: The incidence of hospitalized rhabdomyolysis is not well characterized among patients taking statin-fibrate combination therapies. Objective: To estimate and compare the rates of hospitalized rhabdomyolysis during periods of exposure to different statins and fibrates. Methods: We retrospectively identified a cohort patients who initiated a statin or fibrate between January 1, 1998, and December 31, 2007, using a database of a large US hearth insurer. Patients were followed for the occurrence of hospitalized rhabdomyolysis, determined by clinical review of medical records. Exposure status during the study period was determined by electronic records of statin and fibrate dispensing. Incidence rates (IRs) and incidence rate ratios (IRRs) for various combinations of fibrate and statin exposure were modeled, using Poisson regression. Results: There were 1,116,805 patients who initiated statin and/or fibrate therapy, with 2.4 million person-years of observation. Seventy cases of hospitalized rhabdomyolysis were confirmed. Adjusted analyses showed a persistent increased risk of rhabdomyolysis with combination therapy, while statin and fibrate therapy alone showed similar, nonsignificant increases in risk. The adjusted IRR for a statin and fenofibrate was 3.26 (95% CI 1.21 to 8.60), while the adjusted IRR for a statin and gemfibrozil was 11.93 (95% CI 3.96 to 35.93) versus statin therapy alone. The individual IRs for statin monotherapy ranged from 0.00 to 3.34 per 100,000 person-years. The number needed to harm was tower for combination statin-gemfibrozil therapy (2753) compared with that for statin therapy atone (454,545). Conclusions: The incidence of hospitalized rhabdomyolysis is rare, but higher in patients with concomitant statin-fibrate treatment than in patients on statin therapy atone. The rate found in this study is consistent with the known profile of the statin-fibrate treatment option for mixed dyslipidemia.

The thiazolidinediones rosiglitazone and pioglitazone and the risk of coronary heart disease: A retrospective cohort study using a US health insurance database

BACKGROUND The thiazolidinediones (TZDs), including rosiglitazone maleate and pioglitazone hydrochloride, are commonly prescribed in patients with type 2 diabetes mellitus. Although recent meta-analyses suggest there is an increased risk of myocardial infarction (MI) among rosiglitazone users, these findings were not supported by data from other studies. OBJECTIVE The goal of this research was to compare the risk of MI, coronary revascularization (CR), and sudden death in patients who began rosiglitazone therapy versus those who began pioglitazone therapy. METHODS This was a retrospective cohort study using information from a large health care database (with data available on approximately 14 million individuals). All initiators of rosiglitazone or pioglitazone from July 1, 2000, through March 31, 2007, for whom the first dispensing followed >or=6 months of health plan membership and the members 18th birthday were identified. The propensity score method was used to create matched cohorts of patients in 3 treatment groups: TZD monotherapy, dual therapy (a TZD plus another antidiabetic agent), and TZD therapy with concomitant insulin. Follow-up continued to a change in treatment regimen, defined as regimen switch (ie, the addition of any antidiabetic agent to an existing regimen) or regimen stop (ie, the discontinuation of any component of the therapeutic regimen). Three outcomes that represent coronary heart disease were assessed for this analysis: MI, CR, and sudden death. The proportional hazards model, stratified by therapeutic regimen, was used to estimate hazard ratios (HRs) and 95% CIs of coronary heart disease risk associated with use of rosiglitazone relative to pioglitazone. RESULTS Among 47,501 matched pairs of rosiglitazone and pioglitazone users, 72,104 (75.9%) were receiving TZD monotherapy, 17,822 (18.8%) were receiving dual therapy, and 5076 (5.3%) were receiving TZD therapy with insulin. Mean follow-up was 9.6 months with regimen switch as the censoring event and 8.4 months with regimen stop as the censoring event. For MI, the HR was 1.35 (95% CI, 1.12-1.62) through regimen switch and 1.41 (95% CI, 1.13-1.75) through regimen stop. For the composite outcome of MI, CR, and/or sudden death, the HR was 1.09 (95% CI, 0.97-1.22) through regimen switch and 1.12 (95% CI, 0.98-1.27) through regimen stop. CONCLUSIONS In this retrospective cohort analysis, MI was more common in users of rosiglitazone than in users of pioglitazone. The incidence of a combined end point of MI, CR, and/or sudden death in patients receiving rosiglitazone was not significantly different from that in patients receiving pioglitazone.

Coronary heart disease outcomes in patients receiving antidiabetic agents in the PharMetrics database 2000–2007

The risk of coronary heart disease (CHD) in users of antidiabetic agents must be quantified to permit reasoned therapeutic choices.

Fracture Risk After Bariatric Surgery: Roux-en-Y Gastric Bypass Versus Adjustable Gastric Banding.

The long‐term consequences of bariatric surgery on fracture risk are unclear but are likely to vary by procedure type. In physiologic studies, Roux‐en‐Y gastric bypass (RYGB) and adjustable gastric banding (AGB) have differential effects on rates of bone loss. Therefore, our objective was to compare fracture risk in obese adults after RYGB and AGB procedures. Using claims data from a US commercial health plan, we analyzed rates of nonvertebral fractures within a propensity score–matched cohort (n = 15,032) of morbidly obese adults who received either RYGB or AGB surgery between 2005 and 2013. A total of 281 nonvertebral fractures occurred during a mean follow‐up time of 2.3 ± 1.9 years. RYGB patients had an increased risk of nonvertebral fracture (hazard ratio [HR] = 1.43, 95% confidence interval [CI] 1.13–1.81) compared with AGB patients. In fracture site–specific analyses, RYGB patients had increased risk of fracture at the hip (HR = 1.54, 95% CI 1.03–2.30) and wrist (HR = 1.45, 95% CI 1.01–2.07). Nonvertebral fracture risk associated with RYGB manifested >2 years after surgery and increased in subsequent years, with the highest risk in the fifth year after surgery (HR = 3.91, 95% CI 1.58–9.64). In summary, RYGB is associated with a 43% increased risk of nonvertebral fracture compared with AGB, with risk increasing >2 years after surgery. Fracture risk should be considered in risk/benefit discussions of bariatric surgery, particularly among patients with high baseline risk of osteoporosis who are deciding between RYGB and AGB procedures.

Clinical characteristics and medication uses among fibromyalgia patients newly prescribed amitriptyline, duloxetine, gabapentin, or pregabalin.

Fibromyalgia is a common chronic pain disorder with unclear etiology. No definitive treatment is available for fibromyalgia, and treatment with antidepressants or antiepileptics is often used for symptom management.

Availability and utilization of cardiovascular fixed-dose combination drugs in the United States

BACKGROUND Solid clinical evidence supports the effectiveness and safety of multiple drugs in treating diabetes, dyslipidemia, and hypertension, and numerous fixed-dose combination products (FDCs) containing such drugs have been developed for patients with more severe forms of these diseases. We sought to evaluate the extent to which utilization of treatment combinations for these conditions corresponded to the availability of FDCs. METHODS Using claims data from a large national commercial insurer, we identified 2 cohorts of patients: those who filled multiple single-agent drugs to treat diabetes, dyslipidemia, and hypertension in 2012, and those who used FDCs containing these products during the same period. We determined the fill rate of single-agent pairs and FDCs, availability of FDCs for the most frequently filled single-agent and drug class pairs, and the number of conditions treated by frequently filled single-agent pairs and FDCs. RESULTS During our study period, 848,082 patients filled prescriptions for 3,248 unique single-agent pairs (mean 4.7 per patient, standard deviation [SD] 5.0); and 568,923 patients received prescriptions for 43 unique FDCs (mean 1.1 per patient, SD 0.3). Three (15%) of the 20 most frequently filled single-agent pairs were available as FDCs, whereas 9 (45%) of the 20 most frequently filled drug class pairs were available as FDCs. Nearly all of the frequently filled FDCs had lower fill rates than the most frequently filled single-agent pairs. CONCLUSIONS Utilization of drug combinations to treat cardiovascular conditions does not correspond well with availability of FDCs containing these agents. A concerted set of strategies should be implemented to streamline the development of useful combination products, including expedited approval pathways and increased investment in formulation studies.

Comparative Safety and Effectiveness of Denosumab Versus Zoledronic Acid in Patients With Osteoporosis: A Cohort Study

Limited head‐to‐head comparative safety and effectiveness data exist between denosumab and zoledronic acid in real‐world healthcare. We aimed to examine the safety and effectiveness of denosumab compared to zoledronic acid with regard to risk of serious infection and cardiovascular disease (CVD) and osteoporotic fracture. We conducted a cohort study using claims data (2009–2013) from a US commercial insurance plan database. We included patients aged ≥50 years who were newly initiated on denosumab or zoledronic acid. The primary outcomes were (1) hospitalization for serious infection; (2) composite CVD endpoint including myocardial infarction, stroke, coronary revascularization, and heart failure; and (3) nonvertebral osteoporotic fracture including hip, wrist, forearm, and pelvic fracture. To control for potential confounders, we used 1:1 propensity score (PS) matching. Cox proportional hazards models compared the risk of serious infection, CVD, and osteoporotic fracture within 365 days after initiation of denosumab versus zoledronic acid. After PS matching, a total of 2467 pairs of denosumab and zoledronic acid initiators were selected with a mean age of 63 years and 96% were female. When compared with zoledronic acid, denosumab was not associated with an increased risk of serious infection (HR 0.81; 95% confidence interval [CI], 0.55 to 1.21) or CVD (HR 1.11; 95% CI, 0.60 to 2.03). Similar results were obtained for each component of CVD. The risk of osteoporotic fracture was also similar between groups (HR 1.21; 95% CI, 0.84 to 1.73). This large population‐based cohort study shows that denosumab and zoledronic acid have comparable clinical safety and effectiveness with regard to the risk of serious infection, CVD, and osteoporosis fracture within 365 days after initiation of medications.

A cohort study of the risk of seizures in a pediatric population treated with atomoxetine or stimulant medications.

Stimulant medications used for treating attention deficit hyperactivity disorder (ADHD) can be associated with an increased risk of seizures. Atomoxetine is a non‐stimulant medication approved for treating ADHD. This retrospective cohort analysis evaluated risk of seizures among pediatric patients naïve to ADHD medication therapy, with exposure to atomoxetine relative to stimulant medications.

The effect of federal and state off-label marketing investigations on drug prescribing: The case of olanzapine

In the past decade, the federal government has frequently investigated and prosecuted pharmaceutical manufacturers for illegal promotion of drugs for indications not approved by the Food and Drug Administration (FDA) (“off-label” uses). State governments can choose to coordinate with the federal investigation, or pursue their own independent state investigations. One of the largest-ever off-label prosecutions relates to the atypical antipsychotic drug olanzapine (Zyprexa). In a series of settlements between 2008 and 2010, Eli Lilly paid