Cecilia P. Chung

Atypical Antipsychotic Drugs and the Risk of Sudden Cardiac Death

BACKGROUND Users of typical antipsychotic drugs have an increased risk of serious ventricular arrhythmias and sudden cardiac death. However, less is known regarding the cardiac safety of the atypical antipsychotic drugs, which have largely replaced the older agents in clinical practice. METHODS We calculated the adjusted incidence of sudden cardiac death among current users of antipsychotic drugs in a retrospective cohort study of Medicaid enrollees in Tennessee. The primary analysis included 44,218 and 46,089 baseline users of single typical and atypical drugs, respectively, and 186,600 matched nonusers of antipsychotic drugs. To assess residual confounding related to factors associated with the use of antipsychotic drugs, we performed a secondary analysis of users of antipsychotic drugs who had no baseline diagnosis of schizophrenia or related psychoses and with whom nonusers were matched according to propensity score (i.e., the predicted probability that they would be users of antipsychotic drugs). RESULTS Current users of typical and of atypical antipsychotic drugs had higher rates of sudden cardiac death than did nonusers of antipsychotic drugs, with adjusted incidence-rate ratios of 1.99 (95% confidence interval [CI], 1.68 to 2.34) and 2.26 (95% CI, 1.88 to 2.72), respectively. The incidence-rate ratio for users of atypical antipsychotic drugs as compared with users of typical antipsychotic drugs was 1.14 (95% CI, 0.93 to 1.39). Former users of antipsychotic drugs had no significantly increased risk (incidence-rate ratio, 1.13; 95% CI, 0.98 to 1.30). For both classes of drugs, the risk for current users increased significantly with an increasing dose. Among users of typical antipsychotic drugs, the incidence-rate ratios increased from 1.31 (95% CI, 0.97 to 1.77) for those taking low doses to 2.42 (95% CI, 1.91 to 3.06) for those taking high doses (P<0.001). Among users of atypical agents, the incidence-rate ratios increased from 1.59 (95% CI, 1 .03 to 2.46) for those taking low doses to 2.86 (95% CI, 2.25 to 3.65) for those taking high doses (P=0.01). The findings were similar in the cohort that was matched for propensity score. CONCLUSIONS Current users of typical and of atypical antipsychotic drugs had a similar, dose-related increased risk of sudden cardiac death.

Outcomes With Concurrent Use of Clopidogrel and Proton-Pump Inhibitors: A Cohort Study

BACKGROUND Proton-pump inhibitors (PPIs) and clopidogrel are frequently coprescribed, although the benefits and harms of their concurrent use are unclear. OBJECTIVE To examine the association between concurrent use of PPIs and clopidogrel and the risks for hospitalizations for gastroduodenal bleeding and serious cardiovascular disease. DESIGN Retrospective cohort study using automated data to identify patients who received clopidogrel between 1999 through 2005 after hospitalization for coronary heart disease. SETTING Tennessee Medicaid program. PATIENTS 20,596 patients (including 7593 concurrent users of clopidogrel and PPIs) hospitalized for myocardial infarction, coronary artery revascularization, or unstable angina pectoris. MEASUREMENTS Baseline and follow-up drug use was assessed from automated records of dispensed prescriptions. Primary outcomes were hospitalizations for gastroduodenal bleeding and serious cardiovascular disease (fatal or nonfatal myocardial infarction or sudden cardiac death, stroke, or other cardiovascular death). RESULTS Pantoprazole and omeprazole accounted for 62% and 9% of concurrent PPI use, respectively. Adjusted incidence of hospitalization for gastroduodenal bleeding in concurrent PPI users was 50% lower than that in nonusers (hazard ratio, 0.50 [95% CI, 0.39 to 0.65]). For patients at highest risk for bleeding, PPI use was associated with an absolute reduction of 28.5 (CI, 11.7 to 36.9) hospitalizations for gastroduodenal bleeding per 1000 person-years. The hazard ratio associated with concurrent PPI use for risk for serious cardiovascular disease was 0.99 (CI, 0.82 to 1.19) for the entire cohort and 1.01 (CI, 0.76 to 1.34) for the subgroup of patients who had percutaneous coronary interventions with stenting during the qualifying hospitalization. LIMITATIONS Unmeasured confounding and misclassification of exposure (no information on adherence or over-the-counter use of drugs) and end points (not confirmed by medical record review) were possible. Because many patients entered the cohort from hospitals with relatively few cohort members, the analysis relied on the assumption that after adjustment for observed covariates, PPI users from one such hospital could be compared with nonusers from a different hospital. CONCLUSION In patients with serious coronary heart disease treated with clopidogrel, concurrent PPI use was associated with reduced incidence of hospitalizations for gastroduodenal bleeding. The corresponding point estimate for serious cardiovascular disease was not increased; however, the 95% CI included a clinically important increased risk. PRIMARY FUNDING SOURCE Agency for Healthcare Research and Quality and National Heart, Lung, and Blood Institute.

High prevalence of the metabolic syndrome in patients with systemic lupus erythematosus: association with disease characteristics and cardiovascular risk factors

Background: The metabolic syndrome is an independent risk factor for ischaemic heart disease. Patients with systemic lupus erythematosus (SLE) have accelerated atherosclerosis; however, there are no controlled studies of the metabolic syndrome in patients with SLE. Objective: To compare the prevalence of the metabolic syndrome in patients with SLE and controls and to evaluate its relationship to other cardiovascular risk factors and inflammation. Methods: 102 patients with SLE and 101 controls were studied. The prevalence of the metabolic syndrome was compared in patients and controls using the National Cholesterol Education Program Adult Treatment Panel III (NCEP) and the World Health Organization (WHO) definitions, and associations with cardiovascular risk factors and lupus characteristics were examined. Results: The metabolic syndrome was present in 32.4% of patients and in 10.9% of controls subjects (p<0.001) using the WHO definition that requires direct determination of insulin resistance, and in 29.4% of patients with SLE and in 19.8% of controls (p = 0.14) using the NCEP definition. Among patients with SLE, both definitions were significantly associated with higher concentrations of C reactive protein (p = 0.001) and the NCEP definition was significantly associated with higher concentrations of homocysteine (p<0.001), lipoprotein (a) (p = 0.02) and cholesterol (p = 0.04). Neither lupus disease activity nor damage scores were associated with the metabolic syndrome. Conclusions: Patients with SLE have a higher prevalence of insulin resistance and consequently of the WHO-defined metabolic syndrome than controls. In patients with SLE, the metabolic syndrome was associated with higher levels of inflammation and may provide a link between inflammation and increased cardiovascular risk.

Adipocytokines Are Associated with Radiographic Joint Damage in Rheumatoid Arthritis

OBJECTIVE Obesity protects against radiographic joint damage in rheumatoid arthritis (RA) through poorly defined mechanisms. Adipocytokines are produced in adipose tissue and modulate inflammatory responses and radiographic joint damage in animal models. The purpose of this study was to examine the hypothesis that adipocytokines modulate inflammation and radiographic joint damage in patients with RA. METHODS We compared serum concentrations of leptin, resistin, adiponectin, and visfatin in 167 RA patients and 91 control subjects. The independent association between adipocytokines and body mass index (BMI), measures of inflammation (C-reactive protein [CRP], interleukin-6 [IL-6], and tumor necrosis factor alpha [TNFalpha]), and radiographic joint damage (Larsen score; n = 93 patients) was examined in RA patients by multivariable regression analysis first controlling for age, race, and sex, and then for obesity (BMI) and inflammation (TNFalpha, IL-6, and CRP). RESULTS Concentrations of all adipocytokines were significantly higher in RA patients than in controls; for visfatin and adiponectin, this association remained significant after adjusting for BMI, inflammation, or both. Visfatin concentrations were associated with higher Larsen scores, and this association remained significant after adjustment for age, race, sex, disease duration, BMI, and inflammation (odds ratio [OR] 2.38 [95% confidence interval (95% CI) 1.32-4.29], P = 0.004). Leptin concentrations showed a positive association with the BMI (rho = 0.58, P < 0.01) and showed a negative association with the Larsen score after adjustment for inflammation (OR 0.32 [95% CI 0.17-0.61], P < 0.001), but not after adjustment for BMI (OR 0.86 [95% CI 0.42-1.73], P = 0.67). CONCLUSION Concentrations of adipocytokines are increased in patients with RA and may modulate radiographic joint damage. Visfatin is associated with increased, and leptin with reduced, levels of radiographic joint damage.

Inflammation-Associated Insulin Resistance: Differential Effects in Rheumatoid Arthritis and Systemic Lupus Erythematosus Define Potential Mechanisms

OBJECTIVE Insulin resistance is increased by inflammation, but the mechanisms are unclear. The present study was undertaken to test the hypothesis that decreased insulin sensitivity is differentially associated with mediators of inflammation by studying 2 chronic inflammatory diseases of different pathogenesis, systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). METHODS We measured fasting insulin, glucose, and lipid levels, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor alpha (TNFalpha), and coronary artery calcification in 103 patients with SLE and in 124 patients with RA. Insulin sensitivity was measured using the homeostasis model assessment (HOMA) index. RESULTS The HOMA value was higher in RA patients (median 2.05 [interquartile range (IQR) 1.05-3.54]) than in SLE patients (1.40 [0.78-2.59]) (P = 0.007). CRP and ESR did not differ significantly in RA and SLE patients. Body mass index (BMI) was significantly correlated with the HOMA index in both RA (rho = 0.20) and SLE (rho = 0.54), independently of age, sex, race, and current use of corticosteroids. In RA patients, the HOMA index was also significantly positively correlated with IL-6 (rho = 0.63), TNFalpha (rho = 0.50), CRP (rho = 0.29), ESR (rho = 0.26), coronary calcification (rho = 0.26), and Disease Activity Score in 28 joints (rho = 0.21); associations adjusted for age, sex, race, BMI, and current use of corticosteroids remained significant (P < 0.05). In SLE patients, the HOMA index was also significantly correlated with ESR (rho = 0.35) and CRP (rho = 0.25), but not with other variables. The association between the ESR and the HOMA value in patients with SLE remained significant after adjustment for confounding covariates (P = 0.008). In multivariable models, the major contributing factors to the HOMA index were the BMI in SLE patients, and IL-6 and TNFalpha levels in RA patients. CONCLUSION The pathogenesis of insulin resistance and its contribution to atherogenesis varies in different inflammatory settings.

Inflammatory Mediators and Premature Coronary Atherosclerosis in Rheumatoid Arthritis

OBJECTIVE Rheumatoid arthritis (RA) is an inflammatory disease associated with premature atherosclerosis. We hypothesized that mediators of inflammation associated with atherosclerosis in other populations (interleukin-6 [IL-6], tumor necrosis factor alpha [TNFalpha], serum amyloid A [SAA], vascular endothelial growth factor, neutrophil count, IL-1alpha, E-selectin, intercellular adhesion molecule 1 [ICAM-1], myeloperoxidase [MPO], matrix metalloproteinase 9, and vascular cell adhesion molecule 1) would be increased and associated with the severity of coronary atherosclerosis in patients with RA. METHODS Clinical variables, concentrations of inflammatory mediators, and coronary artery calcification were measured in 169 patients with RA and 92 control subjects. Differences in concentrations of inflammatory mediators were compared using median quantile regression. The relationship of inflammatory mediators with the severity of coronary calcification in RA and control subjects was examined using proportional odds logistic regression, allowing for interaction with disease status. Models were adjusted for traditional cardiovascular risk factors. RESULTS Median serum concentrations of IL-6, SAA, ICAM-1, E-selectin, TNFalpha, and MPO and peripheral blood neutrophil count were higher in patients with RA than controls (all P < 0.05), independent of Framingham risk score and diabetes mellitus (DM). IL-6 (main effect odds ratio [OR] 1.72; 95% confidence interval [95% CI] 1.12, 2.66) and TNFalpha (main effect OR 1.49; 95% CI 1.16, 1.90) concentrations were significantly associated with higher amounts of coronary calcium, independent of Framingham risk score and DM, and such main effects significantly differed from controls (P = 0.001 and 0.03 for interaction, respectively). CONCLUSION TNFalpha and IL-6 are significantly associated with the severity of subclinical atherosclerosis, independent of Framingham risk score, in RA.

Adipocytokines in Systemic Lupus Erythematosus: Relationship to Inflammation, Insulin Resistance and Coronary Atherosclerosis

We tested the hypothesis that concentrations of adipocytokines are altered in SLE and associated with coronary atherosclerosis, insulin resistance and inflammation. Concentrations of resistin, leptin, adiponectin and visfatin were measured in 109 patients with SLE and 78 control subjects. Coronary calcification was measured using electron beam-computed tomography, and insulin resistance was defined by the homeostasis model assessment index. Concentrations of adiponectin (28.7 ± 17.9 vs 22.0 ± 15.3 μg/mL, P = 0.003), leptin (41.1 ± 49.9 vs 19.8 ± 24.6 ng/mL, P < 0.001) and visfatin (7.5 ± 10.5 vs 4.5 ± 2.8 ng/mL, P < 0.001) were higher in patients with SLE than in controls. These differences remained significant after adjustment for age, race, sex and body mass index (BMI; all P values < 0.02). Concentrations of resistin (10.7 ± 7.6 vs 9.1 ± 5.1 ng/mL, P = 0.41) did not differ in patients and controls. In patients with SLE, leptin was positively associated with BMI (ρ = 0.80, P < 0.001), insulin resistance (ρ = 0.46, P < 0.001) and C-reactive protein (CRP) (ρ = 0.30, P = 0.002), whereas adiponectin was negatively associated with the same factors (ρ = –0.40, P < 0.001; ρ = −0.38, P < 0.001; ρ = –0.22, P = 0.02, respectively). None of the adipocytokines were associated with coronary atherosclerosis in SLE. In conclusion, patients with SLE have increased concentrations of adiponectin, leptin and visfatin. Lower concentrations of adiponectin and higher concentrations of leptin are associated with insulin resistance, BMI and CRP in patients with SLE.

An automated database case definition for serious bleeding related to oral anticoagulant use

Bleeding complications are a serious adverse effect of medications that prevent abnormal blood clotting. To facilitate epidemiologic investigations of bleeding complications, we developed and validated an automated database case definition for bleeding‐related hospitalizations.

Cardiovascular Risks of Nonsteroidal Antiinflammatory Drugs in Patients After Hospitalization for Serious Coronary Heart Disease

Background—The cardiovascular safety of individual nonsteroidal antiinflammatory drugs (NSAIDs) is highly controversial, particularly in persons with serious coronary heart disease. Methods and Results—We conducted a multisite retrospective cohort study of commonly used individual NSAIDs in Tennessee Medicaid, Saskatchewan Health, and United Kingdom General Practice Research databases. The cohort included 48 566 patients recently hospitalized for myocardial infarction, revascularization, or unstable angina pectoris with more than 111 000 person-years of follow-up. Naproxen users had the lowest adjusted rates of serious coronary heart disease (myocardial infarction, coronary heart disease death) and serious cardiovascular disease (myocardial infarction, stroke)/death from any cause, with respective incidence rate ratios (relative to NSAID nonusers) of 0.88 (95% CI, 0.66 to 1.17) and 0.91 (0.78 to 1.06). Risk did not increase with doses ≥1000 mg. Relative to NSAID nonusers, serious coronary heart disease risk increased with short term (<90 days) use for ibuprofen (1.67 [1.09 to 2.57]), diclofenac (1.86 [1.18 to 2.92]), celecoxib (1.37 [0.96 to 1.94]), and rofecoxib (1.46 [1.03 to 2.07]), but not for naproxen (0.88 [0.50 to 1.55]). Relative to naproxen, current users of diclofenac had increased risk of serious coronary heart disease (1.44 [0.96 to 2.15], P=0.076) and serious cardiovascular disease/death (1.52 [1.22 to 1.89], P=0.0002), and those of ibuprofen had increased risk of the latter end point (1.25 [1.02 to 1.53], P=0.032). Compared to naproxen in doses ≥1000 mg, serious coronary heart disease incidence rate ratios were increased for rofecoxib >25 mg (2.29 [1.24 to 4.22], P=0.008) and celecoxib >200 mg (1.61 [1.01 to 2.57], P=0.046). Conclusions—In patients recently hospitalized for serious coronary heart disease, naproxen had better cardiovascular safety than did diclofenac, ibuprofen, and higher doses of celecoxib and rofecoxib.

Utility of the Framingham risk score to predict the presence of coronary atherosclerosis in patients with rheumatoid arthritis

The prevalence of ischemic heart disease and atherosclerosis is increased in patients with rheumatoid arthritis (RA). In the general population, but not in patients with systemic lupus erythematosus, the Framingham risk score identifies patients at increased cardiovascular risk and helps determine the need for preventive interventions. We examined the hypothesis that the Framingham score is increased and associated with coronary-artery atherosclerosis in patients with RA. The Framingham score and the 10-year cardiovascular risk were compared among 155 patients with RA (89 with early disease, 66 with long-standing disease) and 85 control subjects. The presence of coronary-artery calcification was determined by electron-beam computed tomography. The Framingham score was compared in patients with RA and control subjects, and the association between the risk score and coronary-artery calcification was examined in patients. Patients with long-standing RA had a higher Framingham score (14 [11 to 18]) (median [interquartile range]) compared to patients with early RA (11 [8 to 14]) or control subjects (12 [7 to 14], P < 0.001). This remained significant after adjustment for age and gender (P = 0.015). Seventy-six patients with RA had coronary calcification; their Framingham risk score was higher (14 [12 to 17]) than that of 79 patients without calcification (10 [5 to 14]) (P < 0.001). Furthermore, a higher Framingham score was associated with a higher calcium score (odds ratio [OR] = 1.20, 95% confidence interval [CI] 1.12 to 1.29, P < 0.001), and the association remained significant after adjustment for age and gender (OR = 1.15, 95% CI 1.02 to 1.29, P = 0.03). In conclusion, a higher Framingham risk score is independently associated with the presence of coronary calcification in patients with RA.