James R. Daugherty

Nonsteroidal Anti-inflammatory Drug Use and Increased Risk for Peptic Ulcer Disease in Elderly Persons

OBJECTIVE To evaluate the relative risk for peptic ulcer disease that is associated with the use of nonaspirin nonsteroidal anti-inflammatory drugs. DESIGN Nested case-control study. SETTING Tennessee Medicaid program. PARTICIPANTS Medicaid enrollees 65 years of age or older were included in the study. The 1415 case patients had been hospitalized for confirmed peptic ulcer disease at some point from 1984 through 1986. The 7063 control persons represented a stratified random sample of other Medicaid enrollees. MEASUREMENTS AND MAIN RESULTS The estimated relative risk for the development of peptic ulcer disease among current users of nonaspirin nonsteroidal anti-inflammatory drugs, compared with that among nonusers, was 4.1 (95% CI, 3.5 to 4.7). For current users, the risk increased with increasing dose, from a relative risk of 2.8 (CI, 1.8 to 4.3) for the lowest to a relative risk of 8.0 (CI, 4.4 to 14.8) for the highest dose category. The risk was greatest in the first month of use (relative risk, 7.2; CI, 4.9 to 10.5). If the association is fully causal, 29% of peptic ulcers in the study sample resulted from the use of these drugs, and the excess risk associated with such use was 17.4 hospitalizations for ulcer disease per 1000 person-years of exposure. CONCLUSIONS These data support other findings indicating that a clinically significant risk for serious ulcer disease is associated with the use of nonaspirin nonsteroidal anti-inflammatory drugs. The data show that this risk increases with dose and recency of use and that use of these drugs may be responsible for a large proportion of peptic ulcer disease among elderly persons.

corticosteroid Use and Peptic Ulcer Disease: Role of Nonsteroidal Anti-inflammatory Drugs

OBJECTIVE To estimate the relative risk for peptic ulcer disease that is associated with the use of oral corticosteroids. DESIGN A nested case-control study. SETTING Tennessee Medicaid program. PARTICIPANTS The case patients (n = 1415) were hospitalized between 1984 and 1986 for gastric or duodenal ulcer or for upper gastrointestinal hemorrhage of unknown cause. The controls (n = 7063) were randomly selected from Medicaid enrollees not meeting the study criteria for inclusion as case patients. MEASUREMENTS AND MAIN RESULTS The estimated relative risk for the development of peptic ulcer disease among current users of oral corticosteroids was 2.0 (95% CI, 1.3 to 3.0). However, the risk was increased only in those who concurrently received nonsteroidal anti-inflammatory drugs (NSAIDs); these persons had an estimated relative risk associated with current corticosteroid use of 4.4 (CI, 2.0 to 9.7). In contrast, the estimated relative risk for those corticosteroid users not receiving NSAIDs was 1.1 (CI, 0.5 to 2.1). Persons concurrently receiving corticosteroids and NSAIDs had a risk for peptic ulcer disease that was 15 times greater than that of nonusers of either drug. CONCLUSION Discrepant findings among earlier studies regarding steroids and the risk for peptic ulcer disease could in part be due to differences in the use of NSAIDs among study participants. The high risk for peptic ulcer disease associated with combined use of NSAIDs and corticosteroids indicates the need to prescribe this drug combination cautiously.

COX-2 selective non-steroidal anti-inflammatory drugs and risk of serious coronary heart disease.

Results of premarketing and postmarketing trials have raised doubts about the cardiovascular safety of the non-steroidal anti-inflammatory drug (NSAID) rofecoxib, especially at doses greater than 25 mg. Between Jan 1, 1999, and June 30, 2001, we did a retrospective cohort study of individuals on the expanded Tennessee Medicaid programme (TennCare), in which we assessed occurrence of serious coronary heart disease (CHD) in non-users (n=202916) and in users of rofecoxib and other NSAIDs (rofecoxib n=24 132, other n=151 728). Participants were aged 50-84 years, lived in the community, and had no life-threatening non-cardiovascular illness. Users of high-dose rofecoxib were 1.70 (95% CI 0.98-2.95, p=0.058) times more likely than non-users to have CHD; among new users this rate increased to 1.93 (1.09-3.42, p=0.024). By contrast, there was no evidence of raised risk of CHD among users of rofecoxib at doses of 25 mg or less or among users of other NSAIDs.

Non-steroidal anti-inflammatory drugs and risk of serious coronary heart disease: an observational cohort study

BACKGROUND Non-aspirin, non-steroidal anti-inflammatory drugs (NANSAIDs) have complex effects that could either prevent or promote coronary heart disease. Comparison of the NANSAID rofexocib with naproxen showed a substantial difference in acute myocardial infarction risk, which has been interpreted as a protective effect of naproxen. We did an observational study to measure the effects of NANSAIDs, including naproxen, on risk of serious coronary heart disease. METHODS We used data from the Tennessee Medicaid programme obtained between Jan 1, 1987, and Dec 31, 1998, to identify a cohort of new NANSAID users (n=181 441) and an equal number of non-users, matched for age, sex, and date NANSAID use began. Both groups were 50-84 years of age, were not resident in a nursing home, and did not have life-threatening illness. The study endpoint was hospital admission for acute myocardial infarction or death from coronary heart disease. FINDINGS During 532634 person-years of follow-up, 6362 cases of serious coronary heart disease occurred, or 11.9 per 1000 person-years. Multivariate-adjusted rate ratios for current and former use of NANSAIDs were 1.05 (95% CI 0.97-1.14) and 1.02 (0.97-1.08), respectively. Rate ratios for naproxen, ibuprofen, and other NANSAIDs were 0.95 (0.82-1.09), 1.15 (1.02-1.28), and 1.03 (0.92-1.16), respectively. There was no protection among long-term NANSAID users with uninterrupted use; the rate ratio among current users with more than 60 days of continuous use was 1.05 (0.91-1.21). When naproxen was directly compared with ibuprofen, the current-use rate ratio was 0.83 (0.69-0.98). INTERPRETATION Absence of a protective effect of naproxen or other NANSAIDs on risk of coronary heart disease suggests that these drugs should not be used for cardioprotection.

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.

Individual Sulfonylureas and Serious Hypoglycemia in Older People

OBJECTIVE: To compare the risk of serious hypoglycemia associated with the use of individual sulfonylureas in older people.

Outpatient adherence to beta-blocker therapy after acute myocardial infarction

OBJECTIVES This study was designed to determine adherence to outpatient beta-blocker therapy following acute myocardial infarction (AMI). BACKGROUND The importance of beta-blocker therapy after AMI is widely recognized. Outpatient adherence with this recommendation, however, is not well described. METHODS Data on 846 patients surviving AMI were studied. Factors associated with filling a beta-blocker prescription within 30 days postdischarge and the proportion of patients who were or were not discharged on beta-blockers who filled prescriptions for them by 30, 180, and 365 days post-AMI discharge were assessed. RESULTS Patients with a discharge order for beta-blocker therapy were more likely to fill a prescription in the first 30 days postdischarge (hazard ratio [HR] 15.82, 95% confidence interval [CI], 10.75 to 23.26). Patients older than age 75 years were less likely than those age <65 years to fill a prescription (HR 0.63, 95% CI 0.42 to 0.93). Gender, race, and being an ideal candidate did not affect beta-blocker use. Among patients who were discharged on beta-blockers, 85% of survivors had filled a prescription by 30 days postdischarge, and 63% and 61% were current users at 180 and 365 days, respectively. In contrast, only 8% of those patients with no discharge order for beta-blockers had filled such a prescription by 30 days, and 13% and 12% of patients were current users at 180 and 365 days, respectively. CONCLUSIONS Patients not discharged on beta-blockers are unlikely to be started on them as outpatients. For patients who are discharged on beta-blockers after AMI, there is a significant decline in use after discharge. Quality improvement efforts need to be focused on improving discharge planning and to continue these efforts after discharge.

Antipsychotics and the risk of type 2 diabetes mellitus in children and youth.

IMPORTANCE The increased prescribing of antipsychotics for children and youth has heightened concerns that this practice increases the risk of type 2 diabetes mellitus. OBJECTIVE To compare the risk of type 2 diabetes in children and youth 6 to 24 years of age for recent initiators of antipsychotic drugs vs propensity score-matched controls who had recently initiated another psychotropic medication. DESIGN, SETTING, AND PARTICIPANTS Retrospective cohort study of the Tennessee Medicaid program with 28 858 recent initiators of antipsychotic drugs and 14 429 matched controls. The cohort excluded patients who previously received a diagnosis of diabetes, schizophrenia, or some other condition for which antipsychotics are the only generally recognized therapy. MAIN OUTCOMES AND MEASURES Newly diagnosed diabetes during follow-up, as identified from diagnoses and diabetes medication prescriptions. RESULTS Users of antipsychotics had a 3-fold increased risk for type 2 diabetes (HR = 3.03 [95% CI = 1.73-5.32]), which was apparent within the first year of follow-up (HR = 2.49 [95% CI = 1.27-4.88]). The risk increased with cumulative dose during follow-up, with HRs of 2.13 (95% CI = 1.06-4.27), 3.42 (95% CI = 1.88-6.24), and 5.43 (95% CI = 2.34-12.61) for respective cumulative doses (gram equivalents of chlorpromazine) of more than 5 g, 5 to 99 g, and 100 g or more (P < .04). The risk remained elevated for up to 1 year following discontinuation of antipsychotic use (HR = 2.57 [95% CI = 1.34-4.91]). When the cohort was restricted to children 6 to 17 years of age, antipsychotic users had more than a 3-fold increased risk of type 2 diabetes (HR = 3.14 [95% CI = 1.50-6.56]), and the risk increased significantly with increasing cumulative dose (P < .03). The risk was increased for use restricted to atypical antipsychotics (HR = 2.89 [95% CI = 1.64-5.10]) or to risperidone (HR = 2.20 [95% CI = 1.14-4.26]). CONCLUSIONS AND RELEVANCE Children and youth prescribed antipsychotics had an increased risk of type 2 diabetes that increased with cumulative dose.

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.