Helen Mogun

Relationship Between Selective Cyclooxygenase-2 Inhibitors and Acute Myocardial Infarction in Older Adults

Background—Although cyclooxygenase-2 inhibitors (coxibs) were developed to cause less gastrointestinal hemorrhage than nonselective nonsteroidal antiinflammatory drugs (NSAIDs), there has been concern about their cardiovascular safety. We studied the relative risk of acute myocardial infarction (AMI) among users of celecoxib, rofecoxib, and NSAIDs in Medicare beneficiaries with a comprehensive drug benefit. Methods and Results—We conducted a matched case-control study of 54 475 patients 65 years of age or older who received their medications through 2 state-sponsored pharmaceutical benefits programs in the United States. All healthcare use encounters were examined to identify hospitalizations for AMI. Each of the 10 895 cases of AMI was matched to 4 controls on the basis of age, gender, and the month of index date. We constructed matched logistic regression models including indicators for patient demographics, healthcare use, medication use, and cardiovascular risk factors to assess the relative risk of AMI in patients who used rofecoxib compared with persons taking no NSAID, taking celecoxib, or taking NSAIDs. Current use of rofecoxib was associated with an elevated relative risk of AMI compared with celecoxib (odds ratio [OR], 1.24; 95% CI, 1.05 to 1.46; P = 0.011) and with no NSAID (OR, 1.14; 95% CI, 1.00 to 1.31; P = 0.054). The adjusted relative risk of AMI was also elevated in dose-specific comparisons: rofecoxib ≤25 mg versus celecoxib ≤200 mg (OR, 1.21; 95% CI, 1.01 to 1.44; P = 0.036) and rofecoxib >25 mg versus celecoxib >200 mg (OR, 1.70; 95% CI, 1.07 to 2.71; P = 0.026). The adjusted relative risks of AMI associated with rofecoxib use of 1 to 30 days (OR, 1.40; 95% CI, 1.12 to 1.75; P = 0.005) and 31 to 90 days (OR, 1.38; 95% CI, 1.11 to 1.72; P = 0.003) were higher than >90 days (OR, 0.96; 95% CI, 0.72 to 1.25; P = 0.8) compared with celecoxib use of similar duration. Celecoxib was not associated with an increased relative risk of AMI in these comparisons. Conclusions—In this study, current rofecoxib use was associated with an elevated relative risk of AMI compared with celecoxib use and no NSAID use. Dosages of rofecoxib >25 mg were associated with a higher risk than dosages ≤25 mg. The risk was elevated in the first 90 days of use but not thereafter.

Noncompliance with antihypertensive medications: the impact of depressive symptoms and psychosocial factors.

OBJECTIVE: Addressing the epidemic of poor compliance with antihypertensive medications will require identifying factors associated with poor adherence, including modifiable psychosocial and behavioral characteristics of patients.DESIGN: Cross-sectional study, comparing measured utilization of antihypertensive prescriptions with patients’ responses to a structured interview.STUDY POPULATION: Four hundred ninety-six treated hypertensive patients drawn from a large HMO and a VA medical center.DATA COLLECTION: We developed a survey instrument to assess patients’ psychosocial and behavioral characteristics, including health beliefs, knowledge, and social support regarding blood pressure medications, satisfaction with health care, depression symptom severity, alcohol consumption, tobacco use, and internal versus external locus of control. Other information collected included demographic and clinical characteristics and features of antihypertensive medication regimens. All prescriptions filled for antihypertensive medications were used to calculate actual adherence to prescribed regimens in a 365-day study period.MAIN OUTCOME OF INTEREST: Adjusted odds ratios (ORs) of antihypertensive compliance, based on ordinal logistic regression models.RESULTS: After adjusting for the potential confounding effects of demographic, clinical, and other psychosocial variables, we found that depression was significantly associated with noncompliance (adjusted OR per each point increase on a 14-point scale, 0.93; 95% confidence interval [95% CI], 0.87 to 0.99); in unadjusted analyses, the relationship did not reach statistical significance. There was also a trend toward improved compliance for patients perceiving that their health is controlled by external factors (adjusted OR per point increase, 1.14; 95% CI, 0.99 to 1.33). There was no association between compliance and knowledge of hypertension, health beliefs and behaviors, social supports, or satisfaction with care.CONCLUSIONS: Depressive symptoms may be an under-recognized but modifiable risk factor for poor compliance with antihypertensive medications. Surprisingly, patient knowledge of hypertension, health beliefs, satisfaction with care, and other psychosocial variables did not appear to consistently affect adherence to prescribed regimens.

Zolpidem use and hip fractures in older people.

OBJECTIVES: The widespread use of sedative‐hypnotics in older populations makes it imperative to identify hazardous regimens that should be avoided and safer regimens that may be used preferentially by older people. Although benzodiazepines have been shown to increase fall and fracture risk, zolpidem, a nonbenzodiazepine hypnotic, has been advocated as a safer alternative.

Predictors of decreased renal function in patients with heart failure during angiotensin-converting enzyme inhibitor therapy: Results from the Studies of Left Ventricular Dysfunction (SOLVD)

BACKGROUND Although angiotensin-converting enzyme inhibitor therapy reduces mortality rates in patients with congestive heart failure (CHF), it may also cause decreased renal function. Little information is available to predict which patients are at highest risk for this complication. OBJECTIVE To quantify specific clinical predictors of reduction in renal function in patients with CHF who are prescribed angiotensin-converting enzyme inhibitor therapy. METHOD We analyzed data from the Studies of Left Ventricular Dysfunction (SOLVD), a randomized, double-blind, placebo-controlled trial of enalapril for the treatment of CHF. There were 3379 patients randomly assigned to enalapril with a median follow-up of 974 days and 3379 patients randomly assigned to placebo with a mean follow-up of 967 days. Decreased renal function was defined as a rise in serum creatinine >/=0.5 mg/dL (44 micromol/L) from baseline. We used time-to-event analysis to identify potential predictors of decrease in renal function including age, baseline ejection fraction, baseline creatinine, low systolic blood pressure (<100 mm Hg), history of hypertension, diabetes, and use of antiplatelet, diuretic, and beta-blocker therapy. RESULTS Patients randomly assigned to enalapril had a 33% greater likelihood of decreased renal function than controls (P =.003). By multivariate analysis, in both the placebo and enalapril groups older age, diuretic therapy, and diabetes were associated with decreased renal function, whereas beta-blocker therapy and higher ejection fraction were renoprotective. Older age was associated with a greater risk of developing decreased renal function in both groups, but significantly more so in the enalapril group (enalapril: risk ratio [RR] 1.42 per 10 years, 95% confidence interval [CI] 1.32-1.52 with enalapril; placebo: RR 1.18, 95% CI 1.12-1.25). Diuretic therapy was likewise associated with a greater risk of decreased renal function in the enalapril group (RR 1.89, 95% CI 1.70-2.08) than in the placebo group (RR 1.35, 95% CI 1.09-1.66). Conversely, enalapril had a relative renoprotective effect (RR 1.33, 95% CI 1.13-1.53) compared with placebo (RR 1.96, 95% CI 1.57-2.44) in patients with diabetes. A lower risk of renal impairment was seen in both groups with beta-blocker therapy (RR 0.70, 95% CI 0.57-0.85) and higher baseline ejection fraction (RR 0.93 per 5% increment, 95% CI 0.91-0. 96). CONCLUSIONS Enalapril use caused a 33% increase in the risk of decreased renal function in patients with CHF. Diuretic use and advanced age increased this risk. Diabetes was associated with an increased risk of renal impairment in all patients with CHF, but this risk was reduced in the enalapril group compared with the placebo group. beta-Blocker therapy and higher ejection fraction were renoprotective in all patients regardless of therapy.

Antidepressant Use in Pregnancy and the Risk of Cardiac Defects

BACKGROUND Whether the use of selective serotonin-reuptake inhibitors (SSRIs) and other antidepressants during pregnancy is associated with an increased risk of congenital cardiac defects is uncertain. In particular, there are concerns about a possible association between paroxetine use and right ventricular outflow tract obstruction and between sertraline use and ventricular septal defects. METHODS We performed a cohort study nested in the nationwide Medicaid Analytic eXtract for the period 2000 through 2007. The study included 949,504 pregnant women who were enrolled in Medicaid during the period from 3 months before the last menstrual period through 1 month after delivery and their liveborn infants. We compared the risk of major cardiac defects among infants born to women who took antidepressants during the first trimester with the risk among infants born to women who did not use antidepressants, with an unadjusted analysis and analyses that restricted the cohort to women with depression and that used propensity-score adjustment to control for depression severity and other potential confounders. RESULTS A total of 64,389 women (6.8%) used antidepressants during the first trimester. Overall, 6403 infants who were not exposed to antidepressants were born with a cardiac defect (72.3 infants with a cardiac defect per 10,000 infants), as compared with 580 infants with exposure (90.1 per 10,000 infants). Associations between antidepressant use and cardiac defects were attenuated with increasing levels of adjustment for confounding. The relative risks of any cardiac defect with the use of SSRIs were 1.25 (95% confidence interval [CI], 1.13 to 1.38) in the unadjusted analysis, 1.12 (95% CI, 1.00 to 1.26) in the analysis restricted to women with depression, and 1.06 (95% CI, 0.93 to 1.22) in the fully adjusted analysis restricted to women with depression. We found no significant association between the use of paroxetine and right ventricular outflow tract obstruction (relative risk, 1.07; 95% CI, 0.59 to 1.93) or between the use of sertraline and ventricular septal defects (relative risk, 1.04; 95% CI, 0.76 to 1.41). CONCLUSIONS The results of this large, population-based cohort study suggested no substantial increase in the risk of cardiac malformations attributable to antidepressant use during the first trimester. (Funded by the Agency for Healthcare Research and Quality and the National Institutes of Health.).

Statins and the Risk of Lung, Breast, and Colorectal Cancer in the Elderly

Background— Although most randomized trials and meta-analyses suggest a slight or no increase in the risk of cancer in statin users, results from observational studies have been conflicting, and some have even suggested a large protective effect of statins on certain cancers. Long-term statin users tend to be healthier, less frail, and more adherent to therapy than nonusers, however. This could explain such apparent “protective” effects. Methods and Results— We conducted the present cohort study by linking data from a large state drug benefit program with cancer registry data and Medicare healthcare utilization data. We identified all initiators of statins; initiators of glaucoma medications, another preventive drug, served as a comparison group. Outcomes included all registry-identified cases of colorectal, lung, and breast cancer. Multivariable Cox proportional models were used to adjust for confounding. Patient characteristics were similar in both groups, but statin initiators (n=24 439) were slightly younger and used some services more frequently than glaucoma drug initiators (n=7284). The mean follow-up was 2.9 years, with the longest follow-up being 8.4 years. Incidence rates of colorectal, lung, and breast cancers in both groups were very similar to rates in the general population. Adjusted hazard ratios were 0.96 (95% CI, 0.70 to 1.31) for colorectal cancer, 1.11 (95% CI, 0.77 to 1.60) for lung cancer, and 0.99 (95% CI, 0.74 to 1.33) for breast cancer. Conclusions— These data from a large population of typical older patients who began using statins indicate that it is unlikely that statins confer a clinically important decrease or increase in the risk of colorectal, lung, or breast cancer over the durations studied.

Nonoccupational Risk Factors for Carpal Tunnel Syndrome

AbstractOBJECTIVE: To examine the relation between selected nonoccupational risk factors and surgery for carpal tunnel syndrome. DESIGN: Case-control study using an administrative database. PARTICIPANTS: Enrollees of New Jersey Medicine or Medicaid programs during 1989 to 1991. MEASUREMENTS: The outcome of interest was open or endoscopic carpal tunnel release. We examined the relation between carpal tunnel release and diabetes mellitus, thyroid disease, inflammatory arthritis, hemodialysis, pregnancy, use of corticosteroids, and hormone replacement therapy. MAIN RESULTS: In multivariate models, inflammatory arthritis was strongly associated with carpal tunnel release (odds ratio [OR] 2.9; 95% confidence interval [CI] 2.2, 3.8). However, corticosteroid use also appeared to be associated with a greater likelihood of undergoing carpal tunnel release, even in the absence of inflammatory arthritis (OR 1.6; 95% CI 1.2, 2.1). Diabetes had a weak but significant association with carpal tunnel release (OR 1.4; 95% CI 1.2, 1.8), as did hypothyroidism (OR 1.7; 95% CI 1.1, 2.8), although patients with hyperthyroidism did not have any change in risk. Women who underwent carpal tunnel release were almost twice as likely to be users of estrogen replacement therapy as controls (OR 1.8; 95% CI 1.0, 3.2). CONCLUSIONS: Although inflammatory arthritis is the most important nonoccupational risk factor for carpal tunnel release, these data substantiate the increase in risk associated with diabetes and untreated hypothyroidism. Further investigation in detailed clinical studies will be necessary to confirm whether changes in corticosteroid use and hormone replacement therapy offer additional means of risk reduction for this common condition.

Antidepressant Use Late in Pregnancy and Risk of Persistent Pulmonary Hypertension of the Newborn

IMPORTANCE The association between selective serotonin reuptake inhibitor (SSRI) antidepressant use during pregnancy and risk of persistent pulmonary hypertension of the newborn (PPHN) has been controversial since the US Food and Drug Administration issued a public health advisory in 2006. OBJECTIVE To examine the risk of PPHN associated with exposure to different antidepressant medication classes late in pregnancy. DESIGN AND SETTING Cohort study nested in the 2000-2010 Medicaid Analytic eXtract for 46 US states and Washington, DC. Last follow-up date was December 31, 2010. PARTICIPANTS A total of 3,789,330 pregnant women enrolled in Medicaid from 2 months or fewer after the date of last menstrual period through at least 1 month after delivery. The source cohort was restricted to women with a depression diagnosis and logistic regression analysis with propensity score adjustment applied to control for potential confounders. EXPOSURES FOR OBSERVATIONAL STUDIES: SSRI and non-SSRI monotherapy use during the 90 days before delivery vs no use. MAIN OUTCOMES AND MEASURES Recorded diagnosis of PPHN during the first 30 days after delivery. RESULTS A total of 128,950 women (3.4%) filled at least 1 prescription for antidepressants late in pregnancy: 102,179 (2.7%) used an SSRI and 26,771 (0.7%) a non-SSRI. Overall, 7630 infants not exposed to antidepressants were diagnosed with PPHN (20.8; 95% CI, 20.4-21.3 per 10,000 births) compared with 322 infants exposed to SSRIs (31.5; 95% CI, 28.3-35.2 per 10,000 births), and 78 infants exposed to non-SSRIs (29.1; 95% CI, 23.3-36.4 per 10,000 births). Associations between antidepressant use and PPHN were attenuated with increasing levels of confounding adjustment. For SSRIs, odds ratios were 1.51 (95% CI, 1.35-1.69) unadjusted and 1.10 (95% CI, 0.94-1.29) after restricting to women with depression and adjusting for the high-dimensional propensity score. For non-SSRIs, the odds ratios were 1.40 (95% CI, 1.12-1.75) and 1.02 (95% CI, 0.77-1.35), respectively. Upon restriction of the outcome to primary PPHN, the adjusted odds ratio for SSRIs was 1.28 (95% CI, 1.01-1.64) and for non-SSRIs 1.14 (95% CI, 0.74-1.74). CONCLUSIONS AND RELEVANCE Evidence from this large study of publicly insured pregnant women may be consistent with a potential increased risk of PPHN associated with maternal use of SSRIs in late pregnancy. However, the absolute risk was small, and the risk increase appears more modest than suggested in previous studies.

Antihypertensive Drug Therapy and the Initiation of Treatment for Diabetes Mellitus

Although several antihypertensive medications have been associated with impaired glucose tolerance [1], thiazide diuretics have received the most attention in this regard. Since the introduction of chlorothiazide in 1957, several cases have been reported in which thiazide diuretics were associated with glucose intolerance [2-5]. In addition, many clinical studies have provided information on the effects of thiazide diuretics on glucose homeostasis. The Veterans Administration Cooperative Study Group on Antihypertensive Agents [6] found that hydrochlorothiazide increased the average fasting plasma glucose level by approximately 0.3 mmol/L after 10 weeks of treatment. In the Systolic Hypertension in the Elderly Program study [7], the treatment group showed an increase of 0.4 mmol/L in mean serum glucose levels over the baseline level after 1 year of thiazide diuretic therapy, whereas the placebo group showed an increase of 0.1 mmol/L. In the study conducted by the European Working Party on Hypertension in the Elderly [8], the thiazide treatment group showed an increase of 0.5 mmol/L in the fasting serum glucose level after 2 years, whereas the placebo group showed a decrease of 0.2 mmol/L (P < 0.001). In a randomized, crossover study of 50 patients, Pollare and coworkers [9] found that, when compared with placebo, hydrochlorothiazide reduced insulin-stimulated glucose uptake in patients with essential hypertension after 18 weeks of treatment. In contrast, patients treated with captopril showed improved carbohydrate metabolism, including an increase in insulin-stimulated glucose uptake, when compared with placebo recipients. Previous efforts to quantify the clinical risk for development of hyperglycemia requiring treatment in patients taking various antihypertensive regimens have been limited by the relative infrequency of this event and the limited range of antihypertensive agents used in large clinical trials [10]. For the same reasons, the risks of different agents have not been adequately compared. To address these issues, we conducted a casecontrol study of 11 855 New Jersey Medicaid enrollees newly started on hypoglycemic therapy. Methods Sources of Data The study sample was drawn from the state of New Jerseys Medicaid program for the years 1981 to 1990. Enrollment in the program was ascertained through the Medicaid eligibility file, which identifies all program participants, their dates of coverage, and demographic characteristics including age, gender, and race. Data on medication use were taken from the Medicaid pharmacy claims file, which contains information on all prescriptions filled by Medicaid recipients, including the National Drug Code and the date dispensed. Medications of interest were identified using the National Drug Code specific for each agent. Hospitalization data for all Medicaid recipients were also ascertained. Medicaid recipients who were eligible to receive Medicare benefits (crossover enrollees) were identified to acquire full information on utilization of hospital services. Medicaid covers payment for medications for these Medicare recipients, which enabled us to ascertain all prescription information for this group. Case Patients Case patients were Medicaid enrollees 35 to 99 years of age who filled a first prescription for a hypoglycemic agent between 1981 and 1990. All oral hypoglycemic medications and insulin preparations were included. The date of the first prescription for a hypoglycemic medication was defined as the index date. To ensure that study patients were active users of the Medicaid system, each case patient was required to be continuously eligible in the program for at least 120 days before the index date and to have filled a prescription for at least one drug of any kind during this period. No claims for a hypoglycemic agent could be made before the index date. Drug claims were searched back to 1981 to ensure that case patients and controls had not previously filled a prescription for a hypoglycemic agent. Of the 35 202 patients who filled a first prescription for a hypoglycemic agent during the defined study period, 443 had deficient eligibility records, and 4753 did not meet the specified age criteria. The additional requirement that case patients be continuously enrolled in Medicaid during the 120 days before the index date eliminated 9292 persons. Another 8859 patients were excluded from the case group because they had not filled a prescription for any other drug during the 120 days preceding the index date. The final case group included 11 855 patients. Controls We identified controls by selecting a random sample of Medicaid enrollees who met the same criteria for eligibility and use of the health care system as did case patients but who had not filled a prescription for a hypoglycemic agent on or before a randomly assigned index date. One control was randomly selected for each case. Definitions of Antihypertensive Drug Use To characterize current exposure to antihypertensive agents, all prescriptions filled during the 120 days before the index date were reviewed for both case patients and controls. Medications of principal interest included thiazide diuretics; angiotensin-converting enzyme inhibitors; centrally acting antiadrenergic agents; peripherally acting antiadrenergic agents; -blockers; calcium-channel blockers; and vasodilators. Categorization of patients taking multiple-agent regimens representing more than one category of antihypertensive agent was based on whether the regimen did or did not contain a thiazide diuretic. Drug-exposure categories were mutually exclusive so that patients were either characterized as exposed to a single category of antihypertensive therapy or placed in one of the multiple-category groups, but not both. Three time windows of exposure before the index date were created: 1 to 45 days, 1 to 90 days, and 91 to 120 days. A patient was considered to be currently exposed to an agent if he or she filled a prescription for a medication of interest in the 45 days before the index date. This was the exposure window of primary interest. In addition, we examined records of patients who filled a prescription for a medication of interest 1 to 90 days before the index date and 91 to 120 days before the index date to study people with evidence of a more prolonged duration of exposure. Covariates Because other medications can also directly and indirectly affect glucose metabolism, we measured exposure to potassium supplements, potassium-sparing diuretics, oral glucocorticoids, estrogen-containing compounds, and niacin. In addition, exposure status for these agents was characterized according to the previously defined exposure windows. Other covariates included demographic variables (age, gender, race, residence in a nursing home) the number of days hospitalized, and the number of prescriptions filled in the 120-day period before the index date. Statistical Analysis Differences in categorical variables between case patients and controls were assessed with chi-square tests. Relative risks for new use of a hypoglycemic agent within each exposure category were estimated from odds ratios calculated by unconditional logistic regression [11] using the SAS CATMOD program [12]. For these analyses, the reference category was the absence of exposure to any antihypertensive medication. Models were constructed with patients characterized according to the study definitions of duration of exposure (current exposure or exposure of more prolonged duration). Covariates in the models included age, gender, race, nursing home residency, number of days in the hospital, number of drug claims, glucocorticoid exposure, potassium supplementation, estrogen exposure, and niacin exposure. Because of temporal trends in the pattern of antihypertensive drug prescribing [13], the study sample was stratified according to index date (pre-1985 or 1985 to 1990), and models were constructed for each subsample. Confidence intervals (CIs) for the estimated odds ratios and significance tests for differences between individual odds ratios were calculated using the estimated standard errors. To control for potential surveillance bias (that is, the possibility that patients receiving antihypertensive agents may have had closer medical supervision and may have had more laboratory tests than patients not receiving antihypertensive therapy) and to make the case and control groups more comparable, we did a separate analysis of the 8005 current users of antihypertensive medications (4794 case patients and 3211 controls). In these models, current exposure to thiazide diuretics was the reference exposure. This model also included the same potential confounding variables mentioned above. Results We found no consistent trend when examining the relation between age and the likelihood of starting a hypoglycemic medication (Table 1) in the age range studied. Patients 55 to 74 years of age were more likely to be started on a hypoglycemic agent than patients 35 to 54 years of age, although no significant difference was found between patients 75 years of age or older and patients 35 to 54 years of age. No significant differences in gender distribution were observed between case patients and controls. Blacks and other non-whites were more likely to be started on hypoglycemic therapy than whites. Patients in nursing homes were less likely to start hypoglycemic therapy than noninstitutionalized patients. Patients who had a greater number of hospital days or who filled more prescriptions were more likely to be started on a hypoglycemic medication. No relation was found between index date (pre-1985 or 1985 to 1990) and the likelihood of being started on hypoglycemic therapy. Table 1. Characteristics of the Study Sample and Their Relation to Starting a Hypoglycemic Medication The relative risk for the initiation of hypoglycemic therapy was significantly increased among patients who were current users

Cancer and the Risk of Suicide in Older Americans

PURPOSE To determine whether the risk of suicide is greater among patients with cancer than among patients with other medical illnesses. PATIENTS AND METHODS A case-control study of the suicide risk associated with medical illness among older Americans that used healthcare utilization data linked to prescription and mortality files. The patient population was comprised of 1,408 New Jersey residents age 65 years or older who were enrolled in Medicare and in a pharmaceutical insurance program. Patient cases (n = 128) died as a result of suicide during the study period of 1994 to 2002. Control patients (n = 1,280) were frequency-matched to patient cases on age and sex. Data were analyzed by using the odds ratio (OR) of suicide adjusted for age, sex, ethnicity, medical and psychiatric comorbidity, and use of prescription medications. RESULTS In adjusted analyses, the only medical condition that remained associated with suicide was cancer (OR, 2.3; 95% CI, 1.1 to 4.8). Suicide also remained associated with a diagnosis of affective disorder (OR, 2.3; 95% CI, 1.3 to 4.2), anxiety/personality disorder (OR, 2.2; 95% CI, 1.3 to 3.6), treatment with antidepressants (OR, 2.0; 95% CI, 1.2 to 3.2), and treatment with opioid analgesics (OR, 1.6; 95% CI, 1.0 to 2.5). CONCLUSION The risk of suicide in older adults is higher among patients with cancer than among patients with other medical illnesses, even after psychiatric illness and the risk of dying within a year were accounted for.