Macarius M. Donneyong

Risk of Heart Failure Among Postmenopausal Women: A Secondary Analysis of the Randomized Trial of Vitamin D Plus Calcium of the Women's Health Initiative

Background—Vitamin D supplementation may be an inexpensive intervention to reduce heart failure (HF) incidence. However, there are insufficient data to support this hypothesis. This study evaluates whether vitamin D plus calcium (CaD) supplementation is associated with lower rates of HF in postmenopausal women and whether the effects differ between those at high versus low risk for HF. Methods and Results—Analyses were restricted to 35 983 (of original 36 282) women aged 50 to 79 years old in the Women’s Health Initiative randomized trial of CaD supplementation who were randomized 1:1 in a double-blinded fashion to receive 1000 mg/d of calcium plus 400 IU/d of vitamin D3 or placebo. Overall, 744 adjudicated incident HF cases (intervention, 363; control, 381) occurred during a median follow-up of 7.1 (interquartile range, 1.6) years. CaD supplementation, compared with placebo, was not associated with reduced HF risk in the overall population, hazard ratio, 0.95; P=0.46. However, CaD supplementation had differential effects (P interaction=0.005) in subgroups stratified by baseline risk status of HF defined by the presence (high risk=17 449) or absence (low risk=18 534) of pre-existing HF precursors including coronary heart diseases, diabetes mellitus, or hypertension: 37% (hazard ratio, 0.63 [95% confidence interval, 0.46–0.87]) lower risk of HF in the low-risk versus hazard ratio, 1.06; P=0.51, in the high-risk subgroups. Conclusions—CaD supplementation did not significantly reduce HF incidence in the overall cohort, however, it was beneficial among postmenopausal women without major HF precursors while of little value in high-risk subgroups. Additional studies are warranted to confirm these findings and investigate the underlying mechanism. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00000611.Background— Vitamin D supplementation may be an inexpensive intervention to reduce heart failure (HF) incidence. However, there are insufficient data to support this hypothesis. This study evaluates whether vitamin D plus calcium (CaD) supplementation is associated with lower rates of HF in postmenopausal women and whether the effects differ between those at high versus low risk for HF. Methods and Results— Analyses were restricted to 35 983 (of original 36 282) women aged 50 to 79 years old in the Women’s Health Initiative randomized trial of CaD supplementation who were randomized 1:1 in a double-blinded fashion to receive 1000 mg/d of calcium plus 400 IU/d of vitamin D3 or placebo. Overall, 744 adjudicated incident HF cases (intervention, 363; control, 381) occurred during a median follow-up of 7.1 (interquartile range, 1.6) years. CaD supplementation, compared with placebo, was not associated with reduced HF risk in the overall population, hazard ratio, 0.95; P =0.46. However, CaD supplementation had differential effects ( P interaction=0.005) in subgroups stratified by baseline risk status of HF defined by the presence (high risk=17 449) or absence (low risk=18 534) of pre-existing HF precursors including coronary heart diseases, diabetes mellitus, or hypertension: 37% (hazard ratio, 0.63 [95% confidence interval, 0.46–0.87]) lower risk of HF in the low-risk versus hazard ratio, 1.06; P =0.51, in the high-risk subgroups. Conclusions— CaD supplementation did not significantly reduce HF incidence in the overall cohort, however, it was beneficial among postmenopausal women without major HF precursors while of little value in high-risk subgroups. Additional studies are warranted to confirm these findings and investigate the underlying mechanism. Clinical Trial Registration— URL: . Unique identifier: [NCT00000611][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00000611&atom=%2Fcirchf%2F8%2F1%2F49.atom

Risk of mortality with concomitant use of tamoxifen and selective serotonin reuptake inhibitors: multi-database cohort study

Objective To compare differences in mortality between women concomitantly treated with tamoxifen and selective serotonin reuptake inhibitors (SSRIs) that are potent inhibitors of the cytochrome-P450 2D6 enzyme (CYP2D6) versus tamoxifen and other SSRIs. Design Population based cohort study. Setting Five US databases covering individuals enrolled in private and public health insurance programs from 1995 to 2013. Participants Two cohorts of women who started taking tamoxifen. In cohort 1, women started taking an SSRI during tamoxifen treatment. In cohort 2, women were already taking an SSRI when they started taking tamoxifen. Main outcome measures All cause mortality in each cohort in women taking SSRIs that are potent inhibitors of CYP2D6 (paroxetine, fluoxetine) versus other SSRIs. Propensity scores were used to match exposure groups in a variable ratio fashion. Results were measured separately for each cohort and combined hazard ratios calculated from Cox regression models across the two cohorts with random effects meta-analysis. Results There were 6067 and 8465 new users of tamoxifen in cohorts 1 and 2, respectively. Mean age was 55. A total of 991 and 1014 deaths occurred in cohorts 1 and 2 during a median follow-up of 2.2 (interquartile range 0.9-4.5) and 2.0 (0.8-3.9) years, respectively. The pooled hazard ratio for death for potent inhibitors (rate 58.6/1000 person years) compared with other SSRIs (rate 57.9/1000 person years) across cohorts 1 and 2 was 0.96 (95% confidence interval 0.88 to 1.06). Results were consistent across sensitivity analyses. Conclusion Concomitant use of tamoxifen and potent CYP2D6 inhibiting SSRIs versus other SSRIs was not associated with an increased risk of death.

Changes in prescribing and healthcare resource utilization after FDA Drug Safety Communications involving zolpidem-containing medications

Products containing the sedative/hypnotic zolpidem were subject to Drug Safety Communications (DSCs) in January and May 2013 describing the risk of next‐morning impairment and recommending lower starting doses particularly for women. This study aimed to assess whether zolpidem DSCs were associated with prescribing‐pattern changes between January 2011 and December 2013.

Time From Emergency Department Evaluation to Operation and Appendiceal Perforation

We examine the influence of time from emergency department evaluation until operation on perforation in a prospective, multicenter cohort of children with appendicitis. BACKGROUND AND OBJECTIVES: In patients with appendicitis, the risk of perforation increases with time from onset of symptoms. We sought to determine if time from emergency department (ED) physician evaluation until operative intervention is independently associated with appendiceal perforation (AP) in children. METHODS: We conducted a planned secondary analysis of children aged 3 to 18 years with appendicitis enrolled in a prospective, multicenter, cross-sectional study of patients with abdominal pain (<96 hours). Time of initial physical examination and time of operation were recorded. The presence of AP was determined using operative reports. We analyzed whether duration of time from initial ED physician evaluation to operation impacted the odds of AP using multivariable logistic regression, adjusting for traditionally suggested risk factors that increase the risk of perforation. We also modeled the odds of perforation in a subpopulation of patients without perforation on computed tomography. RESULTS: Of 955 children with appendicitis, 25.9% (n = 247) had AP. The median time from ED physician evaluation to operation was 7.2 hours (interquartile range: 4.8–8.5). Adjusting for variables associated with perforation, duration of time (≤ 24 hours) between initial ED evaluation and operation did not significantly increase the odds of AP (odds ratio = 1.0, 95% confidence interval, 0.96–1.05), even among children without perforation on initial computed tomography (odds ratio = 0.95, 95% confidence interval, 0.89–1.02). CONCLUSIONS: Although duration of abdominal pain is associated with AP, short time delays from ED evaluation to operation did not independently increase the odds of perforation.

Clinical Outcomes of Concomitant Use of Warfarin and Selective Serotonin Reuptake Inhibitors: A Multidatabase Observational Cohort Study

Background Patients treated with warfarin are often coprescribed selective serotonin reuptake inhibitors (SSRIs) for coexisting depression. Some SSRIs are potent CYP2C9 inhibitors that may increase warfarin plasma concentrations and the risk of bleeding. We aimed to examine the effect of the putative CYP2C9-mediated warfarin-SSRI interaction on clinical outcomes. Methods We conducted an observational cohort study among warfarin initiators who had a subsequent SSRI prescription in 5 US claims databases. Patients were followed for up to 180 days as long as they were exposed to both warfarin and their index SSRI groups. Cox regression models were used to estimate hazard ratios and 95% confidence intervals for bleeding events, ischemic or thromboembolic events, and mortality comparing patients treated with SSRIs that are potent CYP2C9 inhibitors (fluoxetine, fluvoxamine) with those treated with other SSRIs after propensity score matching. Findings The eligible cohort comprised 52,129 patients. Hazard ratios were 1.14 (95% confidence interval [CI], 0.94–1.38) for bleeding events, 1.03 (95% CI, 0.87–1.21) for ischemic or thromboembolic events, and 0.90 (95% CI, 0.72–1.14) for mortality. Results were consistent across individual component outcomes, different warfarin stabilization periods, and subgroup analyses. Conclusions Patients concomitantly treated with warfarin and SSRIs that are potent CYP2C9 inhibitors had comparable rates of bleeding events, ischemic or thromboembolic events, and mortality as did patients cotreated with warfarin and other SSRIs, although small but potentially meaningful effects on bleeding cannot be completely excluded. SSRI inhibition of CYP2C9 does not appear to affect major safety or effectiveness outcomes of warfarin treatment in clinical practice, where patients may be closely monitored.

Trends and Patterns of Corticosteroid Use During Coronary Artery Bypass Grafting Surgery in the United States

Background: Several clinical trials have documented clinical benefits associated with prophylactic corticosteroid administration at the time of coronary artery bypass graft (CABG) surgery, including a reduction in the risk of atrial fibrillation and hospital length of stay. Despite the published data, the extent to which providers have adopted the perioperative use of corticosteroids remains unknown. Objectives: To assess temporal trends, between-hospital variation, and determinants of perioperative intravenous corticosteroid use during CABG surgery. Methods: We identified all patients admitted for CABG surgery in the Premier Healthcare Database (2003-2014), a large US-based inpatient database. We determined the proportion of patients administered prophylactic corticosteroids on the day of CABG surgery. Linear time-series models were used to estimate the rate and trend of corticosteroid use over time. Separate multivariable generalized estimating equation models were used to quantify the variation in and determinants of perioperative corticosteroid use. Results: Of 401 788 eligible patients who underwent a CABG surgery between 2003 and 2014, 20% (n = 80 681) were administered intravenous prophylactic perioperative corticosteroids (methylprednisolone, dexamethasone, or hydrocortisone). Corticosteroid use increased from 17.5% in 2003 to 22.6% in 2014 (annual rate = 0.42%; P < .001). Individual hospitals accounted for >50% of variation in corticosteroid use. High between-hospital variation was also observed, and the probability of utilization was ≥32.4% in the upper versus ≤3.4% in the bottom quartiles of hospitals. Conclusion: Prophylactic corticosteroid administration during CABG has increased gradually since 2003. To further evaluate the risk–benefit trade-off associated with their use, we believe a large-scale outcomes study is warranted to assess this highly variable practice.

Variation in adherence to medications across the healthcare system in two comparative effectiveness research cohorts

AIM To assess heterogeneity in adherence to medications in two example comparative effectiveness research studies. PATIENTS & METHODS We analyzed data from commercially insured patients initiating a statin or anticoagulant during 2005-2012. We calculated the cross-validated R2 from a series of hierarchical linear models to assess variation in 1-year adherence. RESULTS There was less heterogeneity in adherence in the statin cohort compared with the anticoagulant cohort, where patient characteristics explained 7.2% of variation in adherence, and adding therapy and provider characteristics increased the proportion of variation explained to 8.0 and 8.5%, cumulatively. Random effects provided essentially no explanatory power, even in the statin cohort with large numbers of patients clustered within each pharmacy, prescriber and provider. CONCLUSION The dependence of adherence on the healthcare system was stronger when the healthcare system influenced treatment choice and patient access to medication and when indications for treatment were strong.

Risk of Heart Failure Among Postmenopausal WomenCLINICAL PERSPECTIVE: A Secondary Analysis of the Randomized Trial of Vitamin D Plus Calcium of the Women’s Health Initiative

Background—Vitamin D supplementation may be an inexpensive intervention to reduce heart failure (HF) incidence. However, there are insufficient data to support this hypothesis. This study evaluates whether vitamin D plus calcium (CaD) supplementation is associated with lower rates of HF in postmenopausal women and whether the effects differ between those at high versus low risk for HF. Methods and Results—Analyses were restricted to 35 983 (of original 36 282) women aged 50 to 79 years old in the Women’s Health Initiative randomized trial of CaD supplementation who were randomized 1:1 in a double-blinded fashion to receive 1000 mg/d of calcium plus 400 IU/d of vitamin D3 or placebo. Overall, 744 adjudicated incident HF cases (intervention, 363; control, 381) occurred during a median follow-up of 7.1 (interquartile range, 1.6) years. CaD supplementation, compared with placebo, was not associated with reduced HF risk in the overall population, hazard ratio, 0.95; P=0.46. However, CaD supplementation had differential effects (P interaction=0.005) in subgroups stratified by baseline risk status of HF defined by the presence (high risk=17 449) or absence (low risk=18 534) of pre-existing HF precursors including coronary heart diseases, diabetes mellitus, or hypertension: 37% (hazard ratio, 0.63 [95% confidence interval, 0.46–0.87]) lower risk of HF in the low-risk versus hazard ratio, 1.06; P=0.51, in the high-risk subgroups. Conclusions—CaD supplementation did not significantly reduce HF incidence in the overall cohort, however, it was beneficial among postmenopausal women without major HF precursors while of little value in high-risk subgroups. Additional studies are warranted to confirm these findings and investigate the underlying mechanism. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00000611.Background— Vitamin D supplementation may be an inexpensive intervention to reduce heart failure (HF) incidence. However, there are insufficient data to support this hypothesis. This study evaluates whether vitamin D plus calcium (CaD) supplementation is associated with lower rates of HF in postmenopausal women and whether the effects differ between those at high versus low risk for HF. Methods and Results— Analyses were restricted to 35 983 (of original 36 282) women aged 50 to 79 years old in the Women’s Health Initiative randomized trial of CaD supplementation who were randomized 1:1 in a double-blinded fashion to receive 1000 mg/d of calcium plus 400 IU/d of vitamin D3 or placebo. Overall, 744 adjudicated incident HF cases (intervention, 363; control, 381) occurred during a median follow-up of 7.1 (interquartile range, 1.6) years. CaD supplementation, compared with placebo, was not associated with reduced HF risk in the overall population, hazard ratio, 0.95; P =0.46. However, CaD supplementation had differential effects ( P interaction=0.005) in subgroups stratified by baseline risk status of HF defined by the presence (high risk=17 449) or absence (low risk=18 534) of pre-existing HF precursors including coronary heart diseases, diabetes mellitus, or hypertension: 37% (hazard ratio, 0.63 [95% confidence interval, 0.46–0.87]) lower risk of HF in the low-risk versus hazard ratio, 1.06; P =0.51, in the high-risk subgroups. Conclusions— CaD supplementation did not significantly reduce HF incidence in the overall cohort, however, it was beneficial among postmenopausal women without major HF precursors while of little value in high-risk subgroups. Additional studies are warranted to confirm these findings and investigate the underlying mechanism. Clinical Trial Registration— URL: . Unique identifier: [NCT00000611][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00000611&atom=%2Fcirchf%2F8%2F1%2F49.atom

Risk of Heart Failure Among Postmenopausal WomenCLINICAL PERSPECTIVE

Background—Vitamin D supplementation may be an inexpensive intervention to reduce heart failure (HF) incidence. However, there are insufficient data to support this hypothesis. This study evaluates whether vitamin D plus calcium (CaD) supplementation is associated with lower rates of HF in postmenopausal women and whether the effects differ between those at high versus low risk for HF. Methods and Results—Analyses were restricted to 35 983 (of original 36 282) women aged 50 to 79 years old in the Women’s Health Initiative randomized trial of CaD supplementation who were randomized 1:1 in a double-blinded fashion to receive 1000 mg/d of calcium plus 400 IU/d of vitamin D3 or placebo. Overall, 744 adjudicated incident HF cases (intervention, 363; control, 381) occurred during a median follow-up of 7.1 (interquartile range, 1.6) years. CaD supplementation, compared with placebo, was not associated with reduced HF risk in the overall population, hazard ratio, 0.95; P=0.46. However, CaD supplementation had differential effects (P interaction=0.005) in subgroups stratified by baseline risk status of HF defined by the presence (high risk=17 449) or absence (low risk=18 534) of pre-existing HF precursors including coronary heart diseases, diabetes mellitus, or hypertension: 37% (hazard ratio, 0.63 [95% confidence interval, 0.46–0.87]) lower risk of HF in the low-risk versus hazard ratio, 1.06; P=0.51, in the high-risk subgroups. Conclusions—CaD supplementation did not significantly reduce HF incidence in the overall cohort, however, it was beneficial among postmenopausal women without major HF precursors while of little value in high-risk subgroups. Additional studies are warranted to confirm these findings and investigate the underlying mechanism. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00000611.Background— Vitamin D supplementation may be an inexpensive intervention to reduce heart failure (HF) incidence. However, there are insufficient data to support this hypothesis. This study evaluates whether vitamin D plus calcium (CaD) supplementation is associated with lower rates of HF in postmenopausal women and whether the effects differ between those at high versus low risk for HF. Methods and Results— Analyses were restricted to 35 983 (of original 36 282) women aged 50 to 79 years old in the Women’s Health Initiative randomized trial of CaD supplementation who were randomized 1:1 in a double-blinded fashion to receive 1000 mg/d of calcium plus 400 IU/d of vitamin D3 or placebo. Overall, 744 adjudicated incident HF cases (intervention, 363; control, 381) occurred during a median follow-up of 7.1 (interquartile range, 1.6) years. CaD supplementation, compared with placebo, was not associated with reduced HF risk in the overall population, hazard ratio, 0.95; P =0.46. However, CaD supplementation had differential effects ( P interaction=0.005) in subgroups stratified by baseline risk status of HF defined by the presence (high risk=17 449) or absence (low risk=18 534) of pre-existing HF precursors including coronary heart diseases, diabetes mellitus, or hypertension: 37% (hazard ratio, 0.63 [95% confidence interval, 0.46–0.87]) lower risk of HF in the low-risk versus hazard ratio, 1.06; P =0.51, in the high-risk subgroups. Conclusions— CaD supplementation did not significantly reduce HF incidence in the overall cohort, however, it was beneficial among postmenopausal women without major HF precursors while of little value in high-risk subgroups. Additional studies are warranted to confirm these findings and investigate the underlying mechanism. Clinical Trial Registration— URL: . Unique identifier: [NCT00000611][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00000611&atom=%2Fcirchf%2F8%2F1%2F49.atom