Cause of Death and Predictors of All-Cause Mortality in Anticoagulated Patients With Nonvalvular Atrial Fibrillation : Data From ROCKET AF

M. Kaste on työryhmän ROCKET AF Steering Comm jäsen.Background-Atrial fibrillation is associated with higher mortality. Identification of causes of death and contemporary risk factors for all-cause mortality may guide interventions. Methods and Results-In the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) study, patients with nonvalvular atrial fibrillation were randomized to rivaroxaban or dose-adjusted warfarin. Cox proportional hazards regression with backward elimination identified factors at randomization that were independently associated with all-cause mortality in the 14 171 participants in the intention-to-treat population. The median age was 73 years, and the mean CHADS(2) score was 3.5. Over 1.9 years of median follow-up, 1214 (8.6%) patients died. Kaplan-Meier mortality rates were 4.2% at 1 year and 8.9% at 2 years. The majority of classified deaths (1081) were cardiovascular (72%), whereas only 6% were nonhemorrhagic stroke or systemic embolism. No significant difference in all-cause mortality was observed between the rivaroxaban and warfarin arms (P=0.15). Heart failure (hazard ratio 1.51, 95% CI 1.33-1.70, P= 75 years (hazard ratio 1.69, 95% CI 1.51-1.90, P Conclusions-In a large population of patients anticoagulated for nonvalvular atrial fibrillation, approximate to 7 in 10 deaths were cardiovascular, whereasPeer reviewe

Intravenous ibandronate injections given every three months: a new treatment option to prevent bone loss in postmenopausal women

Objective: To investigate the efficacy, safety, and dose response of three doses of ibandronate, given intermittently by intravenous (IV) injection every three months, in preventing postmenopausal osteoporosis. Patients and methods: 629 postmenopausal women, categorised according to time since menopause and baseline lumbar spine (L1–4) bone mineral density (BMD), were enrolled into a multicentre, double blind, placebo controlled trial. They were randomly allocated to receive IV ibandronate 0.5 mg, 1 mg or 2 mg, or placebo every three months. All women received daily calcium supplementation. Results: One year's treatment with intermittent IV ibandronate injections produced a dose dependent gain in mean (SD) lumbar spine BMD from baseline of 2.5 (2.5)%, 1.8 (2.6)%, and 1.0 (2.8)% in the groups receiving 2 mg, 1 mg, and 0.5 mg ibandronate, respectively, compared with a loss of BMD of 0.4 (2.4)% in the women in the placebo group; p=0.0001 for each ibandronate dose v placebo. Highest BMD gains occurred in women with osteopenia receiving 2 mg ibandronate. Similarly, at the hip, all three doses of ibandronate produced significantly better gains in BMD than placebo (p<0.05), with the greatest gains in the women with osteopenia receiving the 2 mg dose. Ibandronate concomitantly and dose dependently suppressed markers of bone turnover in comparison with placebo, and injections were well tolerated. Conclusion: IV ibandronate injections, given every three months, may be an effective alternative to oral bisphosphonates and hormonal therapy in the prevention of bone loss in postmenopausal women

Tests of serial independence for continuous multivariate time series based on a Möbius decomposition of the independence empirical copula process

Serial copula, Test of serial independence, Empirical process, Möbius decomposition, Cramér–von Mises statistic, Bootstrap, Permutation,

Cost of detecting malignant lesions by endoscopy in 2741 primary care dyspeptic patients without alarm symptoms.

BACKGROUND & AIMS: Current guidelines recommend empirical, noninvasive approaches to manage dyspeptic patients without alarm symptoms, but concerns about missed lesions persist; the cost savings afforded by noninvasive approaches must be weighed against treatment delays. We investigated the prevalence of malignancies and other serious abnormalities in patients with dyspepsia and the cost of detecting these by endoscopy. METHODS: We studied 2741 primary-care outpatients, 18-70 years in age, who met Rome II criteria for dyspepsia. Patients with alarm features (dysphagia, bleeding, weight loss, etc) were excluded. All patients underwent endoscopy. The cost and diagnostic yield of an early endoscopy strategy in all patients were compared with those of endoscopy limited to age-defined cohorts. Costs were calculated for a low, intermediate, and high cost environment. RESULTS: Endoscopies detected abnormalities in 635 patients (23%). The most common findings were reflux esophagitis with erosions (15%), gastric ulcers (2.7%), and duodenal ulcers (2.3%). The prevalence of upper gastrointestinal malignancy was 0.22%. If all dyspeptic patients 50 years or older underwent endoscopy, 1 esophageal cancer and no gastric cancers would have been missed. If the age threshold for endoscopy were set at 50 years, at a cost of $500/endoscopy, it would cost$82,900 (95% CI, $35,714-$250,000) to detect each case of cancer. CONCLUSIONS: Primary care dyspeptic patients without alarm symptoms rarely have serious underlying conditions at endoscopy. The costs associated with diagnosing an occult malignancy are large, but an age cut-off of 50 years for early endoscopy provides the best assurance that an occult malignancy will not be missed

Continuing outcomes relevant to Evista: Breast cancer incidence in postmenopausal osteoporotic women in a randomized trial of raloxifene

Background: The randomized, double-blind Multiple Outcomes of Raloxifene Evaluation (MORE) trial found that 4 years of raloxifene therapy decreased the incidence of invasive breast cancer among postmenopausal women with osteoporosis by 72% compared with placebo. We conducted the Continuing Outcomes Relevant to Evista (CORE) trial to examine the effect of 4 additional years of raloxifene therapy on the incidence of invasive breast cancer in women in MORE who agreed to continue in CORE. Methods: Women who had been randomly assigned to receive raloxifene (either 60 or 120 mg/day) in MORE were assigned to receive raloxifene (60 mg/day) in CORE (n = 3510), and women who had been assigned to receive placebo in MORE continued on placebo in CORE (n = 1703). Breast cancer incidence was analyzed by a log-rank test, and a Cox proportional hazards model was used to compute hazard ratios (HRs) and 95% confidence intervals (CIs). All statistical tests were two-sided. Results: During the CORE trial, the 4-year incidences of invasive breast cancer and estrogen receptor (ER)-positive invasive breast cancer were reduced by 59% (HR = 0.41; 95% CI = 0.24 to 0.71) and 66% (HR = 0.34; 95% CI = 0.18 to 0.66), respectively, in the raloxifene group compared with the placebo group. There was no difference between the two groups in incidence of ER-negative invasive breast cancer during CORE (P = .86). Over the 8 years of both trials, the incidences of invasive breast cancer and ER-positive invasive breast cancer were reduced by 66% (HR = 0.34; 95 % CI = 0.22 to 0.50) and 76% (HR = 0.24; 95% CI = 0.15 to 0.40), respectively, in the raloxifene group compared with the placebo group. During the CORE trial, the relative risk of thromboembolism in the raloxifene group compared with that in the placebo group was 2.17 (95% CI = 0.83 to 5.70). This increased risk, also observed in the MORE trial, persisted over the 8 years of both trials. Conclusions: The reduction in invasive breast cancer incidence continues beyond 4 years of raloxifene treatment in postmenopausal women with osteoporosis. No new safety concerns related to raloxifene therapy were identified during CORE. © Oxford University Press 2004, all rights reserved

Once-yearly zoledronic acid and days of disability, bed rest, and back pain: Randomized, controlled HORIZON Pivotal Fracture Trial

The objective of this study was to determine the effect of once-yearly zoledronic acid on the number of days of back pain and the number of days of disability (ie, limited activity and bed rest) owing to back pain or fracture in postmenopausal women with osteoporosis. This was a multicenter, randomized, double-blind, placebo-controlled trial in 240 clinical centers in 27 countries. Participants included 7736 postmenopausal women with osteoporosis. Patients were randomized to receive either a single 15-minute intravenous infusion of zoledronic acid (5 mg) or placebo at baseline, 12 months, and 24 months. The main outcome measures were self-reported number of days with back pain and the number of days of limited activity and bed rest owing to back pain or a fracture, and this was assessed every 3 months over a 3-year period. Our results show that although the incidence of back pain was high in both randomized groups, women randomized to zoledronic acid experienced, on average, 18 fewer days of back pain compared with placebo over the course of the trial (p = .0092). The back pain among women randomized to zoledronic acid versus placebo resulted in 11 fewer days of limited activity (p = .0017). In Cox proportional-hazards models, women randomized to zoledronic acid were about 6% less likely to experience 7 or more days of back pain [relative risk (RR) = 0.94, 95% confidence interval (CI) 0.90–0.99] or limited activity owing to back pain (RR = 0.94, 95% CI 0.87–1.00). Women randomized to zoledronic acid were significantly less likely to experience 7 or more bed-rest days owing to a fracture (RR = 0.58, 95% CI 0.47–0.72) and 7 or more limited-activity days owing to a fracture (RR = 0.67, 95% CI 0.58–0.78). Reductions in back pain with zoledronic acid were independent of incident fracture. Our conclusion is that in women with postmenopausal osteoporosis, a once-yearly infusion with zoledronic acid over a 3-year period significantly reduced the number of days that patients reported back pain, limited activity owing to back pain, and limited activity and bed rest owing to a fracture

Cause of death and predictors of all-cause mortality in anticoagulated patients with nonvalvular atrial fibrillation: Data from ROCKET AF

Background-Atrial fibrillation is associated with higher mortality. Identification of causes of death and contemporary risk factors for all-cause mortality may guide interventions. Methods and Results-In the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) study, patients with nonvalvular atrial fibrillation were randomized to rivaroxaban or dose-adjusted warfarin. Cox proportional hazards regression with backward elimination identified factors at randomization that were independently associated with all-cause mortality in the 14 171 participants in the intentionto- treat population. The median age was 73 years, and the mean CHADS2 score was 3.5. Over 1.9 years of median follow-up, 1214 (8.6%) patients died. Kaplan-Meier mortality rates were 4.2% at 1 year and 8.9% at 2 years. The majority of classified deaths (1081) were cardiovascular (72%), whereas only 6% were nonhemorrhagic stroke or systemic embolism. No significant difference in all-cause mortality was observed between the rivaroxaban and warfarin arms (P=0.15). Heart failure (hazard ratio 1.51, 95% CI 1.33-1.70, P&lt;0.0001) and age 6575 years (hazard ratio 1.69, 95% CI 1.51-1.90, P&lt;0.0001) were associated with higher all-cause mortality. Multiple additional characteristics were independently associated with higher mortality, with decreasing creatinine clearance, chronic obstructive pulmonary disease, male sex, peripheral vascular disease, and diabetes being among the most strongly associated (model C-index 0.677). Conclusions-In a large population of patients anticoagulated for nonvalvular atrial fibrillation, 487 in 10 deaths were cardiovascular, whereas &lt;1 in 10 deaths were caused by nonhemorrhagic stroke or systemic embolism. Optimal prevention and treatment of heart failure, renal impairment, chronic obstructive pulmonary disease, and diabetes may improve survival

Effect of once-yearly zoledronic acid on the spine and hip as measured by quantitative computed tomography: results of the HORIZON Pivotal Fracture Trial.

Changes in bone mineral density and bone strength following treatment with zoledronic acid (ZOL) were measured by quantitative computed analysis (QCT) or dual-energy X-ray absorptiometry (DXA). ZOL treatment increased spine and hip BMD vs placebo, assessed by QCT and DXA. Changes in trabecular bone resulted in increased bone strength. INTRODUCTION: To investigate bone mineral density (BMD) changes in trabecular and cortical bone, estimated by quantitative computed analysis (QCT) or dual-energy X-ray absorptiometry (DXA), and whether zoledronic acid 5 mg (ZOL) affects bone strength. METHODS: In 233 women from a randomized, controlled trial of once-yearly ZOL, lumbar spine, total hip, femoral neck, and trochanter were assessed by DXA and QCT (baseline, Month 36). Mean percentage changes from baseline and between-treatment differences (ZOL vs placebo, t-test) were evaluated. RESULTS: Mean between-treatment differences for lumbar spine BMD were significant by DXA (7.0%, p &lt; 0.01) and QCT (5.7%, p &lt; 0.0001). Between-treatment differences were significant for trabecular spine (p = 0.0017) [non-parametric test], trabecular trochanter (10.7%, p &lt; 0.0001), total hip (10.8%, p &lt; 0.0001), and compressive strength indices at femoral neck (8.6%, p = 0.0001), and trochanter (14.1%, p &lt; 0.0001). CONCLUSIONS: Once-yearly ZOL increased hip and spine BMD vs placebo, assessed by QCT vs DXA. Changes in trabecular bone resulted in increased indices of compressive strength