There are no randomized data evaluating the safety or efficacy of apixaban for stroke prevention in patients with end-stage kidney disease on hemodialysis and with atrial fibrillation (AF).
The ...RENAL-AF trial (Renal Hemodialysis Patients Allocated Apixaban Versus Warfarin in Atrial Fibrillation) was a prospective, randomized, open-label, blinded-outcome evaluation (PROBE) of apixaban versus warfarin in patients receiving hemodialysis with AF and a CHA
DS
-VASc score ≥2. Patients were randomly assigned 1:1 to 5 mg of apixaban twice daily (2.5 mg twice daily for patients ≥80 years of age, weight ≤60 kg, or both) or dose-adjusted warfarin. The primary outcome was time to major or clinically relevant nonmajor bleeding. Secondary outcomes included stroke, mortality, and apixaban pharmacokinetics. Pharmacokinetic sampling was day 1, day 3, and month 1.
From January 2017 through January 2019, 154 patients were randomly assigned to apixaban (n=82) or warfarin (n=72). The trial stopped prematurely because of enrollment challenges. Time in therapeutic range (international normalized ratio, 2.0-3.0) for warfarin-treated patients was 44% (interquartile range, 23%-59%). The 1-year rates for major or clinically relevant nonmajor bleeding were 32% and 26% in apixaban and warfarin groups, respectively (hazard ratio, 1.20 95% CI, 0.63-2.30), whereas 1-year rates for stroke or systemic embolism were 3.0% and 3.3% in apixaban and warfarin groups, respectively. Death was the most common major event in the apixaban (21 patients 26%) and warfarin (13 patients 18%) arms. The pharmacokinetic substudy enrolled the target 50 patients. Median steady-state 12-hour area under the curve was 2475 ng/mL×h (10th to 90th percentiles, 1342-3285) for 5 mg of apixaban twice daily and 1269 ng/mL×h (10th to 90th percentiles, 615-1946) for 2.5 mg of apixaban twice daily. There was substantial overlap between minimum apixaban blood concentration, 12-hour area under the curve, and maximum apixaban blood concentration for patients with and without a major or clinically relevant nonmajor bleeding event.
There was inadequate power to draw any conclusion regarding rates of major or clinically relevant nonmajor bleeding comparing apixaban and warfarin in patients with AF and end-stage kidney disease on hemodialysis. Clinically relevant bleeding events were ≈10-fold more frequent than stroke or systemic embolism among this population on anticoagulation, highlighting the need for future randomized studies evaluating the risks versus benefits of anticoagulation among patients with AF and end-stage kidney disease on hemodialysis.
URL: https://www.
gov; Unique identifier: NCT02942407.
Many patients with atrial fibrillation (AF) remain undiagnosed despite availability of interventions to reduce stroke risk. Predictive models to date are limited by data requirements and theoretical ...usage. We aimed to develop a model for predicting the 2-year probability of AF diagnosis and implement it as proof-of-concept (POC) in a production electronic health record (EHR).
We used a nested case-control design using data from the Indiana Network for Patient Care. The development cohort came from 2016 to 2017 (outcome period) and 2014 to 2015 (baseline). A separate validation cohort used outcome and baseline periods shifted 2 years before respective development cohort times. Machine learning approaches were used to build predictive model. Patients ≥ 18 years, later restricted to age ≥ 40 years, with at least two encounters and no AF during baseline, were included. In the 6-week EHR prospective pilot, the model was silently implemented in the production system at a large safety-net urban hospital. Three new and two previous logistic regression models were evaluated using receiver-operating characteristics. Number, characteristics, and CHA
DS
-VASc scores of patients identified by the model in the pilot are presented.
After restricting age to ≥ 40 years, 31,474 AF cases (mean age, 71.5 years; female 49%) and 22,078 controls (mean age, 59.5 years; female 61%) comprised the development cohort. A 10-variable model using age, acute heart disease, albumin, body mass index, chronic obstructive pulmonary disease, gender, heart failure, insurance, kidney disease, and shock yielded the best performance (C-statistic, 0.80 95% CI 0.79-0.80). The model performed well in the validation cohort (C-statistic, 0.81 95% CI 0.8-0.81). In the EHR pilot, 7916/22,272 (35.5%; mean age, 66 years; female 50%) were identified as higher risk for AF; 5582 (70%) had CHA
DS
-VASc score ≥ 2.
Using variables commonly available in the EHR, we created a predictive model to identify 2-year risk of developing AF in those previously without diagnosed AF. Successful POC implementation of the model in an EHR provided a practical strategy to identify patients who may benefit from interventions to reduce their stroke risk.
Objective: To evaluate inpatient oral anticoagulant (OAC) treatment, discharge location, and post-discharge OAC treatment for patients hospitalized with non-valvular atrial fibrillation (NVAF).
...Research design and methods: Retrospective study using claims data linked to hospital electronic health records (EHR). Patients (n = 2,484) were hospitalized with a primary (38%) or secondary (62%) diagnosis of AF without evidence of mitral valvular heart disease or valve replacement between January 2009 and September 2013. Inpatient OAC treatment was identified from EHR data.
Main outcome measures: Inpatient and post-discharge OAC treatment direct OAC (DOAC; apixaban, rivaroxaban, dabigatran), warfarin, no OAC and discharge location (long-term care, home health-care, home self-care).
Results: Mean age was 72.6 years, 61.2% were male, and 89.5% had a CHA2DS2-VASc score ≥2. Overall, 6.4% received a DOAC, 38.0% warfarin, and 55.6% no OAC during hospitalization. Compared to other treatment groups, patients receiving DOAC were younger and more likely to be male. The majority (72.2%) were discharged to home health-care, 13.2% home self-care, and 6.0% long-term care. Among patients who were treated with warfarin during hospitalization, 40.3% filled a warfarin prescription within 30 days post-discharge, whereas among patients who were treated with a DOAC, 52.4% filled a DOAC prescription within 30 days post-discharge. Some NVAF patients not treated with an OAC during hospitalization filled a prescription for warfarin (18.0%) or DOAC (1.9%) within 30 days post-discharge. Results were similar among patients with CHA2DS2-VASc score ≥2.
Conclusions: Most patients hospitalized for NVAF were discharged to home support, and the majority did not have OAC treatment during hospitalization or the 30 days post-discharge. Additional investigation should be conducted on trends beyond 30 days post-hospitalization, and the reasons for not receiving anticoagulation therapy in patients at moderate-to-severe risk of stroke or systemic embolism. Helping to avoid preventable strokes is an important goal for public health.
To determine whether "continuous" celecoxib is more efficacious than "intermittent" use in preventing osteoarthritis (OA) flares of the knee and/or hip.
A double-blind, randomized, multicenter ...international study comparing efficacy and safety of continuous (daily) versus intermittent (as required during predefined OA flare) celecoxib 200 mg/day in 858 subjects, aged 18-80 years. The study consisted of 3 periods: (I) screening/washout visit; (II) open-label run-in with celecoxib; and (III) 22-week blinded treatment. Only subjects whose OA flares resolved in Period 2 (without subsequent flare) were randomized. The primary endpoint, number of flares per time of exposure during Period III (number of flares per month), was compared using analysis of variance with treatment as the independent variable. Acetaminophen was available as rescue medication.
Of 875 subjects randomized to treatment, 858 subjects received treatment. At randomization > 70% were female; mean age 58.6 years; mean disease duration 6.5 years; total Western Ontario and McMaster Universities Osteoarthritis Index mean score 25.8; ~45% had hypertension; and ~20% were using aspirin (for cardiovascular prophylaxis). Subjects receiving continuous treatment reported 42% fewer OA flares/month than intermittent users (p < 0.0001) or 2.0 fewer OA flares over 22 weeks. Statistical and clinically meaningful benefits in secondary outcomes were also evident with continuous treatment. There were no differences in adverse events (AE) or new-onset/aggravated hypertension.
Continuous treatment with celecoxib 200 mg/day was significantly more efficacious than intermittent use in preventing OA flares of the hip and knee, without an increase in overall AE, including gastrointestinal disorders and hypertension, during 22 weeks of treatment. ClinicalTrials.gov identifier NCT00139776.
Abstract Background Previous gastrointestinal (GI) outcomes of nonsteroidal anti-inflammatory drug (NSAID) trials have focused on upper GI events, although recent evidence suggests NSAID-related ...lower GI effects are important and clinically relevant. Objective We assessed the long-term GI adverse event (AE) profile of celecoxib in a nonarthritis population. The aim of this post hoc analysis was to determine the incidence of serious GI AEs, using a new Clinically Significant Upper and/or Lower GI Events end point. Methods Patients from 2 colorectal adenoma recurrence studies were included. Patients received celecoxib 200 mg/400 mg BID, 400 mg once daily, or placebo over 3 years. The analysis measured noninferiority, using a prespecified definition of noninferiority. Celecoxib was predefined to be noninferior to placebo if the upper limit of the 95% CI for the hazard ratio (HR) with celecoxib was <1.25, at any dose, compared with the placebo (calculated using the Cox proportional hazards model). Results A total of 3588 patients were included; in the primary analysis, the HR for celecoxib (any dose) compared with placebo was 1.22 (95% CI: 0.69–2.18; P = 0.4948). In the secondary dose analyses, the HR associated with a 400-mg daily dose, compared with placebo, was 1.04 (95% CI: 0.55–1.96; P = 0.9149); for 800 mg/d, the HR was 1.79 (95% CI: 0.82–3.89; P = 0.1427). In a third covariate analysis, low-dose aspirin use (HR = 2.33; 95% CI: 1.33–4.08) and age ≥65 years (HR = 1.82; 95% CI, 1.05–3.15) was suggested to have a statistically significant association with increased risk of GI AEs. Study limitations include retrospective evaluation and small sample size of patients with GI AEs. Conclusions The noninferiority of celecoxib to placebo was not established because the HR for the time to the first Clinically Significant Upper and/or Lower GI Event was greater than the prespecified upper limit of 95% CI for noninferiority. In addition, HRs associated with daily doses of 400 or 800 mg celecoxib compared with placebo were not significant. However, a significantly increased risk of clinically significant upper and/or lower GI events was observed in low-dose aspirin users (≤162.5 mg average daily use) and in patients ≥65 years of age. ClinicalTrials.gov identifiers: NCT00005094 and NCT00141193.
Characterize the effect of body mass index (BMI) on the efficacy of continuous daily celecoxib treatment compared with intermittent celecoxib treatment.
Prespecified exploratory analysis of a ...24-week, double-blind, parallel-group, randomized, multicenter international study. 858 patients with knee or hip osteoarthritis (OA) were randomized to receive celecoxib 200 mg daily either as continuous or intermittent treatment. Efficacy was measured by Western Ontario and McMaster Universities Arthritis Index (WOMAC) total and subscale scores and the number of flare events.
Least squares mean increases (worsening) in WOMAC total scores were significantly less in the continuous treatment group than in the intermittent treatment group in patients with a BMI <30 kg/m(2) (1.33 vs 4.85; p=0.016) and in patients with a BMI ≥30 kg/m(2) (1.84 vs 5.12; p=0.019). There was a greater worsening in patients with a BMI ≥30 kg/m(2) than in those with a BMI <30 kg/m(2) in both the continuous and intermittent groups. Fewer flares were reported in the continuous treatment group than in the intermittent group in patients with a BMI <30 kg/m(2) (0.55 vs 0.88; p<0.0001) and ≥30 kg/m(2) (0.54 vs 0.97; p<0.0001). There were no differences in adverse events in the two BMI groups.
Continuous celecoxib treatment was significantly more efficacious than intermittent use in patients with a BMI <30 kg/m(2) compared with obese patients (≥30 kg/m(2)) as assessed by WOMAC total scores and the number of flares. These data suggest that including weight loss as part of a treatment regimen for obese OA patients could be important.
In non-steroidal anti-inflammatory drug (NSAID) users, chronic occult blood loss may lead to decreases in hemoglobin, which may lead to increased healthcare expenditures. This study, therefore, ...sought to quantify healthcare resource utilization of ≥2 g/dL hemoglobin decrease in osteoarthritis patients.
Using a large US managed care database, osteoarthritis patients aged ≥18 years who had exposure to ≥90 days of non-selective or selective COX-2 NSAID use, a hemoglobin value within 6 months before index NSAID, and at least one hemoglobin value 24 months after were evaluated. Resource utilization was evaluated in those with ≥2 g/dL hemoglobin drop vs patients with ≤0.5 g/dL hemoglobin drop (control).
Of 1800 NSAID users meeting inclusion criteria, 228 patients mean (SD) = 59.8 (9.3) years had ≥2 g/dL hemoglobin drop vs 1572 controls mean (SD) = 58.3 (8.0) years. Despite relatively low absolute rates, endoscopic procedures were more commonly observed in the ≥2 g/dL hemoglobin drop group endoscopy: 37/228 (16.2%) vs 65/1572 (4.1%); adjusted odds ratio (AOR) 3.5, (95% confidence interval CI = 2.1-6.0); colonoscopy: 36/228 (15.8%) vs 137/1572 (8.7%); AOR 2.0 (95% CI 1.2-3.2). During the 12-month follow-up, patients with ≥2 g/dL hemoglobin drop utilized significantly more healthcare resources adjusted relative risk (95% CI) for hospitalization, 2.1 (1.5-2.9); outpatient visits, 1.4 (1.3-1.5); physician visits, 1.3 (1.1-1.4) and charges (total adjusted charges $47,766 vs $23,342) across major categories of healthcare services.
This was a retrospective analysis with baseline demographic differences. The source or cause of the hemoglobin drops could not be verified; and it is assumed that they are related to occult gastrointestinal loss. Differences with healthcare utilization and charges were not linked to hemoglobin-associated complications.
In patients exposed to NSAIDs, those with significant hemoglobin drops experienced higher subsequent healthcare utilization and charges than controls who did not have a significant hemoglobin drop.
Compared with nonselective NSAIDs, cyclooxygenase (COX)-2-selective inhibitors have been associated with a lower incidence of gastroduodenal ulcers (in short-term endoscopic studies) and ulcer ...complications (in long-term trials).
The aim of this study was to comparethe effects of valdecoxib 20 mg BID and naproxen 500 mg BID, administered for 6.5 days, on the upper gastrointestinal (UGI) mucosa of healthy older subjects (aged 65–75 years) as assessed by UGI endoscopy.
In this multicenter, double-blind, active-comparator, placebo-controlled, parallel-group study, eligible subjects who were free of NSAID or COX-2-selective inhibitor use for 2 weeks and who had normal UGI mucosa (mucosal grading score of 0, based on endoscopic evaluation of both the stomach and duodenum) were randomized. Serologic testing for
Helicobacter pylori antibodies was conducted at baseline. No antiulcer medications were permitted. The primary end point was the incidence of gastroduodenal ulcers (gastric or duodenal mucosal grading score of 7, as indicated by any lesion with unequivocal depth ≥3 mm in diameter) after 6.5 days of blinded treatment with valdecoxib, naproxen, or placebo. Secondary end points were incidence of gastric ulcers, duodenal ulcers, and gastroduodenal erosions/ulcers, and the incidence of ≥11 gastroduodenal erosions/ulcers. All documented adverse events were self-reported by subjects or were observed by investigators.
Sixty-one patients were randomized to receive valdecoxib, 60 to naproxen, and 60 to placebo. Mean (SD) subject age was 68.8 (3.25) years in the valdecoxib group, 68.6 (2.76) years in the naproxen group, and 68.6 (3.14) years in the placebo group (
P = NS). In the valdecoxib and naproxen groups, 47.5% and 58.3% of subjects were female, respectively, compared with 56.7% of the placebo group (
P = NS). Valdecoxib and placebo were associated with significantly lower incidences of gastroduodenal ulcers than naproxen (1.6% 1 gastroduodenal ulcer/61 patients and 1.7% 1/59, respectively, vs 22.0% 13/59;
P < 0.001). Compared with naproxen, both valdecoxib and placebo were associated with significantly lower incidences of gastric (1.6% 1/61 and 1.7% 1/59 vs 15.3% 9/59; both,
P < 0.03) and duodenal ulcers (0% 0/61 and 0% 0/59 vs 8.5% 5/59; both,
P < 0.03). In all cases, the incidence of ulcers with valdecoxib was not significantly different from placebo. Results were similar for any erosions/ulcers, and when analyzed by
H pylori status. The number of adverse events was low in each group.
In these healthy older subjects (aged65–75 years), valdecoxib 20 mg BID was associated with a significantly lower rate of gastroduodenal, gastric, and duodenal ulcers than naproxen 500 mg BID, even after 6.5 days of therapy.
Objective:
Characterize the effect of body mass index (BMI) on the efficacy of continuous daily celecoxib treatment compared with intermittent celecoxib treatment.
Methods:
Prespecified exploratory ...analysis of a 24-week, double-blind, parallel-group, randomized, multicenter international study. 858 patients with knee or hip osteoarthritis (OA) were randomized to receive celecoxib 200 mg daily either as continuous or intermittent treatment. Efficacy was measured by Western Ontario and McMaster Universities Arthritis Index (WOMAC) total and subscale scores and the number of flare events.
Results:
Least squares mean increases (worsening) in WOMAC total scores were significantly less in the continuous treatment group than in the intermittent treatment group in patients with a BMI <30 kg/m
2
(1.33
vs
4.85; p=0.016) and in patients with a BMI ≥30 kg/m
2
(1.84
vs
5.12; p=0.019). There was a greater worsening in patients with a BMI ≥30 kg/m
2
than in those with a BMI <30 kg/m
2
in both the continuous and intermittent groups. Fewer flares were reported in the continuous treatment group than in the intermittent group in patients with a BMI <30 kg/m
2
(0.55
vs
0.88; p<0.0001) and ≥30 kg/m
2
(0.54
vs
0.97; p<0.0001). There were no differences in adverse events in the two BMI groups.
Conclusions:
Continuous celecoxib treatment was significantly more efficacious than intermittent use in patients with a BMI <30 kg/m
2
compared with obese patients (≥30 kg/m
2
) as assessed by WOMAC total scores and the number of flares. These data suggest that including weight loss as part of a treatment regimen for obese OA patients could be important.
We have discussed several miscellaneous headache disorders not associated with structural brain disease. The first group included those headaches provoked by "exertional" triggers in various forms. ...These include benign cough headache, BEH, and headache associated with sexual activity. The IHS diagnostic criteria were discussed. Benign exertional headache and cough headache were discussed together because of their substantial similarities. In general, BEH is characterized by severe, short-lived pain after coughing, sneezing, lifting a burden, sexual activity, or other similar brief effort. Structural disease of the brain or skull was the most important differential diagnosis for these disorders, with posterior fossa mass lesions being identified as the most common organic etiology. Magnetic resonance imaging with special attention to the posterior fossa and foramen magnum is the preferred method for evaluating these patients. Indomethacin is the treatment of choice. The headache associated with sexual activity is dull in the early phases of sexual excitement and becomes intense at orgasm. This headache is unpredictable in occurrence. Like BEH, the headache associated with sexual activity can be a manifestation of structural disease. Subarachnoid hemorrhage must be excluded, by CT scanning and CSF examination, in patients with the sexual headache. Benign headache associated with sexual activity has been successfully treated with indomethacin and beta-blockers. The second miscellaneous group of headache disorders includes those provoked by eating something cold or food additives, and by environmental stimuli. Idiopathic stabbing headache does not have a known trigger and appears frequently in migraineurs. Its occurrence may also herald the termination of an attack of cluster headache. Indomethacin treatment provides significant relief. Three headaches triggered by substances that are eaten were reviewed: ingestion of a cold stimulus, nitrate/nitrite-induced headache, and MSG-induced headache. For the most part, avoidance of these stimuli can prevent the associated headache. Lastly, we reviewed headache provoked by high altitude and hypoxia. The headache is part of the syndrome of AMS during its early or benign stage and the later malignant stage of HACE. The pain can be exacerbated by exercise. The best treatment is prevention via slow ascent and avoidance of respiratory depressants. Acetazolamide and dexamethasone have proved useful in preventing this syndrome.
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