Doses of apixaban and rivaroxaban prescribed in real-world United States cardiology practices compared to registration trials.

Using an I.M.S. LifeLink dataset (19 September 2014-11 September 2015), we compared U.S. cardiologist prescribing of the reduced dose of apixaban (2.5 mg) or rivaroxaban (15 mg) to utilization in their corresponding nonvalvular atrial fibrillation registration randomized trials. Of all prescriptions written by cardiologists for these agents, 20.8% of apixaban and 21.7% of rivaroxaban prescriptions were for a reduced dose; corresponding to a 4.4-fold (16.1% absolute) increase in the use of reduced dose apixaban and a 3% relative (0.6% absolute) increase in reduced dose rivaroxaban use vs. their respective registration trials. Further research is needed to better understand appropriate dosing of patients with novel anticoagulants.

All-cause mortality and use of antithrombotics within 90 days of discharge in acutely ill medical patients.

Conflicting evidence exists regarding predictors of and antithrombotic benefit on mortality in hospitalised acutely-ill medical patients. We compared mortality risk within 90 days post-discharge among medically ill patients who did and did not receive antithrombotics. This retrospective claims analysis included patients ≥ 40 years with nonsurgical hospitalisation ≥ 2 days between 2005 and 2009 using the HealthCore Integrated Research Database. Antithrombotic use (i.e. anticoagulants and antiplatelets) post-discharge was captured from pharmacy claims. All-cause mortality was determined from Social Security Death Index; cause of death was identified from National Death Index database. Kaplan-Meier survival curves were generated and hazard ratios (HR) for mortality risk were estimated using Cox proportional hazards models. Patients prescribed anticoagulants or antiplatelets post-discharge had lower risk of short-term mortality. For the anticoagulant model, the most significant predictors of mortality were malignant/benign neoplasms (hazard ratio [HR] 1.6, 95% confidence interval [CI] 1.5-1.7), liver disease (HR 1.6, 95% CI 1.5-1.7), anticoagulant omission (HR 1.6, 95% CI 1.4-1.8), gastrointestinal or respiratory tract intubations (HR 1.5, 95% CI 1.3-1.7), and blood dyscrasias (HR 1.4, 95% CI 1.4-1.5). For the antiplatelet model, the most significant predictors of mortality were antiplatelet omission (HR 3.7, 95% CI 3.3-4.1), liver disease (HR 1.6, 95% CI 1.4-1.7), malignant/benign neoplasms (HR 1.6, 95% CI 1.5-1.6), gastrointestinal or respiratory tract intubations (HR 1.5, 95% CI 1.3-1.7), and blood dyscrasias (HR 1.4, 95% CI 1.4-1.5). These mortality risk factors may guide future studies assessing potential benefits of antithrombotics in specific subsets of patients.

International normalized ratio stability in warfarin-experienced patients with nonvalvular atrial fibrillation.

BACKGROUND: Maintaining stable levels of anticoagulation using warfarin therapy is challenging. Few studies have examined the stability of the international normalized ratio (INR) in patients with nonvalvular atrial fibrillation (NVAF) who have had ≥6 months' exposure to warfarin anticoagulation for stroke prevention. OBJECTIVE: Our objective was to describe INR control in NVAF patients who had been receiving warfarin for at least 6 months. METHODS: Using retrospective patient data from the CoagClinic™ database, we analyzed data from NVAF patients treated with warfarin to assess the quality of INR control and possible predictors of poor INR control. Time within, above, and below the recommended INR range (2.0-3.0) was calculated for patients who had received warfarin for ≥6 months and had three or more INR values. The analysis also assessed INR patterns and resource utilization of patients with an INR >4.0. Logistic regression models were used to determine factors associated with poor INR control. RESULTS: Patients (n = 9433) had an average of 1.6 measurements per 30 days. Mean follow-up time was 544 days. Approximately 39% of INR values were out of range, with 23% of INR values being <2.0 and 16% being >3.0. Mean percent time with INR in therapeutic range was 67%; INR <2.0 was 19% and INR >3.0 was 14%. Patients with more than one reading of INR >4.0 (~39%) required an average of one more visit and took 3 weeks to return to an in-range INR. Male sex and age >75 years were predictive of better INR control, whereas a history of heart failure or diabetes were predictive of out-of-range INR values. However, patient characteristics did not predict the likelihood of INR >4.0. CONCLUSIONS: Out-of-range INR values remain frequent in patients with NVAF treated with warfarin. Exposure to high INR values was common, resulting in increased resource utilization.

Characterizing major bleeding in patients with nonvalvular atrial fibrillation: a pharmacovigilance study of 27 467 patients taking rivaroxaban.

BACKGROUND: In nonvalvular atrial fibrillation (NVAF), rivaroxaban is used to prevent stroke and systemic embolism. OBJECTIVE: To evaluate major bleeding (MB) in NVAF patients treated with rivaroxaban in a real-world clinical setting. METHODS: From January 1, 2013, to March 31, 2014, US Department of Defense electronic health care records were queried to describe MB rates and demographics. Major bleeding was identified using a validated algorithm. RESULTS: Of 27 467 patients receiving rivaroxaban, 496 MB events occurred in 478 patients, an incidence of 2.86 per 100 person-years (95% confidence interval: 2.61-3.13). The MB patients were older, mean (SD) age of 78.4 (7.7) vs 75.7 (9.7) years, compared with non-MB patients. Patients with MB had higher rates of hypertension (95.6% vs 75.8%), coronary artery disease (64.2% vs 36.7%), heart failure (48.5% vs 23.7%), and renal disease (38.7% vs 16.7%). Of MB patients, 63.2% were taking 20 mg, 32.2% 15 mg, and 4.6% 10 mg of rivaroxaban. Four percent of MB patients took warfarin within the prior 30 days. Major bleeding was most commonly gastrointestinal (88.5%) or intracranial (7.5%). Although 46.7% of MB patients received a transfusion, none had sufficient evidence of receiving any type of clotting factor. Fourteen died during their MB hospitalization, yielding a fatal bleeding incidence rate of 0.08 per 100 person-years (95% confidence interval: 0.05-0.14). Mean age at death was 82.4 years. CONCLUSIONS: In this large observational study, the MB rate was generally consistent with the registration trial results, and fatal bleeds were rare.

International normalized ratio stabilization in newly initiated warfarin patients with nonvalvular atrial fibrillation.

BACKGROUND: Warfarin is effective for stroke prevention in patients with atrial fibrillation (AF), but international normalized ratio (INR) levels fluctuate and frequent monitoring is necessary. METHODS: This study used data from a large anticoagulation management service database to analyze the relationship between INR stabilization and warfarin utilization for >1 year in patients with nonvalvular AF (NVAF). Anticoagulation records from a large US electronic database collected from 2006 to 2010 were analyzed. RESULTS: Patients with NVAF and ≥ 3 INR values in the dataset were identified (n = 15,276). INR stabilization was defined as the first three consecutive INR values between 2.0 and 3.0 after warfarin initiation. One quarter of patients (n = 3809) failed to reach INR stabilization. After initial stabilization, 30% of subsequent INR values were out of range. The mean (± standard deviation [SD]) follow-up time from stabilization to the end of study for these patients was 494.2 ± 418.1 days. Age ≥ 75 years (odds ratio [OR] = 1.17, 95% confidence interval [CI] = 1.08-1.27), hypertension (OR = 1.19, 95% CI = 1.10-1.29), or prior stroke (OR = 1.29, 95% CI = 1.04-1.61) were positively associated with achieving stabilization; heart failure was negatively associated with stabilization (OR = 0.78, 95% CI = 0.70-0.87). Male gender (p < 0.0001) and hypertension were associated with earlier stabilization (p = 0.0013); heart failure was associated with later stabilization (p = 0.0098). Patients who achieved INR stabilization within 1 year were 10 times more likely to remain on warfarin than patients who did not achieve it. LIMITATIONS: Observational data may contain incomplete records. Data on adherence, concurrent medications, vitamin K intake, genotype, reasons for discontinuation of monitoring, and patient outcomes were not available in the dataset. The study findings were generalizable only to patients with AF who were managed by anticoagulation clinics. CONCLUSION: Given the importance of stroke prevention among patients with AF, the potential for unpredictable INR patterns should be carefully considered during clinical decision-making.

Rationale and design of VENTURE-AF: a randomized, open-label, active-controlled multicenter study to evaluate the safety of rivaroxaban and vitamin K antagonists in subjects undergoing catheter ablation for atrial fibrillation.

PURPOSE: To evaluate the safety of uninterrupted rivaroxaban, a novel oral anticoagulant that directly inhibits factor Xa, and a vitamin K antagonist (VKA) in eligible adult patients with nonvalvular AF (NVAF) who are scheduled for a catheter ablation. METHODS/DESIGN: This is a prospective, randomized, open-label, active-controlled, global multicenter safety study of up to 250 randomized patients. Eligible patients with paroxysmal or persistent NVAF, a left ventricular ejection fraction >40 %, and a creatinine clearance >50 mL/min will be randomized 1:1 to rivaroxaban 20 mg orally once daily or to dose-adjusted oral VKA (recommended international normalized ratio (INR) 2.0-3.0) and stabilized on anticoagulation therapy for 1-7 days (if no intracardiac thrombus on transesophageal echocardiogram (TEE) immediately prerandomization/post-randomization or if 3 weeks of sufficient anticoagulation is documented) or for 4-5 weeks (if no TEE, no documented 3 weeks of sufficient anticoagulation, or by patient choice). During catheter ablation, heparin will be administered (ACT-targeted range = 300-400 s) after catheter ablation, and VKA will be managed per usual care. The next dose of rivaroxaban will be provided at least 6 h after establishment of hemostasis. The primary endpoint will be the incidence of post-procedure major bleeding events observed during the first 30 ± 5 days post-ablation. Secondary endpoints will include post-procedure thromboembolic events, additional bleeding, time-to-event, and medication adherence. RELEVANCE: This study is intended to provide information about the safety characteristics of rivaroxaban in patients with NVAF undergoing catheter ablation.

Rivaroxaban crushed tablet suspension characteristics and relative bioavailability in healthy adults when administered orally or via nasogastric tube.

PURPOSE: Because some patients have difficulty swallowing a whole tablet, we investigated the relative bioavailability of a crushed 20 mg rivaroxaban tablet and of 2 alternative crushed tablet dosing strategies. METHODS: Stability and nasogastric (NG) tube adsorption characteristics of a crushed rivaroxaban tablet were assessed. Then, in 55 healthy adults, relative bioavailability of rivaroxaban administered orally as a whole tablet (Reference [Whole-Oral]), crushed tablet in applesauce suspension (Crushed-Oral), or crushed tablet in water suspension via NG tube (Crushed-NG) were determined. RESULTS: There were no significant changes in mean percent of non-degraded rivaroxaban recovered over 4 hours from crushed tablet suspensions (>98.4% recovery across all suspensions and time points) or after NG tube exposure (recovery: 99.1% for silicone and 98.9% for polyvinyl chloride NG tubes). Relative bioavailability was similar between Crushed-Oral and Reference dosing (Cmax and AUC∞ were within the 80-125% bioequivalence limits). Relative bioavailability was also similar between the Crushed-NG and Reference dosing (AUC∞ was within bioequivalence limits; Cmax [90% CI range: 78.5-85.8%] was only slightly below the 80% lower bioequivalence limit). CONCLUSIONS: A crushed rivaroxaban tablet was stable and when administered orally or via NG tube, displayed similar relative bioavailability compared to a whole tablet administered orally.

Thromboprophylaxis patterns, risk factors, and outcomes of care in the medically ill patient population.

INTRODUCTION: Medically ill, hospitalized patients are at increased risk for venous thromboembolism (VTE) after discharge. This study aimed to examine thromboprophylaxis patterns, risk factors, and post-discharge outcomes. METHODS: This was a retrospective claims analysis involving administrative claims data and in-patient data abstracted from a sample of hospital charts. Patients aged ≥ 40 years hospitalized for ≥ 2 days for nonsurgical reasons between 2005 and 2009 were included. Hospital chart data were abstracted for a random sample of patients without evidence of anticoagulant use at 30 days post-discharge. The combined data determined whether in-patient thromboprophylaxis (anticoagulant or mechanical prophylaxis) reduces risk of VTE at 90 days post-discharge. Hazard ratios (HR) and odds ratios (OR) were calculated using Cox proportional hazard models and logistic regression. RESULTS: Of 141,628 patients in the claims analysis, 3.9% received anticoagulants (3.6% warfarin). VTE, rehospitalization, and mortality rates were 1.9%, 17.2%, and 6.2%, respectively. The strongest predictors of post-discharge VTE were history of VTE (HR=4.0, 95% confidence interval [CI]: 3.3-4.8), and rehospitalization (HR=3.9, 95% CI: 3.6-4.3). Of 504 medical charts, 209 (41.5%) reported in-patient thromboprophylaxis. There was no statistically significant difference in post-discharge VTE rates between patients who did and did not receive in-patient thromboprophylaxis. All-cause mortality was greater among patients without use of VTE prophylaxis. CONCLUSION: Utilization rates of in-hospital and post-discharge VTE prophylaxis were low. In-hospital VTE prophylaxis did not reduce the risk of post-discharge VTE in the absence of post-discharge anticoagulation. Combined in-patient and post-discharge thromboprophylaxis lowered the odds of short-term, all-cause post-discharge mortality.

Impact of co-morbidities and patient characteristics on international normalized ratio control over time in patients with nonvalvular atrial fibrillation.

This study determined the association between co-morbidities, including heart failure (HF) and time in therapeutic range (TTR), in patients with nonvalvular atrial fibrillation. Longitudinal patient-level anticoagulation management records collected from 2006 to 2010 were analyzed. Adult patients with nonvalvular atrial fibrillation who used warfarin for a 12-month period with no gap of >60 days between visits were identified. TTR <55% was defined as "lower" TTR. CHADS2 score of ≥2 was defined as "higher" CHADS2. Logistic regression analyses were conducted to determine the association between co-morbidities and TTR. A total of 23,425 patients met the study criteria. The mean age ± SD was 74.8 ± 9.7 years, with 84.8% aged ≥65 years. The most common co-morbidities were hypertension (41.7%), diabetes (24.1%), HF (11.7%), and previous stroke (11.1%). The mean TTR ± SD was 67.3 ± 14.4%, with 18.6% of patients in the lower TTR range. In multivariate analyses using age, gender, hypertension, diabetes, stroke, and region as covariates, HF (adjusted odds ratio [OR] 1.41, 95% confidence interval [CI] 1.28 to 1.56; p <0.001), diabetes (OR 1.28, 95% CI 1.19 to 1.38; p <0.001), and previous stroke (OR 1.15, 95% CI 1.04 to 1.27; p <0.001) were associated with lower TTR. In a second set of multivariate analyses using gender and region as covariates, a higher CHADS2 score was associated with lower TTR (OR 1.11, 95% CI 1.04 to 1.18; p <0.001). In conclusion, HF was associated with the greatest likelihood of a lower TTR, followed by diabetes, then stroke. Anticoagulation control may be more challenging for patients with these conditions.

Antithrombotic medication use and bleeding risk in medically ill patients after hospitalization.

BACKGROUND: Hospitalized medically ill patients receiving antithrombotic medications experience increased risk of bleeding. We examined antithrombotic use, bleeding rates, and associated risk factors at 30 days post discharge. METHODS: This retrospective database analysis included nonsurgical patients aged ≥40 years hospitalized for ≥2 days during 2005 to 2009. Previously cited, validated International Classification of Diseases, Ninth Revision, Clinical Modification codes for major bleeding were used to define clinically relevant bleeding. RESULTS: Of the 327,578 patients, 9.1% received antithrombotic medications, of which 3.7% were anticoagulants. Rates of major and minor bleeding were 1.8% and 7.1%, respectively. Preindex gastroduodenal ulcer, thromboembolic stroke, blood dyscrasias, liver disease, and rehospitalization were the strongest predictors of major bleeding. Other risk factors included increasing age, male gender, and hospital stay of ≥3 days. CONCLUSIONS: Careful consideration of these demonstrated bleed-associated comorbidities before initiating anticoagulation or combining antithrombotic medications in medically ill patients may improve strategies for prevention of postdischarge thromboembolism.

Trends in hypertension prevalence, awareness, treatment, and control rates in United States adults between 1988-1994 and 1999-2004.

This study assesses trends in hypertension prevalence, blood pressure distributions and mean levels, and hypertension awareness, treatment, and control among US adults, age >or=18 years, between the third National Health and Nutrition Examination Survey (1988-1994) and the 1999-2004 National Health and Nutrition Examination Survey, a period of approximately 10 years. The age-standardized prevalence rate increased from 24.4% to 28.9% (P<0.001), with the largest increases among non-Hispanic women. Depending on gender and race/ethnicity, from one fifth to four fifths of the increase could be accounted for by increasing body mass index. Among hypertensive persons, there were modest increases in awareness (P=0.04), from 68.5% to 71.8%. The rate for men increased from 61.6% to 69.3% (P=0.001), whereas the rate for women did not change significantly. Rates remained higher for women than for men, although the difference narrowed considerably. Improvements in treatment and control rates were larger: 53.1% to 61.4% and 26.1% to 35.1%, respectively (both P<0.001). The greatest increases occurred among non-Hispanic white men and non-Hispanic black persons, especially men. Mexican American persons showed improvement in treatment and control rates, but these rates remained the lowest among race/ethnic subgroups (47.4% and 24.3%, respectively). Among all of the race/ethnic groups, women continued to have somewhat better awareness, treatment, and control, except for control rates among non-Hispanic white persons, which became higher in men. Differences between non-Hispanic black and white persons in awareness, treatment, and control were small. These divergent trends may translate into disparate trends in cardiovascular disease morbidity and mortality.

Absolute stroke mortality burden for non-Hispanic non-Latino whites was disproportionately higher than expected simply based on the US population in 2001.

BACKGROUND AND PURPOSE: The absolute burden of stroke is a major determinant of health care costs and should also be considered when developing and implementing effective health policy. This study evaluated the impact of specific racial-ethnic categorization on absolute stroke mortality burden and population percentages. METHODS: In this population-based analysis, 2001 US data was used to compute absolute values of population and stroke mortality burden for white and black, and other racial-ethnic groups. To test the effect of age-mix, values were age-adjusted using the 2000 US standard population. The z test statistic was computed and a 2-tailed P value of <0.05 was considered significant. RESULT: Whites comprised a majority of the 2001 absolute US stroke mortality burden and US population (86% and 82%, respectively). Surprisingly, nHnL whites comprised a much higher percentage of the absolute US stroke mortality burden than expected based on their percentage of the US population alone (81% and 69%, respectively; P<0.001). Age-adjustment indicated a contribution by age-mix, however, an age-independent residual component remained. CONCLUSIONS: Specific race-ethnicity categorization significantly influences comparisons of the proportion of absolute stroke mortality burden to the population proportion. Accordingly, appropriate caution and care are needed when estimating the societal impact of conditions such as stroke.

The burden of adult hypertension in the United States 1999 to 2000: a rising tide.

This study aims to estimate the absolute number of persons with hypertension (the hypertension burden) and time trends using data from the National Health and Nutrition Examination Survey of United States resident adults who had hypertension in 1999 to 2000. This information is vitally important for health policy, medical care, and public health strategy and resource allocation. At least 65 million adults had hypertension in 1999 to 2000. The total hypertension prevalence rate was 31.3%. This value represents adults with elevated systolic or diastolic blood pressure, or using antihypertensive medications (rate of 28.4%; standard error [SE], 1.1), and adults who otherwise by medical history were told at least twice by a physician or other health professional that they had high blood pressure (rate of 2.9%; SE, 0.4). The number of adults with hypertension increased by approximately 30% for 1999 to 2000 compared with at least 50 million for 1988 to 1994. The 50 million value was based on a rate of 23.4% for adults with elevated blood pressure or using antihypertensive medications and 5.5% for adults classified as hypertensive by medical history alone (28.9% total; P<0.001). The approximately 30% increase in the total number of adults with hypertension was almost 4-times greater than the 8.3% increase in total prevalence rate. These trends were associated with increased obesity and an aging and growing population. Approximately 35 million women and 30 million men had hypertension. At least 48 million non-Hispanic white adults, approximately 9 million non-Hispanic black adults, 3 million Mexican American, and 5 million other adults had hypertension in 1999 to 2000.