Safety and Efficacy of Novel Oral Anticoagulants Versus Warfarin in Medicare Beneficiaries With Atrial Fibrillation and Valvular Heart Disease.

BACKGROUND: We examined a large community-based sample of patients with atrial fibrillation (AF) and valvular heart disease (VHD) (excluding prosthetic valves) with a goal to compare outcomes among patients with AF, with and without VHD, taking warfarin, dabigatran, and rivaroxaban. METHODS AND RESULTS: We identified Medicare beneficiaries enrolled in Medicare Part D benefit plan from 2011 to 2013 with newly diagnosed AF (18 137 patients with VHD [dabigatran, 1979; rivaroxaban, 2027; warfarin, 14 131] and 85 596 patients without VHD [dabigatran, 13 522; rivaroxaban, 14 257; warfarin, 57 817]). Primary outcomes of all-cause mortality, ischemic strokes, major bleeding, and myocardial infarction were compared across the 3 anticoagulants using 3-way propensity-matched samples. After propensity matching, a total of 5871 patients with VHD and 40 221 patients without VHD and AF were studied. Both dabigatran and rivaroxaban were associated with significantly lower risk of death in patients with VHD with AF (dabigatran versus warfarin: hazard ratio, 0.71; 95% confidence interval, 0.52-0.98; P=0.038; rivaroxaban versus warfarin: hazard ratio, 0.68; 95% confidence interval, 0.49-0.95; P=0.022). Nongastrointestinal bleeding was significantly reduced with dabigatran and rivaroxaban versus warfarin in those with VHD (dabigatran versus warfarin: hazard ratio, 0.17; 95% confidence interval, 0.06-0.49; P=0.001; rivaroxaban versus warfarin: hazard ratio, 0.37; 95% confidence interval, 0.17-0.84; P=0.017). Ischemic stroke and gastrointestinal bleeding rates did not differ between rivaroxaban, dabigatran, and warfarin in patients with VHD. The effects of the 3 anticoagulants on outcomes were comparable in patients with and without VHD and with AF. CONCLUSIONS: In this cohort of Medicare beneficiaries with VHD (excluding patients with prosthetic valves) and new-onset AF between 2011 and 2013, novel oral non-vitamin K anticoagulants were safe and effective options for prevention of systemic thromboembolism.

Stroke, Bleeding, and Mortality Risks in Elderly Medicare Beneficiaries Treated With Dabigatran or Rivaroxaban for Nonvalvular Atrial Fibrillation.

Importance: Dabigatran and rivaroxaban are non-vitamin K oral anticoagulants approved for stroke prevention in patients with nonvalvular atrial fibrillation (AF). There are no randomized head-to-head comparisons of these drugs for stroke, bleeding, or mortality outcomes. Objective: To compare risks of thromboembolic stroke, intracranial hemorrhage (ICH), major extracranial bleeding including major gastrointestinal bleeding, and mortality in patients with nonvalvular AF who initiated dabigatran or rivaroxaban treatment for stroke prevention. Design, Setting, and Participants: Retrospective new-user cohort study of 118 891 patients with nonvalvular AF who were 65 years or older, enrolled in fee-for-service Medicare, and who initiated treatment with dabigatran or rivaroxaban from November 4, 2011, through June 30, 2014. Differences in baseline characteristics were adjusted using stabilized inverse probability of treatment weights based on propensity scores. The data analysis was performed from May 7, 2015, through June 30, 2016. Exposures: Dabigatran, 150 mg, twice daily; rivaroxaban, 20 mg, once daily. Main Outcomes and Measures: Adjusted hazard ratios (HRs) for the primary outcomes of thromboembolic stroke, ICH, major extracranial bleeding including major gastrointestinal bleeding, and mortality, with dabigatran as reference. Adjusted incidence rate differences (AIRDs) were also estimated. Results: A total of 52 240 dabigatran-treated and 66 651 rivaroxaban-treated patients (47% female) contributed 15 524 and 20 199 person-years of on-treatment follow-up, respectively, during which 2537 primary outcome events occurred. Rivaroxaban use was associated with a statistically nonsignificant reduction in thromboembolic stroke (HR, 0.81; 95% CI, 0.65-1.01; P = .07; AIRD = 1.8 fewer cases/1000 person-years), statistically significant increases in ICH (HR, 1.65; 95% CI, 1.20-2.26; P = .002; AIRD = 2.3 excess cases/1000 person-years) and major extracranial bleeding (HR, 1.48; 95% CI, 1.32-1.67; P < .001; AIRD = 13.0 excess cases/1000 person-years), including major gastrointestinal bleeding (HR, 1.40; 95% CI, 1.23-1.59; P < .001; AIRD = 9.4 excess cases/1000 person-years), and with a statistically nonsignificant increase in mortality (HR, 1.15; 95% CI, 1.00-1.32; P = .051; AIRD = 3.1 excess cases/1000 person-years). In patients 75 years or older or with CHADS2 score greater than 2, rivaroxaban use was associated with significantly increased mortality compared with dabigatran use. The excess rate of ICH with rivaroxaban use exceeded its reduced rate of thromboembolic stroke. Conclusions and Relevance: Treatment with rivaroxaban 20 mg once daily was associated with statistically significant increases in ICH and major extracranial bleeding, including major gastrointestinal bleeding, compared with dabigatran 150 mg twice daily.

ASSESSMENT OF WARFARIN TREATMENT EFFICACY BY MEANS; OF USING COAGULATION TEST RESULTS WITHIN THE THERAPEUTIC RANGE.

Time in Therapeutic Range (TTR) is a value used to assess the efficacy of Warfarin treatment. The aim of our study is to determine the effective INR levels and the rate of TTR in patients on Warfarin regimen due to Atrial Fibrillation (AF) or Mechanical Prosthetic Valve (MPV). A total of 94 patients (58 female, and 36 male, mean age: 64.9±11years) on Warfarin treatment due to AF or MPV with at least 10 INR levels measurements in the last 6 months were included in this retrospective study. The patients were divided into 2 groups. Group 1 consisted of the patients with Valvular AF (n=47); Group 2 included the patients with Non-Valvular AF (n=47); TTR and INR levels were compared. The average of INR values were found as 2,4 (min: 1,3, max: 4,3) in all patients; 2,3 (min: 1,3, max: 4,2) in Group 1; 2,6 (min: 1,3, max: 4,3) in Group 2. The average of TTR values was found 40.3% (min: 10%, max: 80%) in all patients; 43.8% (min: 10%, max: 80%) in Group 1; 36,8% (min: 10%, max: 80%) in Group 2. INR and TTR values are needed to assess the effectiveness of the Warfarin treatment. The patients in treatment with Warfarin should be well trained and frequently monitored. On the other hand, the underlying factors of the TTR values being determined as lower in the Turkish patient population might be due to the lower socio-economic and socio-cultural status, inadequate education levels, and the insufficient information on use of the medication provided by the doctors to the patients.

Assessment of Anti-Tissue Type Plasminogen Activator Antibodies in Patients With Prosthetic Heart Valve Thrombosis: The ATA Trial.

BACKGROUND: Thrombolysis is an effective treatment strategy for prosthetic valve thrombosis (PVT). Recombinant tissue-type plasminogen activator (rt-PA) is widely used as a thrombolytic agent. Infusion of rt-PA may trigger the production of anti-tissue plasminogen activator (tPA) antibodies (ATAs). We aimed to evaluate the possible relationship between ATA levels and PVT formation, and the role of baseline ATA levels on outcomes of thrombolytic therapy in patients with PVT. METHODS: This prospective, single-center cohort study included 28 patients with PVT undergoing thrombolysis and 31 controls with normal prostheses. Plasma samples were collected from patients with PVT at baseline and at 15th, 30th, 90th, and 180th days after thrombolysis and from controls at baseline only. The ATA levels were assessed in human plasma by an enzyme-linked immunosorbent assay. RESULTS: Baseline ATA-immunoglobulin (Ig) G and IgM were significantly higher in patients with PVT than in controls. The levels of IgM and IgG peaked at 15th and 30th days after rt-PA infusion, respectively. Subtherapeutic international normalized ratio and baseline ATA-IgM were independent predictors of PVT. Thrombolysis failed in 6 patients (21%) in whom baseline IgM levels were significantly higher than successfully lysed patients. Rethrombosis occurred in 9 patients (32%) in whom baseline IgG levels were significantly higher than those without rethrombosis. There was a moderate positive correlation between baseline and 15th-day IgM levels and the dose of rt-PA needed for successful lysis. CONCLUSION: The ATA levels tended to be higher in patients with PVT at the time of initial diagnosis compared to controls without PVT. In addition, such patients with PVT and high ATA levels may be at high risk for failed thrombolysis or rethrombosis.

Postdischarge international normalized ratio testing and long-term clinical outcomes of patients with heart failure receiving warfarin: findings from the ADHERE registry linked to Medicare claims.

BACKGROUND: Effective warfarin thromboprophylaxis requires maintaining anticoagulation within the recommended international normalized ratio (INR) range. INR testing rates and associations between testing and outcomes are not well understood. HYPOTHESIS: INR testing rates after hospitalization for acute decompensated heart failure are suboptimal, and testing is associated with lower risks of mortality and adverse clinical events. METHODS: We conducted a retrospective cohort study of patients who were long-term warfarin users and were hospitalized for heart failure, had a medical history of atrial fibrillation or valvular heart disease, and were enrolled in fee-for-service Medicare. INR testing was defined as ≥1 outpatient INR test within 45 days after discharge. Using Cox proportional hazards models, we examined associations between testing and all-cause mortality, all-cause readmission, and adverse clinical events at 1 year. RESULTS: Among 8558 patients, 7722 (90.2%) were tested. After 1 year, tested patients had lower all-cause mortality (23.5% vs 32.6%; P < 0.001) and fewer myocardial infarctions (2.0% vs 3.3%; P = 0.02). These differences remained significant after multivariable adjustment with hazard ratios of 0.72 (95% confidence interval [CI]: 0.63-0.84; P < 0.001) and 0.58 (95% CI: 0.41-0.83; P = 0.003), respectively. Differences in all-cause readmission, thromboembolic events, ischemic stroke, and bleeding events were not statistically significant. CONCLUSIONS: Postdischarge outpatient INR testing in patients with heart failure complicated by atrial fibrillation or valvular heart disease was high. INR testing was associated with improved survival and fewer myocardial infarctions at 1 year but was not independently associated with other adverse clinical events.

Diagnostic assessment of prosthetic mitral valve thrombosis by real-time three-dimensional transoesophageal echocardiography and successful thrombolytic treatment.

Prosthetic valve thrombosis (PVT) is a rare but serious complication of valve replacement, most often encountered with mechanical prostheses. The different therapeutic modalities for PVT (fibrinolysis with heparin treatment or surgery) will largely be influenced by the presence of valvular obstruction, the valve location (left or right sided), the patient's clinical status, the existence of and expertise in therapeutic modalities at the institution, and the patient's decision. This report describes a patient with thrombosis of a prosthetic mitral valve, which was successfully treated with recombinant streptokinase in a hospital without cardiac surgery. In this context, the authors present the real-time transoesophageal echocardiographic appearance of this complication, and give a brief review of the literature.

Assessment of bone mineral density and markers of bone turnover in children under long-term oral anticoagulant therapy.

Oral anticoagulants antagonize vitamin K action and potentially impair the carboxylation of osteocalcin, a protein essential for normal bone matrix formation. In the present study, bone mineral density (BMD) and bone turnover markers were evaluated in 23 children under long-term oral anticoagulant therapy. BMD of the lumbar spine was assessed (Dual Energy x-ray Absorptiometry) and reported as z score. Osteoblast [bone alkaline phosphatase, osteocalcin (Gla-Oc), amino-terminal procollagen 1 extension peptide] and osteoclast (urinary calcium and deoxypyridinoline, serum cross-linked C telopeptide) activity markers were measured. Vitamin D {[25(OH) D], parathormone, calcium, phosphorus, magnesium} and vitamin K status [factors II, VII, IX, X, protein C, protein S, undercarboxylated osteocalcin (Glu-Oc)] were determined. The above parameters were also evaluated in 25 healthy controls. Patients presented with higher levels in Glu-Oc, parathormone, and bone resorption markers, lower levels in bone formation markers and 25(OH) D, whereas 52% of them showed signs of osteopenia (-1>BMD z score>-2.5). Statistical analysis demonstrated that anticoagulant therapy was an independent predictor of alterations in Glu-Oc, Gla-Oc, bone alkaline phosphatase, amino-terminal procollagen 1 extension peptide, and serum cross-linked C telopeptide levels. It seems that long-term use of coumarin derivatives may cause osteopenia in children with the risk of developing osteoporosis later in life.

Early switch from vancomycin to oral linezolid for treatment of gram-positive heart valve endocarditis.

BACKGROUND: Patients with complicated gram-positive endocarditis are usually treated with a combination of surgical procedure and long-term antibiotic therapy with intravenous vancomycin. However, oral linezolid offers the potential for an early switch from intravenous vancomycin to oral linezolid therapy. METHODS: We conducted a retrospective study from February 2002 to August 2005 to determine the potential for early switch from intravenous vancomycin to oral linezolid in patients surgically treated for a left-sided active gram-positive endocarditis. RESULTS: Fourteen patients were identified; average age was 52 +/- 16 years. There were 10 (85%) and 2 (15%) cases of native and prosthetic valve endocarditis, respectively. Patients were operated on 3 to 10 days after diagnosis. There were no cases of operative mortality. Mean follow-up was 20.8 +/- 7.0 months. Two (14%) patients died of noncardiac causes during follow-up. The mean intensive care unit length of stay was 3.1 +/- 2.3 days, and mean hospital length of stay was 10.5 +/- 3.4 days. No cases of recurrent endocarditis or periprosthetic leakage were observed. CONCLUSIONS: The combination of aggressive surgical treatment and the early switch from intravenous vancomycin to oral linezolid for treatment of active gram-positive heart valve endocarditis is safe and effective, and reduces infection relapses, vancomycin use, hospital length of stay, and economic costs.

Postanalytical external quality assessment of warfarin monitoring in primary healthcare.

BACKGROUND: An increasing number of patients are treated with warfarin worldwide, and many are monitored in general practice, often with office instruments. Bleeding or thromboembolic episodes may be consequences of inadequate treatment. We have therefore examined some important aspects of general practitioners' (GPs') knowledge of warfarin treatment. METHODS: A questionnaire including 2 case histories with familiar indications for warfarin treatment (mechanical heart valve prosthesis and pulmonary embolism) was circulated to 3781 GPs in Norway as a postanalytical quality assessment. RESULTS: A total of 1547 GPs (41%) responded. There were substantial variations among GPs concerning the frequency of international normalized ratio (INR) monitoring, stated therapeutic ranges for arterial (but not venous) indications for anticoagulation therapy, and handling of a moderately high INR result of 5.9. Most GPs estimated an unrealistically high risk of serious bleeding in the latter situation (median, 15%; 10th and 90th percentiles, 4% and 50%, respectively). The critical difference necessary to change the warfarin dose was highly dependent on perceived therapeutic intervals, and about half of the GPs suggested a critical difference of 0.8 INR, which is attainable with office instruments. Sex and age of the GPs, practice size, and availability of an INR instrument in the office laboratory did not influence the results to any substantial degree, as variations within subgroups were similar. CONCLUSIONS: Gross variations in practice were found, especially for aspects of warfarin treatment that lacked uniform guidelines. Evidence-based and practicable recommendations for treatment and monitoring of these patients are still needed.

The efficacy of long-term oral anticoagulant therapy and its laboratory assessment.

The activated partial thromboplastin time is compared with the corresponding prothrombin ratio in 6378 samples of platelet-poor plasma from 446 patients treated for a total of more than 4500 patient/months with oral anticoagulatnts. A relative decrease in the activated partial thromboplastin time following deep vein thrombosis is described, which tends to become less obvious during the first year of treatment and is greater in older patients. Although this relative decrease is also found in patients treated after cerebrovascular accidents, it is not found in patients treated after myocardial infarction or in patients with mitral valve disease treated prophylactically with long-term oral anticoagulants. It is though possible that these changes following deep vein thrombosis might be useful in helping to determine the duration of oral anticoagulant treatment.