Stacy A. Johnson

Risk of deep vein thrombosis following a single negative whole-leg compression ultrasound: a systematic review and meta-analysis

CONTEXT In patients with suspected lower extremity deep vein thrombosis (DVT), compression ultrasound (CUS) is typically the initial test to confirm or exclude DVT. Patients with an initial negative CUS result often require repeat CUS after 5 to 7 days. Whole-leg CUS may exclude proximal and distal DVT in a single evaluation. OBJECTIVE To determine the risk of venous thromboembolism after withholding anticoagulation in patients with suspected lower extremity DVT following a single negative whole-leg CUS result. DATA SOURCES MEDLINE, EMBASE, CINAHL, LILACS, Cochrane, and Health Technology Assessments databases were searched for articles published from January 1970 through November 2009. Supplemental searches were performed of Internet resources, reference lists, and by contacting content experts. STUDY SELECTION Included studies were randomized controlled trials and prospective cohort studies of patients with suspected DVT and a negative whole-leg CUS result who did not receive anticoagulant therapy, and were followed up at least 90 days for venous thromboembolism events. DATA EXTRACTION Two authors independently reviewed and extracted data regarding a single positive or negative whole-leg CUS result, occurrence of venous thromboembolism during follow-up, and study quality. RESULTS Seven studies were included totaling 4731 patients with negative whole-leg CUS examinations who did not receive anticoagulation. Of these, up to 647 patients (13.7%) had active cancer and up to 725 patients (15.3%) recently underwent a major surgery. Most participants were identified from an ambulatory setting. Venous thromboembolism or suspected venous thromboembolism-related death occurred in 34 patients (0.7%), including 11 patients with distal DVT (32.4%); 7 patients with proximal DVT (20.6%); 7 patients with nonfatal pulmonary emboli (20.6%); and 9 patients (26.5%) who died, possibly related to venous thromboembolism. Using a random-effects model with inverse variance weighting, the combined venous thromboembolism event rate at 3 months was 0.57% (95% confidence interval, 0.25%-0.89%). CONCLUSION Withholding anticoagulation following a single negative whole-leg CUS result was associated with a low risk of venous thromboembolism during 3-month follow-up.

Peri-procedural anticoagulation in patients undergoing ablation for atrial fibrillation.

Radiofrequency catheter ablation is being used with increasing frequency as a strategy to manage atrial fibrillation. Patients undergoing this procedure are at increased short-term risk of thromboembolism for several days and up to 4 weeks or longer after their ablation, and anticoagulation management surrounding the ablation procedure remains controversial. Although no conclusive recommendations can be made, published guidelines and data support therapeutic anticoagulation with warfarin for 3 weeks prior and intravenous heparin during the ablation. Warfarin may either be continued through the ablation or stopped 2-5 days prior. If the latter approach is chosen, a pre-ablation bridging strategy of enoxaparin 1mg/kg twice daily is reasonable in selected patients unless the patients bleeding risk dictates using a lower dose regimen (0.5mg/kg twice daily) or avoiding bridging altogether. Fewer data are available for post-ablation management strategies, and current practice patterns are based largely on single-center experiences in smaller, non-randomized studies. For lower risk patients (CHADS(2) 0-1), either warfarin or aspirin may be utilized without bridging. In higher thromboembolic risk patients (CHADS(2) >or=2), either enoxaparin (1mg/kg twice daily) or heparin may be started within the first 12-24h post-procedure. For patients with bleeding risk factors, enoxaparin may be subsequently reduced to 0.5mg/kg until the INR is therapeutic, although the efficacy of this lower dosing regimen has not been well studied. In accordance with national guidelines, warfarin should be continued post-ablation for a minimum of 2 months and then indefinitely in patients with a CHADS(2) score >or= 2.

Pathogenesis, Diagnosis, and Treatment of Venous Thromboembolism in Older Adults

Older adults have a significantly greater risk of venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism, than younger adults. The cause of this greater risk is thought to be multifactorial, including age‐related changes in hemostatic factors and greater comorbid conditions and hospitalizations, but is not completely understood. Moreover, VTE remains underrecognized in older adults and may present atypically. Thus, a low index of clinical suspicion is essential when evaluating older adults with possible VTE. Despite this underrecognition in older adults, the diagnostic approach remains similar for all age groups and includes estimation of pretest probability, measurement of the D‐dimer, and imaging. Antithrombotic agents are the mainstay of VTE treatment and, when used appropriately, substantially reduce VTE recurrence and complications. The approval of novel oral anticoagulants (NOACs), including dabigatran, rivaroxaban, apixaban, and edoxaban, provide clinicians with new therapeutic options. In some individuals, NOACs may offer advantages over warfarin, including fewer drug interactions, more‐predictable anticoagulation, and lower risk of bleeding. Nevertheless, anticoagulation of VTE in older adults should always be performed cautiously, because age is a risk factor for bleeding complications. Identifying modifiable bleeding risk factors and balancing the risks of VTE recurrence with hemorrhage are important considerations when using anticoagulants in older adults.

Gold Standard in Anticoagulation Assessment of Left Ventricular Assist Device Patients? : How About Bronze∗

Continuous-flow left ventricular assist devices (CF-LVADs) have become a standard therapeutic option in the management of eligible patients with advanced forms of heart failure. Although survival after LVAD implant has improved dramatically in the past decade, the cumulative incidence of LVAD-

Correction factor to improve agreement between point-of-care and laboratory International Normalized Ratio values

PURPOSE Results of a research project to quantify and improve the accuracy of point-of-care (POC) International Normalized Ratio (INR) values are reported. METHODS The accuracy of POC INR values relative to laboratory-measured INR values was retrospectively assessed in a cohort of patients with same-day INR determinations by both methods. Univariate linear regression was performed to derive a correction factor for POC INR values of >3; this correction factor was validated in a second cohort. RESULTS In the derivation cohort (259 patients and 344 paired INR results), agreement of POC values with corresponding laboratory INR values at two specified thresholds (±15% and ±25%) was 51.2% and 66.6%, respectively; for POC INR values of >3 (n = 205), agreement was lower (24.9% and 44.9%, respectively). Univariate linear regression yielded a coefficient of 0.77 (95% confidence interval, 0.76-0.79; p < 0.001). Applying a correction factor of 0.8 to POC INR values in a validation cohort (169 patients and 209 paired INR values) significantly improved the accuracy of POC INR values of >3 relative to laboratory values (from 7% to 71.1% at the lower threshold and from 23.5% to 88.8% at the higher threshold, p < 0.0001 for both comparisons). CONCLUSION Agreement between POC and laboratory INR results in one institution was poor, especially when POC INR values exceeded 3. Application of an institution-specific correction factor to POC INR values of >3 improved agreement with laboratory INR results but would not have significantly reduced differences in protocol-based warfarin dosage adjustments.

Patterns and Appropriateness of Thrombophilia Testing in an Academic Medical Center

BACKGROUND: Clinical guidelines recommend against routine use of thrombophilia testing in patients with acute thromboembolism. Thrombophilia testing rarely changes acute management of a thrombotic event. OBJECTIVE: To determine appropriateness of thrombophilia testing in a teaching hospital. DESIGN: Retrospective cohort study. SETTING: One academic medical center in Utah. PARTICIPANTS: All patients who received thrombophilia testing between July 1, 2014, and December 31, 2014. MAIN MEASUREMENTS: Proportion of thrombophilia tests occurring in situations associated with minimal clinical utility, defined as tests meeting at least 1 of the following criteria: discharged before results available; test type not recommended; testing in situations associated with decreased accuracy; duplicate testing; and testing following a provoked thrombotic event. RESULTS: Overall, 163 patients received a total of 1451 thrombophilia tests for stroke (50% of tests; 35% of patients), venous thromboembolism (21% of tests; 21% of patients), and pregnancy‐related conditions (15% of tests; 25% of patients). Of the 39 different test types performed, the most common were cardiolipin IgG and IgM antibodies (9% each), lupus anticoagulant (9%), and &bgr;2‐glycoprotein 1 IgG and IgM antibodies (8% each). In total, 911 tests (63%) were performed in situations associated with minimal clinical utility, with 126 patients (77%) receiving at least one such test. Only 2 patients (1%) had clear documentation of being offered genetic consultation. CONCLUSIONS: Thrombophilia testing in this single‐center study was often associated with minimal clinical utility. Strategies to improve testing practices (eg, hematology specialty consult prior to inpatient testing, improved order panels) might help minimize inappropriate testing and promote value‐driven care.

Prescribing patterns of target-specific oral anticoagulants: an academic hospital perspective.

Target-specific oral anticoagulants have been rapidly adopted into clinical practice for stroke prophylaxis and venous thromboembolism treatment, raising concerns about off-label prescribing practices. We conducted a retrospective review of consecutive patients prescribed dabigatran, rivaroxaban or apixaban prior to inpatient hospitalization over an 18-month period to examine the off-label prescribing frequency, contraindications and related complications. Chart review included baseline demographics, hospital admitting service, outpatient prescribing service, renal function, therapeutic indication, echocardiographic findings, contraindications, major bleeding events and vital status. We identified 160 patients who received a target-specific oral anticoagulant prior to hospitalization. Over half (53.1%) of the patients received rivaroxaban, 43.7% received dabigatran and 3.1% received apixaban. Atrial fibrillation (68.1%) and venous thromboembolism treatment (25.6%) were the most common indications. Ninety percent of patients had a U.S. Foods and Drugs Administration (FDA)-approved indication for therapy. Major bleeding events occurred in 4.4% of patients. Cardiology was the most common prescribing and admitting service (43.8 and 31.3%), and more frequently adhered to FDA-approved indications (97 vs. 84%, P = 0.01). There were no significant differences between prescribing services regarding major contraindications (P = 0.14) and major bleeding events (P = 0.77). Off-label prescription rates for target-specific oral anticoagulants were infrequent and not associated with increased adverse events.

Edoxaban was noninferior to warfarin for preventing stroke or systemic embolism in atrial fibrillation.

Question In patients with atrial fibrillation (AF) who are at moderate-to-high risk for stroke, is edoxaban noninferior to warfarin for preventing stroke or systemic embolism? Methods Design Randomized controlled noninferiority trial (Effective Anticoagulation with Factor Xa Next Generation in Atrial FibrillationThrombolysis in Myocardial Infarction 48 [ENGAGE AF-TIMI 48] trial). ClinicalTrials.gov NCT00781391. Allocation Concealed.* Blinding Blinded* (patients, clinicians, outcome adjudicators, {data collectors, data analysts, and manuscript writers}). Follow-up period Median 2.8 years. Setting 1393 clinical centers in 46 countries. Patients 21105 adults 21 years of age (median age 72 y, 62% men) who had objectively documented AF in the past 12 months, CHADS2 score 2, and anticoagulation therapy planned for the trial duration. Exclusion criteria included AF due to a reversible disorder, estimated creatinine clearance (CrCl) <30 mL/min, moderate-to-severe mitral stenosis, high bleeding risk, use of dual-antiplatelet therapy, acute coronary syndromes, coronary revascularization, other indications for anticoagulation therapy, or stroke within the past 30 days. Intervention Edoxaban, 60 mg/d (n =7035), or 30 mg/d (n =7034), plus warfarin placebo; or warfarin, dose-adjusted to achieve an international normalized ratio of 2.0 to 3.0, plus edoxaban placebo (n =7036). Edoxaban doses were halved if patients had an estimated CrCl 30 to 50 mL/min; weighed 60 kg; or concomitantly used verapamil, quinidine, or dronedarone. Outcomes Composite of ischemic or hemorrhagic stroke or systemic embolic event during the treatment period (noninferiority) and during the study period (superiority). The primary safety endpoint was major bleeding during treatment. Patient follow-up 99% for primary noninferiority outcome (intention-to-treat analysis). Main results Median duration of treatment was 2.5 years. Both doses of edoxaban were noninferior to warfarin for the primary endpoint; neither dose was superior to warfarin (Table). Both doses of edoxaban resulted in less major bleeding than did warfarin (Table). Conclusion In patients with atrial fibrillation who are at moderate-to-high risk for stroke, edoxaban was noninferior to warfarin for preventing stroke or systemic embolism and had less bleeding. Edoxaban, 60 or 30 mg/d, vs warfarin in patients with atrial fibrillation who are at moderate-to-high risk for stroke Outcomes Edoxaban dose Event rate/y RRR/RRI (97.5% CI) P value for noninferiority / NNT (CI) Edoxaban Warfarin Primary noninferiority endpoint 60 mg/d 1.2% 1.5% RRR 21% (1 to 37) <0.001 30 mg/d 1.6% 1.5% RRI 7% (13 to 30) 0.005 Primary superiority endpoint 60 mg/d 1.6% 1.8% RRR 13% (4 to 26) Not significant 30 mg/d 2.0% 1.8% RRI 13% (4 to 33) Not significant Major bleeding 60 mg/d 2.8% 3.4% RRR 19% (9 to 28) 70 (48 to 155) 30 mg/d 1.6% 3.4% RRR 52% (44 to 58) 26 (24 to 31) Abbreviations defined in Glossary. RRR, RRI, NNT, and CI calculated from warfarin event rates and hazard ratios (HRs) in article. Ischemic or hemorrhagic stroke or systemic embolic event during treatment (from first dose of study drug until 3 d after last dose or end of double-blind treatment). Noninferiority criterion was met as the upper limit of the 1-sided 97.5% CI for the HR was 1.38: 60 mg/d HR 0.79 (CI 0.63 to 0.99); 30 mg/d HR 1.07 (CI 0.87 to 1.31) Ischemic or hemorrhagic stroke or systemic embolic event during study (from randomization until 3 d after last study dose or end of double-blind treatment). 95% CI. Commentary The ENGAGE AF-TIMI 48 trial of >20000 moderate-to-high-risk patients with nonvalvular AF showed that edoxaban was noninferior to warfarin for preventing stroke or systemic embolism. Moreover, edoxaban had fewer major bleeding events, including intracranial hemorrhage, than warfarin. Warfarin patients spent a median 68% of time in the therapeutic range. ENGAGE AF-TIMI 48 studied 2 edoxaban doses, and >25% of patients were randomized to the lower edoxaban dose based on prespecified criteria. Another 10% of patients had dose modification after randomization. Patients who received the lower edoxaban dose had fewer major bleeding events, without an increased risk for stroke or systemic embolism, compared with patients who had no dose reduction. This suggests that in patients with a higher bleeding risk, a lower edoxaban dose is safe without compromising efficacy. The investigators had a detailed plan for transitioning patients from edoxaban to open-label warfarin, and the transition was not associated with increased thromboembolic risk as has been seen in other trials (1, 2). However, in routine practice patients are often not transitioned from a novel oral anticoagulant (NOAC) to warfarin. The ENGAGE AF-TIMI 48 findings support the use of edoxaban in nonvalvular AF. Nevertheless, proper patient selection and education remain imperative with any NOAC. Baseline assessment of renal function, weight, and interacting medications will identify patients who need dose reduction to balance potential safety and efficacy concerns. Intermittent assessment of drug compliance, monitoring of renal and liver function, and ongoing education, particularly in higher-risk patients, are also recommended.

Prevalence and correlates of bleeding and emotional harms in a national US sample of patients with venous thromboembolism: A cross-sectional structural equation model

INTRODUCTION Venous thromboembolism (VTE) including deep vein thrombosis (DVT) or pulmonary embolism (PE) is associated with reduced survival, poorer quality of life, and substantial health-care-costs. Limited research, primarily qualitative, suggests that those with VTE may have elevated fear of recurrence, and associated emotional dysfunction and distress. METHODS A national online survey was administered to 907 patients who had experienced a VTE event in the past two years. The survey assessed for the prevalence of self-reported bleeding harms associated with VTE, the levels of anxiety, depression, cognitive dysfunction and distress experienced by patients, and a range of potential psychosocial correlates that may be associated with these bleeding or emotional harms. RESULTS The majority (63.0%) of respondents had experienced at least one bleeding related harm following their VTE diagnosis, and 40.6% indicated they experienced fear of another clot often or almost all the time. One-in-four (24.7%) and one-in-ten (11.6%) had abnormal levels of anxiety and depression, respectively. Structural equation modeling was used to define two composite latent bleeding harm and emotional harm factors. Emotional and bleeding harms were associated with younger age, a belief that ones health is due to luck, having multiple comorbidities, having a history of prior VTE events, having multiple barriers to VTE care, and experiencing medical mistakes in diagnosis or treatment. Emotional harms were uniquely predicted by having poorer health literacy, having low self-reported medication adherence, belief others are responsible for ones health, and more recent VTE events. Bleeding harms were uniquely predicted by having a lower frequency of primary care provider contact and having a history of switching between warfarin and direct oral anticoagulants for VTE treatment. CONCLUSIONS The findings show high levels of self-reported bleeding and emotional harms in a general population of VTE sufferers that are clearly associated with readily identifiable demographic, health status, and psychosocial characteristics. These represent targets for intervention and changes in clinical practice.

Periprocedural Bridging Anticoagulation

The “Things We Do for No Reason” (TWDFNR) series reviews practices that have become common parts of hospital care but that may provide little value to our patients. Practices reviewed in the TWDFNR series do not represent “black and white” conclusions or clinical practice standards, but are meant as a starting place for research and active discussions among hospitalists and patients. We invite you to be part of that discussion.