Apixaban compared with warfarin to prevent thrombosis in thrombotic antiphospholipid syndrome: a randomized trial.

Thrombotic antiphospholipid syndrome (TAPS) is characterized by venous, arterial, or microvascular thrombosis. Patients with TAPS merit indefinite anticoagulation, and warfarin has historically been the standard treatment. Apixaban is an oral factor Xa inhibitor anticoagulant that requires no dose adjustment or monitoring. The efficacy and safety of apixaban compared with warfarin for TAPS patients remain unknown. This multicenter prospective randomized open-label blinded endpoint study assigned anticoagulated TAPS patients to apixaban or warfarin (target international normalized ratio 2-3) for 12 months. The primary efficacy outcome was clinically overt thrombosis and vascular death. Apixaban was first given at 2.5 mg twice daily. Two protocol changes were instituted based on recommendations from the data safety monitoring board. After the twenty-fifth patient was randomized, the apixaban dose was increased to 5 mg twice daily, and after the thirtieth patient was randomized, subjects with prior arterial thrombosis were excluded. Primary outcomes were adjudicated by independent experts blinded to treatment allocation. Patients randomized between 23 February 2015 and 7 March 2019 to apixaban (n = 23) or warfarin (n = 25) were similar. Among the components of the primary efficacy outcome, only stroke occurred in 6 of 23 patients randomized to apixaban compared with 0 of 25 patients randomized to warfarin. The study ended prematurely after the forty-eighth patient was enrolled. Conclusions from our study are limited due to protocol modifications and low patient accrual. Despite these limitations, our results suggest that apixaban may not be routinely substituted for warfarin to prevent recurrent thrombosis (especially strokes) among patients with TAPS. This trial was registered at www.clinicaltrials.gov as #NCT02295475.

Electronic alerts, comparative practitioner metrics, and education improve thromboprophylaxis and reduce venous thrombosis in community hospitals.

BACKGROUND: Venous thromboembolism prophylaxis remains underutilized in hospitalized medical patients at high risk for venous thromboembolism. We previously reported that a multifaceted intervention was associated with a sustained increase in appropriate thromboprophylaxis and reduced symptomatic venous thromboembolism among medical patients hospitalized in two urban teaching hospitals. The effectiveness of this intervention in community hospitals is unknown. METHODS: We performed a prospective multicenter cohort study in three community hospitals. All medical patients admitted from February 1, 2011 to January 31, 2014 were eligible. Consecutive eligible patients were enrolled into the 12-month "control," 12-month "intervention," or 12-month "maintenance" group. We provided electronic alerts, physician performance feedback, and targeted medical education for the intervention group. Only the alert component of the intervention continued in the maintenance group. The primary outcome was the rate of appropriate thromboprophylaxis among patients at high risk for venous thromboembolism defined as the prescription of guideline recommended chemoprophylaxis, or identification of a chemoprophylaxis contraindication. Secondary outcomes included rates of symptomatic venous thromboembolism, major bleeding, all-cause mortality, heparin-induced thrombocytopenia, physician satisfaction, and alert fatigue. RESULTS: Appropriate thromboprophylaxis when compared to the control group rate of 67% was higher for the intervention group (85%) and for the maintenance group (77%; P < .001 for each comparison). A reduction of 90-day symptomatic venous thromboembolism accompanied the intervention (control 4.5%, intervention 3.4%, maintenance 3.0%, P = .04). CONCLUSIONS: This multifaceted intervention was associated with an overall increase in appropriate thromboprophylaxis of medical patients compared with the control period. Hospital-associated venous thrombosis rates decreased.

Preemptive Anticoagulation in Patients With a High Pretest Probability of Pulmonary Embolism: Are Guidelines Followed?

BACKGROUND: Guidelines suggest anticoagulation of patients with high pretest probability of pulmonary embolism (PE) while awaiting diagnostic test results (preemptive anticoagulation). Data relevant to the practice of preemptive anticoagulation are not available. METHODS: We reviewed 3,500 consecutive patients who underwent CT pulmonary angiography (CTPA) at two EDs. We classified the pretest probability for PE using the revised Geneva Score (RGS) as low (RGS 0-3), intermediate (RGS 4-10), or high (RGS 11-18). We classified patients with a high pretest probability of PE as receiving preemptive anticoagulation if therapeutic anticoagulation was given before CTPA completion. Patients with a high bleeding risk and those receiving treatment for DVT before CTPA were excluded from the preemptive anticoagulation analysis. We compared the time elapsed between ED registration and CTPA completion for patients with a low, intermediate, and high pretest probability for PE. RESULTS: We excluded three of 3,500 patients because CTPA preceded ED registration. Of the remaining 3,497 patients, 167 (4.8%) had a high pretest probability for PE. After excluding 29 patients for high bleeding risk and 21 patients who were treated for DVT prior to CTPA, only two of 117 patients (1.7%) with a high pretest probability for PE received preemptive anticoagulation. Furthermore, 37 of the remaining 115 patients (32%) with a high pretest probability for PE had a preexisting indication for anticoagulation but did not receive preemptive anticoagulation. The time from ED registration to CTPA completion did not differ based on the pretest probability of PE. CONCLUSIONS: Physicians rarely use preemptive anticoagulation in patients with a high pretest probability for PE. Clinicians do not expedite CTPA examinations for patients with a high pretest probability for PE.

Electronic Alerts, Comparative Practitioner Metrics, and Education Improves Thromboprophylaxis and Reduces Thrombosis.

BACKGROUND: Venous thromboembolism chemoprophylaxis remains underutilized in hospitalized medical patients at high risk for venous thromboembolism. We assessed the effect of a health care quality-improvement initiative comprised of a targeted electronic alert, comparative practitioner metrics, and practitioner-specific continuing medical education on the rate of appropriate venous thromboembolism chemoprophylaxis provided to medical inpatients at high risk for venous thromboembolism. METHODS: We performed a multicenter prospective observational cohort study in an urban Utah hospital system. All medical patients admitted to 1 of 2 participating hospitals from April 1, 2010 to December 31, 2012 were eligible. Patients were members of the "control" (April 1, 2010 to December 31, 2010), "intervention" (January 1, 2011 to December 31, 2011), or "subsequent year" (January 1, 2012 to December 31, 2012) group. The primary outcome was the rate of appropriate chemoprophylaxis among patients at high risk for venous thromboembolism. Secondary outcomes included rates of symptomatic venous thromboembolism, major bleeding, all-cause mortality, heparin-induced thrombocytopenia, physician satisfaction, and alert fatigue. RESULTS: The rate of appropriate chemoprophylaxis among patients at high risk for venous thromboembolism increased (66.1% control period vs 81.0% intervention period vs 88.1% subsequent year; P <.001 for each comparison). A significant reduction of 90-day symptomatic venous thromboembolism accompanied the quality initiative (9.3% control period, 9.7% intervention period, 6.7% subsequent year; P = .009); 30-day venous thromboembolism rates also significantly decreased. CONCLUSIONS: A multifaceted intervention was associated with increased appropriate venous thromboembolism chemoprophylaxis among medical inpatients at high risk for venous thromboembolism and reduced symptomatic venous thromboembolism. The effect of the intervention was sustained.

Apixaban for the Secondary Prevention of Thrombosis Among Patients With Antiphospholipid Syndrome: Study Rationale and Design (ASTRO-APS).

BACKGROUND: Antiphospholipid syndrome (APS) is an acquired thrombophilia characterized by thrombosis, pregnancy morbidity, and the presence of characteristic antibodies. Current therapy for patients having APS with a history of thrombosis necessitates anticoagulation with the vitamin K antagonist warfarin, a challenging drug to manage. Apixaban, approved for the treatment and prevention of venous thrombosis with a low rate of bleeding observed, has never been studied among patients with APS. AIMS AND METHODS: We report study rationale and design of Apixaban for the Secondary Prevention of Thrombosis Among Patients With Antiphospholipid Syndrome (ASTRO-APS), a prospective randomized open-label blinded event pilot study that will randomize patients with a clinical diagnosis of APS receiving therapeutic anticoagulation to either adjusted-dose warfarin or apixaban 2.5 mg twice a day. We aim to report our ability to identify, recruit, randomize, and retain patients with APS randomized to apixaban compared with warfarin. We will report clinically important outcomes of thrombosis and bleeding. All clinical outcomes will be adjudicated by a panel blinded to the treatment arm. A unique aspect of this study is the enrollment of patients with an established clinical diagnosis of APS. Also unique is our use of electronic medical record interrogation techniques to identify patients who would likely meet our inclusion criteria and use of an electronic portal for follow-up visit data capture. CONCLUSION: ASTRO-APS will be the largest prospective study to date comparing a direct oral anticoagulant with warfarin among patients with APS for the secondary prevention of thrombosis. Our inclusion criteria assure that outcomes obtained will be clinically applicable to the routine management of patients with APS receiving indefinite anticoagulation.

Assessment of the safety and efficiency of using an age-adjusted D-dimer threshold to exclude suspected pulmonary embolism.

BACKGROUND: D-dimer levels increase with age, and research has suggested that using an age-adjusted D-dimer threshold may improve diagnostic efficiency without compromising safety. The objective of this study was to assess the safety of using an age-adjusted D-dimer threshold in the workup of patients with suspected pulmonary embolism (PE). METHODS: We report the outcomes of 923 patients aged > 50 years presenting to our ED with suspected PE, a calculated Revised Geneva Score (RGS), and a D-dimer test. All patients underwent CT pulmonary angiography (CTPA). We compared the false-negative rate for PE of a conventional D-dimer threshold with an age-adjusted D-dimer threshold and report the proportion of patients for whom an age-adjusted D-dimer threshold would obviate the need for CTPA. RESULTS: Among 104 patients with a negative conventional D-dimer test result and an RGS ≤ 10, no PE was observed within 90 days (false-negative rate, 0%; 95% CI, 0%-2.8%). Among 273 patients with a negative age-adjusted D-dimer result and an RGS ≤ 10, four PEs were observed within 90 days (false-negative rate, 1.5%; 95% CI, 0.4%-3.7%). We observed an 18.3% (95% CI, 15.9%-21.0%) absolute reduction in the proportion of patients aged > 50 years who would merit CTPA by using an age-adjusted D-dimer threshold compared with a conventional D-dimer threshold. CONCLUSIONS: Use of an age-adjusted D-dimer threshold reduces imaging among patients aged > 50 years with an RGS ≤ 10. Although the adoption of an age-adjusted D-dimer threshold is probably safe, the CIs surrounding the additional 1.5% of PEs missed necessitate prospective study before this practice can be adopted into routine clinical care.

Adherence to PIOPED II investigators' recommendations for computed tomography pulmonary angiography.

BACKGROUND: Computed tomography (CT) pulmonary angiography use has increased dramatically, raising concerns for patient safety. Adherence to recommendations and guidelines may protect patients. We measured adherence to the recommendations of Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED II) investigators for evaluation of suspected pulmonary embolism and the rate of potential false-positive pulmonary embolism diagnoses when recommendations of PIOPED II investigators were not followed. METHODS: We used a structured record review to identify 3500 consecutive CT pulmonary angiograms performed to investigate suspected pulmonary embolism in 2 urban emergency departments, calculating the revised Geneva score (RGS) to classify patients as "pulmonary embolism unlikely" (RGS≤10) or "pulmonary embolism likely" (RGS>10). CT pulmonary angiograms were concordant with PIOPED II investigator recommendations if pulmonary embolism was likely or pulmonary embolism was unlikely and a highly sensitive D-dimer test result was positive. We independently reviewed 482 CT pulmonary angiograms to measure the rate of potential false-positive pulmonary embolism diagnoses. RESULTS: A total of 1592 of 3500 CT pulmonary angiograms (45.5%) followed the recommendations of PIOPED II investigators. The remaining 1908 CT pulmonary angiograms were performed on patients with an RGS≤10 without a D-dimer test (n=1588) or after a negative D-dimer test result (n=320). The overall rate of pulmonary embolism was 9.7%. Potential false-positive diagnoses of pulmonary embolism occurred in 2 of 3 patients with an RGS≤10 and a negative D-dimer test result. CONCLUSIONS: Nonadherence to recommendations for CT pulmonary angiography is common and exposes patients to increased risks, including potential false-positive diagnoses of pulmonary embolism.

Derivation and validation of a simple model to identify venous thromboembolism risk in medical patients.

BACKGROUND: Fewer than half of eligible hospitalized medical patients receive appropriate venous thromboembolism (VTE) prophylaxis. One reason for this low rate is the complexity of existing risk assessment models. A simple set of easily identifiable risk factors that are highly predictive of VTE among hospitalized medical patients may enhance appropriate thromboprophylaxis. METHODS: Electronic medical record interrogation was performed to identify medical admissions from January 1, 2000-December 31, 2007 (n=143,000), and those patients with objectively confirmed VTE during hospitalization or within 90 days following discharge. Putative risk factors most predictive of VTE were identified, and a risk assessment model (RAM) was derived; 46,000 medicine admissions from January 1, 2008-December 31, 2009 served as a validation cohort to test the predictive ability of the RAM. The newly derived RAM was compared with a published VTE assessment tool (Kucher Score). RESULTS: Four risk factors: previous VTE; an order for bed rest; peripherally inserted central venous catheterization line; and a cancer diagnosis, were the minimal set most predictive of hospital-associated VTE (area under the receiver operating characteristic curve [AUC]=0.874; 95% confidence interval [CI], 0.869-0.880). These risk factors upon validation in a separate population (validation cohort) retained an AUC=0.843; 95% CI, 0.833-0.852. The ability of the 4-element RAM to identify patients at risk of developing VTE within 90 days was superior to the Kucher Score. CONCLUSIONS: The 4-element RAM identified in this study may be used to identify patients at risk for VTE and improve rates of thromboprophylaxis. This simple and accurate RAM is an alternative to more complicated published VTE risk assessment tools that currently exist.

Computer surveillance of patients at high risk for and with venous thromboembolism.

Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), may be the number one preventable cause of death associated with hospitalization. Numerous evidence-based guidelines for effective VTE prophylaxis therapy exist. However, underuse is common due to the difficulty in integrating VTE risk assessment into routine patient care. Previous studies utilizing computer decision support to identify high-risk patients report improved use of prophylaxis therapy and reduced VTE. However, those studies did not report the sensitivity, specificity or positive predictive value of their methods to identify patients at high risk. We report an evaluation of a computerized tool to identify patients at high risk for VTE that found a sensitivity of 98% and positive predictive value of 99%. Another computer program used to detect VTE had a sensitivity of 92%, specificity of 99% and a positive predictive value of 97% to identify DVT and a sensitivity of 100%, specificity of 98% and positive predictive value of 89% to identify PE. These tools were found to provide a dependable method to identify patients at high risk for and with VTE.