ALBERT

Description: Background The Pulmonary Embolism Severity Index (PESI) has been validated in the setting of standard treatment of pulmonary embolism with initial low molecular weight heparin followed by vitamin K antagonists. We evaluated the proposed simplified PESI in a large, phase III randomized trial involving patients with symptomatic pulmonary embolism with or without deep vein thrombosis, who were treated with rivaroxaban or standard therapy. Methods The EINSTEIN PE study was an open-label, randomized, phase III study that compared oral rivaroxaban alone (15 mg twice daily for 3 weeks, followed by 20 mg once daily) with subcutaneous enoxaparin overlapping with and followed by a vitamin K antagonist (warfarin or acenocoumarol, target international normalized ratio 2.0–3.0) for 3, 6, or 12 months in patients with acute, symptomatic pulmonary embolism. At baseline, the simplified PESI score was assessed, with 1 point each assigned for age 〉80 years, history of cancer, chronic cardiopulmonary disease, heart beat ≥110 beats per minute, systolic blood pressure

Description: Abstract 712 Background & Objective: Risk factors for the post-thrombotic syndrome (PTS) remain poorly understood. In a prospective multinational multicenter cohort study of patients with a first episode of unprovoked deep venous thrombosis (DVT), we sought to evaluate whether subtherapeutic anticoagulation was associated with the development of PTS. Methods: The study population was derived from the REVERSE study, a prospective cohort study done to develop a clinical prediction rule to identify patients with unprovoked venous thromboembolism (VTE) at low risk of recurrent VTE. Patients with a first unprovoked VTE (index event) were treated with standard anticoagulant therapy with a target INR of 2–3 for a period of 5–7 months. Patients were then enrolled in the REVERSE study, anticoagulation was stopped, and patients were monitored for VTE recurrence. For the present study, patients with DVT as their index VTE event were assessed for PTS at enrollment into the REVERSE study, using the validated Villalta scale. PTS was defined by a score of 〉 4. Mild PTS was defined by a score of 5–9, moderate PTS by a score of 10–14 and severe PTS was defined by a score of ≥15 or presence of an ipsilateral leg ulcer. Using international normalized ratio (INR) data from the full period of warfarin anticoagulation, time in therapeutic range (TTR) was calculated by the Rosendaal method of linear interpolation. TTR data were analyzed to evaluate whether there was an association between sub-therapeutic INR values during various time windows since the index DVT and development of PTS. Based on published trials of warfarin anticoagulation for VTE, INR

Description: The presence of antiphospholipid antibodies (APLA), which include lupus anticoagulant (LA) and anticardiolipin antibodies (ACA), increases the risk of venous thromboembolism (VTE). Although, the association demonstrated between LA and VTE is strong, that between ACA and VTE is weak with the exception of high titers. This suggestion has been that this may be related to the induction of ACA by acute illness. This may be the explanation for the widely varying frequency of ACA positivity in patients with acute VTE in the current medical literature. The prevalence of LA in patients with acute VTE is more consistent but the value of testing for ACA and LA at presentation of acute VTE remains unknown. We routinely test all idiopathic VTE patients at presentation for LA and ACA. It had been our impression that most positive results revert to normal with subsequent testing. We sough to test this hypothesis. The objective was to determine the prevalence of abnormal LA and ACA results and the frequency of subsequent normalization in patients presenting with a first idiopathic venous thromboembolic event. A retrospective chart review was conducted at the Thrombosis Unit at the Ottawa Hospital. 278 charts of unrelated, consecutive patients with idiopathic VTE were reviewed. 232 patients with single idiopathic venous thromboembolic events with documented LA and ACA results were included. The patients were divided into two groups based on the time between the acute VTE and initial APLA test. The frequency of abnormal LA and ACA on initial and repeat tests was determined in each group. 170 and 177 patients were screened for LA and ACA within one month of the acute VTE. On initial tests, LA and ACA were detected in 14.1% and 7.9% of patients, respectively. However, LA and ACA were present in only 1.2% and 1.7% of patients, respectively, on subsequent tests. In patients screened more than one month after an acute VTE 3.8% of the 52 patients had evidence of LA on initial testing and all were positive on repeat tests. ACA were present in 8% of patients on initial tests and in 6% (75% of the initial positive results) of patients on subsequent tests. A high frequency of positive LA and ACA tests results is observed when these tests are performed at the time of presentation of acute VTE. Repeat testing beyond one month from presentation demonstrates most of the results return to normal suggesting false positive results are common at presentation. However, when the tests are performed one month or longer after the acute VTE, the frequency of positive APLA test is much lower and false positives are uncommon. Screening for APLA should not be performed until at least one month after the diagnosis of idiopathic.

Description: Background: The diagnosis of DVT can be made by determining pretest probability of disease and using this information in combination with DD testing and ultrasound imaging. A number of studies have evaluated the use of clinical probability but this literature has not been summarized. Purpose: To systematically review trials that evaluated DVT prevalence using clinical prediction rules either with or without DD for the diagnosis of DVT. Data Sources: English and French language studies were identified from a MEDLINE search from 1990 to March 2004 and were supplemented by a review of all relevant bibliographies. Study Selection: Prospective management studies of symptomatic outpatients with suspected DVT in which patients were followed for a minimum of 3 months were selected. Clinical prediction rules had to be employed prior to DD and diagnostic tests. Studies were excluded if patients with a history of prior DVT were enrolled or if insufficient information was presented to calculate the prevalence of DVT for each of the 3 clinical probability estimates (low, moderate and high risk). Data Extraction: Two reviewers assessed each study for inclusion/exclusion criteria and collected data on prevalence and on sensitivity, specificity and likelihood ratios of DD in each of the 3 clinical probability estimates (low, moderate and high risk). Data Synthesis: 14 management studies involving a clinical prediction model in the diagnosis of DVT in over 8000 patients were included, of which 11 utilized DD in the diagnostic algorithm. All studies employed the same clinical prediction rule. The inverse variance weighted average prevalence of DVT in the low, moderate and high probability subgroups were 4.9% (95% CI= 4.2% to 5.7%), 17.4% (95% CI= 16.2% to 18.8%), and 53.6% (95% CI= 51.1% to 56.2%), respectively. The overall weighted prevalence was 18.3% (95% CI= 17.4% to 19.2%). The sensitivity of DD for the diagnosis of DVT in the low, moderate and high probability subgroups were 90.4% (95% CI= 84.7% to 94.2%), 92.0 % (95% CI= 89.1% to 94.2%), 93.6% (95% CI= 91.2% to 94.3%); and the specificities were 69.9% (95% CI= 68.0% to 71.8%), 52.4% (95% CI= 49.8% to 55.0%), and 43.2% (95% CI= 38.8% to 47.6%), respectively. The Mantel-Haenszel pooled estimates for diagnostic odds ratios (DOR) were 17.4 (95%CI=10.4–29.1), 10.2 (95% CI=7.1–14.6), and 10.1 (95% CI=6.9–14.9) in low, moderate and high groups respectively. Conclusion: Accurate estimates of the prevalence of DVT can be achieved using the same clinical prediction rule. Using this rule, it is unlikely that low probability patients have a DVT probability of more than 5%. Specificity of the DD seems to have clinically relevant differences depending on pretest probability but the DORs (which incorporate sensitivity and specificity) are similar. The data suggest that DVT can be excluded if patients are low probability even when DDs of lower sensitivity are employed and that DD testing has lower utility in high probability patients since false positives are common.

Description: Introduction. Upper extremity deep vein thrombosis (UEDVT) is a relatively uncommon event with potentially serious complications. Its clinical outcomes are not well studied. The objective of this study was to assess the incidence of post-thrombotic syndrome (PTS) and functional disability in patients with UEDVT. Patients and methods. This was a pre-specified analysis of a prospective cohort study at 5 Canadian centres. We enrolled adult patients with a symptomatic UEDVT confirmed by compression ultrasound involving the brachial or more proximal veins, with or without a pulmonary embolism (PE). Exclusions included pregnancy, dialysis catheter thrombosis, active or high bleeding risk, platelet count

Description: Background: The American College of Chest Physicians (ACCP) guidelines for venous thromboembolism (VTE) disease recommend treatment with anticoagulation for at least 3 months in patients with VTE. Moreover, the EINSTEIN-extension study assessed the effect of rivaroxaban on the risk of VTE recurrences in patients who had completed 6 to 12 months of treatment for VTE. Results showed that rivaroxaban significantly reduced the risk of VTE recurrences with a small increased risk of major bleeding. The objective of this study was to assess the risk of VTE recurrences and major bleeding associated with extended rivaroxaban treatment in a real-world setting among all VTE patients (i.e., unprovoked, provoked, and cancer related). Methods: A retrospective study was conducted using Truven Health Analytics MarketScan Databases from 02/2011 to 04/2015. The study included adult patients who initiated rivaroxaban therapy within 7 days after their first VTE and continuously used rivaroxaban for at least 3 months. The end of the initial 3-month rivaroxaban treatment was defined as the index date and patients were categorized into discontinued (treatment ended) and continued cohorts. Patients were followed from index date until end of continuous treatment for the continued cohort or end of data or re-initiation of oral anticoagulant therapy for the discontinued cohort. The outcomes included VTE recurrences identified as a primary diagnosis documented during a hospitalization and major bleeding events identified by a validated algorithm (Cunningham et al., 2011). Kaplan-Meier rates for VTE recurrences and major bleeding events at 3, 6, 9, and 12 months after the index date were compared between cohorts with adjustment for baseline confounding using the inverse probability of treatment weights (IPTW) method based on propensity score. Patients with unprovoked VTEs, defined as not having recent surgery, cancer, pregnancy or estrogen therapy, were also evaluated. Sample sizes of patients with provoked VTEs and cancer were too small to analyze these populations. A sensitivity analysis was also conducted among VTE patients receiving rivaroxaban for at least 6 months. Results: Among the 3-month treatment population, a total of 5,933 (63.4% unprovoked VTE) and 1,536 (68.4% unprovoked VTE) rivaroxaban users formed the continued and discontinued cohorts, respectively. The mean (SD) observation period was 149.3 (124.4) days in the continued cohort and 211.1 (191.6) days in the discontinued cohort. The Kaplan-Meier analysis (Figure 1) showed that patients in the continued cohort had significantly lower rates of VTE recurrences after an additional 3 months (0.70% vs. 1.70%), 6 months (1.41% vs. 2.34%), 9 months (1.82% vs. 3.01%), and 12 months (1.97% vs. 3.01%; all p-values 〈 0.05) of treatment. No statistically significant differences in the cumulative event rates for major bleeding (Figure 2) were observed between the continued and the discontinued cohort at 3 months (0.58% vs. 0.82%), 6 months (0.91% vs. 0.88%), 9 months (1.33% vs. 1.18%), and 12 months (1.44% vs. 1.44%; all p-values 〉 0.05). Among the 6-month treatment population, a total of 2,676 (65.9% unprovoked VTE) and 1,127 (70.4% unprovoked VTE) rivaroxaban users formed the continued and discontinued cohorts, respectively. The mean (SD) observation period was 158.5 (130.6) days in the continued cohort and 206.5 (171.5) days in the discontinued cohort. Patients in the continued cohort had lower rates of VTE recurrences after an additional 3 months (0.82% vs. 1.41%), 6 months (1.22% vs. 2.69%), 9 months (1.35% vs. 3.02%), and 12 months (1.72% vs. 3.70%; except at 3 months all p-values 〈 0.05) of treatment. No differences in the cumulative event rates for major bleeding were observed between the continued and the discontinued cohorts. Similar results were found among patients with unprovoked VTE for the 3- and 6-month analyses. The interaction term between the cohort variable (Continued vs. Discontinued) and the type of VTE (unprovoked vs. other types of VTE) was non-significant in both populations (p-value 〉 0.05), which suggests that the benefit of extended treatment do not depend on the type of VTE events. Conclusions: Our study results suggest that all patients with VTE who continued rivaroxaban therapy after the first 3-month and 6-month treatment periods had significantly lower risk of VTE recurrences without an increased risk of major bleeding. Disclosures Khorana: Halozyme: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Leo: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Janssen Scientific Affairs, LLC: Consultancy, Honoraria, Research Funding. Berger:AZ: Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees. Wells:BMS/Pfizer: Research Funding; Itreas: Other: Served on a Writing Committee; Janssen Pharmaceuticals: Consultancy; Bayer Healthcare: Other: Speaker Fees and Advisory Board. Seheult:Janssen Scientific Affairs, LLC: Consultancy. Ashton:Janssen Scientific Affairs, LLC, Raritan, New Jersey: Employment. Laliberté:Janssen Scientific Affairs: Research Funding. Crivera:Janssen Scientific Affairs, LLC, Raritan, New Jersey: Employment, Equity Ownership. Lejeune:Janssen Scientific Affairs: Research Funding. Schein:Johnson & Johnson: Employment, Equity Ownership, Other: Own in excess of $10,000 of J&J stock. Wildgoose:Janssen Scientific Affairs, LLC, Raritan, New Jersey: Employment, Equity Ownership. Lefebvre:Janssen Scientific Affairs: Research Funding. Kaatz:Bristol Myer Squibb: Honoraria; Pfizer: Honoraria; CSL Behring: Honoraria; Boehringer Ingelheim: Consultancy; Pfizer: Consultancy; Janssen: Consultancy; Daiichi Sankyo: Consultancy; Bristol-Myers Squibb: Consultancy; Boehringer Ingelheim: Honoraria; Janssen: Honoraria.

Description: Background: Many hospitalized patients with PE die. A large registry study described a mortality rate of 17.4% in patients with PE and suggested 45% of these deaths were due to the PE. Data on death and PE is usually derived retrospectively from hospital databases without chart confirmation and to our knowledge no study has attempted to determine the accuracy of coding for PE deaths. Furthermore, it is unclear how often deaths caused by PE could have been prevented. Methods: A retrospective chart review of PE cases hospitalized at a tertiary care center. Charts over an 8 year period ending in 2004 were reviewed if the hospital database record identified PE as a diagnosis by the ICD-10 coding system. Charts of those who died were independently reviewed by two thrombosis experts with discrepancies resolved by consensus or a third reviewer. Prior to chart review definitions were agreed upon. The coding as PE was considered correct (confirmed PE) if there was supportive imaging, an autopsy, or in the case of death without imaging or autopsy, the clinical scenario was such that PE could have occurred. The degree of certainty that PE contributed to the death was classified as certain (unexplained hypotension, hypoxia, cardiac arrest with no other explanation other than PE and autopsy confirmation or radiographic confirmation), highly probable (same as certain but no autopsy confirmation), probable (criteria for highly probable but another disease could have caused the death). We considered these cases to be death due to PE. Deaths were also classified as possible (other cause suspected based on clinical evidence but 100% certainty not available), or unlikely due to PE (all other cases). In cases defined as death due to PE we determined whether any further intervention could have prevented death. Results: 612 cases were identified of whom 68 had radiographic or autopsy data that ruled out the diagnosis and in 46 the coding was clearly an error. 498 cases of PE were identified, 111 of whom died during hospitalization; the mortality rate in those the hospital coded as PE was 18% vs 22% of those with confirmed PE. Death due to PE was diagnosed in 70 patients (14% of patients with confirmed PE and 11% of all patients coded as PE). In the remaining 41 deaths, PE was possible in 24 and unlikely in 17. Disagreement was uncommon. There was no difference between the likelihood of death from PE in the group diagnosed by imaging and autopsy compared with the group where PE death was confirmed by an appropriate clinical scenario. 38 deaths due to PE may have been prevented with an additional intervention: prophylaxis (55%), earlier diagnosis (45%), inferior vena cava filter (IVCF) (32%), anticoagulation (18%), embolectomy 5%, thrombolytics (3%). The remaining deaths due to PE were not preventable since 15 patients were palliative and did not receive active treatment, 9 died before a diagnosis was made and in 8 another disease prevented treatment. Conclusions: Using hospital database records is a reasonable means to evaluate PE mortality and our death due to PE rates are similar to those in registry publications. Surprisingly imaging and autopsy results do not increase the probability of reaching the conclusion that death is due to PE. Over half of preventable PE deaths may have been prevented by prophylaxis and one third with an IVCF.

Description: Rivaroxaban is an ideal potential alternative for treatment of heparin-induced thrombocytopenia because it is administered orally by fixed dosing, requires no routine coagulation monitoring and has been proven effective in the treatment of venous and arterial thromboembolism in other settings. The Rivaroxaban for HIT Study prospectively evaluated the efficacy and safety of patients with suspected or confirmed HIT who were treated with rivaroxaban [NCT01598168 - investigator sponsored study funded by Bayer] Methods: Canadian multicenter, single-arm, prospective cohort study of patients with confirmed or suspected HIT (4Ts score ≥4) treated with rivaroxaban 15 mg bid until the diagnosis was supported or refuted using the local HIT assay. Participants with HIT (positive local assay result) received rivaroxaban 15 mg bid until platelet recovery (or until Day 21 if the patient had acute thrombosis; HITT) then stepped down to rivaroxaban 20 mg daily until Day 30. Central testing with the serotonin-release assay (SRA) was performed (not in real-time at all centres). HIT positive was defined as a 4Ts score ≥4 plus serotonin release ≥50%. The primary outcome measure was the incidence of new symptomatic, objectively-confirmed venous and arterial thromboembolism in the combined cohort of patients with suspected and confirmed HIT at 30 days. Secondary objectives included incidence of symptomatic thromboembolism while on treatment with rivaroxaban (combined cohort) and the following outcomes among SRA-positive participants while on treatment with rivaroxaban: incidence of venous and arterial thromboembolism, incidence of major bleeding, and time to platelet recovery. Sample size of 200 participants (10 to 30 with SRA-confirmed HIT) was based on feasibility and an anticipated thrombotic event rate in the study population (combined cohort) of 6.5% at 30 days (5% in HIT negative; 11% in HIT positive while on rivaroxaban). Results: 22 participants (12 HIT positive) were enrolled between January 2013 and July 2015. The study was terminated early due to poor recruitment, but after enrolling the minimum expected number of HIT positive participants. Of the 12 HIT positive participants (SRA, mean release 95%), 3(25%) had HITT at time of study entry and 6 had received at least one dose of fondaparinux prior to study enrolment. Half of the HIT positive participants were enrolled in study after the SRA result had already been reported as positive. After 371 days of exposure to rivaroxaban (combined cohort), 1 HIT positive participant had possible symptomatic recurrent VTE (4.5%, 95% CI: 0 to 23.5%), 1 HIT positive participant had major bleeding (9 days after rivaroxaban was held) and there were 4 deaths (cancer 2, sepsis 1, end-stage COPD 1). The single episode of possible recurrent VTE was extension of previously documented apheresis catheter-related arm DVT in a HIT positive participant who presented on Day 7 with worsening arm pain. A repeat ultrasound showed extension of DVT; however a baseline scan had not been performed at time of study entry. Interestingly, the same participant failed treatment with fondaparinux prior to study enrolment (development of erythematous plaques at injection sites and failure of platelets to rise). His apheresis catheter was removed on Day 8, rivaroxaban was continued and complete resolution of his symptoms as well as platelet recovery was achieved. One HIT positive participant presented with evidence of bilateral lower limb arterial ischemia (HIT-related acute arterial thrombosis on documented chronic peripheral vascular disease) at the time of study enrolment. Despite achieving platelet recovery, he underwent bilateral below knee amputation on Day 16. Out of the 12 HIT positive participants, 11 achieved platelet recovery with mean time to recovery 9 days. The single participant who did not achieve platelet recovery received only 2 doses of rivaroxaban before it was held due to a transient rise in liver enzymes. Rivaroxaban was never restarted because he bled while receiving fondaparinux as an alternative. Conclusions: Rivaroxaban appears to be effective for treating patients with confirmed HIT, although lack of a comparator and a small sample size are limitations of our findings. The advantages of rivaroxaban over other agents currently used to treat HIT such as ease of administration, lack of routine coagulation monitoring and low cost make it an attractive option. Disclosures Linkins: Pfizer: Honoraria; Bayer: Honoraria, Research Funding. Off Label Use: rivaroxaban has not been approved for treatment of heparin-induced thrombocytopenia. Warkentin:W.L. Gore: Consultancy, Research Funding; Instrumentation Laboratory: Consultancy, Honoraria; Pfizer: Consultancy. Pai:Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS-Pfizer: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees. Shivakumar:Bayer: Honoraria. Wells:Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS-Pfizer: Research Funding. Wu:Pfizer Canada: Membership on an entity's Board of Directors or advisory committees; Leopharma: Membership on an entity's Board of Directors or advisory committees.

Description: Ventilation-perfusion (VQ) lung scanning and computerized tomographic pulmonary angiography (CTPA) have been validated as imaging procedures for the evaluation of patients with suspected pulmonary embolism and are used widely. To compare the safety and utility of VQ scanning and CTPA we performed a multi-centre randomized controlled trial in patients presenting with clinically suspected acute pulmonary embolism. All patients were evaluated using an explicit clinical model to determine pretest probability (Wells score) and with D-dimer. Patients considered at low likelihood of pulmonary embolism (score 〈 4.5 and negative D-dimer) did not undergo further testing and were followed as a separate cohort. The remaining patients were randomized to undergo either VQ scanning or CTPA. Patients diagnosed with pulmonary embolism on the basis of a high probability VQ scan or a positive CTPA were treated. Other patients underwent bilateral venous ultrasound imaging of the proximal veins of lower extremities and those confirmed to have DVT were treated. Physicians were able to refer patients for traditional pulmonary angiography or serial ultrasonography after initial testing but switching of patients to have the alternative pulmonary imaging procedure was not permitted by the protocol. Patients in whom pulmonary embolism was considered excluded did not receive antithrombotic therapy and were followed for a three month period. The primary outcome was the development of symptomatic pulmonary embolism or proximal deep vein thrombosis in the follow-up period in patients in whom the diagnosis of pulmonary embolism had initially been excluded. 1577 patients were enrolled in the study of whom 172 entered the low risk cohort. 1405 patients were randomized, 694 to CTPA and 711 to VQ scanning. 19.2% (133) of patients in the CTPA versus 14.2% (101) were diagnosed with pulmonary embolism in the initial evaluation period (difference 5.0%, 95% CI 1.1% to 8.9%). Of those in whom pulmonary embolism was considered excluded 0.4% (2/561) patients undergoing CTPA versus 1.0% (6/610) patients undergoing VQ scanning developed venous thromboembolism in follow-up (difference −0.6%, 95% CI −1.6% to 0.3%) including one with fatal pulmonary embolism in the VQ group. All cause mortality was higher in the three month follow-up for patients undergoing VQ scanning (30/610, 4.9%) than for CTPA (17/694, 2.4%) in whom pulmonary embolism was considered excluded. Most of these deaths were from cancer. Management practices using bilateral ultrasonography with either VQ scanning or CTPA to exclude the diagnosis of pulmonary embolism resulted in low rates of venous thromboembolic complications. More patients were diagnosed intitally with pulmonary embolism using the CTPA approach and fewer patients died in this cohort in the three month follow-up period.