June 2023: New In Coagulation
by Donna Castellone, MS, MT(ASCP)S • June 08, 2023
Our Monthly complilation of the latest studies, guidelines and discussions in coagulation.
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Postpartum Hemorrhage Risks Averted With Monitoring, Bundled Treatment
The E-MOTIVE trial showed that early detection of hemorrhage post childbirth and implementing all treatment strategies at once reduced severe maternal outcomes. In 200,000 vaginal deliveries, intervention decreased the composite risk 1000mL or more of blood loss, laparotomy for bleeding or maternal death from bleeding by 60% when compared with usual care. Additionally secondary bleeding endpoints and transfusions also dropped with randomization to use of a calibrated drape to catch blood for better assessment of volume lost and concurrent use of WHO recommended interventions such as uterine massage, oxytocic drugs, tranexamic acid, IV fluids, and a process for examination and escalation to advanced treatment. Blood loss is usually visually estimated resulting in an underestimation of loss resulting in delaying treatment. Interventions that respond to postpartum bleeding in a timely manner could greatly improve women’s chances of surviving childbirth globally.
The study included 80 hospitals in Kenya, Nigeria, South Africa and Tanzania from August-October 2021 looking at usual care versus trial intervention for 7 months after a 7 month baseline period of usual care for postpartum hemorrhage. Eligible hospitals had a case volume of 1000-5000 vaginal births annually with a capacity for OB care including surgery for post-partum hemorrhage. This was defined as at least 500mL of blood loss when compared with the usual group.
Control hospitals estimated blood loss visually with drapes that could be used to measure bleeding for study purposes. Their interventions for postpartum hemorrhage followed local or national guidelines. The difference in use of the treatment bundle showed the expected gap between the intervention group and usual care patients (91.2% vs 19.4%). Postpartum blood transfusions occurred in 1.2% and 1.9% in each of the groups. E-MOTIVE used the treatment bundle at a blood loss of 300mL or more with accompanying abnormality in vital signs or clinical observations.
Despite the trial being underpowered (17 cases compared to 28 cases in the usual care group) results trended in favor of the intervention. Limitations also included some date including postnatal hemoglobin and anemia. Also, the trial was conducted in low and middle income countries and research in needed in high income settings.
Pulmonary Clot Thrombectomy Has Lasting Benefits
The PEERLESS trial compares the FlowTriever System against catheter-directed thrombolysis. The trial included 800 subjects at 50 US sites with 599 completing the study at 6 months. Of the participants 8% had high-risk PE and 77% had intermediate-risk PE with 65% having concomitant DVT. The most serious adverse event to 6 months were recurrent VTE and bleeding from anticoagulation, however no events appeared to be related to the procedure.
The FLASH registry revealed that the benefits of mechanical thrombectomy in for acute intermediate- to high-risk pulmonary embolism (PE) persisted to 6 months. This was demonstrated by the improvement of Medical Research Council dyspnea scores. The proportion of patients with a score of 0, indicating no shortness of breath except with vigorous exercise, rose from 12% at baseline to 41.6% at 48 hours after thrombectomy, 59.3% at 30 days and 70.3% at 6 months. Results reinforce long term benefits as well as quality of life.
With Preliminary Win for DOAC, Sights Set on Supplanting DAPT After LAA Closure
ADALA randomized patients to either low dose DOAC or standard DAPT for 3 months 4 hours after successful LAA occlusion. Initial enrollment was to be 160 patients, however the study was stopped after 90 participants (mean age 76.6, men were two-thirds) due to an interim analysis led to abbreviated enrollment that stopped at 90 people with 46 assigned to the DOAC and 44 to DAPT. It was found that low-dose apixaban was better when compared to DAPT in balancing thrombotic and bleeding events. The DOAC performed better in the 3 month primary endpoint of thrombotic events and device related thrombosis. Also supporting the investigators' decision to halt enrollment was that the low-dose DOAC did not significantly triumph over DAPT for major bleeding at 3 months), though the totality of bleeds, major and minor, pointed to a significant safety advantage with apixaban.
The LAA occlusion devices included the Amulet (67.8%), Watchman (23.3%) and the LAmbre (8.9%).
Future trials are needed, but the findings may support guidelines giving a class 1 recommendation to low-dose DOACs and a class III recommendation to DAPT after LAA occlusion. These results may be confirmed in the ANDES trial of 400 patients who are on different drugs and different doses.
Antibodies associated with rare disorder may signal future risk of heart attack and stroke
A study from UTSW has indicated that laboratory tests may be able to predict cardiovascular disease. Healthy people who had antibodies associated with antiphospholipid syndrome (APS) were more likely to experience a cardiovascular event including a heart attack or stroke when compared with patients who did not present with the antibodies. This may be a new way to predict cardiovascular disease risk.
The Dallas Heart study looked at cardiovascular disease risk from thousands of subjects. From that cohort, blood was tested on participants from 2007 and 2009 to look for the presence and amount of 8 different APA. This was compared to a questionnaire during a follow-up period that averaged eight years to see which participants experienced a heart attack, stroke, coronary bypass surgery, or death from cardiovascular disease.
Antibodies were detected in 14.5% of 2427 participants of those a third had moderate or high antibody levels, of those 125 individuals experienced cardiovascular events. The presence of two particular antibodies aCL IgA and ab2GPI IgA was associated with a future cardiovascular event. In participants with relatively higher levels of these two antibodies, this connection was even stronger. These antibodies may impair the ability of good cholesterol to absorb lipids in the blood and send them to the liver for disposal as well as encouraging the formation of atherosclerotic plaque for the heart and brain.
DOACs Safe to Start Soon After Acute Ischemic Stroke
Improved outcomes were seen in the ELAN trial in patients with AF placed on DOAC’s earlier post ischemic stroke. Those who received a DOAC within 48 hours for mild or moderate stroke or 6-7 days post major stroke had a 2.9% rate of recurrent ischemic stroke, systemic embolism, major extracranial bleeding, symptomatic intracranial hemorrhage, or vascular death witin 30 days. This was different than the 4.1% rate seen when anticoagulation was initiated later.
Included were 2013 acute ischemic stroke patients with a median age of 77, 55% male patients. The study was conducted at 103 sites in 15 countries using open label treatment with a DOAC within the 2 time frames. There were 37% who had minor strokes, 40% had a moderate stroke and 23% had a major stroke. Rating was based on a standardized visual rating scheme for MRI or CAT prior to randomization. Median National Institutes of Health Stroke Scale (NIHSS) score was 5 at admission and 3 at randomization.
Limitations of the study included the exclusion of patients already receiving therapeutic anticoagulation at baseline as well as the low NIHSS score. The study lacked demographic data despite the trial being conducted in Europe, the Middle East and Asia, the majority of data came from white European areas.
JOURNAL CLUB
Anticoagulation Regimens in Pregnancy
Antonio Saad, Melody Safarzadeh, Megan Shepherd
Obstet Gynecol Clin North Am, 2023 Mar;50(1):241-249.
Abstract
This article explores current recommendations for anticoagulation therapy in pregnancy, including antepartum, intrapartum, and postpartum guidelines. The authors review various screening strategies used to assess whether a patient is an appropriate candidate for anticoagulation during pregnancy and the postpartum period. The article includes dosing regimens, optimal surveillance, and medication reversal. The authors also address the challenges of transitioning between low-molecular-weight heparin and unfractionated heparin. Finally, there is a discussion of intrapartum anticoagulation management, especially as it relates to the administration of regional anesthesia, and the indications for and timing of thromboprophylaxis following delivery.
Final Study Report of Andexanet Alfa for Major Bleeding With Factor Xa Inhibitors
Truman J Milling Jr, Saskia Middeldorp, Lizhen Xu, Bruce Koch, Andrew Demchuk, John W Eikelboom, Peter Verhamme, Alexander T Cohen, Jan Beyer-Westendorf, C Michael Gibson, Jose Lopez-Sendon, Mark Crowther, Ashkan Shoamanesh, Michiel Coppens, Jeannot Schmidt, Pierre Albaladejo, Stuart J Connolly; ANNEXA-4 Investigators
Circulation 2023 Mar 28;147(13):1026-1038.
Abstract
Background: Andexanet alfa is a modified recombinant inactive factor Xa (FXa) designed to reverse FXa inhibitors. ANNEXA-4 (Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of Factor Xa Inhibitors) was a multicenter, prospective, phase-3b/4, single-group cohort study that evaluated andexanet alfa in patients with acute major bleeding. The results of the final analyses are presented.
Methods: Patients with acute major bleeding within 18 hours of FXa inhibitor administration were enrolled. Co-primary end points were anti-FXa activity change from baseline during andexanet alfa treatment and excellent or good hemostatic efficacy, defined by a scale used in previous reversal studies, at 12 hours. The efficacy population included patients with baseline anti-FXa activity levels above predefined thresholds (≥75 ng/mL for apixaban and rivaroxaban, ≥40 ng/mL for edoxaban, and ≥0.25 IU/mL for enoxaparin; reported in the same units used for calibrators) who were adjudicated as meeting major bleeding criteria (modified International Society on Thrombosis and Haemostasis definition). The safety population included all patients. Major bleeding criteria, hemostatic efficacy, thrombotic events (stratified by occurring before or after restart of either prophylactic [ie, a lower dose, for prevention rather than treatment] or full-dose oral anticoagulation), and deaths were assessed by an independent adjudication committee. Median endogenous thrombin potential at baseline and across the follow-up period was a secondary outcome.
Results: There were 479 patients enrolled (mean age, 78 years; 54% male; 86% White); 81% were anticoagulated for atrial fibrillation, and the median time was 11.4 hours since last dose, with 245 (51%) on apixaban, 176 (37%) on rivaroxaban, 36 (8%) on edoxaban, and 22 (5%) on enoxaparin. Bleeding was predominantly intracranial (n=331 [69%]) or gastrointestinal (n=109 [23%]). In evaluable apixaban patients (n=172), median anti-FXa activity decreased from 146.9 ng/mL to 10.0 ng/mL (reduction, 93% [95% CI, 94-93]); in rivaroxaban patients (n=132), it decreased from 214.6 ng/mL to 10.8 ng/mL (94% [95% CI, 95-93]); in edoxaban patients (n=28), it decreased from 121.1 ng/mL to 24.4 ng/mL (71% [95% CI, 82-65); and in enoxaparin patients (n=17), it decreased from 0.48 IU/mL to 0.11 IU/mL (75% [95% CI, 79-
67]). Excellent or good hemostasis occurred in 274 of 342 evaluable patients (80% [95% CI, 75-84]). In the safety population, thrombotic events occurred in 50 (10%) patients; in 16 patients, these occurred during treatment with prophylactic anticoagulation that began after the bleeding event. No thrombotic episodes occurred after oral anticoagulation restart. Specific to certain populations, reduction of anti-FXa activity from baseline to nadir significantly predicted hemostatic efficacy in patients with intracranial hemorrhage (area under the receiver operating characteristic curve, 0.62 [95% CI, 0.54-0.70]) and correlated with lower mortality in patients <75 years of age (adjusted
Conclusions: In patients with major bleeding associated with the use of FXa inhibitors, treatment with andexanet alfa reduced anti-FXa activity and was associated with good or excellent hemostatic efficacy in 80% of patients.
Direct Oral Anticoagulants in Obese Patients with Venous Thromboembolism: Results of an Expert Consensus Panel
Rachel P Rosovsky, Eva Kline-Rogers, Leslie Lake, Tracy Minichiello, Gregory Piazza, Bishoy Ragheb, Beth Waldron, Daniel M Witt, Stephan Moll
Am J Med, 2023 Feb 16;S0002-9343(23)00055-4.
Abstract
In clinical practice, direct oral anticoagulants (DOACs) are increasingly used for venous thromboembolism treatment and prevention. A substantial proportion of patients with venous thromboembolism are also obese. International guidance published in 2016 stated that DOACs could be used in standard doses in patients with obesity up to a body mass index (BMI) of 40 kg/m2, but should not be used in those with severe obesity (BMI >40 kg/m2) owing to limited supporting data at the time. Although updated guidance in 2021 removed this limitation, some health care providers still avoid DOACs even in patients with lower levels of obesity. Furthermore, there are still evidence gaps regarding treatment of severe obesity, the role of peak and trough DOAC levels in these patients, use of DOACs after bariatric surgery, and appropriateness of DOAC dose reduction in the setting of secondary venous thromboembolism prevention. This document describes proceedings and outcomes of a multidisciplinary panel convened to review these and other key issues regarding DOAC use for treatment or prevention of venous thromboembolism in individuals with obesity.
The Impact of Clinical Pharmacy Services on Direct Oral Anticoagulant Medication Selection and Dosing in the Ambulatory Care Setting
Naomi Y Yates, Stephanie A Hale, Nathan P Clark
J Pharm Pract, 2023 Mar 29;8971900231166555.
Abstract
Background: Off-label dosing of direct oral anticoagulants (DOACs) is both common and associated with adverse patient outcomes. Evidence describing best practices to support optimal direct oral anticoagulant (DOAC) dosing is limited.
Objective: To describe the impact of clinical pharmacist intervention on DOAC prescribing.
Methods: This retrospective study was a descriptive analysis conducted within an integrated healthcare system with a centralized, pharmacist-led Anticoagulation Management Service (AMS). Patients prescribed a DOAC between January 1, 2020 and December 31, 2020 were included. Pharmacy dispensing reports were generated for pharmacist review and anticoagulant drug therapy changes were recommended to physicians where appropriate. The primary objective was to describe the number and type of recommendations made. Secondary objectives were to determine the provider acceptance rate based on the intervention type and on clinical vs formulary recommendations.
Results: Clinical pharmacists made 147 recommendations for 2331 unique patients included in the analysis. Twenty-three recommendations (16%) were to decrease the dose, 46 (31%) were to increase the dose, 14 (10%) were to change the medication due to clinical scenario, 62 (42%) were to change the medication due to cost, and 2 (1%) were another issue. One hundred twenty-three (84%) recommendations were accepted. The provider acceptance rate was similar for clinical and formulary recommendations (85% and 82% respectively).
Conclusion: Implementation of report-driven clinical pharmacist intervention led to an improvement in appropriate DOAC medication selection and dosing.