May 2025: New In Coagulation
by Donna Castellone • May 19, 2025
Our Monthly complilation of the latest studies, guidelines and discussions in coagulation.
Please Note: many linked teasers require account/subscription in order to view full articles.
Medscape registration is free of charge.
Clot-Busting Ultrasound Gives Carotid Endarterectomy a Step Up
Clinical benefits were seen in patients averaging 80% internal carotid artery stenosis by using a steady ultrasound beam during carotid endarterectomy as seen by the SONOBIRDIE phase III trial. Reductions occurred in 30 days for combined ischemic stroke, TIA, death, as well as ischemic stroke and TIA alone. There were no significant between group differences in mortality, however few ischemic lesions were seen. Results suggest that sonolysis can be used to reduce the risk of periprocedural cerebrovascular events during carotid endarterectomy and could be a safer and higher benefit for patients in particular patients with asymptomatic carotid stenosis. Sonolylsis uses a continuous application of low intensity pulsed wave ultrasound beam using a standard ultrasound machine and transcranial Doppler probe. The exact mechanism it works is unknown, but it is thought to reduce thrombotic risk by activating the fibrinolytic enzymes in tandem with directly breaking existing clots using mechanics. The trial was stopped early for effectiveness. There were no intracranial bleeds and up to 95% of participants were free from adverse events 30 days post procedure, however there was one case on ICH versus none in the control group.
Think Twice Before Quitting Oral Anticoagulants After Afib Ablation?
Stopping OAC in patients with AF post successful catheter ablation left them at an increased risk. Using a Japanese data set, clinical outcomes differed between ablation who discontinued OAC after 1 year versus those who remained on therapy. This was a retrospective study (n=1821, 63.6 average age, 73.5% male) who did not have recurrent AF or adverse events 12 months post first catheter ablation. Half had stopped OAC based on physician recommendations. Groups differed in that OAC discontinuation group having a higher prevalence of paroxysmal and symptomatic Afib and lower CHA2DS2-VASc and HAS-BLED scores. More thromboembolic events occurred in patients who discontinued therapy, however there were fewer bleeding events. Those at the highest risk were patients with asymptomatic AF with left ventricular ejection less than 60%, but more favorable for reduction in bleeding (HAS-BLEED score >/= 2). Discontinuing OAC may be safe in those with a low risk profile.
Patients who were included in the study had a successful first time AF ablation and did not present with recurrent AF 1 year post. Excluded patients were those who had any thromboembolic events or major bleeding during that year. From 1 year out to a mean of 4.8 years, thromboembolic events, major bleeding events, and death occurred in 2.4%, 2.3%, and 3.9% of patients, respectively.
Ablation may not cure AF. This may be due to AF triggers exist throughout the atria, and it is a progressive condition that can be stalled but not stopped despite aggressive interventions. It is not certain that a single ablation will prevent recurrent AF.
Managing long term risk in high risk ( elevated CHA2DS2-VASc scores) may not be advisable to stop OAC.
Fitusiran Approved for Hemophilia A and B
Fitusiran (Qfitlia) has been FDA approved as prophylaxis to prevent or reduce bleeding in both adults and children (12 years and over) with hemophilia A or B wwith or without FVIII or IX inhibitors. This can be administered less frequently than other existing options. This is a subcutaneous prophylactic RNA therapy that targets AT to restore thrombin generation and rebalance hemostasis in hemophilia patients. It was approved based on the results from two randomized trials which enrolled 177 adult and pediatric male patients that had previously been treated with on demand treatment of bypassing agents or factor concentrates. ATLAS-INH looked at patients with inhibitors and ATLAS-A/B looked at patients without inhibitors. Patients received either their usual on demand treatment or a fixed dose of fitusiran monthly for 9 months.
Participants subsequently entered a long-term extension study in which they received an adjustable dose of fitusiran based on periodic measurements of antithrombin activity. This antithrombin-based dosing regimen is the approved regimen, while the fixed dose of fitusiran was not approved because it led to excessive clotting in some patients.
There was a 73% reduction rate in the estimated annualized bleeding rate (ABR) in those who had inhibitors versus those who received on demand treatment. In non- inhibitor patients who were on fitusiran there was a 71% reduction in ABR versus on demand treatment with factor concentrates.
Boxed warnings for thrombotic events, gallbladder disease as well as liver toxicity required monitoring of liver enzymes are placed on fitusiran.
Lower-Dose Extended Anticoagulation Just as Effective for VTE With Active Cancer
The API-CAT (Apixaban Cancer Associated Thrombosis) trial included (n= 1,766, median age 69, 43% male) consecutive patients in 11 countries who had active cancer and proximal DVT or PE who had completed at least 6 months of anticoagulant therapy without documented symptomatic recurrence. They were randomized to double-blind treatment with oral apixaban at a reduced (2.5 mg) or full (5.0 mg) dose twice daily for 12 months. The API-CAT randomized trial demonstrated that after VTE in patients with active cancer a lower dose of apixaban was as effective and safer as a higher dose. After 12 months of treatment the 2.5 mg twice daily met noninferiority criteria compared with 5.0mg twice daily for recurrent VTE ( 2.1 vs 2.8%) which was statistically significant. It also reducereduces clinically relevant bleeding ( 12.1 vs 15.6%) supporting utilization of the lower dose.
Guidelines suggest that after cancer related VTE anticoagulation continues as long as the cancer is active or patient is undergoing treatment. It is important to balance the patients bleeding risk.
There have been many advances in oncology and as a result patients are living longer with metastatic disease and continuing to receive anticancer therapies resulting in an increase in VTE. This trial establishes reduced dose apixaban for anticoagulation after the first 6 months. Prior trials (EINSTEIN – rivaroxaban and AMPLIFY-EXT- apixaban) extended anticoagulation to 12 months demonstrated better efficacy in preventing VTE however there were few active cancer cases. However, the DOAC arms had similar rates of major and clinically relevant non major bleeding, whereas this trial showed a decrease in bleeding with the lower dose.
Clopidogrel Bests Aspirin for Long-Term Monotherapy After PCI
Clopidogrel reduced a composite of death from any cause, myocardial infarction (MI), or stroke events by an absolute 2.2 percentage points, to 4.4% compared with 6.6% on aspirin during a median of 2.3 years of follow-up (HR 0.71, 95% CI 0.54-0.93,
After initial dual antiplatelet therapy (DAPT). The HOST-EXAM trial had previously shown that clopidogrel beat aspirin for net clinical impact, pooling all-cause mortality, MI, stroke, readmission due to acute coronary syndrome, and major bleeding.
The new data suggest that "once you've completed that 12 months or prespecified duration of dual antiplatelet therapy and you de-escalate to antiplatelet monotherapy, that clopidogrel is a very reasonable and favorable choice in this population that was studied," said ACC press conference study discussant Akshay Khandelwal, MD, of Allegheny Health Network in Pittsburgh.
Bleeding events (Bleeding Academic Research Consortium type 2, 3, or 5) occurred in an identical 3.0% of patients in both groups (HR 0.97, 95% CI 0.67-1.42).
However, the patient population studied had some specific characteristics that might have contributed to that finding.
Underrepresentation of high-bleeding risk (HBR) patients "probably contributed to lower rates of bleeding complication," seen in the study, Hahn said at the late-breaking trial session. "However, in real-world practice, patients with high bleeding risk are likely to receive abbreviated antibody therapy rather than standard DAPT and therefore did not meet our inclusion criteria at the completion of a standard DAPT. That's why the proportion of HBR was low in our study and the proportion of women is also low."
Also, there was low racial and ethnic diversity in the Korean population studied, noted session study discussant Anthony Fletcher, MD, of CHI St. Vincent Cardiology and Medicine Clinic in Little Rock, Arkansas.
"As we move forward with long term management of this complex group of patients, ... that gives us some challenges in terms of extrapolating that to the diverse population that we see in the United States," he said.
On the other hand, "the Korean population tends to have a higher rate of clopidogrel non-responders. So the postulation which I would support at least the question of, is that perhaps in other populations where there's less of that concern, actually the benefit perhaps might even be greater," said Khandelwal.
Hahn noted that an exploratory analysis by
Given generic availability of both clopidogrel and aspirin, the cost differential is pretty minimal, Khandelwal noted. But because aspirin can actually increase gastrointestinal bleeding, he predicted that economic analysis would favor clopidogrel long term.
Roxana Mehran, MD, of Icahn School of Medicine at Mount Sinai in New York City and ACC press conference moderator, suggested that the findings challenge the guidelines by suggesting a preferred drug for long-term anticoagulation, but "I don't think it works for everyone in acute coronary syndromes. It might be a more potent agent. And I think these are the kinds of things that we need to see. The evidence keeps building that there could be other possibilities other than aspirin."
More broadly, the recommendation for lifelong antiplatelet monotherapy for secondary prevention is based on trials from decades ago, "all of which had relatively short follow-up durations of 1-4 years," Rossello and Kristensen noted. "The SMART-CHOICE 3 trial addresses the issue of which antiplatelet monotherapy is superior in the mid-term in patients with chronic coronary syndromes. However, it does not answer the important question of whether they should receive lifelong antiplatelet therapy based on the current body of evidence."
Clopidogrel Better Than Aspirin Long-Term After PCI
A randomized trial SMART-CHOICE 3 demonstrated treatment after percutaneous coronary intervention (PCI) clopidogrel monotherapy was more effective and as least as safe as aspirin monotherapy. Current guidelines suggest DAPT (both aspirin and a P2Y12 inhibitor) for 6 months to a year post PCI to prevent blood clots and then continue with aspirin alone. This study demonstrated monotherapy with clopidogrel faired better than aspirin monotherapy as a lifelong maintenance.
The trial out of Korea (n= 5,506, average age 65, 18% women) about 46% had prior MI, about 38% had medication-treated diabetes, and around 76% had complex PCI. They were randomized to 75 mg clopidogrel once daily or 100 mg aspirin once daily in a 1:1 ratio. The results of the SMART -CHOICE 3 trial showed that after PCI patients who received long-term antiplatelet therapy (median 2.3 years) with clopidogrel were 29% less likely to die than those who received aspirin as well as being less likely to experience a heart attack or stroke (4.4 % vs 6.6%). There was no significant difference in the number of major bleeding events between the two groups.
Two important issues with the study is that 80% of the participants were men, which can impact the interpretation of the results in relation to women, since they bleed more easily. It is also possible that the study underestimated the benefits of clopidogrel due to the study occurring in South Korea, since they have a high rate of clopidogrel non-responders.
For Pregnant Women With Mechanical Valves, LMWH Tied to Worse Outcomes
Data is limited on pregnant women with prosthetic values and outcomes. A prospective global registry looked at 600 high risk pregnancies. Results showed the odds of an uncomplicated pregnancy with a live birth was 54% in women with a mechanical valve compared with 79% in peers with a biological valve. Those with a mechanical valve hads more bleeding and thrombotic complications if they were put on LMWH early in pregnancy, regardless if they resumed a vitamin K antagonist in the second trimester.
In those that were monitored with anti-Xa levels, there was a reduction in thromboembolic events, however it did not reach statistical significance. Current guidelines recommend anti-Xa monitoring of LMWH treatment since it is not harmful and may be beneficial to determine if levels are optimal.
An important consideration to consider when a valve replacement is required in women of a reproductive age since biological valves deteriorate over time and faster in young patients therefore requiring intervention, however a biological valve may be beneficial in this cohort.
This data from ROPAC [the Registry of Pregnancy and Cardiac disease] is observational and does not allow a scientifically valid comparison between monitoring and its absence. The latest guidelines recommend oral anticoagulants throughout pregnancy with mechanical valves using either LMWH with monitoring and changing to UFH prior to delivery. Monitoring should occur weekly, however this recommendation is based on expert opinion and not data.
The study reviewed 613 pregnancies, average age 30.7, 35% were nulliparous. First valve replacement occurred at the average age of 19.7 years, years with mechanical valve (n=411) and biological valve (n=202). Prepregnancy prosthetic valve malfunction was significantly more common with biological valves (24% vs 4%, P<0.001).
Mechanical valves were more likely attributed to rheumatic heart disease causing the valve disease (60% vs 18%), whereas biologic valves were more often attributed to congenital heart disease (69% vs 26%). Caesarean delivery occurred in 52% of pregnancies. Anti-Xa levels were not measured 26% of women using therapeutic LMWH.
.Valve thrombosis occurred in 6% of women, with the position of the valve (mitral position) and BMI were predictors of thrombosis. Fetal death occurred in 20% of cases, a lower risk was observed in women with a warfarin dose of <4.0 mg.
FDA Approves Generic Form of Rivaroxaban for CAD and PAD
Samantha Anderer
The FDA approved generic rivaroxaban used to reduce the risk of major cardiovascular events in adults with coronary artery disease (CAD) and major thromboricthrombotic vascular events in adults with peripheral artery disease (PAD). It is the second DOAC to receive FDA approval in the generic form. The first was apixaban in 2019, however they are still not available to consumers in the US due to patent protection.
JOURNAL CLUB
Asundexian or Apixaban in Patients With Atrial Fibrillation According to Prior Oral Anticoagulant Use - A Subgroup Analysis of the OCEANIC-AF Randomized Clinical Trial
John H. Alexander, MD, MHS; Elizabeth J. Lydon, MB, MS; Jonathan P. Piccini, MD; et alThomas Viethen, MD, MHBA; Jonas Oldgren, MD, PhD; Shaun G. Goodman, MD, MSc; Jan Steffel, MD; Andrea M. Russo, MD; Isabelle C. van Gelder, MD, PhD; Keith C. Ferdinand, MD; Renato D. Lopes, MD, PhD; Hardi Mundl, MD; Bela Benczur, MD; Juan José Gómez-Doblas, MD; Michael Glikson, MD; Assen Goudev, MD, DSc; Erik L. Grove, MD, PhD; Sigrun Halvorsen, MD, PhD; Tuomas Kiviniemi, MD, PhD; Anne-Céline Martin, MD, PhD; Roopinder K. Sandhu, MD, MPH; Dragos Vinereanu, MD, PhD; Frank W. Rockhold, PhD; Valeria Caso, MD, PhD; Rosa Coppolecchia, DO, MPH; Manesh R. Patel, MD
Abstract
Importance In patients with atrial fibrillation (AF), oral anticoagulants (OACs) reduce the risk of stroke.
Objective To investigate if patients with less prior OAC exposure respond differently to a new OAC than patients with more OAC exposure.
Design, Setting, and Participants In this prespecified exploratory subgroup analysis of the Oral Factor 11a Inhibitor Asundexian as Novel Antithrombotic–Atrial Fibrillation (OCEANIC-AF) randomized clinical trial, patients enrolled in the OCEANIC-AF trial were categorized as OAC naive or OAC experienced based on whether they had 6 or fewer weeks or more than 6 weeks of prior OAC use. The effect of asundexian vs apixaban was then compared on outcomes among patients who were OAC naive and OAC experienced. The study setting included 1035 sites in 38 countries, and participants were those enrolled in the OCEANIC-AF trial. Data were analyzed from June to July 2024.
Interventions Asundexian, a novel factor XIa inhibitor, was compared with apixaban in patients with AF.
Main Outcomes and Measures The primary efficacy outcome was stroke or systemic embolism. The main safety outcome was major bleeding.
Results Of patients in the OCEANIC-AF trial, 2493 (17%) were OAC naive (mean [SD] age, 72.6 [8.6] years; 1464 male [59%]) and 12 317 (83%) were OAC experienced (mean [SD] age, 74.2 [7.5] years; 8132 male [66%]). In the asundexian arm, patients who were OAC naive had a stroke or systemic embolism rate of 0.8% (10 of 1238) compared with 1.4% (88 of 6177) in those who were OAC experienced. In the apixaban arm, patients who were OAC naive had a stroke or systemic embolism rate of 0.6% (7 of 1255) compared with 0.3% (19 of 6140) in those who were OAC experienced. Thus, patients who were OAC naive had a smaller increase in stroke or systemic embolism with asundexian compared with apixaban (hazard ratio [HR], 1.42; 95% CI, 0.54-3.73) than patients who were OAC experienced (HR, 4.66; 95% CI, 2.84-7.65; P for interaction =.03). Bleeding rates were lower among both OAC-naive patients (0.2% [2 of 1228]) and OAC-experienced patients (0.2% [15 of 6145]) assigned asundexian than among OAC-naive patients (1.0% [13 of 1249]) and OAC-experienced patients (0.7% [40 of 6115]) assigned apixaban.
Conclusions and Relevance In the OCEANIC-AF randomized clinical trial, patients with AF who were OAC naive had a smaller increase in stroke or systemic embolism and a similar lower rate of bleeding with asundexian compared with apixaban than patients who were OAC experienced. The mechanism of these findings is unknown and deserves further research.
Long-Term Risk of Stroke After Transient Ischemic Attack or Minor Stroke A - Systematic Review and Meta-Analysis
Writing Committee for the PERSIST Collaborators
Abstract
Importance After a transient ischemic attack (TIA) or minor stroke, the long-term risk of stroke is not well-known.
Objective To determine the annual incidence rates and cumulative incidences of stroke up to 10 years after TIA or minor stroke.
Data Sources MEDLINE, Embase, and Web of Science were searched from inception through June 26, 2024.
Study Selection Prospective or retrospective cohort studies reporting stroke risk during a minimum follow-up of 1 year in patients with TIA or minor stroke.
Data Extraction and Synthesis Two reviewers independently performed data extraction and assessed study quality. Unpublished aggregate-level data on number of events and person-years during discrete follow-up intervals were obtained directly from the authors of the included studies to calculate incidence rates in individual studies. Data across studies were pooled using random-effects meta-analysis.
Main Outcomes and Measures The primary outcome was any stroke. Study-level characteristics were investigated as potential sources of variability in stroke rates across studies.
Results The analysis involved 171 068 patients (median age, 69 years [IQR, 65-71]; median proportion of male patients, 57% [IQR, 52%-60%]) from 38 included studies. The pooled rate of stroke per 100 person-years was 5.94 events (95% CI, 5.18-6.76; 38 studies;
Conclusions and Relevance Patients who have had a TIA or minor stroke are at a persistently high risk of subsequent stroke. Findings from this study underscore the need for improving long-term stroke prevention measures in this patient group.
Prothrombin Complex Concentrate vs Frozen Plasma for Coagulopathic Bleeding in Cardiac Surgery - The FARES-II Multicenter Randomized Clinical Trial
Keyvan Karkouti, MD; Jeannie L. Callum, MD; Justyna Bartoszko, MD; et alKenichi,A. Tanaka, MD; Sigurd Knaub, PhD; Sukhpal Brar, MD; Kamrouz Ghadimi, MD; Antoine Rochon, MD; Darren Mullane, MB; Etienne J. Couture, MD; Yulia Lin, MD; Christopher Harle, MD; Michelle Zeller, MD; DiemT. Tran, MD; Cristina Solomon, MD; Vivek Rao, MD; Michael Law, MD; Amir L. Butt, MD; Edward P. Chen, MD; Maria Rosal Martins, MD; Tarit Saha, MD; Andrew W. Shih, MD; Marie-Claude Vézina, MD; Fuad Moussa, MD; Raffael Pereira Cezar Zamper, MD; Summer Syed, MD; Hakan Buyukdere, MD; Sylvia Werner, MS; Deep Grewal, MD; Daniel Wong, MD; Kofi B. Vandyck, MD; Robert Tanzola, MD; Bevan Hughes, MD; Olivier Royer, MD; Sophia Wong, MD; Jerrold H. Levy, MD; for the FARES-II Study Group
Abstract
Importance Excessive bleeding is a common and prognostically important complication of cardiac surgery. For bleeding related to coagulation factor deficiency, frozen plasma is the most used therapy. Preliminary trials indicate that 4-factor prothrombin complex concentrate (PCC) may be a suitable alternative.
Objective To compare the efficacy and safety of PCC with frozen plasma in patients undergoing cardiac surgery with coagulopathic bleeding.
Design, Setting, and Participants Unblinded randomized noninferiority controlled clinical trial at 12 hospitals in Canada and the US involving adults (≥18 years) who had developed bleeding related to coagulation factor deficiency after termination of cardiopulmonary bypass during surgery (November 30, 2022, to May 28, 2024). Final 30-day follow-up visit was completed on June 28, 2024.
Intervention A total of 265 patients were randomized to receive PCC (1500 IU ≤60 kg; 2000 IU >60 kg) and 263, frozen plasma (3 U ≤60 kg; 4 U >60 kg) in the operating room. A second dose was allowed over the next 24 hours if indicated; thereafter, only frozen plasma could be used.
Main Outcomes and Measures The primary outcome was hemostatic response (effective if no hemostatic interventions occurred from 60 minutes to 24 hours after treatment initiation). The noninferiority of PCC vs frozen plasma was assessed using a 10% margin and a 1-sided α of .025, with subsequent testing for superiority if noninferiority was demonstrated. Secondary outcomes included allogeneic blood transfusions and adverse events. Patients were followed up until postoperative day 30.
Results Of 538 enrolled patients, 420 patients (median age, 66 years [IQR, 57-73 years]; 74%, male; 10%, Asian; 1%, Black; and 65%, White) were included in the primary analysis; of those, 296 (70%) underwent complex surgeries. Compared with the 207 patients in the frozen plasma group, the 213 patients in the PCC group had higher hemostatic effectiveness (166 [77.9%] vs 125 [60.4%]; difference, 17.6%; 95% CI, 8.7%-26.4%;
Conclusions and Relevance In this unblinded randomized clinical trial, PCC had superior hemostatic efficacy and safety advantages to frozen plasma among patients requiring coagulation factor replacement for bleeding during cardiac surgery.
Prophylactic Enoxaparin Dosing and Anti-Xa Levels in Medicine Patients With Obesity
Wint War Phyo, Karishma Deodhar, Amy Chang, Mary Blair, Allison N Boyd, Christopher Geik
Abstract
Introduction: Previous studies have shown that the manufacturer's standard fixed dosing of enoxaparin for venous thromboembolism (VTE) prophylaxis leads to sub-prophylactic anti-Xa levels in medicine patients with obesity. Yet, there is limited literature describing higher dosing strategies in this patient population, and an optimal dosing regimen has not been well-established.
Objective: The primary objective was to evaluate mean doses (mg/kg/d) of prophylactic enoxaparin that are associated with goal anti-Xa levels in medicine patients with obesity across 3 body mass index (BMI) groups (40-49 kg/m2, 50-59 kg/m2, ≥60 kg/m2).
Methods: This is a single-center, retrospective cohort study of adult patients (age ≥18 years) with BMI ≥40 kg/m2 admitted to a medicine team with at least 1 appropriately drawn anti-Xa level between January 2018 and July 2023. The institution's goal anti-Xa level for VTE prophylaxis was 0.2 to 0.4 units/mL. The primary outcome was the comparison of mean dose between those within anti-Xa at goal and not at goal. Secondary outcomes included the percentages of initial anti-Xa levels below, within, or above goal range and the incidence of new VTE and major bleeding events during hospitalization while on enoxaparin. All outcomes were stratified into 3 BMI groups: 40-49 kg/m2, 50-59 kg/m2, and ≥60 kg/m2.
Results: Median dose of those with final anti-Xa level at goal was significantly higher than that of those not in goal anti-Xa range across all 3 BMI groups (0.57 vs 0.50 mg/kg/d;
Conclusion: Findings suggest that medicine patients with BMI ≥40 kg/m2 may require enoxaparin doses higher than 0.5 mg/kg/d to reach goal prophylactic anti-Xa level. However, more robust data are necessary to further validate these results and the clinical implications.
Hemorrhage Causes Most Maternal Deaths Worldwide
Samantha Anderer
JAMA. Published online April 11, 2025. doi:10.1001/jama.2025.4027
Obstetric hemorrhage remains the leading cause of maternal mortality, accounting for about 27% of deaths during pregnancy and the following 6 weeks, a new study has found.
Most hemorrhage deaths occurred during the postpartum period, which historically has lower care coverage than prepartum and intrapartum care. The existence of effective clinical interventions means these deaths are largely preventable, with women in low- and lower-middle-income countries facing greater barriers to care, according to the systematic review published in The Lancet Global Health.
Hypertensive disorders including preeclampsia accounted for the next most common direct obstetric cause of death from 2009 to 2020. Other causes included sepsis, embolism, and abortion complications. Underlying infectious and chronic diseases such as HIV/AIDS, malaria, and diabetes were responsible for 23% of pregnancy- and childbirth-related mortality.
In 2020, the global maternal mortality ratio was 223 deaths per 100 000 live births, far more than the World Health Organization (WHO) Sustainable Development Goal target of less than 70 deaths per 100 000 live births by 2030. In a news release, WHO pointed to the need to strengthen prenatal services to detect pregnancy risks early, obstetrics care to manage birth-related emergencies, and postnatal care, while also addressing underlying health conditions that increase women's risks.