October 2025: New In Coagulation
by Donna Castellone • October 09, 2025
Our Monthly complilation of the latest studies, guidelines and discussions in coagulation.
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Are Women With Acute Coronary Syndromes Subject to Unnecessary Bleeding Risk?
Two European cardiology organizations (European Association of Percutaneous Cardiovascular Interventions and the European Society of Cardiology Working Group on Thrombosis) agree that compared to men women who are treated for acute coronary syndromes (ACS) are at a greater risk for bleeding in relation to invasive cardiac procedures. Therapies such as heparin and fondaparinux have similar efficacy in both sexes but women have a higher bleeding risk with these agents. It would help to adjust dosing to body weight and kidney function. They also tend to be underrepresented in trials.
Hormonal differences play an important role since estrogen promotes the productions of prostacyclin, increases nitric oxide and reduces platelet aggregation. Fluctuations due to menstrual cycle, oral contraceptives, menopause and HRT can influence thrombotic and bleeding risk. ACS typically affects postmenopausal women, but it is increasing in premenopausal women who have an even higher risk of bleeding due to lower platelet reactivity due to estrogen receptors on the platelet surface. Data shows that women younger than 50 were 4 times more likely than men to have major and minor bleeding associated with stenting. However, there is still a lack of evidence to address sex differences. Results from clinical trials should be analyzed and published separately for men and women. In the SAFE-PCI for Women, radial access was compared to femoral access and showed radial access had less bleeding.
Study Clears Vaginal Estrogen of Recurrent Stroke Risk After Menopause
There was no link found between vaginal estrogen therapy and recurrent stokes in a study from Denmark. The study looked at over 56,000 women with prior ischemic stroke who were 45 or older (median age 75 years). There were 3,353 recurrent stroke cases matched 1:1 to controls for comparison. No association was seen when vaginal estrogen tablets were used during or right before a recurrent stroke, or 3-24 months prior, or even an older history of using vaginal estrogen. It has been demonstrated that taking systemic hormone replacement therapy may increase the risk of stroke post menopause. However, this was not seen in vaginal estrogen in healthy women. It was thought that vaginal estrogen tablets are systemically absorbed and mildly elevate plasma estradiol which may be concerning for women with a history of stroke since it may lead to a prothrombotic state.
You Say NOAC, I Say DOAC: Medicine's Love of Confusing Jargon
Diversity of nomenclature is complicated, if you have a sudden acute blockage in a coronary artery it may be a heart attack, or myocardial infarction or acute coronary syndrome. It would be nice to have it standardized.
The TAVI vs TAVR debate is similarly pointless. Although transcatheter aortic valve implantation (TAVI) tends to predominate in Europe. In the United States everyone talks about a transcatheter aortic valve replacement (TAVR), however the valve is not replaced so TAVIi is correct.
NOAC, DOAC, TSOAC? Novel oral anticoagulants (NOACs) were rebranded to DOACs which made sense. But many people felt that they should be named based on their specific target and mode of administration or TSOAC (target-specific oral anticoagulant).
DAPT 'Too Strong' After CABG for Heart Attacks, Trial Says
The TACSI randomized trial showed that DAPT didn’t improve outcomes after CABG for ACS but it did increase risks. The use of ticagrelor plus aspirin, resulted in no lower risk of the primary endpoint of death, MI, stroke or repeat revascularization when compared to just aspirin alone. However, major bleeding risk more than doubled when a P2Y12 inhibitor was added. The results of the trial were unexpected. Those guidelines were largely based on evidence from percutaneous coronary intervention and were extrapolated to CABG patients without evidence. In reality, DAPT may be too strong for these patients.
The study included 2201 patients getting CABG for ACS in 22 Nordic centers. They were randomly assigned to open-label treatment with either ticagrelor plus aspirin or aspirin alone for 1 year. Average age was 66, 14.4% were women, and 27.5% had diabetes. In terms of the indication for CABG, 57.6% had a non-ST-segment elevation MI, 32.1% had unstable angina, and 10.2% had ST-segment elevation MI.
Nonadherence was substantial possibly due to side effects of dyspnea and bleeding. Three times more DAPT than aspirin alone patients discontinued the trial. DAPT showed 45% more bleeding. Major bleeding was based on hospitalization; less severe events were likely underestimated. Patients will be followed for 10 years.
Year of Low-Dose DOAC Slashes Recurrence After Provoked VTE
The HI-PRO trial showed that extended low dose apixaban after VTE that has been provoked by trauma or surgery in patients with obesity, greatly reduced recurrence without Bleeding. Twice daily dosing (2.5 mg) over 12 months decreased the rate of symptomatic VTE by 87%. Major bleeding occurred in one out of 300 in the apixaban group and none in the placebo group. Clinical nonmajor bleeding was 4.8% and 1.7% respectively. However, there was a high risk of unprovoked VTE in the placebo group.
The original practice was to treat a provoked VTE for 3-6 months, but with safer anticoagulants this practice has been challenged. The most common provoking factors for the index VTE were surgery (33.5%), immobility (31.3%), trauma (19.2%), and acute medical illness (18.3%). But minor triggers were not uncommon, such as long-haul travel (16.7%). Only 9.3% of the patients had been hospitalized in the 3 months preceding the index VTE event.
There were 600 adults mean age of 59.5 with 57% female 19.2% non-white assigned to oral apixaban or placebo. Extending anticoagulant can offer benefit to select patients with a provoked VTE as long as they are identified accurately and understand the risks and benefits.
Stopping Anticoagulant Safe After Afib Ablation Without Recurrence
The ALONE-AF trial found that stopping anticoagulation after ablation for AF improved outcomes in patients without recurrence. The trial included 840 patients without symptoms or evidence of AF on intermittent monitoring for at least 1 year after catheter ablation at 18 hospitals in South Korea. Mean age 64, 24.9% were women, 67.6% had paroxysmal AF participants were at an intermediate or high risk for stroke, and randomized to discontinue or continue DOACs. In reviewing the primary composite outcome of stroke, embolism and major bleeding at 2 years only one event occurred when compared with eight events in those who continued anticoagulation. There was no significant incidence in stroke, but there was a difference in major bleeding. These findings support stopping OAC for AF patients after 1 year.
The subgroups that benefited from stopping DOACs were patients older than 65 years, men, patients without key comorbidities and those with a HAS-BLED score greater than 2. Limitations of the study include exclusion of subjects over 80 and the ability to generalize the subject other than East Asian population who may present with higher bleeding risks.
First BTK Inhibitor Approved for Immune Thrombocytopenia
Ritzabrutinib has been approved by the FDA for treating persistent or chronic ITP. This is the first Bruton’s tyrosine kinase (BTK) inhibitor for ITP. It is used in patients with insufficient response to immunoglobins, anti-D therapy or corticosteroids. The drug is designed to simultaneously reduce the production of platelet-targeting autoantibodies and to inhibit B-cell activation and inflammatory pathways.
The LUNA 3 trial showed that 23% of patients had a durable platelet response at week 25 without the use of rescue therapy versus 0% on placebo. That primary endpoint was defined as a platelet count of 50,000/μL or higher for at least 8 of the last 12 weekly visits. Less bleeding events were recorded. This drug offers a new option for patients who do not respond to steroids or existing treatment. Warnings include hepatotoxicity, and embryo-fetal toxicity as well as interactions with CYP3A inhibitors and inducers.
Aspirin Plus Oral Anticoagulants Raises Mortality, Bleeding
The results of the AQUATIC double blind trial demonstrated that pPatients with ACS CCS and at high atherothrombotic risk taking an OAC, when aspirin was added, it led to a higher risk for major bleeding and all cause death, with no reduction in atherothrombotic events, and may cause significant harm. These results may cause a change in clinical practice. AQUATIC patients had a sevenfold higher thrombotic risk than patients in the previous studies, with all patients having received a stent. The calculated number that caused harm due to aspirin was 46, that translates to one additional death for every 46 patients treated with aspirin resulting in 30,000-50,000 deaths caused by aspirin annually.
Patients with chronic coronary syndrome long-term single antiplatelet therapy is used to prevent recurrent therothrombotic events, of these patients 15% also receive long term anticoagulation for AF.
Previous studies have shown an increased risk of bleeding in patients taking a full dose of OAC and antiplatelet, but these trials were low-risk population, and not all patients had undergone stenting. The treatment for chronic coronary syndrome remains unclear.
The AQUATIC trial was conducted at 51 centers in France and enrolled 872 patients, however the trial was stopped early due to an excess of deaths in the aspirin group after a follow up of 2.2 years. Patients had undergone previous stent implantation and were at high atherothrombotic risk and receiving long term OAC. The primary outcome (CV death, MI, stroke, systemic embolism, coronary revascularization or acute limb ischemia) had occurred in 16.9% of the aspirin group and 12.1% in the placebo. Death from any cause occurred in 13.4% in the aspirin group and in 8.4% in the placebo group. Major bleeding occurred in 10.2% in the aspirin group and in 3.4% in the placebo group. There was no difference in actual atherothrombotic events between the two groups, with the difference in the efficacy composite endpoint driven entirely by cardiovascular death.
First Year Is Worst for Clotting Events in Lupus Patients
Antiphospholipid antibodies are common in lupus, often becoming antiphospholipid syndrome (APS), and appear to drive increased risk for thromboembolic events seen in lupus patients. However, most patients with these antibodies never develop such events, complicating risk stratification and management for individual patients. This study found that thromboembolic events were most common in lupus patients with antiphospholipid syndrome, and most often occurred in the first year after lupus diagnosis.
In 700 new SLE patients, 79 were diagnosed with APS with a thromboembolic event occurring at a rate of 59/100 person years during the first year after lupus diagnosis. In the following year the rate fell for 12/100 person years. In patients that were APS negative, the clotting events were less common: 2.6 and 0.9 per 100 person-years during the first year and the years thereafter, respectively.
APS also contributed to increased mortality of 4.7 over 8 years compared with 1.7 in patients without APS.
Antiphospholipid antibodies are a feature of lupus and drive thromboembolic events, however most patients do not have events resulting in a major knowledge gap around APS, SLE and thrombosis, making them difficult to manage and study.
This study looked at registry based medical records for 2.9 million people in southeast Norway, with 700 people meeting the criteria. The mean age was 39 and 85% were women. Half had a history of current or former smoking and 40% were positive for at least one APS, 34% had 2 or more. Prior to getting a lupus diagnosis, 25 were diagnosed with APS, and had a thromboembolic event long before lupus was diagnosed. The greatest number of first thromboembolic events was in the year after lupus. Up to 87% of the APS subgroup had experienced a thromboembolic event by the end of follow up, versus 14% of non- APS patients. There were 11% of APS patients that had both an arterial and VTE, versus 1% of those without APS had both.
In the 630 patients who did not have a thrombotic event prior to lupus diagnosis, 94% still had not had one a year later, and 83% remained free of events when followed out to 10 years and those with negative antiphospholipid antibodies were less likely to have an event. Risk for an event is aligned with 2 processes: (1) where systemic inflammation and endothelial activation likely contribute or (2) an accumulating risk related to age, sex and smoking.
A major limitation was that traditional risk factors for thromboembolism were not tracked in registry data, and not all patients in the registry were tested for antiphospholipid antibodies.
Blood Thinners Tied to Risk of Eye Hemorrhage in Wet Macular Degeneration
Prior research has suggested that 7% to 8% of patients with AMD develop hemorrhagic complications. In this study, the use of anticoagulants or antiplatelets was linked to a higher risk of intraocular hemorrhage requiring vitrectomy in patients with exudative AMD. The highest risk was observed with the combined use of anticoagulants and antiplatelets, and higher medication adherence was tied to increased odds of hemorrhage.
A study conducted in South Korea linked the use of anticoagulants or antiplatelets with a higher risk of intraocular hemorrhage requiring vitrectomy in patients with wet age related macular degeneration (AMD) with a HR of 1.15. Data was obtained using a retrospective, longitudinal cohort study design. When using a cross-sectional case control design intraocular hemorrhage was associated with anticoagulants (OR of 1.88). The highest OR of 2.28 was seen in patients who used both anticoagulants and antiplatelets. The Korean Health Insurance Review and Assessment Service database was used to identify patients for the review. There were 149,620 patients with exudative AMD older than 40. A total of 94,.449 patients were included in the retrospective cohort with a mean age of 71.8, 59% male, and 8,110 patients in the case controlled study (mean age 70.2, 62.8% men).
Research has suggested that 6.7-8.0% of AMD patients develop hemorrhagic complications and can be associated with severe vision loss. Those with larger and more central macular hemorrhages vision loss is more severe. The risk is due to the drugs increasing the patients risk of bleeding. Neovascular membranes in AMD are fragile. However, in an observational study causality can't be proven. In patients, risk needs to be addressed without compromising safety, such as discussions to avoid unnecessary dual therapy, having closer ophthalmic surveillance such as more follow up and control of exudation with anti-VEGF treatment.
Reduce DAPT to 3 Months After MI: DUAL-ACS
The DUAL-ACS trial demonstrated that DAPT in patients with MI should be shortened from 1 year to 3 months. The study was randomized and used real world trial data. DAPT should be given in the first 3 months and then continue with single antiplatelet therapy. This resulted in lower all cause mortality than DAPT for 12 months. The secondary endpoint, CV death or recurrent MI, did not differ between groups, but there was an increase in major bleeding in those with 12 months of DAPT. The trial was underpowered due to recruitment during the pandemic and none of the results reached significance. Many of the initial studies looking at shorter durations of DAPT have been done in Asian population and there are concerns about generalizability.
Some meta-analysis raises concerns that DAPT used in longer durations may be causing harm or even an increase in all cause morality. However, current guidelines give a 1A recommendation for 12 months of DAPT post MI, unless they have a high bleeding risk. The first trial that looked at DAPT- the CURE trial with clopidogrel and aspirin - showed the benefit occurred in the first 3 months and diminished after that, with an ongoing background bleeding risk. Many trials since then have looked at DAPT, mostly in patients with drug-eluting stents. Results have suggested that longer durations are associated with harm and shorter duration with lower bleeding and mortality risks. However, most patients in these trials are not at a high risk for bleeding which is different in real world practice.
The DUAL-ACS trial looked at real world patients with MI. In the study, 5000 patients were enrolled, but the initial enrollment was 17,000 which was not met due to pandemic complications to enrollment. Patients were predominantly from Scotland, white, mean age 63, 73% male with a range of risk factors for MI. Around 25% of patients were managed medically, two thirds underwent percutaneous coronary intervention, and 6%-7% underwent bypass surgery.
Patients, 2 days post MI were randomly assigned to 3 or 12 months of DAPT with aspirin plus a P2Y12 inhibitor. Clinical events were evaluated using medical records. Primary endpoint of all-cause death was lower with the shorter duration of DAPT; 2.7% of patients on 3 months of DAPT vs. 3.4% of those on 12 months of DAPT. The principle secondary endpoint of cardiovascular death or nonfatal MI was similar in both groups; 9.3% in 3 months versus 8.9% in 12 months. While the main safety endpoint, fatal or major nonfatal bleeding, was numerically reduced in the 3 month DAPT group.
Why would anyone give 12 months of DAPT, do the guidelines needed to be revisited?. Previous studies using prasugrel or ticagrelor with aspirin suggest a reduction in events up to a year versus aspirin alone which is why there is this recommendation despite the risk of increased bleeding. Shorter times may be linked to a higher risk for stent thrombosis and MI. So, what is worse a MI or a bleed. DUAL-ACS looked at all- cause mortality. Despite the results not being significant, a lower rate of mortality was seen with a shorter duration of DAPT, and a slightly higher occurrence of MI or stent thrombosis.
In this study the P2Y12 inhibitor was stopped at 3 months and the aspirin alone was continued, but doing the reverse of stopping the aspirin and continuing the P2Y12 drug has been associated with better outcomes. This may be the best option moving forward. Guidelines may consider de-escalating strategies shown to reduce bleeding risk or net clinical outcomes as well as reduce mortality.
JOURNAL CLUB
Age-Stratified Effect of Rivaroxaban Monotherapy for Atrial Fibrillation in Stable Coronary Artery Disease - A Post Hoc Analysis of the AFIRE Randomized Clinical Trial
Junichi Yamaguchi, MD, PhD; Hiroyuki Arashi, MD; Nobuhisa Hagiwara, MD, PhD
JAMA Cardiol, Published Online: August 13, 2025
Abstract
Importance Antithrombotic therapy is crucial for older patients with coronary artery disease (CAD) and atrial fibrillation (AF) who are at a high risk of bleeding and thrombotic events.
Objective To examine the age-stratified effects of rivaroxaban monotherapy compared with those of rivaroxaban plus antiplatelet agent combination therapy.
Design, Setting, and Participants This was a post hoc secondary analysis of the Atrial Fibrillation and Ischemic Events With Rivaroxaban in Patients With Stable Coronary Artery Disease (AFIRE) open-label randomized clinical trial. This was a multicenter study conducted in Japan from February 23, 2015, to July 31, 2018. Patients with AF and stable CAD who had undergone percutaneous coronary intervention or coronary artery bypass grafting 1 or more years earlier or who had angiographically confirmed CAD that did not require revascularization were enrolled. Participants were stratified into 4 groups by age (<70 years, 70-74 years, 75-79 years, and ≥80 years). Study data were analyzed from August 2024 to July 2025.
Interventions Rivaroxaban monotherapy or rivaroxaban plus antiplatelet agent therapy.
Main Outcomes and Measures The primary efficacy end point was a major adverse cardiovascular event, defined as a composite of stroke, systemic embolism, myocardial infarction, unstable angina requiring revascularization, or death from any cause. The primary safety end point was major bleeding.
Results This study included a total of 2215 participants (mean [SD] age, 74.3 [8.2] years; 1751 male [79.1%]). The incidence of primary efficacy end points per patient-year for rivaroxaban monotherapy vs rivaroxaban plus antiplatelet agent therapy was 3.2% vs 4.3% (<70 years), 3.2% vs 2.8% (70-74 years), 3.8% vs 5.3% (75-79 years), and 6.2% vs 10.3% (≥80 years). The hazard ratios were 0.74 (95% CI, 0.40-1.37) for those younger than 70 years, 1.16 (95% CI, 0.55-2.45) for those aged 70 to 74 years, 0.72 (95% CI, 0.41-1.26) for those aged 75 to 79 years, and 0.61 (95% CI, 0.40-0.93) for those 80 years and older (
Conclusions and Relevance Results of this post hoc analysis of the AFIRE randomized clinical trial reveal that rivaroxaban monotherapy reduced the risk of major cardiovascular events and major bleeding across the broad range of age in patients with AF and stable CAD. Possible age-related differences in trends, with more pronounced efficacy in older patients and more pronounced safety in younger patients, should be considered as hypothesis generating and require further research.
Safety of Factor XI Inhibition With Abelacimab in Atrial Fibrillation by Kidney Function - A Prespecified Analysis of the AZALEA-TIMI 71 Randomized Clinical Trial
Siddharth M. Patel, MD, MPH; Robert P. Giugliano, MD, SM; David A. Morrow, MD, MPH1et al
JAMA Cardiol
Published Online: September 1, 2025
Abstract
Importance Chronic kidney disease is common in patients with atrial fibrillation (AF) and is associated with higher rates of bleeding with anticoagulation. In the AZALEA-TIMI 71 randomized clinical trial, abelacimab, a novel factor XI inhibitor, reduced rates of major or clinically relevant nonmajor (CRNM) bleeding compared with rivaroxaban in patients with AF.
Objective To examine the safety of abelacimab vs rivaroxaban across a range of kidney function.
Design, Setting, and Participants The AZALEA-TIMI 71 study randomized patients with AF to 1 of 2 abelacimab doses (150 mg or 90 mg monthly) or to rivaroxaban, with stratification by creatinine clearance (CrCl). Patients with CrCl less than 15 mL/min or receiving dialysis were excluded. This secondary analysis of AZALEA-TIMI 71 examines outcomes by randomized treatment and CrCl at randomization.
Intervention Patients randomized to rivaroxaban with a CrCl greater than 50 mL/min received rivaroxaban, 20 mg, daily, and those with a CrCl of 50 mL/min or less received rivaroxaban, 15 mg, daily. Patients randomized to abelacimab received the assigned dose irrespective of CrCl.
Main Outcomes and Measure The primary outcome was major bleeding or CRNM bleeding.
Results Among 1284 patients, median (IQR) age was 74 (69-78) years and 572 patients (44.5%) were female. Median (IQR) CrCl was 71 (54-90) mL/min, with 264 patients (20.6%) having a CrCl of 50 mL/min or less. In the rivaroxaban group, patients with CrCl of 50 mL/min or less experienced higher rates of major or CRNM bleeding compared with those with CrCl greater than 50 mL/min despite dose reduction (incidence rates, 13.6 vs 7.0 per 100 person-years). Abelacimab reduced major or CRNM bleeding vs rivaroxaban irrespective of CrCl (CrCl ≤50 mL/min: hazard ratio [HR], 0.26; 95% CI, 0.12-0.54; >50 mL/min: HR, 0.40; 95% CI, 0.26-0.62; P value for interaction = .33), with absolute risk reductions of 10.1 vs 4.2 per 100 person-years in those with CrCl of 50 mL/min or less vs greater than 50 mL/min, respectively (P value for interaction = .09). This risk reduction was consistent for major bleeding alone and for a broader composite inclusive of major, CRNM, and minor bleeding. Results were similar when comparing the individual abelacimab doses to rivaroxaban.
Conclusions and Relevance In this secondary analysis of the AZALEA-TIMI 71 randomized clinical trial, abelacimab consistently reduced the risk of bleeding relative to rivaroxaban irrespective of kidney function. These findings suggest that abelacimab may offer a particularly favorable safety profile among those with chronic kidney disease; however, larger studies are necessary to characterize the efficacy of abelacimab for stroke prevention in AF.
Long-Term Anticoagulation Discontinuation After Catheter Ablation for Atrial Fibrillation - The ALONE-AF Randomized Clinical Trial
Daehoon Kim, MD1; Jaemin Shim, MD2; Eue-Keun Choi, MD3, et al
JAMA
Published Online: August 31, 2025
Abstract
Importance Data from randomized clinical trials on a long-term anticoagulation strategy for patients after catheter-based ablation for atrial fibrillation (AF) are lacking.
Objective To evaluate whether discontinuing oral anticoagulant therapy provides superior clinical outcomes compared with continuing oral anticoagulant therapy in patients without documented atrial arrhythmia recurrence after catheter ablation for AF.
Design, Setting, and Participants A randomized clinical trial including 840 adult patients (aged 19-80 years) who were enrolled and randomized from July 28, 2020, to March 9, 2023, at 18 hospitals in South Korea. Enrolled patients had at least 1 non–sex-related stroke risk factor (determined using the CHA2DS2-VASc score [range, 0-9]) and no documented recurrence of atrial arrhythmia for at least 1 year after catheter ablation for AF. The CHA2DS2-VASc score is used as an assessment of stroke risk among patients with AF (calculated using point values for congestive heart failure, hypertension, ≥75 years of age, diabetes, stroke or transient ischemic attack, vascular disease, between 65 and 74 years of age, and sex category). The date of final follow-up was June 4, 2025.
Interventions The patients were randomly assigned in a 1:1 ratio to discontinue oral anticoagulant therapy (n = 417) or continue oral anticoagulant therapy (with direct oral anticoagulants; n = 423).
Main Outcomes and Measures The primary outcome was the first occurrence of a composite of stroke, systemic embolism, and major bleeding at 2 years. Individual components of the primary outcome (such as ischemic stroke and major bleeding) were assessed as secondary outcomes.
Results Of the 840 adults randomized, the mean age was 64 (SD, 8) years, 24.9% were women, the mean CHA2DS2-VASc score was 2.1 (SD, 1.0), and 67.6% had paroxysmal AF. At 2 years, the primary outcome occurred in 1 patient (0.3%) in the discontinue oral anticoagulant therapy group vs 8 patients (2.2%) in the continue oral anticoagulant therapy group (absolute difference, –1.9 percentage points [95% CI, −3.5 to −0.3];
Conclusions and Relevance Among patients without documented atrial arrhythmia recurrence after catheter ablation for AF, discontinuing oral anticoagulant therapy resulted in a lower risk for the composite outcome of stroke, systemic embolism, and major bleeding vs continuing direct oral anticoagulant therapy.