February 2024: New In Coagulation
by Donna Castellone, MS, MT(ASCP)S • February 07, 2024
Our Monthly complilation of the latest studies, guidelines and discussions in coagulation.
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Oral Factor XIa Inhibitor Disappoints for Secondary Stroke Prevention
The phase II trial ACIOMATIC-SS the factor XIa inhibitor milvexian this is an oral inhibitor of activated factor XIa and is rapidly absorbed with a half life of 12 hours. The basis of the drug being used as an antithrombotic is due to people with factor XI deficiency haveing lower rates of ischemic stroke than the general population.The study was conducted at 367 hospitals and enrolled 2366 individuals with acute ischemic stroke or TIA, median age of 71, 36% women and 80% were white. They were randomized to one of five doses of milvexian or placebo for 90 days. All participants received clopidogrel for the first 21 days followed by 100mg of aspirin for 90 days. This however did not provide meaningful secondary prevention over dual antiplatelet therapy for stroke survivors. When compared with a placebo in patients with ischemic stroke or TIA there was no significant reduction in the combined incidence of ischemic stroke or covert brain infarct despite using randomization of five doses of milvexian. There was also no observed major bleeding. The highest dose of milvexian was associated with renal adverse events and the study was discontinued.
Disappointing results were also seen with another FXIa inhibitor asundexian when compared with a placebo. These results suggest that these FXI and FXIa inhibitors may not prevent noncardioembolic stroke.
A phase III study LIBREXIA-STROKE is looking at a 25mg twice daily does of milvexian versus placebo in 15,000 stroke or TIA patients.
Gene Therapy for Hemophilia Becomes a Reality
The FDA approved valococogene roxaparvovec (ROCTAVIAN) use in adults with severe hemophilia A earlier in 2023. This is an update regarding that approval. Etranacogene dezaparvovec (HEMGENIX) was approved for hemophilia B late in 2023 and despite these approvals the use of these therapies have been relatively slow.
The GENEr8-1 study provided the data from a global phase III study for ROCTAVIAN which showed this therapy reduce the average annualized bleeding rate by 52% when compared with patients on routine factor VIII prophylaxis. In 112 patients, bleeds decreased from 5.4 to 2.6 bleeds per year during a 3 year follow up. After gene therapy, spontaneous bleeds were also reduced from 2.3 to 0.5 bleeds per year as well a decrease in joint bleeds from 3.1 to 0.6.
The drug developer BioMarin at it's approval stated it would begin to educate physicians and patients via hemophilia treatment centers throughout the US so that readiness plans would be in place before the end of 2023. Additionally they would work with private and public payers in the US to enable access of the drug. It has a list price of $2.9 million. No announcement has been made when patients in the US will begin therapy.
HEMGENIX used for hemophilia B is given to adults currently use IX prophylaxis therapy. CSL Behring who developed the drug has reported that as of May, payers covering up to 60% of the US have established polices covering the treatment which is priced at $3.5 million. In June the first patient received treatment. Results of the HOPE-B study provides 3 year follow up data which reveals that of 52 individuals the mean factor IX levels were 41.5 IU/dL at year 1, 36.7 IU/dL at year 2, and 38.6 IU/dL at year 3 post-treatment. In addition, 94% of patients remained free of continuous prophylactic therapy. This demonstrates that HEMEGENIX provided elevated and sustained factor IX levels and reduced the rate of annual bleeds.
Another factor IX gene fidanacogene elaparvovecopens, which is an adeno-associated virus capsid, high activity variant of the FIX gene as studied in the BENEGEE-2 phase III trial. Results show the average bleeding rate was 1.3 versus 4.43, resulting in a 71% reduction in bleeds.
New Stroke Prevention: Clopidogrel Aspirin Within 72 Hours
The INSPIRES trial was a double blind, placebo controlled study that included patients with mild ischemic stroke of high-risk TIA presumably caused by atherosclerosis who had not undergone a thrombectomy. It included 6100 patients who were randomly assigned dual antiplatelet therapy (DAPT) of either clopidogrel plus aspirin or matching clopidogrel placebo within 72 hours post symptom onset. Efficacy was measured by the onset of new stroke within 90 days and safety was measured by the occurrence of moderate to severe bleeding within 90 days. At 24 hours of symptom onset, 12.8% were assigned to each treatment group and 87.2% were assigned to the time window of 24-72 hours.
Results showed that the occurrence of a new stroke event at 90 days was 2 percentage points lower with clopidogrel plus aspirin vs aspirin alone (7.3% vs 9.2%) while the risk of a composite cardiovascular event and ischemic stroke were also 20%-25% lower with aspirin-clopidogrel combo vs aspirin alone. Bleeding was <1% in both groups, but the risk was double in patients who received DAPT. These findings support expanding the window to 72 hours as well as not using DAPT in patients with a history of bleeding.
Do Statins Offset Venous Thrombosis Risk With Hormone Therapy?
An report in JAMA discussed whether statin therapy may offset some excess risk for VTE among women taking menopausal hormone therapy which can lead to almost doubling the risk of VTE. The JUPITER trail showed this may help due to ani-inflammatory or antithrombotic effects of statin therapy.
Using a data base, Optum Health, which included 15 million members, 2000 women were identified as having VTE. They were between the age of 50-64 and compared to 200,000 controls without VTE. Of these 50% were on oral hormone therapy, and 50% were on non-oral transdermal or other non-oral formulations of hormone therapy. In those who were additionally on low to intermediate dose statins the odds ratio was 1.29 and those on a high dose was 1.06, which showed a mitigation of elevated risk.
Additional research would include a meta-analysis of all existing randomized trials of hormone therapy as well as an increased uptake of statins. This should be looked at also for CHD, stroke as well as other CVD disease to look at outcomes to determine if there is a decreased risk. A purposeful trial that looked at statin versus placebo to determine risk would helpful.
Direct Thrombin Inhibitor Shows Benefit for Progressing Stroke
The EASE study looked at the use of aArgatroban in reducing disability after a stroke and increasing good functional outcome without the risk of excess bleeding such as ICH. Accumulated data throughout the years have shown that IV heparin has not been as beneficial as previously thought. EASE looked at 628 stroke patients at 28 Chinese sites with an average age of 65 with 63.7% being men. In tThe Aargatroban group, 98% underwent the complete procedure of aArgatroban at a median of 24 hours from symptom onset to randomization. In the control group, 89.8% were treated according to study protocol.
Stroke patients were selected within 48 hours of symptom onset to either standard therapy with or without Argatroban. The Argatroban group received IV Argatroban at a continuous infusion of 60mg/day for 2 days, followed by 20mg/day for 5 days. Controls received standard therapy such as antiplatelets. The low dose of Argatroban may explain the low rates of bleeding as opposed to results seen in the ARAIS trial.
Combining antiplatelet therapy with low dose anticoagulation has demonstrated efficacy for reducing vascular events. These results may suggest it to also be helpful in acute stroke. Limitations included that the study was not sufficiently powered, nor targeted at this treatment effect and was conducted on only one population.
Long-term Clopidogrel Has Advantages After Coronary Stenting
The one year results from the STOPDAPT-2 trial showed that clopidogrel monotherapy after 1 month of DAPT substantially reduced major bleeding without increased cardiovascular events when compared to continued DAPT in patients undergoing PCI. The 5 year results in 3005 patients with a mean age of 68.6, with 22.3% women and 38.3% with acute coronary syndrome showed that clopidogrel was noninferior to aspirin for net adverse clinical events in patients who have undergone percutaneous coronary intervention (PCI) using drug-eluting stents but was superior to aspirin in reducing secondary endpoints of myocardial infarction (MI) and ischemic stroke. The incidence of major secondary bleeding was not lower in the clopidogrel group (4.44% vs 4.92%).
This study supports that protection of ischemia post-PCI is better ensured by clopidogrel than aspirin from 1 month to 5 years. This may become the standard of care.
Limitation of the study includes the enrollment of only Japanese patients and there may be risk differences in different populations. There was no information on additional medications other than antithrombotic medicines.
Warfarin Benefits Patients After Surgical Aortic Valve Replacement
New research has shown that postoperative anticoagulation early after a surgical aortic valve replacement (SAVR) shows improved survival and a lower risk for thrombotic events, but with an increased risk for major bleeding.
Data from insured and Medicare Advantage enrollees in the US who underwent SAVR from 2007-2019 were investigated. They were matched for a 1:1 match for clinical propensity score, and studied patients who had isolated SAVT (n= 10,589) and those who had concomitant coronary artery bypass grafting (CABG). Of the SAVT patients 2930 got early anticoagulation for 30 days, 7659 did not. After subjects were matched 2930 pairs were analyzed. Primary outcomes were all cause mortality, thromboembolic events including ischemic stroke, systemic thromboembolism, PE and VTE.
Results showed that at 2 years, patients who had early use postoperative warfarin were associated with a 32% reduced risk for overall mortality. It was also associated with decreased mortality in patients undergoing isolated SAVR as week as those having concomitant CABG. There was also reduced overall thromboembolism in the warfarin group. However, there was a 1.94 increased risk for major bleeding events.
A limitation of the study was incomplete knowledge of aspirin use and the ability to assess the impact of postoperative aspirin. All patients were insured, so it may not be generalizable to the US population.
JOURNAL CLUB
Oral anticoagulation after atrial fibrillation catheter ablation: benefits and risks
Koshiro Kanaoka, Taku Nishida, Yoshitaka Iwanaga, Michikazu Nakai, Reina Tonegawa-Kuji, Yuichi Nishioka, Tomoya Myojin, Katsuki Okada, Tatsuya Noda, Kengo Kusano
European Heart Journal, ehad798,
20 December 2023
Background and Aims
Few recent large-scale studies have evaluated the risks and benefits of continuing oral anticoagulant (OAC) therapy after catheter ablation (CA) for atrial fibrillation (AF). This study evaluated the status of continuation of OAC therapy and the association between continuation of OAC therapy and thromboembolic and bleeding events according to the CHADS2 score.
Methods
This retrospective study included data from the Japanese nationwide administrative claims database of patients who underwent CA for AF between April 2014 and March 2021. Patients without AF recurrence assessed by administrative data of the treatment modalities were divided into two groups according to continuation of OAC therapy 6 months after the index CA. The primary outcomes were thromboembolism and major bleeding after a landmark period of 6 months. After inverse probability of treatment weighting analysis, the association between OAC continuation and outcomes was determined according to the CHADS2 score.
Results
Among 231 374 patients included, 69.7%, 21.6%, and 8.7% had CHADS2 scores of ≤1, 2, and ≥3, respectively. Of these, 71% continued OAC therapy at 6 months. The OAC continuation rate was higher in the high CHADS2 score group than that in the low CHADS2 score group. Among all patients, 2451 patients (0.55 per 100 person-years) had thromboembolism and 2367 (0.53 per 100 person-years) had major bleeding. In the CHADS2 score ≤1 group, the hazard ratio of the continued OAC group was 0.86 [95% confidence interval (CI): 0.74–1.01,
Conclusion:
This observational study suggests that the benefits and risks of continuing OAC therapy after CA for AF differ based on the patient's CHADS2 score. The risk of major bleeding due to OAC continuation seems to outweigh the risk reduction of thromboembolism in patients with lower thromboembolic risk.
Abbreviated or Standard Dual Antiplatelet Therapy by Sex in Patients at High Bleeding Risk: A Prespecified Secondary Analysis of a Randomized Clinical Trial
Antonio Landi, MD; Mirvat Alasnag, MD; Dik Heg, PhD; et al Enrico Frigoli, MD; Fazila Tun Nesa Malik, MBBS; Ivan Gomez-Blazquez, MD; Suzanne Pourbaix, MD; Alaide Chieffo, MD; Christian Spaulding, MD, PhD; Fermin Sainz, MD; Helen Routledge, MD; Giuseppe Andò, MD; Luca Testa, MD; Alessandro Sciahbasi, MD, PhD; Hussain Contractor, MD; Nigel Jepson, MD; Juan Mieres, MD; Syed Saqib Imran, MD; Husam Noor, MD; Pieter C. Smits, MD, PhD; Marco Valgimigli, MD, PhD; for the MASTER DAPT Investigators
JAMA Cardiol. 2024;9(1):35-44. doi:10.1001/jamacardio.2023.4316
Abstract
Importance Abbreviated dual antiplatelet therapy (DAPT) reduces bleeding with no increase in ischemic events in patients at high bleeding risk (HBR) undergoing percutaneous coronary intervention (PCI).
Objectives To evaluate the association of sex with the comparative effectiveness of abbreviated vs standard DAPT in patients with HBR.
Design, Setting, and Patients This prespecified subgroup comparative effectiveness analysis followed the Management of High Bleeding Risk Patients Post Bioresorbable Polymer Coated Stent Implantation With an Abbreviated vs Standard DAPT Regimen (MASTER DAPT) trial, a multicenter, randomized, open-label clinical trial conducted at 140 sites in 30 countries and performed from February 28, 2017, to December 5, 2019. A total of 4579 patients with HBR were randomized at 1 month after PCI to abbreviated or standard DAPT. Data were analyzed from July 1 to October 31, 2022.
Interventions Abbreviated (immediate DAPT discontinuation, followed by single APT for ≥6 months) or standard (DAPT for ≥2 additional months, followed by single APT for 11 months) treatment groups.
Main Outcomes and Measures One-year net adverse clinical events (NACEs) (a composite of death due to any cause, myocardial infarction, stroke, or major bleeding), major adverse cardiac or cerebral events (MACCEs) (a composite of death due to any cause, myocardial infarction, or stroke), and major or clinically relevant nonmajor bleeding (MCB).
Results Of the 4579 patients included in the analysis, 1408 (30.7%) were women and 3171 (69.3%) were men (mean [SD] age, 76.0 [8.7] years). Ischemic and bleeding events were similar between sexes. Abbreviated DAPT was associated with comparable NACE rates in men (hazard ratio [HR], 0.97 [95% CI, 0.75-1.24]) and women (HR, 0.87 [95% CI, 0.60-1.26];
Conclusions and Relevance These findings suggest that women with HBR did not experience higher rates of ischemic or bleeding events compared with men and may derive particular benefit from abbreviated compared with standard DAPT owing to these numerically lower rates of events.
Effectiveness of Bivalent mRNA COVID-19 Vaccines in Preventing COVID-19–Related Thromboembolic Events Among Medicare Enrollees Aged ≥65 Years and Those with End Stage Renal Disease — United States, September 2022–March 2023
Amanda B. Payne, PhD; Shannon Novosad, MD; Ryan E. Wiegand, PhD; Morgan Najdowski, MPH; Danica J. Gomes, MD; Megan Wallace, DrPH; Jeffrey A. Kelman, MD; Heng-Ming Sung, MPH; Yue Zhang, MS; Bradley Lufkin, MPA, MSES; Yoganand Chillarige, MPA; Ruth Link-Gelles, PhD
Abstract
COVID-19 has been associated with an increased risk for thromboembolic events, including ischemic stroke, venous thromboembolism, and myocardial infarction. Studies have reported lower rates of COVID-19–related thromboembolic events among persons who received the COVID-19 vaccine compared with persons who did not, but rigorous estimates of vaccine effectiveness (VE) in preventing COVID-19–related thromboembolic events are lacking. This analysis estimated the incremental benefit of receipt of a bivalent mRNA COVID-19 vaccine after receiving an original monovalent COVID-19 vaccine. To estimate VE of a bivalent mRNA COVID-19 dose in preventing thromboembolic events compared with original monovalent COVID-19 vaccine doses only, two retrospective cohort studies were conducted among Medicare fee-for-service enrollees during September 4, 2022–March 4, 2023. Effectiveness of a bivalent COVID-19 vaccine dose against COVID-19–related thromboembolic events compared with that of original vaccine alone was 47% (95% CI = 45%–49%) among Medicare enrollees aged ≥65 years and 51% (95% CI = 39%–60%) among adults aged ≥18 years with end stage renal disease receiving dialysis. VE was similar among Medicare beneficiaries with immunocompromise: 46% (95% CI = 42%–49%) among adults aged ≥65 years and 45% (95% CI = 24%–60%) among those aged ≥18 years with end stage renal disease. To help prevent complications of COVID-19, including thromboembolic events, adults should stay up to date with COVID-19 vaccination.
An architecturally rational hemostat for rapid stopping of massive bleeding on anticoagulation therapy
Vivian K. Lee, Taewoo Lee, Amrit Ghosh , Hae Lin Jang et al
January 22, 2024
Significance
Approximately 35% of hemorrhagic deaths occur before hospital arrival, with the risk amplified by anticoagulant therapies. To address this, our research introduces a next-generation chitosan hemostat, rationally designed with optimized pore size and connectivity. This design allows the hemostat to quickly absorb blood and concentrate clotting components, effectively counteracting anticoagulant effects. Contrary to previous beliefs that chitosan does not participate in the physiological clotting process, we identified its direct role in activating platelets via the TLR-2 (Toll-like receptor 2), thereby initiating the coagulation cascade in the presence of currently approved anticoagulants. This study presents an approach in hemostat development for emergency care, especially valuable for patients on anticoagulants.
Abstract
Hemostatic devices are critical for managing emergent severe bleeding. With the increased use of anticoagulant therapy, there is a need for next-generation hemostats. We rationalized that a hemostat with an architecture designed to increase contact with blood, and engineered from a material that activates a distinct and undrugged coagulation pathway can address the emerging need. Inspired by lung alveolar architecture, here, we describe the engineering of a next-generation single-phase chitosan hemostat with a tortuous spherical microporous design that enables rapid blood absorption and concentrated platelets and fibrin microthrombi in localized regions, a phenomenon less observed with other classical hemostats without structural optimization. The interaction between blood components and the porous hemostat was further amplified based on the charged surface of chitosan. Contrary to the previous beliefs that chitosan does not directly affect physiological clotting mechanism, the hemostat induced coagulation via a direct activation of platelet Toll-like receptor 2. Our engineered porous hemostat effectively stopped the bleeding from murine liver wounds, swine liver and carotid artery injuries, and the human radial artery puncture site within a few minutes with significantly reduced blood loss, even under the anticoagulant treatment. The integration of engineering design principles with an understanding of the molecular mechanisms can lead to hemostats with improved functions to address emerging medical needs.
Mortality Still Significant in High-Risk PE Despite Advances
Taisei Kobayashi, MD,January 1, 2024, in the Journal of the American College of Cardiology.
1 in 5 patients with high-risk pulmonary embolism (PE) and more than 2 in 5 with catastrophic PE with hemodynamic collapse die in the hospital, a large contemporary analysis showed.
METHODOLOGY:
- Researchers evaluated contemporary care patterns and outcomes of high-risk PE using data from the Pulmonary Embolism Response Team (PERT) Consortium Registry, a prospective collaboration of 35 centers in the United States with dedicated multidisciplinary PERTs.
- The cohort included 2976 patients with intermediate-risk PE and 1442 with high-risk PE. The high-risk PE group included 197 patients with catastrophic PE with hemodynamic collapse.
- The co-primary endpoints were in-hospital mortality and major bleeding; multivariable regression analysis was used to identify baseline factors independently associated with the primary endpoints.
TAKEAWAY:
- Patients with high-risk PE were more likely than those with intermediate-risk PE to undergo advanced therapies (41.9% vs 30.2%), including systemic thrombolysis, surgical embolectomy, and mechanical circulatory support, with no difference in catheter-based therapies.
- The risk for in-hospital major bleeding increased proportionally with the severity of PE presentation.
- In-hospital mortality was 20.6% in high-risk PE vs 3.7% in intermediate-risk PE; it was 42.1% in catastrophic high-risk PE with hemodynamic collapse vs 17.2% in noncatastrophic high-risk PE.
- Factors associated with in-hospital mortality were vasopressor use (odds ratio [OR], 4.56), extracorporeal membrane oxygenation use (OR, 2.86), identified clot-in-transit (OR, 2.26), and malignancy (OR, 1.70).
IN PRACTICE:
"Disappointingly, our data continue to show significant mortality in patients experiencing high-risk PE despite technological advancements in catheter-based and surgical strategies, as well as the larger national implementation of PERT teams," the authors concluded. "This study underlines the need for a larger societal role and a call to action to produce more high-quality research in this devastating condition, as well as consideration of standardized practices across the nation, given that similar efforts in the past have led to decreased mortality in other cardiovascular emergencies such as acute myocardial infarctions and stroke."
LIMITATIONS:
The findings are limited to the experience of mainly tertiary care centers with active PERTs. The designation of catastrophic PE was interpreted based on local PERT centers' discretion and could not be individually adjudicated. Factors associated with in-hospital mortality should be viewed as hypothesis-generating, with confirmation needed.