January 2024: New In Coagulation
by Donna Castellone • January 17, 2024
Our Monthly complilation of the latest studies, guidelines and discussions in coagulation.
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High-Sensitivity Troponin Test May Overestimate Risk in PE
The PROTECT cohort study did not find any prognostic value resulting from mild elevation found only in high-sensitive cardiac troponin (hs-cTnI) in patients with a stable pulmonary embolism (PE) in the ED. This was opposed to the findings of the conventional cardiac troponin (cTnI). An elevation of this test was associated with a complicated course including a hemodynamic collapse, recurrent PE, or all cause death within 30 days post PE. This was not seen with hs-cTnl which classified fewer patients as low risk, but none of these patients with a normal hs-cTnl has a complicated course of the disease. Relying on the hs-cTnl may result in clinicians overestimating risk in patients with stable PE. This could result in increased LOS without any better patient outcomes. A higher cut off for the hs-cTnl may be needed for risk stratification in PE patients. This test is becoming more utilized than cTnl.
The PROTECT main finding was that RV dysfunction was not a predictor of outcomes for the 848 patients with acute PE. Results showed a positive cTnl in 16.7% of patients, with 31.7% positive using hs-cTnl. Based on conventional troponin results 29.6% of PE patients were considered low-risk vs 20.3% with hs -cTnl. None of the 78 patients designated as low risk with cTnl but not hs-cTnl resulted with a complicated course.
VTE Risk After Joint Replacement: Does Anticoagulant Choice Matter?
A retrospective study that looked at younger patients undergoing total hip or knee replacement, demonstrated no difference in risk for VTE post surgery whether they were given aspirin or DOACs. However, bleeding risks were higher with DOACs.
VTE risk was almost entirely predicted by standard patient-related factors, including previous VTE, hereditary hypercoagulability, male, knee versus hip replacement. These findings suggest patient-centric thrombophylaxis to the individuals risk of thrombosis and bleeding.
Three years of data from Medicare supplemental insurance looked at patients that had left and right joints replaced. Patients were excluded if they received anticoagulants 2 weeks prior to procedure or if they didn't receive post operative anticoagulants, There were 132,000 patients who met this criteria however more than 95,000 didn't reflect a thromboprophylaxis prescription. In the 29,284 patients 63% had knee replacements, 42% were male, and 82% were younger than 65. Of this cohort, 34.5% received aspirin, 19.7% enoxaparin, 11.1% warfarin, 24.2% rivaroxaban and 10.6% apixaban. Results showed 30 day rates for VTE were 1.19% and 3.43% for bleeding versus 90 days 1.86% and 5.33% respectively. VTE was lowest at 30 days in those on aspirin.
When comparing aspirin with the two DOACs, 7844 patients in each group, differences in VTE were insignificant despite the higher bleeding risk with the DOACs and remained the same at 90 days regarding VTE and bleeding. This may be the result that aspirin was taken for 31 days versus 18 days on DOACs.
But in a propensity-matched comparison of aspirin with the two DOACs -- with 7,844 patients in each group -- the differences in VTE risk shrank into insignificance, even as the higher bleeding risk with DOACs became clearer. Findings were similar for 90-day risks for VTE and bleeding. One factor driving these results might have been that aspirin was taken for longer than were DOACs: median durations were 31 days for aspirin versus 18 days for DOACs.
Limitations of the study included this study included a small fraction of the 1.5 million knee and hip replacements and information was obtained from administrative date which may not include relevant information.
Inappropriate Aspirin Use Continues, Research Suggests
Two retrospective studies found that some patients may be taking aspirin inappropriately. One study at an academic medical center 93/225 patients on both a DOAC and aspirin with coronary artery disease were eligible for aspirin but only 20.4% were prescribed it at discharge. The AHA Chronic Coronary Disease suggests that patients on a DOAC, aspirin may be deprescribed due to bleeding risk.
A second study showed that 18.4% of patients in a primary care clinic ages 60 years and older used aspirin for prevention of cardiovascular disease. In 2022 the recommendation changed so as not to initiate aspirin in this group of people due to increased bleeding risk. These guidelines are not often implemented in routine care. Pharmacist led interventions was an excellent way to improve adherence to guidelines.
Emicizumab Safe, Effective, in Infants With Hemophilia A
The HAVEN-7 study showed that giving emicizumab to infants with severe hemophilia who were previously untreated or minimally treated, who did not have a FVIII inhibitor is effective and safe.The previous approach to treating hemophilia was prophylactic FVIII concentrates via frequent IV infusions due to a short half life. Emicizumab is a bispecifc human monoclonal antibody that works by bridging FIX and FX to substitute for the deficient activated FVIII.
A median follow-up of 101.9 weeks showed the annualized treated bleeding rate was 0.4. With a total of 55 all male participants (median age=29 months; 45.5% under the age of 3 months, and 54.5% between the age of 3 months and 1 year), All received the drug for a minimum of 52 weeks. 54.5% had no treated bleeds. The rate for all bleeds was 2.0 with no treated spontaneous bleeds. Most children don't start receiving prophylaxis until after their first year of life mostly due to venous access and the need for central venous access devices. Emicizumab can be administered subcutaneously and can be given early on in life and can mitigate the risk of untreated or spontaneous bleed which can lead to damaged into joints as well as the risk of intracranial hemorrhage.
Prior to the study 54.5% of infants were minimally treated and 45.5% were previously untreated. Emicizumab was given for 4 weeks (3mg/kg) then every 2 weeks. For the seven year follow up they could stay on this regimen or switch to either 1.5 mg/kg weekly or 6 mg/kg every 4 weeks. There were 207 bleeds in 46 participants, 42 traumatic treated bleeds were reported in 25 participants. There were no children that had more than 3 treated bleeds and 9 had no bleeds. Two children had more than 10 bleeds all untreated and no joint bleeds.
All 55 participants were evaluable for immunogenicity in order to show they had no anti-drug antibodies to emicizumab, and that in about half (28) there was at least one factor VIII exposure. Following factor VIII exposure, 24 participants were evaluated for a factor VIII inhibitor; only two tested positive, but still continued with treatment.
FDA approves first gene therapies to treat patients with sickle cell disease
Casgevy and Lyfgenia was given FDA approval as the first cell-based gene therapy for treatment of sickle cell disease (SCD) in patients 12 and older.
Casgevy uses CRISPR/Cas9 a genome editing technology which uses patients' stem cells. This technology is directed to cut DNA in targeted areas and edit DNA where it was cut. Stem cells are then transplanted back into the patient via infusion and increase the production of fetal hemoglobin which increased oxygen deliver and preventing the sickling of RBCs.
Lyfgenia is a cell-based gene therapy that uses a lentiviral vector for genetic modification. The patient's blood stem cells are genetically modified to produce HbAT87Q, a gene-therapy derived hemoglobin that functions similarly to hemoglobin A resulting in cells having a lower risk of sickling.
Prior to treatment patients must undergo myeloablative conditioning before receiving a one time infusion. In the study primary outcome was freedom from VOC episodes for at least 12 consecutive months during the 24 month follow up. There were 44 patients treated with Casgevy and 31 patients had sufficient follow up time. Of those 93.5% achieved successful engraftment. The effectiveness of Lyfgenia was based on complete resolution of VOEs between 6-18 months post infusion. This was achieved in 28/32 patients.
Novel Monoclonal Antibody Reduces Bleeds in Hemophilia A and B
Martacimab (Pfizer) is targeted to the tissue factor pathway inhibitor protein to improve hemostasis via the extrinsic pathway. BASIS included 128 patients, 108 adults and 20 adolescents with hemophilia A or B receiving either on demand (37 patients) or routine prophylaxis (n=91) of FVIII or FIX, and this was completed by 116 patients. They crossed over to a 12 month active treatment getting a single subQ loading dose of 300mg followed by once/week 150mg.
The BASIS trial demonstrated that the monoclonal antibody marstacimab (Pfizer) reduced the rate of bleeding in patients with hemophilia A or B without inhibitors to FVIII or FIX by 91.6% when compared to on-demand therapy and by 35.2% when compared to prophylactic care. This lasted through the 12 months of the study as well as an additional 16 months in the long-term extension study.
A decision for acceptance should be made in the fourth quarter of 2024 and will be the first once-weekly subcutaneous treatment for people living with hemophilia B, and as a flat dose in people living with hemophilia A.
It also showed superiority compared with previous on demand therapy for joint bleeds, spontaneous bleeds, target joint bleeds and total bleeds. Marstacimab was non-inferior to routine prophylaxis with factor concentrates across these categories. There were no embolic or thrombotic events observed with marstacimab.
Anticoagulants Safe With Enzyme-Inducing Meds for Epilepsy
Preliminary results of a study have shown that in patients with epilepsy, combining an enzyme-inducing antiseizure medication with a DOAC doesn't significantly increase the risk of thromboembolic events and may be associated with a reduction in major bleeding events. These enzyme-inducing drugs may result in wide ranging interactions but the clinical significance of their pharmacokinetics is not completely understood. Based on in-vitro and animal studies evidence has suggested that these drugs may accelerate metabolism of DOACs and potentially lowering DOAC levels ad elevating thromboembolism risk.
To address the clinical uncertainty, healthcare claims from October 2010 to September 2021 were analyzed since a clinical trial would not be feasible or ethical. An active comparator looked a new user cohorts among epilepsy adults who had been co-prescribed these drugs. Thromboembolic and major bleeding events were compared between exposure to DOACs with enzyme-inducing antiseizure medications (carbamazepine, oxcarbazepine, phenobarbital, phenytoin, primidone, and topiramate) vs exposure to DOACs with non-enzyme inducing antiseizure medications (gabapentin, lacosamide, lamotrigine, levetiracetam, and pregabalin).
There cohorts were analyzed for outcomes: DOACs for any indication; DOACs for AF, and those on DOACs for VTE. There were 5989 thromboembolic events in patients on DOACs and enzyme antiseizure medications compared with a reference group of 14671 episodes in patients on DOACs and non-enzyme antiseizure medications. With the reference group being older, and with major comorbidities.
Results showed that there is no significant elevation of thromboembolic events in patients on DOACs and enzyme inducing antiseizure medication. However, each patient's risk should be evaluated individually.
Pomalidomide Cuts Severe Epistaxis in Genetic Bleeding Disorder
Hereditary hemorrhagic telangiectasia (HHT) is the second most common bleeding disorder behind von Willebrand Disease. It is characterized by formation of telangiectasia, or spider veins, along with arteriovenous malformations (AVMs) on mucosal surfaces and in the lungs, brain, liver, and spinal cord. Severe epistaxis is the most common occurrence and can lead to iron deficiency anemia. HHT pathogenesis involves altered TGF-β signaling, with mutations in ENG, ACVRL1, and SMAD4 associated with the condition in more than 90% of cases.
A double blind study PATH-HHT conducted rom 2019-2023 randomized 144 HHT patients to 24 weeks of daily treatment with pomalidomide or matched placebo who had a confirmed diagnosis of HHT based on Curacao Diagnostic Criteria. HHT is considered a systemic vascular dysplasia of dysregulated angiogenesis, and pomalidomide has been shown to have anti-angiogenic activity. Mean age was 59, 48% female, 11% non-white and 3% Hispanic. In 134 patients who had genetic testing ENG mutations were detected in 37%, ACVRL1 in 51%, and SMAD4 in 1%. Patients at baseline had a mean daily epistaxis duration of 16 minutes, and in the preceding 6 months 84% required iron infusions and 19% blood transfusions, more than a third had GI bleeding and 40% had pulmonary AVMs.
Results showed that at up to 24 weeks, daily treatment with the multiple myeloma drug pomalidomide demonstrated a greater reduction in patients epistaxis severity score compare with placebo. A 4-mg dose improved quality of life, increased hemoglobin, hematocrit and MCV.
Patients (14%) assigned to pomalidomide discontinued the drug due to toxicity. Adverse events included neutropenia, rash, constipation, diarrhea and mild tremor. No Thrombosis or opportunistic infections occurred in these patients.
JOURNAL CLUB
Comparing Efficacy and Safety Between Patients With Atrial Fibrillation Taking Direct Oral Anticoagulants or Warfarin After Direct Oral Anticoagulant Failure
Meng-Tsang Hsieh, Chi-Hung Liu, Sheng-Hsiang Lin, Po-Yu Lin, Yu-Ming Chang, Chun-Min Wang, Chih-Hung Chen and Pi-Shan Sung
Dec 2023, Journal of the American Heart Association. 2023
Abstract: An increased risk of recurrent stroke is noted in patients with atrial fibrillation despite direct oral anticoagulant (DOAC) use. We investigated the efficacy and safety of treatment with each of 4 different DOACs or warfarin after DOAC failure.
Methods and Results: We retrospectively analyzed patients with atrial fibrillation with ischemic stroke despite DOAC treatment between January 2002 and December 2016. The different outcomes of patients with DOAC failure were compared, including recurrent ischemic stroke, major cardiovascular events, intracranial hemorrhage and subarachnoid hemorrhage, mortality, and net composite outcomes according to switching to different DOACs or vitamin K antagonist after index ischemic stroke. We identified 3759 patients with DOAC failure. A total of 84 patients experienced recurrent ischemic stroke after switching to different oral anticoagulants, with a total follow-up time of 14 years. Using the vitamin K antagonist group as a reference, switching to any of the 4 DOACs was associated with a 69% to 77% reduced risk of major cardiovascular events (adjusted hazard ratio [aHR], 0.25 [95% CI, 0.16–0.39] for apixaban, 0.23 [95% CI, 0.14–0.37] for dabigatran, 0.23 [95% CI, 0.09–0.60] for edoxaban, and 0.31 [95% CI, 0.21–0.45] for rivaroxaban), and a 69% to 83% reduced risk of net composite outcomes (aHR, 0.25 [95% CI, 0.18–0.35] for apixaban, 0.17 [95% CI, 0.11–0.25] for dabigatran, 0.31 [95% CI, 0.17–0.56] for edoxaban, and 0.31 [95% CI, 0.23–0.41] for rivaroxaban).
Conclusions: In Asian patients with DOAC failure, continuing DOACs after index stroke was associated with fewer undesirable outcomes than switching to a vitamin K antagonist. Alternative pharmacologic and nonpharmacologic strategies warrant investigation.
Severity of Ischemic Stroke After Left Atrial Appendage Closure vs Nonwarfarin Oral Anticoagulants
Mohit K. Turagam, Iwanari Kawamura, Petr Neuzil, Devi Nair, Shephal Doshi, Miguel Valderrabano, Pavel Hala, Domenico Della Rocca, Douglas Gibson, Moritoshi Funasako, Grace Ha, Bridget Lee, Daniel Musikantow
J Am Coll Cardiol EP. Nov 22, 2023.
Abstract
Background
Strokes after left atrial appendage closure (LAAC) prophylaxis are generally less severe than those after warfarin prophylaxis—thought to be secondary to more hemorrhagic strokes with warfarin. Hemorrhagic strokes are similarly infrequent with direct oral anticoagulant (DOAC) prophylaxis, so the primary subtype after either LAAC or DOAC prophylaxis is ischemic stroke (IS).
Objectives
The purpose of this study was to compare the severity of IS using the modified Rankin Scale in atrial fibrillation patients receiving prophylaxis with DOACs vs LAAC.
Methods
A retrospective analysis was performed of consecutive patients undergoing LAAC at 8 centers who developed an IS (ISLAAC) compared with contemporaneous consecutive patients who developed IS during treatment with DOACs (ISDOAC). The primary outcome was disabling/fatal stroke (modified Rankin Scale 3-5) at discharge and 3 months later.
Results
Compared with ISDOAC patients (n = 322), ISLAAC patients (n = 125) were older (age 77.2 ± 13.4 years vs 73.1 ± 11.9 years;
Conclusions
Ischemic strokes in patients with atrial fibrillation are less often disabling or fatal with LAAC than DOAC prophylaxis.
Tranexamic Acid for Traumatic Injury in the Emergency Setting: A Systematic Review and BiasAdjusted Meta-Analysis of Randomized Controlled Trials
Pieter Francsois Fouche, MScMed (ClinEpi), PhD*; Christopher Stein, PhD; Martin Nichols, MHlthSc, MBA; Benjamin Meadley, PhD;Jason C. Bendall, MBBS, MM (ClinEpi), PhD; Karen Smith, BSc (Hons), Grad Dip Epi&Biostats, Grad Cert Exec BA, PhD; David Anderson, MBChB; Suhail A. Doi, MBBS, MClinEpid, PhD
Annuals of Emergency Medicine: Published:November 22, 2023
Study objective: Traumatic injury causes a significant number of deaths due to bleeding. Tranexamic acid (TXA), an antifibrinolytic agent, can reduce bleeding in traumatic injuries and potentially enhance outcomes. Previous reviews suggested potential TXA benefits but did not consider the latest trials.
Methods: A systematic review and bias-adjusted meta-analysis were performed to assess TXA's effectiveness in emergency traumatic injury settings by pooling estimates from randomized controlled trials. Researchers searched Medline, Embase, and Cochrane Central for randomized controlled trials comparing TXA's effects to a placebo in emergency trauma cases. The primary endpoint was 1-month mortality. The methodological quality of the trials underwent assessment using the MASTER scale, and the meta-analysis applied the quality-effects method to adjust for methodological quality.
Results: Seven randomized controlled trials met the set criteria. This meta-analysis indicated an 11% decrease in the death risk at 1 month after TXA use (odds ratio [OR] 0.89, 95% confidence interval [CI] 0.84 to 0.95) with a number needed to treat of 61 to avoid 1 additional death. The meta-analysis also revealed reduced 24-hour mortality (OR 0.76, 95% CI 0.65 to 0.88) for TXA. No compelling evidence of increased vascular occlusive events emerged (OR 0.96, 95% CI 0.73 to 1.27). Subgroup analyses highlighted TXA's effectiveness in general trauma versus traumatic brain injury and survival advantages when administered out-of hospital versus in hospital.
Conclusions: This synthesis demonstrates that TXA use for trauma in emergencies leads to a reduction in 1-month mortality, with no significant evidence of problematic vascular occlusive events. Administering TXA in the out-of-hospital setting is associated with reduced mortality compared to inhospital administration, and less mortality with TXA in systemic trauma is noted compared with traumatic brain injury specifically.
Dual Antiplatelet Therapy De-Escalation in Stabilized Myocardial Infarction With High Ischemic Risk
Post Hoc Analysis of the TALOS-AMI Randomized Clinical Trial
Myunhee Lee, MD; Sungwook Byun, MD, PhD; Sungmin Lim, MD, PhD; et alEun Ho Choo, MD, PhD; Kwan Yong Lee, MD, PhD; Donggyu Moon, MD; Ik Jun Choi, MD, PhD; Byung-Hee Hwang, MD, PhD; Chan Joon Kim, MD, PhD; Mahn-Won Park, MD, PhD; Yun Seok Choi, MD, PhD; Hee-Yeol Kim, MD, PhD; Ki-Dong Yoo, MD, PhD; Doo-Soo Jeon, MD, PhD; Hyeon Woo Yim, MD, PhD; Kiyuk Chang, MD, PhD; for the TALOS-AMI Investigators
JAMA Cardiol. Published online December 20, 2023.
Question Is the de-escalation strategy of switching from ticagrelor to clopidogrel after 1 month of percutaneous coronary intervention suitable for patients with acute myocardial infarction with high ischemic risk?
Findings In this post hoc analysis of the Ticagrelor vs Clopidogrel in Stabilized Patients With Acute Myocardial Infarction (TALOS-AMI) randomized clinical trial, 1371 patients (50.8%) were classified as having high ischemic risk. Compared with ticagrelor-based dual antiplatelet therapy, the ischemic and bleeding outcomes of an unguided de-escalation strategy were consistent regardless of the presence of high ischemic risk features, with no heterogeneity.
Meaning The findings suggest that the de-escalation strategy is a safe and reasonable option following myocardial infarction in patients with high ischemic risk.
Importance In patients with acute myocardial infarction (AMI) who have high ischemic risk, data on the efficacy and safety of the de-escalation strategy of switching from ticagrelor to clopidogrel are lacking.
Objective To evaluate the outcomes of the de-escalation strategy compared with dual antiplatelet therapy (DAPT) with ticagrelor in stabilized patients with AMI and high ischemic risk following percutaneous coronary intervention (PCI).
Design, Setting, and Participants This was a post hoc analysis of the Ticagrelor vs Clopidogrel in Stabilized Patients With Acute Myocardial Infarction (TALOS-AMI) trial, an open-label, assessor-blinded, multicenter, randomized clinical trial. Patients with AMI who had no event during 1 month of ticagrelor-based DAPT after PCI were included. High ischemic risk was defined as having a history of diabetes or chronic kidney disease, multivessel PCI, at least 3 lesions treated, total stent length greater than 60 mm, at least 3 stents implanted, left main PCI, or bifurcation PCI with at least 2 stents. Data were collected from February 14, 2014, to January 21, 2021, and analyzed from December 1, 2021, to June 30, 2022.
Intervention Patients were randomly assigned to either de-escalation from ticagrelor to clopidogrel or ticagrelor-based DAPT.
Main Outcomes and Measures Ischemic outcomes (composite of cardiovascular death, myocardial infarction, ischemic stroke, ischemia-driven revascularization, or stent thrombosis) and bleeding outcomes (Bleeding Academic Research Consortium type 2, 3, or 5 bleeding) were evaluated.
Results Of 2697 patients with AMI (mean [SD] age, 60.0 [11.4] years; 454 [16.8%] female), 1371 (50.8%; 684 assigned to de-escalation and 687 assigned to ticagrelor-based DAPT) had high ischemic risk features and a significantly higher risk of ischemic outcomes than those without high ischemic risk (1326 patients [49.2%], including 665 assigned to de-escalation and 661 assigned to ticagrelor-based DAPT) (hazard ratio [HR], 1.74; 95% CI, 1.15-2.63;
Conclusions and Relevance In stabilized patients with AMI, the ischemic and bleeding outcomes of an unguided de-escalation strategy with clopidogrel compared with a ticagrelor-based DAPT strategy were consistent without significant interaction, regardless of the presence of high ischemic risk.