August 2024: New In Coagulation
by Donna Castellone • August 07, 2024
Our Monthly complilation of the latest studies, guidelines and discussions in coagulation.
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A More Selective Enoxaparin Thromboprophylaxis Protocol May Be Safer for New Moms
Treating postpartum women using a selective risk-stratified approach was linked to reduced rates of wound hematomas from delivery to 6 weeks post partum (0,.3% vs. 0.7%) without increasing the rate of VTE (0.008% vs 0.0014%). A retrospective observational study was conducted on 17,000 patients. Patients receiving outpatient anticoagulation for active VTE or considered high risk for VTE during pregnancy were excluded.
In 2016 a risk- stratified enoxaparin protocol was implemented based on observational data and expert opinions as well as recommendations from the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine. Results showed an increase in wound hematomas. In 2021 a more selective risk-stratified approach was compared to the original protocol and results were compared. The more selective protocol used enoxaparin if patients had a history of VTE, or nephrotic syndrome and three additional risk factors. Other changes included: Removal of preeclampsia, ages 40 and older, and thrombophilia as risk factors; Downgrading pre-pregnancy BMI ≥40 to a secondary risk factor; Making sepsis a risk factor instead of any major infection; Raising the bar for systemic lupus erythematosus patients to those already taking at least two medications for it. As a result of using this criteria, enoxaparin use went from 16% to 8%.
Confounding variables could not be addressed due to the retrospective design and if the results transfer to other institutions/populations.
Is Elevated Lp(a) a Prescription for Aspirin?
A consensus statement from the European Atherosclerosis Society in 2022 supported a causal association between Lp(a) concentration and cardiovascular outcomes, despite patients having low LDL cholesterol levels. This is due to the pro-inflammatory and pro-atherosclerotic properties. High levels are associated with both micro and macrocalcification of the aortic valve. Lp(a) is genetically determined and there are no drugs that decrease levels. It is recommended that all adults be tested at least once in their lifetime. However, there is not a good mechanism for testing and physician knowledge of testing is limited. Also, there is the question if you can't lower Lp(a) why should you test it?
If patients have an intermediate to high cardiovascular risk and find out they have an elevated Lp(a) they should be treated to ensure their LDL cholesterol and BP is lower, weight loss and statin therapy. What is the role of aspirin in these patients? A recent study showed that regular aspirin use was associated with a significantly lower rate of ASCVD mortality in adults without clinical ASCVD but who had elevated Lp(a) which may be prothrombotic, so aspirin may be useful. However, the risk of bleeding must be evaluated for each patient.
Which Anticoagulant Is Safest for Afib Patients With Cirrhosis?
Results from 12,000 patients showed those who were on rivaroxaban had a 47% higher rate of major hemorrhage when compared with patients on apixaban in patients with cirrhosis and AF. Increased rates of bleeding with rivaroxaban was also seen in the general population when compared with apixaban. Patients on warfarin presented with a 38% higher rate of major hemorrhage. The preferred drugs for AF are rivaroxaban and apixaban and used more often than warfarin, including in cirrhosis patients.
Data was analyzed from 2013-2022 using Medicare and Optum's Clinformatics Data Mart Database. The study incorporated a clinical trial emulation analytical framework and a new-user, active comparator design, which has been shown to replicate findings from clinical trials. Adjustments were made for more than 100 baseline variables. A primary outcome was major hemorrhagic events (stroke, ICH, GI bleed) as well as major ischemic events (stroke, embolism). Subgroup analysis showed excess bleeding risk with rivaroxaban tended to be higher in patients initiating reduced-dose rivaroxaban versus apixaban but were not statistically significant, but may be due to pharmacokinetic profiles. Apixaban has less inter subject variability, smaller peak to trough fluctuations in plasma concentrations when compared to rivaroxaban suggesting more constant anticoagulation.
Oral Anticoagulation, AF, and Recurrent Stroke Risk: New Data
Ischemic stroke risk is still high in patients on OAC with AF, but when the OAC was discontinued the risk was doubled when compared with those still on OAC. In 8000 patients with AF and IS were studied who were initiating or restarting treatment. Those with IS were matched to patients receiving OAC who had an IS. Patients were followed for 3 years.
Of those taking OACs who sustained a recurrent stroke during the study, 80% were taking currently OACS. However, those who discontinued OAC doubled the risk for recurrent IS compared with those who continued OAC. Most studies have looked at the increased risk prior to the initial IS and not OAC discontinuation and the risk of recurrent IS.
The study included 8119 patients (mean age 78.4, 54.1% men) with follow up of 2.9 years. Of these patients, 663 patients had recurrent IS and 80.4% were taking OAC. At 1 year, recurrent IS and all cause mortality were 4.3% and 15.4%, while in those who discontinued OAC had a twofold higher risk for IS with more severe strokes and higher mortality rates.
Limitations of the study include underreporting of IS, only acute strokes are reported so milder ones may not be captured. Data on alcohol intake and socioeconomic information were not included as possible cofounders. The study was performed on a Danish population and may not be transferable to other populations.
Experts Debate the Pros and Cons of Early Anticoagulation in Severe Stroke With AF
A debate about the pros and cons of early versus late initiation of a OAC post IS in the setting of AF for secondary prevention revealed 77% in favor of early anticoagulation versus 23% for no early anticoagulation. While clinicians are scared of recurrent IS, they also risk hemorrhage in particular ICH which is more severe than IS. As a result many hospitals initiate OAC later. Also, older patients have a higher risk due to comorbidities and poly pharmacy, so this needs to be considered. Approach to OAC should be individualized. More focused guidelines are needed based on whether the stroke is severe or patient is at a risk of hemorrhage. Current practices of stroke centers include initiating oral anticoagulation 3 or 4 days after minor stroke, 6 or 7 days after moderate stroke, and up to 14 days after a major stroke will be slowly abandoned.
The TIMING study looked at early vs delayed non-Vitamin K antagonist OAC after IS in AF patients in 880 patients. These were randomly assigned to receive OAC within 4 days of stroke or delayed 5-10 days with a primary outcome of recurrent IS, ICH, or all cause mortality at 90 days. Results showed lower rates of IS and death with no ICH in those with early OAC.
In the ELAN trial which included 2000 patients, OAC was started within 48 hours of a minor or moderate stroke, and those with a major stroke began on day 6 or 7. The alternate later-treatment strategy started at day 3 or 4 after a minor stroke; day 6 or 7 after a moderate stroke; or day 12, 13, or 14 after a major stroke. Results showed starting treatment earlier was not associated with an increased risk for ICH, but a lower risk of IS again pointing to early treatment. A post hoc analysis showed that in all infarct size groups, there were less primary outcome events in those receiving early anticoagulation. Those with a major stroke may have the largest benefit of early anticoagulation.
The fear in treating strokes is the risk of bleeding. The median age of ELAN was 77 with the oldest patient being 84. Older patients had a 2.5 fold increased risk for stroke or systemic embolism and major bleeding with OAC. It is important to consider the risks vs benefits of early OAC in this cohort.
The European Heart Rhythm Association (EHRA) recommends starting OAC after 12 or 14 days in major stroke. The 2020 European Society of Cardiology (ESC) guidelines on the diagnosis and management of AF don't have timing recommendations. Neither do the 2019 guidelines from the European Stroke Organisation (ESO) "because of the low quality of evidence"; ESO recommends initiating OAC treatment after 14 days in patients with major ischemic stroke.
When should OAC be reinitiated post hemorrhage, a survey from EHRA showed most people started within 30 days. A retrospective study showed 15-30 days after brain hemorrhage is best because there is a benefit from anticoagulation but no increased risk in bleeding. An observational study from the Swedish Registry said 7-8 weeks post brain hemorrhage.
Guidelines have different opinions: EHRA suggest beginning OAC 4-8 weeks after removing brain hematoma. ESC guidelines recommend 4 weeks, ESO make no specific recommendation about timing but to consider the risks and benefits. While those from the AHA/ASA have changed from 4 weeks in 205 to 7-8 weeks in 2022.
There is still no definitive answer as when to start OAC, but certain groups of patients should start later including older people will comorbidities and polypharmacy, and those with cerebral microbleeds.
Efanesoctocog Alfa Prevented Bleeding in Kids With Severe Hemophilia A
In the phase III XTEND-kids study eflanesoctocog alfa was given once weekly prophylactically and results showed sustained Factor VIII activity and prevented bleeding in children with severe hemophilia A. The study included 74 males under the age of 12 median age of 5, 74% were white, 11% were Asian and 4% Black. No treated bleeding episodes occurred in 64% of patients, 88% did not have spontaneous bleeds and 82% did not have hemoarthrosis. Poor joint health can have an impact on quality of life. No VIII inhibitors developed.
In 2023, the FDA approved eflanesoctocog alfa for the treatment of adults and children with hemophilia A based on the phase III XTEND-1. Only patients without inhibitors and prior exposure to FVIII were enrolled in the trial. Immunogenicity needs to be assessed in other patients, in particular those with no previous treatment of FVIII.
JOURNAL CLUB
A More Selective vs a Standard Risk-Stratified, Heparin-Based, Obstetric Thromboprophylaxis Protocol
Macie L. Champion, MD; Christina T. Blanchard, MS; Michelle Y. Lu, MD; et alAshley E. Shea, MD, MPH; Anna I. Lively, BS; J. Morgan Jenkins, BS; Samantha E. Howell, MD; Grace M. Lee, MD; Brian M. Casey, MD; Ashley N. Battarbee, MD, MSCR; Akila Subramaniam, MD, MPH
Abstract
Importance In 2016, our institution adopted a pregnancy-related venous thromboembolism (VTE) prophylaxis protocol based on American College of Obstetricians and Gynecologists guidelines that recommended postpartum heparin-based chemoprophylaxis (enoxaparin) based on a risk-stratified algorithm. In response to increased wound hematomas without significant reduction in VTE using this protocol, a more selective risk-stratified approach was adopted in 2021.
Objective To evaluate outcomes of the more selective risk-stratified approach to heparin-based obstetric thromboprophylaxis (enoxaparin) protocol.
Design, Setting, and Participants Retrospective observational study of 17 489 patients who delivered at a single tertiary care center in the southeast US between January 1, 2016, and December 31, 2018 (original protocol), and between December 1, 2021, and May 31, 2023 (more selective protocol). Patients receiving outpatient anticoagulation for active VTE or high VTE risk during pregnancy were excluded.
Exposure Standard risk-stratified and more selective postpartum VTE chemoprophylaxis protocols.
Main Outcomes and Measures The primary outcome was clinical diagnosis of wound hematoma up to 6 weeks pos tpartum. The secondary outcome was new diagnosis of VTE up to 6 weeks post partum. We compared baseline characteristics and outcomes between groups and estimated adjusted odds ratios with 95% CIs of primary and secondary outcomes using the original protocol group as reference.
Results Of 17 489 patients included in the analysis, 12 430 (71%) were in the original protocol group and 5029 (29%) were in the more selective group. Rates of chemoprophylaxis decreased from 16% (original protocol) to 8% (more selective protocol). Patients in the more selective group were more likely to be older, be married, and have obesity or other comorbidities (hypertension, diabetes, cardiac disease). Compared with the original protocol, the more selective protocol was associated with a decrease in any wound hematoma (0.7% vs 0.3%; adjusted odds ratio [aOR], 0.38; 95% CI, 0.21-0.67), specifically due to a lower rate of superficial wound hematomas (0.6% vs 0.3%; aOR, 0.43; 95% CI, 0.24-0.75). There was no significant increase in VTE or individual types of VTE (0.1% vs 0.1%; aOR, 0.40; 95% CI, 0.12-1.36).
Conclusions and Relevance A more selective risk-stratified approach to an enoxaparin thromboprophylaxis protocol for VTE was associated with decreased rates of wound hematomas without increased rates of postpartum VTE.
Dose Reduction of Edoxaban in Patients 80 Years and Older With Atrial Fibrillation: Post Hoc Analysis of the ENGAGE AF-TIMI 48 Randomized Clinical Trial
André Zimerman, MD, PhD; Eugene Braunwald, MD; Jan Steffel, MD; et alNicolas M. Van Mieghem, MD, PhD; Michael G. Palazzolo, MS; Sabina A. Murphy, MPH; Cathy Zi Li Chen, MD, MSc; Martin Unverdorben, MD, PhD; Christian T. Ruff, MD, MPH; Elliott M. Antman, MD; Robert P. Giugliano, MD, SM
Abstract
Importance In older patients with atrial fibrillation who take anticoagulants for stroke prevention, bleeding is increased compared with younger patients, thus, clinicians frequently prescribe lower than recommended doses in older patients despite limited randomized data.
Objective To evaluate ischemic and bleeding outcomes in patients 80 years and older with atrial fibrillation receiving edoxaban, 60 mg vs 30 mg, and edoxaban, 30 mg vs warfarin.
Design, Setting, and Participants The ENGAGE AF-TIMI 48 trial (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48) was a parallel-design, double-blind, global clinical trial that randomized patients with atrial fibrillation to either one of 2 edoxaban dosing regimens or warfarin. This secondary analysis focused on patients 80 years or older without dose-reduction criteria receiving edoxaban, 60 mg vs 30 mg, as well as patients with or without dose-reduction criteria receiving edoxaban, 30 mg, vs warfarin. Study data were analyzed between October 2022 and December 2023.
Interventions Oral edoxaban, 30 mg once daily; edoxaban, 60 mg once daily; or warfarin.
Main Outcomes and Measures Primary net clinical outcome of death, stroke or systemic embolism, and major bleeding and each individual component.
Results The current analysis included 2966 patients 80 years and older (mean [SD] age, 83 [2.7] years; 1671 male [56%]). Among 1138 patients 80 years and older without dose-reduction criteria, those receiving edoxaban, 60 mg vs 30 mg, had more major bleeding events (hazard ratio [HR], 1.57; 95% CI, 1.04-2.38;
Conclusions and Relevance In this post hoc analysis of the ENGAGE AF-TIMI 48 randomized clinical trial, in patients 80 years and older with atrial fibrillation, major bleeding events were lower in patients randomized to receive edoxaban, 30 mg per day, compared with either edoxaban, 60 mg per day (in patients without dose-reduction criteria), or warfarin (irrespective of dose-reduction status), without an offsetting increase in ischemic events. These data support the concept that lower-dose anticoagulants, such as edoxaban, 30 mg, may be considered in older patients with atrial fibrillation even in the absence of dose-reduction criteria.
Co-administration of Four-Factor Prothrombin Complex Concentrate With Andexanet alfa for Reversal of Nontraumatic Intracranial Hemorrhage
Sophia Pathan
Hosp Pharm 2024 Aug;59(4):394-406.
Abstract
Objective: Andexanet alfa is approved for the reversal of life-threatening or uncontrolled bleeding due to factor-Xa inhibitors. Data are limited on outcomes for patients who receive both andexanet alfa and 4-factor prothrombin complex concentrate (4F-PCC). The aim of this case series is to evaluate the safety and efficacy outcomes in patients receiving the two agents in combination.
Methods: Electronic medical records of patients who received both 4F-PCC and andexanet alfa for nontraumatic intracranial hemorrhage from January 2019 to March 2022 were retrospectively reviewed. Hemostatic efficacy and complications related to concurrent use of 4F-PCC with andexanet alfa were documented.
Results: Nine patients received 4F-PCC and andexanet alfa for reversal of factor Xa inhibitor-associated intracranial bleeding, eight of whom required reversal of apixaban. Of these nine patients, five patients died within 28 days for a 56% incidence of mortality. The average time from 4F-PCC administration to andexanet alfa administration was 3 hours and 9 minutes. Most doses of andexanet alfa were given for concern for bleed expansion after 4F-PCC administration. Hemostatic efficacy based on stability of repeat computed tomography scans post-administration of both agents was found in six patients (66.67%), with a 55.56% n incidence of thromboembolism, including two pulmonary embolisms, two deep vein thromboses, and one renal artery thrombosis.
Conclusion: Risks and benefits should be weighed to determine if there is benefit to adding andexanet alfa to 4F-PCC in patients with incomplete hemostasis and life-threatening hemorrhage. The combination of andexanet alfa and 4F-PCC may increase the risk of thrombotic complications without improving mortality.
Anticoagulation reversal (vitamin K, prothrombin complex concentrates, idarucizumab, andexanet-α, protamine)
Elias Bekka, Evangelia Liakoni
Br J Clin Pharmacol 2024 Jun 26.
Abstract
Bleeding events are common in patients prescribed anticoagulants and can have devastating consequences. Several specific and nonspecific agents have been developed to reverse the effects of anticoagulant drugs or toxins. Vitamin K, as the oldest of these antidotes, specifically counteracts the effects of pharmaceuticals and rodenticides designed to deplete stores of vitamin K-dependent factors. In cases of life-threatening bleeding, the addition of prothrombin complex concentrates (PCCs) allows for the immediate replacement of coagulation factors. While the use of PCCs has been extended to the non-specific reversal of the effects of newer direct oral anticoagulants, the specific agents idarucizumab, targeting dabigatran and andexanet-α, binding factor Xa inhibitors, have recently been developed and are being preferentially recommended by most guidelines. However, despite having rapid effects on correcting coagulopathy, there is to date a lack of robust evidence establishing the clear superiority of direct oral anticoagulant-specific reversal agents over PCCs in terms of haemostatic efficacy, safety or mortality. For andexanet-α, a potential signal of increased thromboembolic risks, comparatively high costs and low availability might also limit its use, even though emerging evidence appears to bolster its role in intracranial haemorrhage. Protamine is the specific agent for the reversal of unfractionated heparin anticoagulation used mainly in cardiovascular surgery. It is much less effective for low molecular weight heparin fragments and is usually reserved for cases with life-threatening bleeding.
Postpartum pharmacologic thromboprophylaxis and complications in a US cohort
Ann M Bruno, Grecio J Sandoval, Brenna L Hughes, William A Grobman, George R Saade, Tracy A Manuck, Monica Longo, Torri D Metz, Hyagriv N Simhan, Dwight J Rouse, Hector Mendez-Figueroa, Cynthia Gyamfi-Bannerman, Jennifer L Bailit, Maged M Costantine, Harish M Sehdev, Alan T N Tita, Eunice Kennedy, Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network, Bethesda, MD
Am J Obstet Gynecol, 2024 Jul;231(1):128.e1-128.e11.
Abstract
Background: Venous thromboembolism accounts for approximately 9% of pregnancy-related deaths in the United States. National guidelines recommend postpartum risk stratification and pharmacologic prophylaxis in at-risk individuals. Knowledge on modern rates of postpartum pharmacologic thromboprophylaxis and its associated risks is limited.
Objective: This study aimed to describe the rate of, and factors associated with, initiation of postpartum pharmacologic prophylaxis for venous thromboembolism, and to assess associated adverse outcomes.
Study design: This was a secondary analysis of a multicenter cohort of individuals delivering on randomly selected days at 17 US hospitals (2019-2020). Medical records were reviewed by trained and certified personnel. Those with an antepartum diagnosis of venous thromboembolism, receiving antepartum anticoagulation, or known SARS-CoV-2 infection were excluded. The primary outcome was use of postpartum pharmacologic thromboprophylaxis. Secondary outcomes included bleeding complications, surgical site infection, hospital readmission, and venous thromboembolism through 6 weeks postpartum. The rate of thromboprophylaxis administration was assessed by mode of delivery, institution, and continuance to the outpatient setting. Multivariable regression models were developed using k-fold cross-validation with stepwise backward elimination to evaluate factors associated with thromboprophylaxis administration. Univariable and multivariable logistic models with propensity score covariate adjustment were performed to assess the association between thromboprophylaxis administration and adverse outcomes.
Results: Of 21,114 individuals in the analytical cohort, 11.9% (95% confidence interval, 11.4%-12.3%) received postpartum pharmacologic thromboprophylaxis; the frequency of receipt was 29.8% (95% confidence interval, 28.7%-30.9%) following cesarean and 3.5% (95% confidence interval, 3.2%-3.8%) following vaginal delivery. Institutional rates of prophylaxis varied from 0.21% to 34.8%. Most individuals (83.3%) received thromboprophylaxis only as inpatients. In adjusted analysis, cesarean delivery (adjusted odds ratio, 19.17; 95% confidence interval, 16.70-22.00), hysterectomy (adjusted odds ratio, 15.70; 95% confidence interval, 4.35-56.65), and obesity (adjusted odds ratio, 3.45; 95% confidence interval, 3.02-3.95) were the strongest factors associated with thromboprophylaxis administration. Thromboprophylaxis administration was not associated with surgical site infection (0.9% vs 0.6%; odds ratio, 1.48; 95% confidence interval, 0.80-2.74), bleeding complications (0.2% vs 0.1%; odds ratio, 2.60; 95% confidence interval, 0.99-6.80), or postpartum readmission (0.9% vs 0.3%; adjusted odds ratio, 1.38; 95% confidence interval, 0.68-2.81). The overall rate of venous thromboembolism was 0.06% (95% confidence interval, 0.03%-0.10%) and was higher in those receiving prophylaxis (0.2%) compared with those not receiving prophylaxis (0.04%).
Conclusion: Approximately 1 in 10 patients received postpartum pharmacologic thromboprophylaxis in this US cohort. Rates of prophylaxis varied widely by institution. Cesarean delivery, hysterectomy, and obesity were predominant factors associated with postpartum thromboprophylaxis administration.