September 2024: New In Coagulation
by Donna Castellone, MS, MT(ASCP)S • September 12, 2024
Our Monthly complilation of the latest studies, guidelines and discussions in coagulation.
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FDA Approves Additional Indication for Fibryga® for Fibrinogen Supplementation in Bleeding Patients with Acquired Fibrinogen Deficiency, Potentially Ushering in a New Standard of Care
Fibryga, a fibrinogen replacement factor to be used in patients with acquired fibrinogen deficiency has received expanded approval from the FDA. It is a rapid and more precise treatment for severe bleeding when compared to cryoprecipitate standard of care. Fibrinogen is the first factor to drop critically low during severe bleeding episodes and rapid replacement is essential in achieving hemostasis. Acquired fibrinogen deficiency (AFD) can result in severe bleeding and impaired clot formation. Since 1964 Cryoprecipitate has been used, however there are drawbacks including long thawing and prep, variable levels of fibrinogen, and a higher risk of viral transmission. Fibryga can be stored at room temperature or refrigerated and can be quickly reconstituted and has a highly purified and consistent amount of fibrinogen.
Approval was based on the head to head multicenter, randomized clinical trial FIBRES conducted in 735 patients. Results showed it to be non-inferior to cryoprecipitate and may be used in AFD. It is also approved for acute bleeding episodes in adults and adolescents and pediatric patients under 12, with congenital fibrinogen deficiency (afibrinogenemia, hypofibrinogenemia). It also provides targeted and faster treatment in maternal hemorrhage however, it is not indicated for use in dysfibrinogenemia.
The largest adverse event is the risk of thrombotic events and its risk needs to be considered. The risk may be greater when the fibrinogen level is above 150 mg/dl.
Bleeding Better Controlled When Protamine Is Part of TAVR Wrap-Up Routine
The ACE-PROTAVI trial demonstrated hemostasis quicker when protamine was given at the end of transcatheter aortic valve replacement (TAVR) or implantation (TAVI). Hemostasis was achieved after 20 minutes when protamine was versus a placebo (97.9% vs 91.6%, P=0.006). Vascular complications are an important cause of procedure related morbidity from transfemoral TAVR in people with aortic stenosis.
Protamine is established in cardiac surgery but more controversial in interventional cardiology. ACE-PROTAVI was a double blind trial conducted in Australian hospitals which included 410 participants undergoing transfemoral TAVR randomized to protamine or placebo. Median age was 80 with less than 40% were women. Trial endpoints were defined as hemostasis within 20 minutes (time between sheath removal and confirmed arterial hemostasis). The secondary endpoint was a composite of all cause deaths, major and minor bleeding complications and vascular complications post 30 days. This was significantly lower than the placebo group (5.2% vs 12.8%) driven by the reduction in minor vascular complications (2.1% vs 8.4%).
No Effect of Tranexamic Acid on Bleeding in Surgery for Liver Cancer
The HeLiX trial placebo controlled results showed that tranexamic acid (TXA) failed to reduce red blood cell (RBC) transfusion post surgery for liver cancer, including colorectal liver metastases. TXA transfusion rates were 16.3% versus 14.5% with placebo. Patients who received TXA had more complications. There were no subgroups in the trial who benefited from TXA.
Previously, positive results were seen with TXA in traumatic brain injury, cardiac surgery as well as noncardiac surgeries including orthopedic surgery. There is minimal evidence that supports use in oncologic surgery where the mechanism of bleeding and risk factors for thrombosis are different. Bleeding from major abdominal surgery such as liver resection comes from large blood vessels. This supports the hypothesis that different sources of bleeding may account for different outcomes.
The HeLiX trial was conducted at 11 centers who enrolled patients for invasive liver resection related to malignancy and randomly allocated to either TXA or placebo. There were 1245 patients (mean age 63.2, with 39.8% being women) of which 56.1% were diagnosed with colorectal liver metastases. Primary analysis showed no difference in blood loss, 817.3ml with TXA versus 836.7ml with the placebo and at 7 days 1504 versus 1551.2ml respectively. Thrombosis did not differ between groups.
JOURNAL CLUB
Low-Dose Direct Oral Anticoagulation vs Dual Antiplatelet Therapy After Left Atrial Appendage Occlusion: The ADALA Randomized Clinical Trial
Xavier Freixa, PhD; Ignacio Cruz-González, PhD; Pedro Cepas-Guillén, PhD; et alXavi Millán, PhD; Pablo Antúnez-Muiños, MD; Eduardo Flores-Umanzor, PhD; Lluís Asmarats, PhD; Ander Regueiro, PhD; Sergio López-Tejero, PhD; Chi-Hion Pedro Li, PhD; Laura Sanchis, PhD; Josep Rodés-Cabau, PhD,; Dabit Arzamendi, PhD
Abstract
Importance Optimal antithrombotic therapy after percutaneous left atrial appendage occlusion (LAAO) is not well established as no randomized evaluation has been performed to date.
Objective To compare the efficacy and safety of low-dose direct oral anticoagulation (low-dose DOAC) vs dual antiplatelet therapy (DAPT) for 3 months after LAAO.
Design, Setting, and Participants The ADALA (Low-Dose Direct Oral Anticoagulation vs Dual Antiplatelet Therapy After Left Atrial Appendage Occlusion) study was an investigator-initiated, multicenter, prospective, open-label, randomized clinical trial enrolling participants from June 12, 2019, to August 28, 2022 from 3 European sites. Patients who underwent successful LAAO were randomly assigned 1:1 to low-dose DOAC vs DAPT for 3 months after LAAO. The study was prematurely terminated when only 60% of the estimated sample size had been included due to lower recruitment rate than anticipated due to the COVID-19 pandemic.
Interventions The low-dose DOAC group received apixaban, 2.5 mg every 12 hours, and the DAPT group received aspirin, 100 mg per day, plus clopidogrel, 75 mg per day, for the first 3 months after LAAO.
Main Outcomes and Measures The primary end point was a composite of safety (major bleeding) and efficacy (thromboembolic events including stroke, systemic embolism, and device-related thrombosis [DRT]) within the first 3 months after successful LAAO. Secondary end points included individual components of the primary outcome and all-bleeding events.
Results A total of 90 patients (mean [SD] age, 76.6 [8.1] years; 60 male [66.7%]; mean [SD] CHADS-VASc score, 4.0 [1.5]) were included in the analysis (44 and 46 patients in the low-dose DOAC and DAPT groups, respectively). A total of 53 patients (58.8%) presented with previous major bleeding events (60 gastrointestinal [66.7%] and 16 intracranial [17.8%]). At 3 months, low-dose DOAC was associated with a reduction of the primary end point compared with DAPT (2 [4.5%] vs 10 [21.7%]; hazard ratio, 0.19; 95% CI, 0.04-0.88;
Conclusions and Relevance This was a small, randomized clinical trial comparing different antithrombotic strategies after LAAO. Results show that use of low-dose DOAC for 3 months after LAAO was associated with a better balance between efficacy and safety compared with DAPT. However, the results of the study should be interpreted with caution due to the limited sample size and will need to be confirmed in future larger randomized trials.
Ingestion of the Non-Nutritive Sweetener Erythritol, but Not Glucose, Enhances Platelet Reactivity and Thrombosis Potential in Healthy Volunteers
Marco Witkowski, Jennifer Wilcox, Valesha Province, Zeneng Wang,, Ina Nemet , W.H. Wilson Tang and Stanley L. Hazen
Abstract
Background: Although artificial and non-nutritive sweeteners are widely used and generally recognized as safe by the US and European Union regulatory agencies, there have been no clinical trials to assess either long-term cardiovascular disease risks or short-term cardiovascular disease–relevant phenotypes. Recent studies report that fasting plasma levels of erythritol, a commonly used sweetener, are clinically associated with heightened incident cardiovascular disease risks and enhance thrombosis potential in vitro and in animal models. Effects of dietary erythritol on thrombosis phenotypes in humans have not been examined.
Methods: Using a prospective interventional study design, we tested the impact of erythritol or glucose consumption on multiple indices of stimulus-dependent platelet responsiveness in healthy volunteers (n=10 per group). Erythritol plasma levels were quantified with liquid chromatography tandem mass spectrometry. Platelet function at baseline and following erythritol or glucose ingestion was assessed via both aggregometry and analysis of granule markers released.
Results: Dietary erythritol (30 g), but not glucose (30 g), lead to a >1000-fold increase in erythritol plasma concentration (6480 [5930–7300] versus 3.75 [3.35–3.87] μmol/L;
Conclusions: Ingestion of a typical quantity of the non-nutritive sweetener erythritol, but not glucose, enhances platelet reactivity in healthy volunteers, raising concerns that erythritol consumption may enhance thrombosis potential. Combined with recent large-scale clinical observational studies and mechanistic cell-based and animal model studies, the present findings suggest that discussion of whether erythritol should be reevaluated as a food additive with the Generally Recognized as Safe designation is warranted.
Heparin-Induced Thrombocytopenia in Patients Suffering Cardiogenic Shock
Enzo Lüsebrink, Hugo Lanz, Leonhard Binzenhöfer , Sabine Hoffmann, Julia Höpler, Marie Kraft, Nils Gade, Jonas Gmeiner , Daniel Roden , Inas Saleh , Christian Hagl , Georg Nickenig , Steffen Massberg , Sebastian Zimmer , Raúl Nicolás Jamin , Clemens Scherer
Crit Care Explor 2024 Jul 22;6(7):e1117.
Abstract
Objectives: Cardiogenic shock (CS) is associated with high mortality. Patients treated for CS mostly require heparin therapy, which may be associated with complications such as heparin-induced thrombocytopenia (HIT). HIT represents a serious condition associated with platelet decline and increased hypercoagulability and remains a poorly researched field in intensive care medicine. Primary purpose of this study was to: 1) determine HIT prevalence in CS, 2) assess the performance of common diagnostic tests for the workup of HIT, and 3) compare outcomes in CS patients with excluded and confirmed HIT.
Design: Retrospective dual-center study including adult patients 18 years old or older with diagnosed CS and suspected HIT from January 2010 to November 2022.
Setting: Cardiac ICU at the Ludwig-Maximilians University hospital in Munich and the university hospital of Bonn.
Patients and interventions: In this retrospective analysis, adult patients with diagnosed CS and suspected HIT were included. Differences in baseline characteristics, mortality, neurologic and safety outcomes between patients with excluded and confirmed HIT were evaluated.
Measurements and main results: In cases of suspected HIT, positive screening antibodies were detected in 159 of 2808 patients (5.7%). HIT was confirmed via positive functional assay in 57 of 2808 patients, corresponding to a prevalence rate of 2.0%. The positive predictive value for anti-platelet factor 4/heparin screening antibodies was 35.8%. Total in-hospital mortality (58.8% vs. 57.9%; p > 0.999), 1-month mortality (47.1% vs. 43.9%; p = 0.781), and 12-month mortality (58.8% vs. 59.6%; p > 0.999) were similar between patients with excluded and confirmed HIT, respectively. Furthermore, no significant difference in neurologic outcome among survivors was found between groups (Cerebral Performance Category [CPC] score 1: 8.8% vs. 8.8%; p > 0.999 and CPC 2: 7.8% vs. 12.3%; p = 0.485).
Conclusions: HIT was a rare complication in CS patients treated with unfractionated heparin and was not associated with increased mortality. Also, HIT confirmation was not associated with worse neurologic outcome in survivors. Future studies should aim at developing more precise, standardized, and cost-effective strategies to diagnose HIT and prevent complications.
Perioperative Management of Patients Taking Direct Oral Anticoagulants - A Review
James D. Douketis, MD1; Alex C. Spyropoulos, MD
Abstract
Importance Direct oral anticoagulants (DOACs), comprising apixaban, rivaroxaban, edoxaban, and dabigatran, are commonly used medications to treat patients with atrial fibrillation and venous thromboembolism. Decisions about how to manage DOACs in patients undergoing a surgical or nonsurgical procedure are important to decrease the risks of bleeding and thromboembolism.
Observations For elective surgical or nonsurgical procedures, a standardized approach to perioperative DOAC management involves classifying the risk of procedure-related bleeding as minimal (eg, minor dental or skin procedures), low to moderate (eg, cholecystectomy, inguinal hernia repair), or high risk (eg, major cancer or joint replacement procedures). For patients undergoing minimal bleeding risk procedures, DOACs may be continued, or if there is concern about excessive bleeding, DOACs may be discontinued on the day of the procedure. Patients undergoing a low to moderate bleeding risk procedure should typically discontinue DOACs 1 day before the operation and restart DOACs 1 day after. Patients undergoing a high bleeding risk procedure should stop DOACs 2 days prior to the operation and restart DOACs 2 days after. With this perioperative DOAC management strategy, rates of thromboembolism (0.2%-0.4%) and major bleeding (1%-2%) are low and delays or cancellations of surgical and nonsurgical procedures are infrequent. Patients taking DOACs who need emergent (<6 hours after presentation) or urgent surgical procedures (6-24 hours after presentation) experience bleeding rates up to 23% and thromboembolism as high as 11%. Laboratory testing to measure preoperative DOAC levels may be useful to determine whether patients should receive a DOAC reversal agent (eg, prothrombin complex concentrates, idarucizumab, or andexanet-α) prior to an emergent or urgent procedure.
Conclusions and Relevanc When patients who are taking a DOAC require an elective surgical or nonsurgical procedure, standardized management protocols can be applied that do not require testing DOAC levels or heparin bridging. When patients taking a DOAC require an emergent, urgent, or semiurgent surgical procedure, anticoagulant reversal agents may be appropriate when DOAC levels are elevated or not available.
Aspirin Dosing for Secondary Prevention of Atherosclerotic Cardiovascular Disease in Male and Female Patients: A Secondary Analysis of the ADAPTABLE Randomized Clinical Trial
Catherine P. Benziger, MD; Amanda Stebbins, MS; Lisa M. Wruck, PhD; et alMark B. Effron, MD; Guillaume Marquis-Gravel, MD; Peter M. Farrehi, MD; Saket Girotra, MD; Kamal Gupta, MD; Sunil Kripalani, MD; Daniel Munoz, MD; Tamar S. Polonsky, MD; Amber Sharlow, MBA; Jeffrey Whittle, MD, MPH; Robert A. Harrington, MD; Russell L. Rothman, MD; Adrian F. Hernandez, MD, MHS; W. Schuyler Jones, MD
Abstract
Importance Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of morbidity and mortality in the US. Although aspirin is recommended for secondary prevention of ASCVD, there was no difference in safety and effectiveness of aspirin dosed daily at 81 mg or 325 mg in the ADAPTABLE (Aspirin Dosing: A Patient-Centric Trial Assessing Benefits and Long-Term Effectiveness) randomized clinical trial. However, it is unknown whether differences by sex exist in the safety and effectiveness of the different aspirin doses.
Objective To evaluate sex-specific differences in the safety and effectiveness of 2 aspirin doses in the ADAPTAPLE trial.
Design, Setting, and Participants The ADAPTABLE study was an open-label, pragmatic, randomized clinical trial that randomly assigned participants with chronic, stable ASCVD to 81 mg vs 325 mg of aspirin daily. Using Cox proportional-hazard models, male and female participants were compared for outcomes. In addition, it was assessed whether sex was an effect modifier in the association between aspirin dose and outcomes. The ADAPTABLE trial was conducted at 40 medical centers and 1 health plan. Eligible patients were 18 years and older and had established ASCVD. Study data were analyzed from December 2021 to March 2024.
Interventions Patients received 81 mg or 325 mg of aspirin daily for the secondary prevention of ASCVD.
Main Outcomes and Measures The primary effectiveness outcomes included all-cause death and hospitalization for myocardial infarction (MI) or stroke. The primary safety outcome was hospitalization for major bleeding requiring transfusion.
Results A total of 15 076 patients (median [IQR] age, 67.6 [60.7-73.6] years; 10 352 male [68.7%]) were followed up for a median (IQR) of 26.2 (19.0-34.9) months. Overall, 4724 (31.3%) were female, and 2307 of the female participants (48.8%) received aspirin 81 mg. Compared with males, female participants were younger (median [IQR] age, 66.3 [59.4-72.6] years vs 68.2 (61.4-73.9) years, less likely to self-report White race (3426 [72.5%] vs 8564 [82.7%]), more likely to smoke (564 [12.9%] vs 818 [8.4%]), and more likely to have a history of peripheral arterial disease (1179 [25.7%] vs 2314 [23.0%]). The primary effectiveness outcome of all-cause death and hospitalization for MI or stroke occurred in 379 female participants (8.1%) and 780 male participants (7.1%). There was no significant interaction by sex for the primary effectiveness end point between the 2 aspirin doses (female adjusted hazard ratio [aHR], 1.01; 95% CI, 0.82-1.26 and male aHR, 1.06; 95% CI, 0.91-1.23; P interaction term for sex = .74). During the trial, female participants had fewer revascularization procedures (237 [5.0%] vs 680 [6.6%]; aHR, 0.79; 95% CI, 0.68-0.92; P = .002) but had a higher risk of hospitalization for stroke (aHR, 1.72; 95% CI, 1.27-2.33; P < .001). Among female participants, there was a slightly higher rate of bleeding in the 81-mg aspirin cohort compared with the 325-mg cohort (20 [0.83%] vs 13 [0.52%]; aHR, 2.21; 95% CI, 1.04-4.70; P interaction term for sex = .07). There were no significant differences between female and male participants regarding aspirin dose adherence.
Conclusions and Relevance In this secondary analysis of the ADAPTABLE trial, there were no significant sex-specific differences in the effectiveness and safety of 2 aspirin doses for secondary prevention of ASCVD events.
Vitamin K Antagonist Reversal for Urgent Surgery Using 4-Factor Prothrombin Complex Concentrates: A Randomized Clinical Trial
Ravi Sarode , Joshua N Goldstein Gregory Simonian , Doris Hinterberger , Dmitrii Matveev , Michelle Gareis , Truman J Milling Jr
JAMA Netw Open 2024 Aug 1;7(8):e2424758.
Abstract
Importance: Millions of people take vitamin K antagonists (VKAs). Some people who need urgent surgical procedures require rapid VKA reversal to prevent excessive intraoperative bleeding.
Objective: To evaluate the hemostatic noninferiority of an investigational 4-factor prothrombin complex concentrate (4F-PCC) to a control 4F-PCC for rapid VKA reversal before urgent surgery.
Design, setting, and participants: This phase 3, double-blind, noninferiority randomized clinical trial (LEX-209) was conducted in 24 hospitals in the US, Russia, Georgia, Belarus, Ukraine, and Romania from June 7, 2017, through November 8, 2021; the study was stopped in February 2022. Participants were adult patients taking VKA who had an international normalized ratio (INR) of 2 or higher and needed urgent surgery with a substantial bleeding risk (≥50 mL). Patients were randomized 1:1 to a single infusion of either the investigational 4F-PCC or the control 4F-PCC. Data analysis followed intention-to-treat and per-protocol approaches.
Interventions: Single intravenous infusion was dosed by body weight and baseline INR. A dose of 25, 35, or 50 IU/kg of investigational 4F-PCC or control 4F-PCC was administered for baseline INR of 2 to less than 4, 4 to 6, or over 6, respectively.
Main outcome and measure: The primary end point was hemostatic efficacy at surgery end. An independent adjudication board, blinded to the 4F-PCC treatment allocation, assessed hemostatic efficacy using an objective 4-point scale.
Results: A total of 208 patients (median [range] age, 67.5 [31-92] years; 118 males [56.7%]) received the investigational (n = 105) or the control (n = 103) 4F-PCC. The median (range) dose was 25 (16-50) IU/kg in the investigational group and 25 (15-50) IU/kg in the control group, with a median (range) infusion time of 12 (8-50) minutes and 13 (7-30) minutes and a median (range) time from infusion to surgery start of 1.42 (0.25-15.25) hours and 1.50 (0.42-18.50) hours, respectively. Baseline median (range) INR was 3.05 (1.97-21.10) in the investigational group and 3.00 (2.00-11.30) in the control group. In the intention-to-treat analysis, the investigational 4F-PCC was noninferior to the control 4F-PCC, resulting in effective hemostasis in 94.3% of patients vs 94.2% of patients (proportion difference, 0.001; 95% CI, -0.080 to 0.082; P < .001), meeting the prespecified noninferiority margin of 0.15. An INR of 1.5 or lower at 30 minutes after infusion occurred in 78.1% of patients in the investigational group vs 71.8% of patients in the control group (proportion difference, 0.063; 95% CI, -0.056 to 0.181). Thrombotic events (2.9% vs 0%, respectively) and mortality (4.8% vs 1.0%, respectively) were no different than expected for 4F-PCC use. One patient in each treatment group discontinued due to adverse events (cardiac disorders unrelated to 4F-PCC).
Conclusions and relevance: This randomized clinical trial found that the investigational 4F-PCC was hemostatically noninferior to the control 4F-PCC for rapid VKA reversal in patients needing urgent surgery with considerable bleeding risk; the safety profile of these two 4F-PCCs was similar. These results support the investigational 4F-PCC as a therapeutic option for surgical patients requiring rapid VKA reversal.
CYP2C19 Genetic Testing for Oral P2Y12 Inhibitor Therapy: A Scientific Statement From the American Heart Association
Naveen L Pereira, Sharon Cresci, Dominick J Angiolillo, Wayne Batchelor, Quinn Capers 4th, Larisa H Cavallari, Dana Leifer, Jasmine A Luzum, Dan M Roden, Konstantinos Stellos, Stephanie L Turrise, Sony Tuteja; American Heart Association Professional/Public Education and Publications Committee of the Council on Genomic and Precision Medicine; Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Cardiovascular and Stroke Nursing; Council on Clinical Cardiology; Council on Peripheral Vascular Disease; and Stroke Council
Circulation 2024 Aug 6;150(6):e129-e150.
Abstract
There is significant variability in the efficacy and safety of oral P2Y12 inhibitors, which are used to prevent ischemic outcomes in common diseases such as coronary and peripheral arterial disease and stroke. Clopidogrel, a prodrug, is the most used oral P2Y12 inhibitor and is activated primarily after being metabolized by a highly polymorphic hepatic cytochrome CYP2C219 enzyme. Loss-of-function genetic variants in CYP2C219 are common, can result in decreased active metabolite levels and increased on-treatment platelet aggregation, and are associated with increased ischemic events on clopidogrel therapy. Such patients can be identified by CYP2C19 genetic testing and can be treated with alternative therapy. Conversely, universal use of potent oral P2Y12 inhibitors such as ticagrelor or prasugrel, which are not dependent on CYP2C19 for activation, has been recommended but can result in increased bleeding. Recent clinical trials and meta-analyses have demonstrated that a precision medicine approach in which loss-of-function carriers are prescribed ticagrelor or prasugrel and noncarriers are prescribed clopidogrel results in reducing ischemic events without increasing bleeding risk. The evidence to date supports CYP2C19 genetic testing before oral P2Y12 inhibitors are prescribed in patients with acute coronary syndromes or percutaneous coronary intervention. Clinical implementation of such genetic testing will depend on among multiple factors: rapid availability of results or adoption of the concept of performing preemptive genetic testing, provision of easy-to-understand results with therapeutic recommendations, and seamless integration in the electronic health record.