August 2023: New In Coagulation
by Donna Castellone, MS, MT(ASCP)S • August 03, 2023
Our Monthly complilation of the latest studies, guidelines and discussions in coagulation.
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TXA Holds Its Own for Heavy Menstrual Bleeding in von Willebrand Disease
In women with VWD, about four in five have heavy menstrual bleeding that impact quality of life. VWF concentrate does reduce bleeding events in patients with VWD, however it is costly and requires IV infusion.
A phase III study (VWDMin) was conducted at 13 US centers with 36 patients (Type I and 2, Type 3 patients were excluded) comparing 1 day of recombinant VWF or oral TXA for 5 days. This was done for 2 cycles and then patients switched to the opposite treatment. The trial showed that treatment with recombinant von Willebrand factor (vWF) was not superior to tranexamic acid (TXA) for managing heavy menstrual bleeding in women with mild or moderate VWD. When menstrual blood loss was measured, they were significantly lower with TXA, however neither treatment corrected scored to normal. TXA is also lower in cost that recombinant VWF and could be an approach to managing heavy bleeding.
FDA Gives Nod to Gene Therapy for Hemophilia A
Roctavian (valoctocogene roxaparvovec) is the first FDA approved gene therapy for the treatment of adults with severe hemophilia A. Severe hemophiliacs (< 1% FVIII) receive a one-time, single dose treatment as long as they don't present with antibodies to adeno-associated virus serotype 5 (AAV5). This was based on data from global phase III results. The gene is expressed in the liver to increase FVIII levels and reduce the risk of uncontrolled bleeding. The gene reduced the average annualized bleeding rate by 52% compared with those on routine FVIII prophylaxis. The data decreased bleeds from 5.4 to 2.6 per year over 3 years of follow-up. A reduction was also seen in spontaneous bleeds (2.3-0.5) and joint bleeds (3.1-0.6) annually. There was also a 96.8% reduction in FVIII usage.
Abnormal laboratory tests were alanine transaminase (ALT), aspartate transaminase, lactate dehydrogenase, creatine kinase, factor VIII activity levels, gamma-glutamyl transferase, and bilirubin greater than the upper levels of normal.
Pulmonary Embolism Confers Higher Mortality Long Term
Patients who present with a PE have significantly higher long term mortality rates than the general population. Long term outcomes were investigated on 896 patients over 14 years between 2005 and 2017 which translated to a total follow up time of 3908 patient years. At one and five year, mortality rates were 19.7% and 37.1% in patients with PE. The most frequent cause of death were cancer, PE, infections and cardiovascular events.
"Long-term Mortality in Pulmonary Embolism: Results in a Single-Center Registry," J. Eckelt, et al, was accepted for publication in Research and Practice in Thrombosis and Haemostasis I (2023)on May 31, 2003.
Which Antiplatelet Agent for Patients With TIA and Obesity?
A secondary analysis of the CHANCE-2 trail that looked at ticagrelor or clopidogrel with aspirin in high-risk patients with acute nondisabling CV events in those who carried the CYP2C19 loss of function allele. The trial of 6412 patients 13.7% were found to be obese. Ticagrelor plus ASA was associated with a 49% lower rate of stroke in obese patients when compared with clopidogrel plus ASA. Clopidogrel appears to lose its efficacy among patients who are obese. There were no difference between the regimens in non-obese patients. Severe and moderate bleeding were similar between the BMI groups.
Aspirin Not the Best Antiplatelet for CAD Secondary Prevention in Meta-Analysis
A meta-analysis of 24,000 patients ( mean age 64, 22% female) from seven randomized trials called PANTHER, revealed the antiplatelet of choice for long term secondary prevention for patients with CAD appears to be a P2Y12 inhibitor as opposed to aspirin. Half the patients in the study received monotherapy of either a P2Y12 inhibitor (clopidogrel or ticagrelor) versus the other half received aspirin, with a follow up of 6 months to 3 years.
Patients taking the P2Y12 inhibitors had a 12% reduction in risk (death, MI and stroke) with a 23% reduction in MI. Both groups were similar in major bleeding events, but were reduced in the P2Y12 group for GI bleeding, stent thrombosis.
The current guidelines recommend aspirin for antiplatelet monotherapy for patients with established CAD, however this information is based on historical trials conducted in the 1970 and 1980 and may not be applicable to today’s practices.
Trials that compared P2Y12 inhibitors with aspirin for secondary prevention produced "inconsistent results," possibly owing to their heterogeneous populations of patients with coronary, cerebrovascular, or peripheral vascular disease. Study-level meta-analyses in this area "provide inconclusive evidence" because they haven't evaluated treatment effects exclusively in patients with established CAD.
JOURNAL CLUB
Stroke Mortality Among Black and White Adults Aged ≥35 Years Before and During the COVID-19 Pandemic
United States, 2015-2021
Quanhe Yang, PhD; Xin Tong, MPH; Linda Schieb, MSPH; Fátima Coronado, MD; Robert Merritt, MS
Morbidity and Mortality Weekly Report. 2023;72(16):431-436.
Abstract
Stroke is the fifth leading cause of death and a leading cause of long-term disability in the United States. Although stroke death rates have declined since the 1950s, age-adjusted rates remained higher among non-Hispanic Black or African American (Black) adults than among non-Hispanic White (White) adults. Despite intervention efforts to reduce racial disparities in stroke prevention and treatment through reducing stroke risk factors, increasing awareness of stroke symptoms, and improving access to treatment and care for stroke, Black adults were 45% more likely than were White adults to die from stroke in 2018.* In 2019, age-adjusted stroke death rates (AASDRs) (stroke deaths per 100,000 population) were 101.6 among Black adults and 69.1 among White adults aged ≥35 years. Stroke deaths increased during the early phase of the COVID-19 pandemic (March–August 2020), and minority populations experienced a disproportionate increase. The current study examined disparities in stroke mortality between Black and White adults before and during the COVID-19 pandemic. Analysts used National Vital Statistics System (NVSS) mortality data accessed via CDC WONDER† to calculate AASDRs among Black and White adults aged ≥35 years prepandemic (2015–2019) and during the pandemic (2020–2021). Compared with that during the prepandemic period, the absolute difference in AASDR between Black and White adults during the pandemic was 21.7% higher (31.3 per 100,000 versus 38.0). During the pandemic period, an estimated 3,835 excess stroke deaths occurred among Black adults (9.4% more than expected) and 15,125 among White adults (6.9% more than expected). These findings underscore the importance of identifying the major factors contributing to the widened disparities; implementing prevention efforts, including the management and control of hypertension, high blood cholesterol, and diabetes; and developing tailored interventions to reduce disparities and advance health equity in stroke mortality between Black and White adults.
Clinical Outcomes of Anticoagulated Patients With Atrial Fibrillation After Falls or Head Injury
Daniel Caldeira, MD, PhD; Pedro Alves da Silva, MD; Fausto J. Pinto, MD, PhD
Stroke. 2023;54(6):1656-1659.
Abstract
Background: Falls are always a concern regarding the balance of risk/benefit in patients with atrial fibrillation treated with anticoagulants. In this analysis, we aimed to evaluate the outcomes of patients that had a fall/head injury reported in the RE-LY clinical trial (Randomized Evaluation of Long-Term Anticoagulation Therapy) and to explore the safety of dabigatran (a nonvitamin K antagonist oral anticoagulant).
Methods: We performed a post hoc retrospective analysis of intracranial hemorrhage and major bleeding outcomes in the RE-LY trial with 18 113 individuals with atrial fibrillation, according to the status occurrence of falls (or head injury) reported as adverse events. Multivariate Cox regression models were used to provide adjusted hazard ratio (HR) and 95% CI.
Results: In the study, 974 falls or head injury events were reported among 716 patients (4%). These patients were older and had more frequently comorbidities such as diabetes, previous stroke, or coronary artery disease. Patients with fall had a higher risk of major bleeding (HR, 2.41 [95% CI, 1.90–3.05]), intracranial hemorrhage (HR, 1.69 [95% CI, 1.35–2.13]), and mortality (HR, 3.91 [95% CI, 2.51–6.10]) compared to those who did not have reported falls or head injury. Among patients who had falls, those allocated to dabigatran showed a lower intracranial hemorrhage risk (HR, 0.42 [95% CI, 0.18–0.98]) compared with warfarin.
Conclusions: In this population, the risk of falls is important and confers a worse prognosis, increasing intracranial hemorrhage, and major bleeding. Patients who fell and were under dabigatran was associated with lower intracranial hemorrhage risk than those anticoagulated with warfarin, but the analysis was merely exploratory.
Bleeding related to oral anticoagulants: Trends in US emergency department visits: 2016- 2020.
Geller, AI., Shehab, N., Lovegrove, MC., Weidle, NJ, Budnitz, DN.
Thrombosis Research, Volume 224, p 110-115, May 2023.
Abstract
Background: Clinical trials suggest lower rates of major bleeding with direct-acting oral anticoagulants (DOACs) than with warfarin, but anticoagulant-related bleeding remains one of the most common outpatient adverse drug events.
Methods: We estimated the number of emergency department (ED) visits and subsequent hospitalizations for oral anticoagulant-related bleeding in 2016–2020 based on active surveillance in a nationally representative, size-stratified probability sample of 60 U.S. hospitals. We estimated rates of ED visits using a nationally-projected retail prescription dispensing database.
Results: Based on 19,557 cases, oral anticoagulant-related bleeding resulted in an estimated 1,270,259 (95 % Confidence Interval [CI], 644,686-1,895,832) ED visits for the five years 2016–2020, of which 47.8 % (95 % CI, 40.6 %–
55.0 %) resulted in hospitalization. Oral anticoagulant-related bleeding resulted in an estimated 230,163 (95% CI, 109,598
-350,728) ED visits in 2016 and 301,433 (95% CI, 138,363-464,503) in 2020. During 2016–2020, ED visits for DOAC-
related bleeding increased by an average of 27.9 % (95 % CI, 24.0 %–32.0 %;
Conclusions: Although the rates of ED visits for anticoagulant-related bleeding may be lower for DOACs than for warfarin, persistently large numbers of patients requiring ED visits for anticoagulant-related bleeding despite increased use of DOACs and declining use of warfarin suggest that efforts to improve appropriate prescribing and monitoring of anticoagulants remain important.
The role of anticoagulation clinics needs to be reassessed to include follow up of patients on direct oral anticoagulants
Armando Tripodi, Veena Chantarangkul, Daniela Poli, Sophie Testa, Paolo Bucciarelli, Flora Peyvandi
Thrombosis Research, Volume 225, May 2023, Pages 11-15
Abstract
A survey was carried out to assess the state of organization of care (including clinical and laboratory) delivered to patients on vitamin K antagonists (VKA) or direct oral anticoagulants (DOAC) followed by clinics affiliated with the Italian Federation of Thrombosis Centers (FCSA), traditionally engaged to assist anticoagulated outpatients within the country. Participants were asked to answer questions concerning (i) proportion of patients on VKA-vs-DOAC and (ii) whether dedicated testing for DOAC is available. The proportion of patients on VKA-vs-DOAC was 60 % vs 40 %. This proportion is in sharp contrast with the real-life distribution where DOAC outweigh VKA prescriptions. Furthermore, the proportion of anticoagulation clinics that provide DOAC testing (even in special situations) is relatively small (i.e., 31 % of the respondents). Furthermore, 25 % of those that declared to follow DOAC patients do not provide any testing at all. The answers to the above questions cause concerns as (i) most patients on DOAC within the country are probably on self- management, or they are managed by general practitioners or specialists outside thrombosis centers. (ii) Most patients on DOAC have no access to testing even in special situations where it would be needed. We feel that there is a (false) perception that the care needed for DOAC treatment can be much less than that required for VKA, as DOAC require prescription and not regular follow-up. A call for action should be urgently made to reassess the role of anticoagulation clinics, which should pay the same attention to patients on DOAC as those on VKA.
Rivaroxaban to prevent major clinical outcomes in non-hospitalised patients with COVID-19: the CARE - COALITION VIII randomised clinical trial
Álvaro Avezum, Haliton Alves Oliveira Junior, Precil Diego M M Neves, Lucas Bassolli O Alves, Alexandre B Cavalcanti, Regis G Rosa, Viviane C Veiga, Luciano C P Azevedo, Sérgio Luiz Zimmermann, Odilson Marcos Silvestre, Raphael Cruz Seabra Prudente, Adrian Paulo Morales Kormann, Frederico Rafael Moreira, Icaro Boszczowski, Edgar de Brito Sobrinho, André da Silva E Souza, Renato Seligman, Bruno de Souza Paolino, Alvaro Razuk, Audes Diogenes de Magalhaes Feitosa, Pedro Luiz Monteiro Belmonte, Priscila Freitas das Neves Gonçalves, Mauro Esteves Hernandes, Ariovaldo Leal Fagundes, José Maria Sarmet Esteves, Alexandre Pereira Tognon, John Eikelboom, Otávio Berwanger, Renato D Lopes, Gustavo B F Oliveira; Coalition VIII COVID-19 Brazil Investigators
EClinicalMedicine. 2023 Jun;60:102004.
Abstract
Background: COVID-19 progression is associated with an increased risk of arterial and venous thrombosis. Randomised trials have demonstrated that anticoagulants reduce the risk of thromboembolism in hospitalised patients with COVID-19, but a benefit of routine anticoagulation has not been demonstrated in the outpatient setting.
Methods: We conducted a randomised, open-label, controlled, multicentre study, evaluating the use of rivaroxaban in mild or moderate COVID-19 patients. Adults ≥18 years old, with probable or confirmed SARS-CoV-2 infection, presenting within ≤7 days from symptom onset with no clear indication for hospitalization, plus at least 2 risk factors for complication, were randomised 1:1 either to rivaroxaban 10 mg OD for 14 days or to routine care. The primary efficacy endpoint was the composite of venous thromboembolic events, need of mechanical ventilation, acute myocardial infarction, stroke, acute limb ischemia, or death due to COVID-19 during the first 30 days. ClinicalTrials.gov: NCT04757857.
Findings: Enrollment was prematurely stopped due to sustained reduction in new COVID-19 cases. From September 29th, 2020, through May 23rd, 2022, 660 patients were randomised (median age 61 [Q1-Q3 47-69], 55.7% women). There was no significant difference between rivaroxaban and control in the primary efficacy endpoint (4.3% [14/327] vs 5.8% [19/330], RR 0.74; 95% CI: 0.38-1.46). There was no major bleeding in the control group and 1 in the rivaroxaban group.
Interpretation: On light of these findings no decision can be made about the utility of rivaroxaban to improve outcomes in outpatients with COVID-19. Metanalyses data provide no evidence of a benefit of anticoagulant prophylaxis in outpatients with COVID-19. These findings were the result of an underpowered study, therefore should be interpreted with caution.
Predicting post-discharge venous thromboembolism and bleeding among medical patients: External validation of a novel risk score utilizing ubiquitous biomarkers
S Nabeel Hyder, Henry B Han, Scott Ash, Benjamin D Horne, Scott M Stevens, Scott C Woller, Geoffrey D Barnes
Thromb Res. 2023 Jul;227:45-50.
Abstract
Background: Post-hospitalization thromboprophylaxis can reduce venous thromboembolism (VTE) risk for non-surgical patients but may carry bleeding risks. We aimed to externally validate the Intermountain Risk Scores for hospital-associated venous thromboembolism (HA-VTE IMRS) and major bleeding (HA-MB IMRS) for VTE and bleeding outcomes.
Methods: Retrospective cohort study of adult patients discharged alive from medical services between 2015 and 2019. HA-VTE IMRS and HA-MB IMRS were calculated at the time of hospital discharge and dichotomized as high- or low-risk as described in the derivation manuscript. 90-day post-discharge VTE outcomes were assessed from diagnostic radiology reports, and bleeding outcomes were assessed using ICD-10 codes and blood bank transfusion records.
Results: Among 113,578 patients in the study, 66,340 patients (58.4 %) had a low-risk HA-VTE IMRS <7, versus 47,238 (41.6 %) high-risk ≥7. For bleed prediction, 71,576 patients (63 %) had a low-risk HA-MB IMRS <8, versus 42,002 (37 %) high-risk ≥8. VTE incidence was 1.1 % and 0.6 % while major bleeding incidence was 1.3 % and 0.1 % in high-risk versus low-risk cohorts, respectively. AUCs for VTE and bleed outcome discrimination were 0.59 and 0.78, respectively. Patients with a combined high-risk VTE score and low-risk bleeding score comprised 14.5 % of the population.
Conclusion: In this external validation study, the HA-VTE IMRS had poor discrimination for VTE but the HA-MB IMRS had good discriminatory ability for major bleeding events. A sizable minority of patients were categorized as high VTE risk with low bleed risk, a population which may have an optimal risk-benefit profile for post-hospital thromboprophylaxis.
Keywords: Deep vein thrombosis; Post-discharge thromboprophylaxis; Predictive modeling; Pulmonary embolism; Venous thromboembolism.
Direct Oral Anticoagulants vs Low- Molecular-Weight Heparin and Recurrent VTE in Patients With Cancer: A Randomized Clinical Trial
Deborah Schrag, Hajime Uno, Rachel Rosovsky, Cynthia Rutherford, Kristen Sanfilippo, John L Villano, Monic Drescher, Nagesh Jayaram, Chris Holmes, Lawrence Feldman, Ottavia Zattra, Haley Farrar-Muir, Christine Cronin, Ethan Basch, Anna Weiss, Jean M Connors; CANVAS Investigators
JAMA 2023 Jun 13;329(22):1924-1933.
Abstract
Importance: In patients with cancer who have venous thromboembolism (VTE) events, long-term anticoagulation with low-molecular-weight heparin (LMWH) is recommended to prevent recurrent VTE. The effectiveness of a direct oral anticoagulant (DOAC) compared with LMWH for preventing recurrent VTE in patients with cancer is uncertain.
Objective: To evaluate DOACs, compared with LMWH, for preventing recurrent VTE and for rates of bleeding in patients with cancer following an initial VTE event.
Design, setting, and participants: Unblinded, comparative effectiveness, noninferiority randomized clinical trial conducted at 67 oncology practices in the US that enrolled 671 patients with cancer (any invasive solid tumor, lymphoma, multiple myeloma, or chronic lymphocytic leukemia) who had a new clinical or radiological diagnosis of VTE. Enrollment occurred from December 2016 to April 2020. Final follow-up was in November 2020.
Intervention: Participants were randomized in a 1:1 ratio to either a DOAC (n = 335) or LMWH (n = 336) and were followed up for 6 months or until death. Physicians and patients selected any DOAC or any LMWH (or fondaparinux) and physicians selected drug doses.
Main outcomes and measures: The primary outcome was the recurrent VTE rate at 6 months. Noninferiority of anticoagulation with a DOAC vs LMWH was defined by the upper limit of the 1-sided 95% CI for the difference of a DOAC relative to LMWH of less than 3% in the randomized cohort that received at least 1 dose of assigned treatment. The 6 prespecified secondary outcomes included major bleeding, which was assessed using a 2.5% noninferiority margin.
Results: Between December 2016 and April 2020, 671 participants were randomized and 638 (95%) completed the trial (median age, 64 years; 353 women [55%]). Among those randomized to a DOAC, 330 received at least 1 dose. Among those randomized to LMWH, 308 received at least 1 dose. Rates of recurrent VTE were 6.1% in the DOAC group and 8.8% in the LMWH group (difference, -2.7%; 1-sided 95% CI, -100% to 0.7%) consistent with the prespecified noninferiority criterion. Of 6 prespecified secondary outcomes, none were statistically significant. Major bleeding occurred in 5.2% of participants in the DOAC group and 5.6% in the LMWH group (difference, -0.4%; 1-sided 95% CI, -100% to 2.5%) and did not meet the noninferiority criterion. Severe adverse events occurred in 33.8% of participants in the DOAC group and 35.1% in the LMWH group. The most common serious adverse events were anemia and death.
Conclusions and relevance: Among adults with cancer and VTE, DOACs were noninferior to LMWH for preventing recurrent VTE over 6-month follow-up. These findings support use of a DOAC to prevent recurrent VTE in patients with cancer.
Association of race and in-hospital outcomes following acute pulmonary embolism: A retrospective cohort study
Alexander E Sullivan, Carlos E Barbery, Tara Holder, Cynthia L Green, Manesh R Patel, Kevin L Thomas, W Schuyler Jones
Clin Cardiol 2023 Jul;46(7):768-776.
Abstract
Background: Racial disparities in health care are well established, with Black patients frequently experiencing the most significant consequences of this inequality. Acute pulmonary embolism (PE) is increasing in incidence and an important cause of morbidity and mortality in the United States, but little is known about racial disparities in the inpatient setting.
Hypothesis: Black and White patients admitted with acute PE will have different in-hospital outcomes.
Methods: All PE patients from January 1, 2016 to June 30, 2017 were retrospectively identified using ICD-10 codes. Data were abstracted by manual chart review for all image-confirmed PEs.
Results: A total of 782 patients with acute PE were identified, of which 319 (40.8%) were Black and 463 (59.2%) were White. Black patients had higher BMI (median [Q1-Q3]: 30.3 [25.4-36.6] vs. 29.3 [24.5-33.8] kg/m2, p = .017), were younger (61 [48-74] vs. 67 [54-75] years, p = .001), and were more likely to have a history of heart failure (16.0 vs. 7.1%, p < .001), while White patients had higher rates of malignancy (46.9 vs. 34.5%, p = .001) and recent surgery (29.6 vs. 18.2%, p < .001). Black patients were more likely to receive systemic thrombolysis (3.1% vs. 1.1%, p = .040), while White patients had numerically higher rates of surgical embolectomy (0.3% vs. 1.1%, p = .41). No difference in inpatient mortality was observed; however, Black patients had longer hospital length of stay (5.0 [3-9] vs. 4.0 [2-9] days, p = .007) and were more likely to receive warfarin (23.5 vs. 12.1%, p < .001).
Conclusions: Similar in-hospital mortality rates were observed in Black and White patients following acute PE. However, Black patients had longer hospital stays, higher warfarin prescription, and fewer traditional PE-related risk factors.
Ischemic Stroke in the Setting of Supratherapeutic International Normalized Ratio Following Coronavirus Disease 2019 Infection
Gokhan Demir; Rama Hommos; Sally Sami Al-Sirhan; Hashem Abu Serhan; Muhannad Haddadin; Umar Bin Rashid; Yamane Chawa
J Med Case Reports. 2023;17(223)
Abstract
Background: SARS-CoV-19 infection is associated with an increased risk of thrombotic events. We present a case of acute middle cerebral artery ischemic stroke in a patient with SARS-CoV-19 infection despite being on warfarin with supratherapeutic INR (International Normalized Ratio).
Case Presentation: A 68-year-old Caucasian female with multiple comorbidities was admitted to the hospital with symptoms of upper respiratory tract infection. A rapid antigen test confirmed the diagnosis of COVID-19 pneumonia, and intravenous remdesivir was initiated. On the fifth day of admission, the patient experienced sudden onset confusion, slurred speech, left-sided hemiplegia, right-sided eye deviation, and left-sided facial droop. Imaging studies revealed an occlusion of the distal anterior M2 segment of the right middle cerebral artery, and an MRI of the brain confirmed an acute right MCA infarction. Notably, the patient was receiving warfarin therapy with a supratherapeutic INR of 3.2.
Conclusions: This case report highlights the potential for thromboembolic events, including stroke, in patients with COVID-19 infection, even when receiving therapeutic anticoagulation therapy. Healthcare providers should be vigilant for signs of thrombosis in COVID-19 patients, particularly those with pre-existing risk factors. Further research is necessary to understand the pathophysiology and optimal management of thrombotic complications in COVID-19 patients.