May 2024: New In Coagulation

by Donna Castellone, MS, MT(ASCP)S • May 03, 2024

Our Monthly complilation of the latest studies, guidelines and discussions in coagulation.
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The interpretations below are provided by Donna Castellone, MS, MT (ASCP) SH for Aniara Diagnostica.

Most Popular DOAC Holds Its Own Against Edoxaban in Those Age 80 and Up

In elderly patients with Afib, stroke prevention was found to be the same with edoxaban and apixaban. These DOACs were found to have similar primary effectiveness in ischemic stroke, TIA and systemic embolism, but major bleeding rates were lower for apixaban. This was demonstrated in gastrointestinal bleeding and other non-specified bleeding. This was seen in both standard and low dose edoxaban.

Based on medicare records, older people with Afib had better outcomes using apixaban. This population based study used the UK Clinical Practice Research Datalink using all patients with incident nonvalvular Afib, 80 years or older were newly treated with edoxaban (n=7,251) or apixaban (n=39,991) from 2015 to 2021.

There is limited information and trials on DOACs in patients with Afib and the elderly population which is a high risk bleeding population. This makes it difficult for clinicians to treat this population since a preferred DOAC has not been identified. They remain an undertreated cohort.

Concomitant SSRI and Oral Anticoagulant Use Tied to Major Bleeding Risk

An increased risk of major bleeding was seen in patients who used serotonin reuptake inhibitors (SSRIs) and oral anticoagulants (OACs) in patients with atrial fibrillation. For this study, a total of 42,190 atrial fibrillation patients who were hospitalized with major bleeding were matched with over 1.1 million controls. About 60% of both groups were men who presented with a slightly higher bleeding risk. While the mean age was 74, elevated bleeding risks were seen in ages 60 and older. Patients with major bleeding tended to have slightly higher rates of hypertension, coronary artery disease, congestive heart failure, peripheral arterial disease, venous thromboembolism, stroke or transient ischemic attack, diabetes, a history of bleeding, and anemia. Taken together, there was a 33% increased risk of bleeding when compared with OAC alone.

The increased risk occurred during the first few months and persisted for the first 6 months. Risks included: Gastrointestinal bleeding: adjusted IRR 1.38 (95% CI 1.24-1.53): tracranial hemorrhage: aIRR 1.56 (95% CI 1.32-1.85) and other major bleeding: aIRR 1.23 (95% CI 1.12-1.36)

It has been shown previously that SSRIs reduce serotonin content in platelets by 80-90% within 2 weeks. This concurred with the findings that major bleeding was higher in the first 6 months of concurrent use. Direct OACs had a slightly lower bleeding risk and they may be preferred over VKAs since they have less of a pharmacokinetic interaction. Also to minimize GI bleeding a proton pump inhibitor may be used.

This is an observational study, so results should be interpreted with caution.

Nontraditional Risk Factors Play an Outsized Role in Young Adult Stroke Risk

The incidence of stroke risk in young adults under the age of 45 has more than doubled in the last 20 years. Risk factors include nontraditional factors such as migraine and autoimmune diseases as opposed to traditional factors such as hypertension, high cholesterol and smoking. The most important traditional risk factor is hypertension and increased with age.

There were 2618 stroke cases evaluated (52% female; 73% ischemic stroke) and 7827 controls matched for age, sex and insurance type. Traditional risk factors were more common in stroke cases except in the 18-34 age group in which nontraditional risk factors in men (31% vs 25%, respectively) and in women (43% vs 33%, respectively). Migraine was the most common factor in 20% of men and 35% of women.

Other notable nontraditional risk factors included heart valve disease in both men and women (OR, 3.1 and OR, 4.2, respectively); renal failure in men (OR, 8.9); and autoimmune diseases in women (OR, 8.8). Women had more risk factors for stroke than men. In controls 52% and 34% of women had one traditional and nontraditional risk factor versus 48% and 22% in men.

Factor D Inhibitor Wins Approval for PNH With Extravascular Hemolysis

Danicopan is an oral factor D inhibitor u sed to treat extravascular hemolysis in adults with paroxysmal nocturnal hemoglobinuria (PNH) has been FDA approved. Between 10-20% of patients with PNH develop significant extravascular hemolysis when treated with a C5 inhibitor. The ALPHA trail investigated standard treatment with or without danicopan in 73 patients with PNH and extravascular hemolysis. The endpoint was change in hemoglobin from baseline to 12 weeks. These patients had a mean improved hemoglobin of 2.94 g/dL as compared with 0.50 g/dL in the placebo arm (P<0.0001). The drug works by selectively inhibiting factor D. This is a complement system protein that plays a significant role in the amplification of the complement system response.

Ticagrelor Alone Cuts Bleeding Without More Events Post-PCI

The ULTIMATE-DAPT trial showed that stopping aspirin reduced the risk for major by 60% and minor bleeding by 55%. However, the question remained if it is safe to stop aspirin without increasing the risk for ischemic events. After one month of DAPT using aspirin and ticagrelor post-, percutaneous coronary intervention for acute coronary syndrome, dropping aspirin cut bleeding risk without any increase in ischemic event risks. In 3400 randomized patients (mean age 63, 74.1% male), no difference was seen in the randomized groups (3.7% vs. 3.6%). Guidelines should be revisited and after 1 month, aspirin should be dropped and a potent P2Y12 inhibitor should be used. Current guidelines recommend 12 months of DAPT to reduce the risk for MI and stent thrombosis.

Patients were randomly assigned to receive ticagrelor plus placebo, or ticagrelor plus aspirin for 11 months. The study was double blinded with two primary outcomes: clinically relevant bleeding, and major adverse cardiovascular or cerebrovascular events. Clinically relevant bleeding occurred in 2.1% of placebo group and 4.6% of aspirin group. Major bleeding occurred less frequently in the placebo group. Results suggest that DAPT can be stopped after a month in this population and risk stratification should be used for older patients.

It should also be noted that most study participants were from China or Pakistan with only 1.3% from Europe. A higher bleeding risk has been observed in patients from eastern Asia, so applying these results to other populations may require additional evaluation.

Surgical Clot Removal Superior to Meds Alone in ICH: ENRICH Published

The current guidelines do not support the use of surgery to improve the outcomes after an ICH. The ENRICH trial showed improved functional outcomes with surgical clot evacuation plus medical management. It compared in 300 patients the directed medical management as suggested by the guidelines alone or with early trans sulcal MIPS using the BrainPath minimal access port. Eligibility of patients were determined by a hematoma volume of 30-80ml, a Glasgow Coma Scale score between 5-14, and if surgery could be performed within 24 hours of their last known normal. Patients presented with lobar hemorrhages (3/4 of patients) and 30.7% had anterior basal ganglia hemorrhages, this included up to 175 patients. The remaining enrolled patients only had lobar hemorrhages.

The mean difference was 0.127 in lobar hemorrhage and -0.013 in basal ganglia hemorrhages. This was a significant effect for lobar hemorrhages, the same conclusion could not be established for basal ganglia since they stopped enrollment. The primary endpoint of 30 day mortality was halved from 18% with medical treatment alone to 9,3% in the surgery group. At the 180 day follow up, 20% in the surgery group and 23% in the control group died from any cause. There were one or more serious adverse events in 63,3% of the surgery group versus 78.7% in the control group. Length of stay in the ICU fell from 9.7 days in the control group to 6.9 in the surgical group, minimizing the occurrence of ICU related complications.


Systemic Lupus Erythematosus | A Review

Caroline H. Siegel, MD, MS; Lisa R. Sammaritano, MD
JAMA. Published online April 8, 2024. doi:10.1001/jama.2024.2315


Importance Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by inflammation and immune-mediated injury to multiple organ systems, including the mucocutaneous, musculoskeletal, hematologic, and kidney systems. Approximately 3.4 million people worldwide have received a diagnosis of SLE.

Observations Approximately 90% of people with SLE are female. Although there are no uniformly accepted diagnostic criteria for SLE, the 2019 European Alliance of Associations for Rheumatology (formerly the European League Against Rheumatism)/American College of Rheumatology classification criteria developed for scientific study are an estimated 96.1% sensitive and 93.4% specific for SLE. These classification criteria include both clinical factors, such as fever, cytopenia, rash, arthritis, and proteinuria, which may be indicative of lupus nephritis; and immunologic measures, such as SLE-specific autoantibodies and low complement levels. Approximately 40% of people with SLE develop lupus nephritis, and an estimated 10% of people with lupus nephritis develop end-stage kidney disease after 10 years. The primary goal of treatment is to achieve disease remission or quiescence, defined by minimal symptoms, low levels of autoimmune inflammatory markers, and minimal systemic glucocorticoid requirement while the patient is treated with maintenance doses of immunomodulatory or immunosuppressive medications. Treatment goals include reducing disease exacerbations, hospitalizations, and organ damage due to the disease or treatment toxicity. Hydroxychloroquine is standard of care for SLE and has been associated with a significant reduction in mortality. Treatments in addition to hydroxychloroquine are individualized, with immunosuppressive agents, such as azathioprine, mycophenolate mofetil, and cyclophosphamide, typically used for treating moderate to severe disease. Three SLE medications were recently approved by the Food and Drug Administration: belimumab (for active SLE in 2011 and for lupus nephritis in 2020), voclosporin (for lupus nephritis), and anifrolumab (for active SLE).

Conclusions and Relevance Systemic lupus erythematosus is associated with immune-mediated damage to multiple organs and increased mortality. Hydroxychloroquine is first-line therapy and reduces disease activity, morbidity, and mortality. When needed, additional immunosuppressive and biologic therapies include azathioprine, mycophenolate mofetil, cyclophosphamide, belimumab, voclosporin, and anifrolumab.

Anticoagulation Stewardship to Bridge the Implementation Gap in Perioperative Anticoagulation Management

Alfonso J Tafur, Geoffrey D Barnes, Vinai C Bhagirath, James Douketis
TH Open 2024 Mar 11;8(1):e114-e120


Lack of alignment of care protocols among providers in health care is a driver of increased costs and suboptimal patient outcomes. Perioperative anticoagulation management is a good example of a complex area where protocol creation is a clinical challenge that demands input from multiple experts. Questions regarding the need for anticoagulation interruptions are frequent. Yet, due to layers of complexity involving analysis of anticoagulation indication, surgical risk, and anesthesia-associated bleeding risk as well as institutional practices, there is heterogeneity in how these interruptions are approached. The recent perioperative anticoagulation guidelines from the American College of Chest Physicians summarize extensive evidence for the management of anticoagulant and antiplatelet medications in patients who undergo elective interventions. However, implementation of these guidelines by individual clinicians is highly varied and often does not follow the best available clinical evidence. Against this background, anticoagulation stewardship units, which exist to improve safety and quality monitoring for the anticoagulated patient, are of growing interest. These units provide a bridge for the implementation of value-based, high-quality guidelines for patients who need perioperative anticoagulation interruption. We use a case to pragmatically illustrate the problem and tactics for change management and implementation science that may facilitate the adoption of perioperative anticoagulation guidelines.

Anticoagulation with edoxaban in patients with long atrial high-rate episodes ≥24 h


Background and aims: Patients with long atrial high-rate episodes (AHREs) ≥24 h and stroke risk factors are often treated with anticoagulation for stroke prevention. Anticoagulation has never been compared with no anticoagulation in these patients.

Methods: This secondary pre-specified analysis of the Non-vitamin K antagonist Oral anticoagulants in patients with Atrial High-rate episodes (NOAH-AFNET 6) trial examined interactions between AHRE duration at baseline and anticoagulation with edoxaban compared with placebo in patients with AHRE and stroke risk factors. The primary efficacy outcome was a composite of stroke, systemic embolism, or cardiovascular death. The safety outcome was a composite of major bleeding and death. Key secondary outcomes were components of these outcomes and electrocardiogram (ECG)-diagnosed atrial fibrillation.

Results: Median follow-up of 2389 patients with core lab-verified AHRE was 1.8 years. AHRE ≥24 h were present at baseline in 259/2389 patients (11%, 78 ± 7 years old, 28% women, CHA2DS2-VASc 4). Clinical characteristics were not different from patients with shorter AHRE. The primary outcome occurred in 9/132 patients with AHRE ≥24 h (4.3%/patient-year, 2 strokes) treated with anticoagulation and in 14/127 patients treated with placebo (6.9%/patient-year, 2 strokes). Atrial high-rate episode duration did not interact with the efficacy (P-interaction = .65) or safety (P-interaction = .98) of anticoagulation. Analyses including AHRE as a continuous parameter confirmed this. Patients with AHRE ≥24 h developed more ECG-diagnosed atrial fibrillation (17.0%/patient-year) than patients with shorter AHRE (8.2%/patient-year; P < .001).

Conclusions: This hypothesis-generating analysis does not find an interaction between AHRE duration and anticoagulation therapy in patients with device-detected AHRE and stroke risk factors. Further research is needed to identify patients with long AHRE at high stroke risk.

European expert consensus recommendations on the primary care use of direct oral anticoagulants in patients with venous thromboembolism

Carter Patrice, Fuat Ahmet, Haas Sylvia, Smyth Elizabeth, Brotons Carlos, Cools Frank, Bauersachs Rupert, Hobbs F D Richard
BMC Prim Care 2024 Mar 18;25(1):90.


Background: Direct oral anticoagulants for the treatment of venous thromboembolism are supported by robust clinical trial evidence. Despite published guidance, general practitioners are faced with increasingly complex decisions and implementation remains sub-optimal in certain real-world scenarios.

Methods: A two stage formal consensus exercise was performed to formulate consensus statements and a summary guide, facilitating optimal management of direct oral anticoagulants in venous thromboembolism patients by generalist physicians across Europe. An online questionnaire distributed to a broad panel (Phase 1), followed by a virtual panel discussion by an expert group (Phase 2) were conducted. Phase 1 statements covered nine management domains, and were developed via a literature review and expert steering committee. Participants rated statements by their level of agreement. Phase 1 responses were collated and analysed prior to discussion and iterative refinement in Phase 2.

Results: In total 56 participants from across Europe responded to Phase 1. The majority had experience working as general practitioners. Consensus indicated that direct oral anticoagulants are the treatment of choice for managing patients with venous thromboembolism, at initiation and for extended treatment, with a review at three to six months to re-assess treatment effect and risk profile. Direct oral anticoagulant choice should be based on individual patient factors and include shared treatment choice between clinicians and patients; the only sub-group of patients requiring specific guidance are those with cancer.

Conclusion: Results demonstrate an appreciation of best practices, but highlight challenges in clinical practice. The patient pathway and consensus recommendations provided, aim to highlight key considerations for general practice decision making, and aid optimal venous thromboembolism treatment.

Keywords: Cancer associated thromboembolism, Primary Care; Direct oral anticoagulants (DOACs); Formal consensus; Venous thromboembolism (VTE).

Serious Bleeding in Patients With Atrial Fibrillation Using Diltiazem With Apixaban or Rivaroxaban

Wayne A. Ray, PhD; Cecilia P. Chung, MD, MPH; C. Michael Stein, MB, ChB; et alWalter Smalley, MD, MPH; Eli Zimmerman, MD; William D. Dupont, PhD; Adriana M. Hung, MD, MPH; James R. Daugherty, MS; Alyson Dickson, MA; Katherine T. Murray, MD
JAMA. Published online April 15, 2024.


Importance Diltiazem, a commonly prescribed ventricular rate–control medication for patients with atrial fibrillation, inhibits apixaban and rivaroxaban elimination, possibly causing overanticoagulation.

Objective To compare serious bleeding risk for new users of apixaban or rivaroxaban with atrial fibrillation treated with diltiazem or metoprolol.

Design, Setting, and Participants This retrospective cohort study included Medicare beneficiaries aged 65 years or older with atrial fibrillation who initiated apixaban or rivaroxaban use and also began treatment with diltiazem or metoprolol between January 1, 2012, and November 29, 2020. Patients were followed up to 365 days through November 30, 2020. Data were analyzed from August 2023 to February 2024.

Exposures Diltiazem and metoprolol.

Main Outcomes and Measures The primary outcome was a composite of bleeding-related hospitalization and death with recent evidence of bleeding. Secondary outcomes were ischemic stroke or systemic embolism, major ischemic or hemorrhagic events (ischemic stroke, systemic embolism, intracranial or fatal extracranial bleeding, or death with recent evidence of bleeding), and death without recent evidence of bleeding. Hazard ratios (HRs) and rate differences (RDs) were adjusted for covariate differences with overlap weighting.

Results The study included 204 155 US Medicare beneficiaries, of whom 53 275 received diltiazem and 150 880 received metoprolol. Study patients (mean [SD] age, 76.9 [7.0] years; 52.7% female) had 90 927 person-years (PY) of follow-up (median, 120 [IQR, 59-281] days). Patients receiving diltiazem treatment had increased risk for the primary outcome (RD, 10.6 [95% CI, 7.0-14.2] per 1000 PY; HR, 1.21 [95% CI, 1.13-1.29]) and its components of bleeding-related hospitalization (RD, 8.2 [95% CI, 5.1-11.4] per 1000 PY; HR, 1.22 [95% CI, 1.13-1.31]) and death with recent evidence of bleeding (RD, 2.4 [95% CI, 0.6-4.2] per 1000 PY; HR, 1.19 [95% CI, 1.05-1.34]) compared with patients receiving metoprolol. Risk for the primary outcome with initial diltiazem doses exceeding 120 mg/d (RD, 15.1 [95% CI, 10.2-20.1] per 1000 PY; HR, 1.29 [95% CI, 1.19-1.39]) was greater than that for lower doses (RD, 6.7 [95% CI, 2.0-11.4] per 1000 PY; HR, 1.13 [95% CI, 1.04-1.24]). For doses exceeding 120 mg/d, the risk of major ischemic or hemorrhagic events was increased (HR, 1.14 [95% CI, 1.02-1.27]). Neither dose group had significant changes in the risk for ischemic stroke or systemic embolism or death without recent evidence of bleeding. When patients receiving high- and low-dose diltiazem treatment were directly compared, the HR for the primary outcome was 1.14 (95% CI, 1.02-1.26).

Conclusions and Relevance In Medicare patients with atrial fibrillation receiving apixaban or rivaroxaban, diltiazem was associated with greater risk of serious bleeding than metoprolol, particularly for diltiazem doses exceeding 120 mg/d.

Extended Clopidogrel Monotherapy vs DAPT in Patients With Acute Coronary Syndromes at High Ischemic and Bleeding Risk | The OPT-BIRISK Randomized Clinical Trial

Yi Li, MD; Jing Li, MD; Bin Wang, MD; etalQuanmin Jing, MD; Yujie Zeng, MD; Aijie Hou, MD; Zhifang Wang, MD; Aijun Liu, MD; Jinliang Zhang, MD; Yaojun Zhang, MD; Ping Zhang, MD; Daming Jiang, MD; Bin Liu, MD; Jiamao Fan, MD; Jun Zhang, MD; Li Li, MD; Guohai Su, MD; Ming Yang, MD; Weihong Jiang, MD; Peng Qu, MD; Hesong Zeng, MD,PhD; Lu Li, MD; Miaohan Qiu, MD; Leisheng Ru, MD; Shaoliang Chen, MD; Yujie Zhou, MD; Shubin Qiao, MD; Gregg W. Stone, MD; Dominick J. Angiolillo, MD, PhD; Yaling Han, MD; for the OPT-BIRISK Investigators
JAMA Cardiol. Published online April 17, 2024.


Importance Purinergic receptor P2Y12 (P2Y12) inhibitor monotherapy after a certain period of dual antiplatelet therapy (DAPT) may be an attractive option of maintenance antiplatelet treatment for patients undergoing percutaneous coronary intervention (PCI) who are at both high bleeding and ischemic risk (birisk).

Objective To determine if extended P2Y12 inhibitor monotherapy with clopidogrel is superior to ongoing DAPT with aspirin and clopidogrel after 9 to 12 months of DAPT after PCI in birisk patients with acute coronary syndromes (ACS).

Design, Setting, and Participants This was a multicenter, double-blind, placebo-controlled, randomized clinical trial including birisk patients with ACS who had completed 9 to 12 months of DAPT after drug-eluting stent implantation and were free from adverse events for at least 6 months at 101 China centers between February 2018 and December 2020. Study data were analyzed from April 2023 to May 2023.

Interventions Patients were randomized either to clopidogrel plus placebo or clopidogrel plus aspirin for an additional 9 months.

Main Outcomes and Measures The primary end point was Bleeding Academic Research Consortium (BARC) types 2, 3, or 5 bleeding 9 months after randomization. The key secondary end point was major adverse cardiac and cerebral events (MACCE; the composite of all-cause death, myocardial infarction, stroke or clinically driven revascularization). The primary end point was tested for superiority, and the MACCE end point was tested for sequential noninferiority and superiority.

Results A total of 7758 patients (mean [SD] age, 64.8 [9.0] years; 4575 male [59.0%]) were included in this study. The primary end point of BARC types 2, 3, or 5 bleeding occurred in 95 of 3873 patients (2.5%) assigned to clopidogrel plus placebo and 127 of 3885 patients (3.3%) assigned to clopidogrel plus aspirin (hazard ratio [HR], 0.75; 95% CI, 0.57-0.97; difference, −0.8%; 95% CI, −1.6% to −0.1%; P = .03). The incidence of MACCE was 2.6% (101 of 3873 patients) in the clopidogrel plus placebo group and 3.5% (136 of 3885 patients) in the clopidogrel plus aspirin group (HR, 0.74; 95% CI, 0.57-0.96; difference, −0.9%; 95% CI, −1.7% to −0.1%; P < .001 for noninferiority; P = .02 for superiority).

Conclusions and Relevance Among birisk patients with ACS who completed 9 to 12 months of DAPT after drug-eluting stent implantation and were free from adverse events for at least 6 months before randomization, an extended 9-month clopidogrel monotherapy regimen was superior to continuing DAPT with clopidogrel in reducing clinically relevant bleeding without increasing ischemic events.