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General Hematology

Non-inferiority RCT: Reduced-Dose vs Full-Dose Direct Oral Anticoagulants for Extended VTE Treatment

8 Mar, 2025 | 17:46h | UTC

Background: Venous thromboembolism (VTE) carries a high risk of recurrence once anticoagulation is stopped, particularly in those with unprovoked events or persistent risk factors. Extended anticoagulation is therefore recommended for patients at high risk, but optimal dosing remains uncertain. Reduced-dose direct oral anticoagulants (DOACs) may lower bleeding risk compared with full-dose regimens. However, prior trials that tested reduced-dose anticoagulation enrolled patients with less definitive indications for continuation and were not powered for head-to-head efficacy comparisons.

Objective: The RENOVE trial aimed to determine whether reduced-dose DOACs (apixaban 2.5 mg twice daily or rivaroxaban 10 mg once daily) are non-inferior to full-dose DOACs (apixaban 5 mg twice daily or rivaroxaban 20 mg once daily) in preventing VTE recurrence during extended treatment, while potentially reducing bleeding risk.

Methods: RENOVE was a non-inferiority, multicenter, randomized, open-label, blinded-endpoint trial conducted in 47 French hospitals. It included adult patients (n=2768) who had completed 6–24 months of uninterrupted full-dose anticoagulation for symptomatic pulmonary embolism or proximal deep vein thrombosis and were deemed at high risk for recurrence. Participants were randomly assigned 1:1 to a reduced-dose or a full-dose DOAC regimen. The primary outcome was symptomatic recurrent VTE (non-fatal or fatal). The main secondary outcomes included major bleeding or clinically relevant non-major bleeding, and a net clinical benefit composite of recurrent VTE plus major or clinically relevant non-major bleeding.

Results: After a median follow-up of 37.1 months, the primary outcome occurred in 19/1383 patients (5-year cumulative incidence 2.2%) in the reduced-dose arm and 15/1385 (1.8%) in the full-dose arm (adjusted HR 1.32; 95% CI 0.67–2.60; p=0.23 for non-inferiority). Major or clinically relevant non-major bleeding was significantly lower in the reduced-dose group (9.9% vs 15.2% at 5 years; HR 0.61; 95% CI 0.48–0.79). Major bleeding was 2.1% vs 4.0%, respectively. Net clinical benefit (recurrent VTE or clinically relevant bleeding) was 11.8% in the reduced-dose group versus 16.5% in the full-dose group (HR 0.67; 95% CI 0.53–0.86). Mortality and arterial events were similar between groups.

Conclusions: Reduced-dose DOACs did not meet the formal non-inferiority criterion for preventing VTE recurrence in patients requiring extended anticoagulation. Nonetheless, absolute recurrence rates were low in both arms. The reduced-dose strategy substantially lowered the risk of clinically relevant bleeding without increasing all-cause mortality. Although full-dose anticoagulation remains an option, these findings suggest that reduced-dose regimens may be clinically reasonable for many patients who need ongoing therapy.

Implications for Practice: Clinicians could consider a reduced-dose DOAC regimen for extended VTE treatment, especially in individuals at high bleeding risk, given the observed safety benefits. Treatment decisions should still account for patient-specific factors (e.g., obesity, history of severe VTE) where full-dose regimens might remain preferable.

Study Strengths and Limitations: Major strengths include the large sample size, well-defined endpoints adjudicated by a blinded committee, and extended follow-up. Limitations include the open-label design and the low rate of recurrence, which led to a sample size increase mid-study. Subgroup analyses may be underpowered to detect meaningful differences in specific populations.

Future Research: Further trials or pooled analyses are needed to clarify whether certain high-risk subgroups (e.g., those with severe obesity or active malignancy) might benefit more from continuing a full-dose regimen. Additional prospective studies could refine criteria for safe dose reductions.

Reference:

  1. Couturaud F, Schmidt J, Sanchez O, et al. Extended treatment of venous thromboembolism with reduced-dose versus full-dose direct oral anticoagulants in patients at high risk of recurrence: a non-inferiority, multicentre, randomised, open-label, blinded endpoint trial. The Lancet. 2025;405(10480). DOI: https://doi.org/10.1016/S0140-6736(24)02842-3
  2. Middeldorp S, Leentjens J. Anticoagulation for extended venous thromboembolism treatment: less is really more. The Lancet. 2025;405(10480). DOI: https://doi.org/10.1016/S0140-6736(25)00099-6

 

Phase 2b RCT: Abelacimab Significantly Reduces Bleeding Events Compared with Rivaroxaban in Patients with Atrial Fibrillation

27 Jan, 2025 | 11:00h | UTC

Background: Atrial fibrillation (AF) elevates stroke risk roughly fivefold, necessitating anticoagulation therapy to reduce embolic events. Direct oral anticoagulants (DOACs) have replaced vitamin K antagonists as the preferred agents, given their comparable efficacy and lower risk of intracranial hemorrhage. However, significant bleeding—especially gastrointestinal bleeding—still occurs with DOACs, prompting ongoing efforts to develop safer anticoagulants. Abelacimab, a fully human monoclonal antibody targeting factor XI (and its active form, XIa), is hypothesized to “uncouple” thrombosis from hemostasis, potentially lowering bleeding risk. Early data in knee arthroplasty prevention suggested reduced venous thromboembolism (VTE) without increased bleeding. This trial (AZALEA–TIMI 71) aimed to compare the bleeding rates of monthly subcutaneous abelacimab with once-daily rivaroxaban in patients with AF and moderate-to-high stroke risk.

Objective: To evaluate whether subcutaneous abelacimab at two doses (150 mg or 90 mg monthly) leads to fewer major or clinically relevant nonmajor bleeding events than rivaroxaban (20 mg or 15 mg daily) in patients with AF.

Methods: In this phase 2b, parallel-group, partially blind, randomized trial, 1287 adults with AF (CHA2_2DS2_2-VASc ≥3–4 and moderate/high stroke risk) were assigned 1:1:1 to abelacimab 150 mg, abelacimab 90 mg, or open-label rivaroxaban. Treatment continued for a median of 2.1 years. The primary endpoint was major or clinically relevant nonmajor bleeding, adjudicated by a blinded events committee. Levels of free factor XI were measured to gauge abelacimab’s pharmacodynamics. The trial was halted early based on a recommendation from the independent data monitoring committee due to unexpectedly large reductions in bleeding with abelacimab.

Results: Median age was 74 years, and 44% of participants were female. In the final analysis of the complete dataset, major or clinically relevant nonmajor bleeding occurred at rates of 3.2 and 2.6 events per 100 person-years for abelacimab 150 mg and 90 mg, respectively, versus 8.4 per 100 person-years for rivaroxaban. Corresponding hazard ratios were 0.38 (95% CI, 0.24–0.60) for the 150-mg dose and 0.31 (95% CI, 0.19–0.51) for the 90-mg dose (P<0.001 for both comparisons). The incidence of major gastrointestinal bleeding was notably lower with abelacimab (0.5% in both arms) compared with rivaroxaban (4.2%). Although not powered for stroke prevention, ischemic stroke rates were numerically higher with abelacimab, underscoring the need for larger efficacy trials.

Conclusions: Monthly abelacimab led to substantial and sustained reduction of free factor XI and demonstrated significantly lower bleeding rates than rivaroxaban in patients with AF. While these findings suggest a potentially safer profile for abelacimab, definitive conclusions about stroke prevention require phase 3 studies.

Implications for Practice: Should abelacimab maintain efficacy in preventing thromboembolism in forthcoming trials, it may offer an alternative to existing DOACs, particularly for patients at elevated bleeding risk (e.g., gastrointestinal). However, clinicians must consider real-world factors such as possible high drug cost, insurance coverage, and the logistics of monthly subcutaneous injections. Abelacimab is investigational and not yet approved; its role will depend on phase 3 efficacy and cost-effectiveness outcomes.

Study Strengths and Limitations: Strengths include randomized design, relatively long follow-up (median 2.1 years), and direct comparison to an established DOAC. The major limitation is that the trial was not sufficiently powered to evaluate stroke or systemic embolism. Moreover, the open-label design between abelacimab and rivaroxaban could introduce bias, partly mitigated by blinded dose assignments for abelacimab and blinded endpoint adjudication. The predominantly White population may limit generalizability.

Future Research: Ongoing phase 3 studies (e.g., LILAC–TIMI 76) will clarify abelacimab’s efficacy and safety in larger cohorts, particularly regarding stroke prevention. Comparative cost analyses, real-world adherence, and exploration of subcutaneous administration logistics will be crucial in determining abelacimab’s long-term clinical value. Additional investigations into factor XIa inhibitors (e.g., small molecules, antisense oligonucleotides) may further expand this therapeutic class.

Reference:

  1. Ruff CT, Patel SM, Giugliano RP, Morrow DA, Hug B, Kuder JF, et al. “Abelacimab versus Rivaroxaban in Patients with Atrial Fibrillation.” New England Journal of Medicine. 2025;392:361–371. DOI: https://doi.org/10.1056/NEJMoa2406674
  2. Angiolillo DJ, Capodanno D. “Uncoupling Thrombosis and Hemostasis by Inhibiting Factor XI.” New England Journal of Medicine. 2025;392:400–403. DOI: https://doi.org/10.1056/NEJMe2414209
  3. Mandrola JM. “Factor XI Inhibitors May Not Be Dead.” This Week in Cardiology Podcast. January 24, 2025. https://www.medscape.com/viewarticle/1002184#vp_3

 

Meta-analysis: Therapeutic-Dose Heparin Improves 28-Day Mortality in COVID-19 Hospitalized Patients

6 Jan, 2025 | 12:00h | UTC

Background: High rates of thrombotic events and systemic inflammation among COVID-19 hospitalized patients led researchers to test whether intensified anticoagulation strategies could reduce morbidity and mortality. Previous trials yielded conflicting results, partly due to varying doses of anticoagulants—prophylactic, intermediate, or therapeutic—and heterogeneous patient severity. This comprehensive investigation, conducted by the WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group, aimed to clarify the benefits and risks of escalated anticoagulation dosing in patients hospitalized for COVID-19.

Objective: To estimate whether higher-dose anticoagulation (therapeutic or intermediate) improves 28-day all-cause mortality compared with lower-dose anticoagulation (prophylactic or intermediate), and to evaluate secondary outcomes, including progression to mechanical ventilation, thromboembolic events, and major bleeding.

Methods: This prospective meta-analysis included randomized trials comparing higher- versus lower-dose anticoagulation for hospitalized COVID-19 patients. Investigators collected trial-level summary data, focusing primarily on heparins. Dosing categories—therapeutic, intermediate, and prophylactic—were predefined. The main outcome was 28-day mortality; secondary outcomes included progression to invasive mechanical ventilation (IMV), venous or arterial thrombotic events, and major hemorrhage. Data were analyzed using a fixed-effects model, with odds ratios (ORs) pooled across trials.

Results: Overall, 22 trials (over 11 000 total participants) contributed data, primarily evaluating heparins. For therapeutic versus prophylactic-dose heparin, 28-day mortality was significantly reduced (OR, 0.77; 95% CI, 0.64–0.93), especially among patients requiring low-flow oxygen or no supplemental oxygen. Therapeutic dose reduced thromboembolic events (OR 0.48; 95% CI, 0.36-0.64) but increased major bleeding (OR 1.90; 95% CI, 1.19-3.05) compared to prophylactic dose. In contrast, when therapeutic was compared to intermediate-dose heparin, the summary OR for 28-day mortality was 1.21 (CI, 0.93–1.58), suggesting a potential trend toward higher mortality that did not reach statistical significance. Intermediate versus prophylactic-dose comparisons revealed no conclusive mortality difference (OR, 0.95; CI, 0.76–1.19). Across all higher-dose arms, thromboembolic events decreased, while the risk of major bleeding increased, underscoring the delicate risk–benefit balance. Subgroup analyses by respiratory support level, D-dimer, and baseline severity did not indicate strong interaction effects, although sample sizes were limited in more severe illness subgroups.

Conclusions: Therapeutic-dose heparin reduces 28-day mortality relative to prophylactic-dose in hospitalized patients with COVID-19, mainly among those not requiring invasive ventilation. Mortality was similar or potentially worse when therapeutic was compared to intermediate-dose. Clinicians must weigh the lower rate of thrombotic complications against the higher bleeding risk, particularly in critically ill patients.

Implications for Practice: Although higher anticoagulant dosing appears beneficial for certain hospitalized COVID-19 patients, especially those with mild to moderate respiratory compromise, individualized assessment remains key. Current guidelines broadly recommend prophylactic dosing for the critically ill and suggest considering higher doses only in carefully selected patients. Evolving viral variants and changes in standard of care further complicate direct application of these findings to present-day hospital settings.

Study Strengths and Limitations: Strengths include prospective planning, collaboration with multiple trials, and a large pooled sample. Limitations encompass heterogeneity in dose definitions, partial reliance on published data where individual-level parameters could not be fully harmonized, and potential temporal changes in COVID-19 clinical profiles. Moreover, bleeding severity beyond major hemorrhage was not universally reported, limiting robust safety assessments.

Future Research: Further studies should focus on individualized anticoagulant strategies that consider biomarkers (for example, D-dimer) and evolving treatment protocols. Investigations examining optimal timing, duration, and post-discharge management will help refine anticoagulation practices.

Reference:

The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group. Anticoagulation Among Patients Hospitalized for COVID-19: A Systematic Review and Prospective Meta-analysis. Annals of Internal Medicine. DOI: https://doi.org/10.7326/ANNALS-24-00800

Shappell CN, Anesi GL. Anticoagulation for COVID-19: Seeking Clarity and Finding Yet More Gray. Annals of Internal Medicine. DOI: https://doi.org/10.7326/ANNALS-24-03244

AGA Clinical Practice Update on Managing Portal Vein Thrombosis in Cirrhotic Patients: Expert Review

3 Jan, 2025 | 10:00h | UTC

Introduction: This summary highlights key recommendations from an AGA expert review on portal vein thrombosis (PVT) in cirrhotic patients. PVT is common in cirrhosis, with an estimated five-year incidence of around 11%, and may worsen portal hypertension and elevate mortality. Management is challenging because of limited evidence, the potential complications of both PVT and anticoagulation, and significant heterogeneity regarding clot characteristics, host factors, and cirrhosis severity. This review presents the latest guidance on identifying clinically relevant PVT, selecting anticoagulation, and considering endovascular interventions, including TIPS (transjugular intrahepatic portosystemic shunt).

Key Recommendations:

  1. No Routine Screening: Asymptomatic patients with compensated cirrhosis do not require regular screening for PVT in the absence of suggestive clinical changes.
  2. Imaging Confirmation: When Doppler ultrasound reveals suspected PVT, contrast-enhanced CT or MRI is recommended to confirm the diagnosis, exclude malignancy, and characterize clot extent and occlusion.
  3. Hypercoagulability Testing: Extensive thrombophilia workup is not indicated unless there is family or personal history of thrombotic events, or associated laboratory abnormalities.
  4. Intestinal Ischemia Management: Patients who develop PVT with evidence of intestinal ischemia should receive prompt anticoagulation and, ideally, multidisciplinary team care involving gastroenterology, hepatology, interventional radiology, hematology, and surgery.
  5. Observation of Minor or Recent Thrombi: In cirrhotic patients without ischemia, with recent (<6 months) thrombi that are <50% occlusive, close imaging follow-up every three months is a reasonable option to track potential spontaneous clot regression.
  6. Anticoagulation for Significant PVT: Consider anticoagulation for more extensive or obstructive (>50%) recent PVT, especially if the main portal vein or mesenteric vessels are involved. Candidates for liver transplantation and those with inherited thrombophilia may derive additional benefit.
  7. Chronic Cavernous PVT: Anticoagulation is generally not advised in patients with long-standing (>6 months) complete occlusion and well-formed collateral channels.
  8. Variceal Screening: Perform endoscopic screening or ensure prophylaxis for varices. Avoid delays in initiating anticoagulation, as timeliness is essential for better recanalization outcomes.
  9. Choice of Anticoagulant: Vitamin K antagonists, low-molecular-weight heparin, and direct oral anticoagulants (DOACs) are all viable options in cirrhosis. DOACs may be appropriate in well-compensated (Child-Turcotte-Pugh class A or certain class B) cirrhosis but should be avoided in class C. Treatment selection should consider patient preferences, monitoring feasibility, and risk of bleeding.
  10. Duration of Therapy: Reassess clot status with cross-sectional imaging every three months. Continue anticoagulation for transplant-eligible individuals who show partial or complete recanalization, and consider discontinuation in nonresponders after six months if futility is evident.
  11. TIPS Revascularization: Portal vein revascularization using TIPS may be pursued in patients who have other TIPS indications (like refractory ascites or variceal bleeding) or to improve transplant feasibility by recanalizing portal flow.

Conclusion: PVT in cirrhosis remains a complex clinical issue requiring careful evaluation of clot extent, timing, and the potential need for transplantation. The recommendations presented here underscore prompt imaging, timely anticoagulation for high-risk thrombi, and individualized therapy based on Child-Turcotte-Pugh classification and bleeding risk. When necessary, multidisciplinary collaboration is key to achieving optimal patient outcomes. Prospective randomized trials and standardized classifications of PVT will be instrumental in refining future guidelines.

Reference:
Davis JPE, Lim JK, Francis FF, Ahn J. AGA Clinical Practice Update on Management of Portal Vein Thrombosis in Patients With Cirrhosis: Expert Review. Gastroenterology. 2024. DOI: http://doi.org/10.1053/j.gastro.2024.10.038

 

Review: Diagnosis and Management of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)

18 Dec, 2024 | 11:08h | UTC

Introduction: DRESS is a severe T-cell–mediated hypersensitivity reaction triggered by prolonged exposure to certain medications, characterized by extensive rash, fever, hematologic abnormalities (notably eosinophilia or atypical lymphocytosis), lymphadenopathy, and involvement of internal organs such as the liver, kidneys, and lungs. Common culprits include aromatic anticonvulsants, allopurinol, and specific antibiotics. Although relatively rare, DRESS accounts for a substantial proportion of severe cutaneous adverse drug reactions (SCARs) in hospitalized patients and can be life-threatening, with mortality rates around 5%. Its pathogenesis involves complex immune dysregulation, including Th2 predominance, possible viral reactivation (e.g., HHV-6), and genetic predispositions related to certain HLA alleles. Diagnosis typically relies on clinical criteria, such as the validated RegiSCAR scoring system, and on excluding other SCARs like Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and acute generalized exanthematous pustulosis (AGEP).

Key Recommendations:

  • Identify and Discontinue the Culprit Drug: Prompt removal of the offending medication is the cornerstone of therapy.
  • Supportive Care and Monitoring: Hospitalization, often in an intensive care setting, may be required for organ function support and close monitoring of disease progression. Regular assessment of liver enzymes, renal function, blood counts, and cardiac and pulmonary status is critical.
  • Systemic Glucocorticoids: High-dose corticosteroids (e.g., prednisone 0.5–1 mg/kg/day) are first-line therapy. A gradual taper over 6–12 weeks is recommended to minimize relapse.
  • Steroid-Sparing and Targeted Therapies: In refractory cases or when steroids are contraindicated, consider other immunosuppressants (e.g., cyclosporine, mycophenolate mofetil) or targeted biologic agents (e.g., anti–IL-5 therapies) to control persistent eosinophilia and organ involvement.
  • Diagnostic Testing and Specialist Involvement: Although no single test confirms DRESS, dermatology or allergy/immunology consultation may help identify culprit drugs and safer therapeutic alternatives. Patch testing, delayed intradermal testing, and HLA genotyping can sometimes clarify drug causality.
  • Long-Term Follow-Up: Patients require prolonged observation due to risks of relapse, potential autoimmune sequelae (e.g., thyroiditis, type 1 diabetes), and psychological distress. Ongoing multidisciplinary care and support are essential.

Conclusion: Early recognition of DRESS, prompt discontinuation of the offending drug, and initiation of systemic corticosteroids are key steps in management. Emerging therapies offer additional treatment options for severe or refractory cases. Long-term follow-up is vital to address relapses, organ damage, and autoimmune complications. A coordinated, multidisciplinary approach improves clinical outcomes and quality of life for affected patients.

Reference: Kroshinsky D, Cardones ARG, Blumenthal KG. Drug Reaction with Eosinophilia and Systemic Symptoms. New England Journal of Medicine. 2024;391:2242-2254. DOI: https://doi.org/10.1056/NEJMra2204547

 

RCT: Liberal vs Restrictive Transfusion Yields No Neurologic Outcome Benefit in Aneurysmal Subarachnoid Hemorrhage

16 Dec, 2024 | 11:26h | UTC

Background: Aneurysmal subarachnoid hemorrhage (SAH) is a critical neurologic condition associated with high morbidity and mortality. Anemia is common in this setting and may worsen cerebral oxygenation and outcomes. However, the impact of a liberal transfusion threshold compared with a restrictive approach on long-term neurologic outcomes has been uncertain.

Objective: To determine whether a liberal red blood cell transfusion strategy (transfusion at hemoglobin ≤10 g/dL) improves 12-month neurologic outcomes compared with a restrictive strategy (transfusion at hemoglobin ≤8 g/dL) in patients with aneurysmal SAH and anemia.

Methods: This was a multicenter, pragmatic, open-label, randomized controlled trial conducted at 23 specialized neurocritical care centers. Critically ill adults with a first-ever aneurysmal SAH and hemoglobin ≤10 g/dL within 10 days of admission were randomized to a liberal or restrictive transfusion strategy. The primary outcome was unfavorable neurologic outcome at 12 months, defined as a modified Rankin scale score ≥4. Secondary outcomes included the Functional Independence Measure (FIM), quality of life assessments, and imaging-based outcomes such as vasospasm and cerebral infarction. Outcome assessors were blinded to group allocation.

Results: Among 742 randomized patients, 725 were analyzed for the primary outcome. At 12 months, unfavorable neurologic outcome occurred in 33.5% of patients in the liberal group and 37.7% in the restrictive group (risk ratio 0.88; 95% CI, 0.72–1.09; p=0.22). There were no clinically meaningful differences in secondary outcomes. Mortality at 12 months was similar (approximately 27% in both arms). Radiographic vasospasm was more frequently detected in the restrictive group, though this did not translate into improved functional outcomes in the liberal arm. Adverse events and transfusion reactions were comparable between groups.

Conclusions: In patients with aneurysmal SAH and anemia, a liberal transfusion strategy did not lead to a significantly lower risk of unfavorable neurologic outcome at 12 months compared with a restrictive approach.

Implications for Practice: These findings suggest that routinely maintaining higher hemoglobin levels does not confer substantial long-term functional benefit. Clinicians may consider a more restrictive threshold (≤8 g/dL) to minimize unnecessary transfusions without compromising outcomes. Some skepticism toward adopting a more liberal transfusion policy is warranted given the lack of demonstrable benefit.

Study Strengths and Limitations: Strengths include the randomized, multicenter design, blinded outcome assessment, and a 12-month follow-up. Limitations include potential unmeasured subtle benefits, the inability to blind clinical teams, and the challenge of capturing all aspects of functional recovery with current measurement tools. Further research may clarify if more tailored transfusion strategies can yield modest but meaningful improvements.

Future Research: Future studies should evaluate intermediate hemoglobin thresholds, develop more sensitive measures of functional and cognitive recovery, and consider individualized transfusion strategies based on specific patient factors and biomarkers of cerebral ischemia.

Reference: English SW, et al. Liberal or Restrictive Transfusion Strategy in Aneurysmal Subarachnoid Hemorrhage. New England Journal of Medicine. Published December 9, 2024. DOI: http://doi.org/10.1056/NEJMoa2410962

 

Cohort Study: Oral Hormone Therapy and Tibolone Increase Cardiovascular Risk in Menopausal Women

28 Nov, 2024 | 18:42h | UTC

Background: Cardiovascular disease is the leading cause of mortality worldwide, with incidence in women increasing notably during the menopausal transition. Menopausal hormone therapy (MHT) effectively alleviates menopausal symptoms but has been associated with cardiovascular risks in previous studies. The impact of contemporary MHT formulations and administration routes on cardiovascular disease risk in women aged 50–58 remains unclear.

Objective: To assess the effect of different types of contemporary MHT on the risk of cardiovascular disease, focusing on various hormone combinations and administration methods.

Methods: This nationwide register-based emulated target trial included 919,614 Swedish women aged 50–58 years between 2007 and 2020 who had not used MHT in the previous two years. Participants were assigned to one of eight treatment groups—including oral and transdermal therapies—or to a non-initiator group. The primary outcomes were hazard ratios (HRs) for venous thromboembolism (VTE), ischemic heart disease (IHD), cerebral infarction, and myocardial infarction, analyzed separately and as a composite cardiovascular disease outcome.

Results: Among the participants, 77,512 were MHT initiators and 842,102 were non-initiators. During follow-up, 24,089 cardiovascular events occurred. In intention-to-treat analyses, tibolone was associated with an increased risk of cardiovascular disease (HR 1.52, 95% CI 1.11 to 2.08) compared with non-initiators. Initiation of tibolone or oral estrogen-progestin therapy was linked to a higher risk of IHD (HRs 1.46 and 1.21, respectively). A higher risk of VTE was observed with oral continuous estrogen-progestin therapy (HR 1.61), sequential therapy (HR 2.00), and estrogen-only therapy (HR 1.57). Per protocol analyses showed that tibolone use was associated with increased risks of cerebral infarction (HR 1.97) and myocardial infarction (HR 1.94).

Conclusions: Use of oral estrogen-progestin therapy was associated with increased risks of IHD and VTE, while tibolone was linked to higher risks of IHD, cerebral infarction, and myocardial infarction but not VTE. These findings underscore the varying cardiovascular risks associated with different MHT types and administration methods.

Implications for Practice: Clinicians should exercise caution when prescribing oral estrogen-progestin therapy or tibolone for menopausal symptom relief, considering the elevated cardiovascular risks. Alternative MHT options, such as transdermal therapies, may offer a safer profile and should be considered.

Study Strengths and Limitations: Strengths include the large, nationwide cohort and the emulated target trial design, which reduces selection bias and confounding. Limitations involve the lack of data on menopausal status, smoking, and body mass index, which may affect cardiovascular risk. Potential misclassification of exposure and adherence could also impact results.

Future Research: Further studies should investigate the cardiovascular effects of specific progestins within MHT formulations and explore the impact of different doses and durations of therapy.

Reference: Johansson T, Karlsson T, Bliuc D, et al. Contemporary menopausal hormone therapy and risk of cardiovascular disease: Swedish nationwide register based emulated target trial. BMJ. 2024;387:e078784. DOI: http://doi.org/10.1136/bmj-2023-078784

 

News Release: Anticoagulation Does Not Prevent Cognitive Decline in Younger Low-Risk AFib Patients

20 Nov, 2024 | 20:17h | UTC

Introduction: A recent large-scale trial has found that anticoagulation therapy does not reduce the risk of cognitive decline, stroke, or transient ischemic attack (TIA) in adults under 65 years old with atrial fibrillation (AFib) who have no additional stroke risk factors. AFib is the most common type of irregular heart rhythm and is known to increase the risk of stroke, especially in older individuals or those with comorbidities. This study aimed to determine if blood thinners could offer neurocognitive and cerebrovascular protection in younger, low-risk AFib patients.

Highlights: The Blinded Randomized Trial of Anticoagulation to Prevent Ischemic Stroke and Neurocognitive Impairment in Atrial Fibrillation (BRAIN-AF) enrolled over 1,200 participants with an average age of 53 years, none of whom had standard indications for anticoagulation therapy. Participants were randomly assigned to receive either rivaroxaban (15 mg daily) or a placebo and were followed for an average of 3.7 years.

Key findings from the trial include:

  • No Significant Difference in Primary Outcomes: There was no significant difference between the rivaroxaban and placebo groups in the combined outcome of cognitive decline (a decrease of two or more points on the Montreal Cognitive Assessment), stroke, or TIA. The annual rates were 7% for rivaroxaban and 6.4% for placebo.
  • High Rate of Cognitive Decline: Approximately 1 in 5 participants experienced cognitive decline, accounting for 91% of the primary outcome events. Despite this high rate, anticoagulation did not mitigate the risk.
  • Low Incidence of Stroke: The incidence of stroke was low in this population, at less than 1 in 100 participants per year.
  • Early Termination of the Trial: The study was terminated early due to futility, as continuing was unlikely to demonstrate a benefit from anticoagulation in preventing cognitive decline or stroke in this group.
  • Safety Profile: Major bleeding events were rare and did not differ significantly between the rivaroxaban and placebo groups.

These results confirm that younger AFib patients without additional stroke risk factors have a low incidence of stroke and that anticoagulation does not reduce the risk of cognitive decline or cerebrovascular events in this population.

Conclusion: The BRAIN-AF trial supports current clinical guidelines that do not recommend anticoagulation therapy for AFib patients under 65 years old without other stroke risk factors. The findings suggest that anticoagulation is not effective in preventing cognitive decline or stroke in this low-risk group. Clinicians should continue to focus on standard recommendations for maintaining cognitive health, such as promoting a healthy lifestyle, engaging in brain-stimulating activities, and encouraging regular physical activity, rather than prescribing anticoagulation therapy for neurocognitive protection in these patients.

Source: This study was conducted by researchers at the Montreal Heart Institute and Université de Montréal and was presented at the American Heart Association’s Scientific Sessions 2024.

Additional commentaries:

 

News Release: Edoxaban Comparable to Warfarin for Stroke Prevention After Bioprosthetic Valve Surgery

20 Nov, 2024 | 20:05h | UTC

Introduction: A recent multicenter trial from Japan, presented at the American Heart Association’s Scientific Sessions 2024, has found that edoxaban, a direct oral anticoagulant, is as effective as warfarin in preventing stroke and systemic embolism in patients following bioprosthetic heart valve replacement surgery. This addresses the ongoing need for alternative anticoagulant therapies that simplify post-surgical management and enhance patient quality of life.

Highlights: The ENBALV trial enrolled approximately 400 adults aged 41 to 84 who underwent bioprosthetic valve replacement at the aortic and/or mitral position. Participants were randomly assigned to receive either edoxaban (60 mg or 30 mg once daily) or warfarin for 12 weeks post-surgery. Unlike warfarin, edoxaban does not require regular blood tests to monitor clotting activity and has fewer interactions with food and other medications.

Key findings include:

  • Efficacy: Stroke or systemic embolism occurred in 0.5% of patients receiving edoxaban compared to 1.5% in the warfarin group, indicating comparable effectiveness.
  • Thrombus Formation: No intracardiac thrombus was observed in the edoxaban group, whereas it occurred in 1% of patients on warfarin.
  • Bleeding Risks: Major bleeding events were higher in the edoxaban group (4.1% vs. 1% with warfarin). While no fatal bleeding or intracranial hemorrhage occurred with edoxaban, one fatal cerebral hemorrhage was reported in the warfarin group. Gastrointestinal bleeding was more common with edoxaban (2.1% vs. 0% with warfarin).

Lead author Dr. Chisato Izumi noted that edoxaban’s fixed dosing and minimal dietary interactions reduce the treatment burden, potentially improving patient adherence during the critical post-operative period.

Conclusion: The findings suggest that edoxaban is a viable alternative to warfarin for anticoagulation after bioprosthetic valve surgery, offering similar protection against stroke and blood clots with the convenience of simplified management. However, the increased incidence of bleeding events with edoxaban underscores the need for careful patient selection and further research to identify individuals at higher risk. These results may inform future clinical guidelines and improve patient care by providing more flexible anticoagulant options.

Source: This study was conducted by the National Cerebral and Cardiovascular Center in Suita, Japan, and presented at the American Heart Association’s Scientific Sessions 2024. The full news release is available at: http://newsroom.heart.org/news/patients-taking-edoxoban-after-heart-valve-surgery-had-lower-risk-of-stroke-blood-clots

Additional commentaries can be found at:

 

RCT: Early DOACs Safe and Non-Inferior to Delayed Initiation Post-Stroke with Atrial Fibrillation

28 Oct, 2024 | 17:52h | UTC

Background: Atrial fibrillation increases ischaemic stroke risk, and patients are prone to recurrence. Prompt anticoagulation post-stroke is critical, but optimal timing is unclear due to bleeding concerns. Guidelines often delay DOAC initiation without strong evidence.

Objective: To determine if early DOAC initiation (≤4 days) is non-inferior to delayed initiation (7–14 days) in preventing recurrent ischaemic events without increasing intracranial haemorrhage risk in patients with acute ischaemic stroke and atrial fibrillation.

Methods: In this multicentre, open-label, blinded-endpoint, phase 4 randomised controlled trial at 100 UK hospitals, 3,621 adults with atrial fibrillation and acute ischaemic stroke were randomised to early or delayed DOAC initiation. Eligibility required physician uncertainty about timing. Participants and clinicians were unmasked; outcomes were adjudicated by a masked committee. The primary outcome was a composite of recurrent ischaemic stroke, symptomatic intracranial haemorrhage, unclassifiable stroke, or systemic embolism within 90 days.

Results: Among 3,621 patients (mean age 78.5; 45% female), the primary outcome occurred in 59 patients (3.3%) in both early and delayed groups (adjusted risk difference 0.0%, 95% CI –1.1 to 1.2%). Upper confidence limit below the 2% non-inferiority margin (p=0.0003) confirmed non-inferiority. Symptomatic intracranial haemorrhage rates were similar (0.6% early vs 0.7% delayed; p=0.78). No significant differences in mortality or heterogeneity across subgroups.

Conclusions: Early DOAC initiation within 4 days is non-inferior to delayed initiation in preventing recurrent events without increasing intracranial haemorrhage risk. Findings challenge guidelines advising delayed anticoagulation and support early initiation regardless of stroke severity.

Implications for Practice: Clinicians should consider starting DOACs within 4 days post-stroke in atrial fibrillation patients. Early initiation is safe and effective, potentially improving outcomes and suggesting guidelines may need revision.

Study Strengths and Limitations: Strengths include large sample size and masked outcome adjudication. Limitations include exclusion of patients with very severe strokes and low event rates, potentially limiting detection of rare adverse events.

Future Research: Further studies should explore optimal DOAC timing within 4 days and assess safety in patients with severe strokes or extensive haemorrhagic transformation.

Reference: Werring DJ, Dehbi HM, Ahmed N, et al. Optimal timing of anticoagulation after acute ischaemic stroke with atrial fibrillation (OPTIMAS): a multicentre, blinded-endpoint, phase 4, randomised controlled trial. Lancet. 2024; DOI: http://doi.org/10.1016/S0140-6736(24)02197-4

 

RCT: Liberal Transfusion Strategy Reduced Unfavorable Neurological Outcomes in Acute Brain Injury

12 Oct, 2024 | 11:01h | UTC

Background: Patients with acute brain injury frequently develop anemia, and the optimal hemoglobin threshold for red blood cell transfusion in this population remains uncertain. Previous studies have shown conflicting results regarding the benefits of liberal versus restrictive transfusion strategies on neurological outcomes.

Objective: To determine whether a liberal transfusion strategy (hemoglobin threshold <9 g/dL) reduces the occurrence of unfavorable neurological outcomes at 180 days compared to a restrictive strategy (hemoglobin threshold <7 g/dL) in patients with acute brain injury.

Methods: The TRAIN trial, a multicenter, phase 3, randomized clinical trial, was conducted across 72 ICUs in 22 countries. It included patients with traumatic brain injury, aneurysmal subarachnoid hemorrhage, or intracerebral hemorrhage, who had hemoglobin levels below 9 g/dL within the first 10 days post-injury. Participants were randomized to a liberal strategy (transfusion triggered by hemoglobin <9 g/dL) or a restrictive strategy (transfusion triggered by hemoglobin <7 g/dL), with primary outcomes measured by the occurrence of an unfavorable neurological outcome, defined by a Glasgow Outcome Scale Extended score of 1-5 at 180 days.

Results: Among 820 patients who completed the trial (mean age 51 years; 45.9% women), 806 had data on the primary outcome (393 liberal, 413 restrictive). The liberal group received a median of 2 units of blood (IQR, 1–3), while the restrictive group received a median of 0 units (IQR, 0–1), with an absolute mean difference of 1.0 unit (95% CI, 0.87–1.12 units). At 180 days, 62.6% of patients in the liberal group had an unfavorable neurological outcome compared to 72.6% in the restrictive group (absolute difference –10.0%; 95% CI, –16.5% to –3.6%; adjusted relative risk 0.86; P = .002). The effect was consistent across prespecified subgroups. Cerebral ischemic events were lower in the liberal group (8.8% vs 13.5%; relative risk 0.65; 95% CI, 0.44–0.97). No significant differences were observed in 28-day survival or other secondary outcomes.

Conclusions: In patients with acute brain injury and anemia, a liberal transfusion strategy resulted in a lower rate of unfavorable neurological outcomes at 180 days compared to a restrictive strategy.

Implications for Practice: A liberal transfusion threshold of 9 g/dL may improve neurological outcomes in patients with acute brain injury by reducing cerebral ischemic events. Clinicians should consider adopting a higher hemoglobin threshold for transfusion in this population, weighing the benefits against potential risks associated with transfusions, such as infection or lung injury.

Study Strengths and Limitations: Strengths include the large, multicenter international design and blinding of outcome assessors. Limitations involve the open-label nature, potential detection bias in assessing cerebral ischemic events, lack of standardized neuroprognostication, and incomplete assessment of concomitant interventions.

Future Research: Further studies are needed to confirm these findings in specific subgroups of acute brain injury, to explore optimal transfusion strategies, and to assess long-term outcomes and potential risks associated with liberal transfusion thresholds.

Reference: Taccone FS, et al. (2024) Restrictive vs Liberal Transfusion Strategy in Patients With Acute Brain Injury: The TRAIN Randomized Clinical Trial. JAMA. DOI: http://doi.org/10.1001/jama.2024.20424

 

Meta-Analysis: Oral Anticoagulant Monotherapy Reduced Bleeding Without Increasing Ischemic Events in AF and Stable CAD

9 Oct, 2024 | 11:13h | UTC

Background: Atrial fibrillation (AF) patients with stable coronary artery disease (CAD) often require both oral anticoagulants (OACs) for stroke prevention and antiplatelet therapy for CAD management. However, dual antithrombotic therapy (DAT) increases bleeding risk. The optimal antithrombotic regimen in this population remains unclear.

Objective: To evaluate whether OAC monotherapy reduces major bleeding without increasing ischemic events compared to DAT in patients with AF and stable CAD.

Methods: This meta-analysis followed PRISMA guidelines, pooling data from three randomized controlled trials (RCTs) involving 3,945 patients with AF and stable CAD. The trials included used various OACs (rivaroxaban, edoxaban, or warfarin/DOAC) and compared them with DAT. The primary outcomes were all-cause death, cardiovascular death, and major bleeding. Secondary outcomes included stroke (ischemic and hemorrhagic) and myocardial infarction (MI).

Results: OAC monotherapy significantly reduced the risk of major bleeding compared to DAT (3.4% vs 5.8%; RR: 0.55; 95% CI: 0.32–0.95; p=0.03). There were no significant differences between groups in all-cause death (4.2% vs 5.4%; RR: 0.85; 95% CI: 0.49–1.48; p=0.57), cardiovascular death (2.4% vs 3.0%; RR: 0.84; 95% CI: 0.50–1.41; p=0.50), any stroke event (2.2% vs 3.1%; RR: 0.74; 95% CI: 0.46–1.18; p=0.21), or myocardial infarction (RR: 1.57; 95% CI: 0.79–3.12; p=0.20).

Conclusions: In patients with AF and stable CAD, OAC monotherapy significantly reduces major bleeding risk compared to DAT without increasing the risk of ischemic events or mortality.

Implications for Practice: OAC monotherapy may be a preferable antithrombotic strategy in patients with AF and stable CAD, balancing effective thromboembolic protection with a lower bleeding risk. Clinicians should consider OAC monotherapy to simplify antithrombotic regimens and reduce bleeding complications, especially beyond one year after coronary events or interventions.

Study Strengths and Limitations: Strengths include the inclusion of recent large-scale RCTs and the focus on a clinically relevant patient population. Limitations involve reliance on study-level data, limited number of trials, and potential heterogeneity among included studies. The duration of DAT was not consistently available, and individual patient data meta-analysis may provide more detailed insights.

Future Research: Additional large-scale RCTs and individual patient data meta-analyses are needed to confirm these findings and to determine the optimal duration and type of antithrombotic therapy in patients with AF and stable CAD.

Reference: Ahmed M., et al. (2024). Meta-Analysis Comparing Oral Anticoagulant Monotherapy Versus Dual Antithrombotic Therapy in Patients With Atrial Fibrillation and Stable Coronary Artery Disease. Clin Cardiol, 47(10), e70026. DOI: http://doi.org/10.1002/clc.70026

 

Aspirin vs. Clopidogrel Monotherapy After PCI: 1-Year Follow-Up of the STOPDAPT-3 Trial

6 Oct, 2024 | 16:51h | UTC

Background: Following percutaneous coronary intervention (PCI) with drug-eluting stents (DES), patients are typically managed with dual antiplatelet therapy (DAPT). Recent evidence suggests that monotherapy with a P2Y12 inhibitor may reduce bleeding risks compared to aspirin monotherapy, but no prior trials have directly compared these regimens beyond one month of DAPT. The STOPDAPT-3 trial aimed to evaluate the cardiovascular and bleeding outcomes of aspirin versus clopidogrel monotherapy following a short duration of DAPT.

Objective: To compare the efficacy and safety of aspirin monotherapy with clopidogrel monotherapy from 1 month to 1 year after PCI with DES, focusing on cardiovascular and bleeding outcomes.

Methods: The STOPDAPT-3 trial was a prospective, multicenter, open-label, randomized clinical trial conducted in Japan. A total of 6002 patients with acute coronary syndrome (ACS) or high bleeding risk (HBR) were randomized to either a 1-month DAPT regimen followed by aspirin monotherapy (aspirin group, n=2920) or 1-month prasugrel monotherapy followed by clopidogrel monotherapy (clopidogrel group, n=2913). The primary endpoints were a composite of cardiovascular events (cardiovascular death, myocardial infarction, stent thrombosis, or ischemic stroke) and major bleeding (Bleeding Academic Research Consortium 3 or 5).

Results: At the 1-year follow-up, both the aspirin and clopidogrel groups had comparable cardiovascular outcomes (4.5% incidence in both groups; HR 1.00, 95% CI 0.77–1.30, P=0.97). Bleeding rates were also similar between groups (aspirin: 2.0%; clopidogrel: 1.9%; HR 1.02, 95% CI 0.69–1.52, P=0.92). No significant differences were observed in secondary outcomes, including all-cause mortality, myocardial infarction, stent thrombosis, or revascularization. Additionally, adherence to the assigned monotherapy at 1 year was high in both groups (87.5% for aspirin; 87.2% for clopidogrel).

Conclusions: Aspirin monotherapy, compared to clopidogrel monotherapy, resulted in similar cardiovascular and bleeding outcomes during the 1-year follow-up after PCI with DES. Both therapies appear equally effective and safe for use following short-duration DAPT.

Implications for Practice: These findings suggest that either aspirin or clopidogrel monotherapy could be safely used following a short course of DAPT, with similar clinical outcomes. In regions where more potent P2Y12 inhibitors are not widely used, aspirin monotherapy remains a cost-effective and safe alternative.

Study Strengths and Limitations: The study’s strengths include a large sample size and a well-structured, multicenter design. Limitations include the lack of randomization after 1 month and the high prescription of proton pump inhibitors, which may have affected bleeding outcomes. Additionally, the follow-up period of 1 year may be too short to detect long-term differences.

Future Research: Longer-term studies are needed to confirm the findings, particularly regarding cardiovascular outcomes beyond 1 year. Further research is also required to evaluate the impact of aspirin versus more potent P2Y12 inhibitors in diverse populations and clinical settings.

Reference: Watanabe H., et al. (2024). Aspirin vs. clopidogrel monotherapy after percutaneous coronary intervention: 1-year follow-up of the STOPDAPT-3 trial. European Heart Journal. DOI: https://doi.org/10.1093/eurheartj/ehae617

 

Summary: Perioperative Management of Patients Taking Direct Oral Anticoagulants

19 Sep, 2024 | 21:12h | UTC

Direct oral anticoagulants (DOACs)—including apixaban, rivaroxaban, edoxaban, and dabigatran—are increasingly used for stroke prevention in atrial fibrillation and for treating venous thromboembolism. Effective perioperative management of DOACs is essential to minimize bleeding and thromboembolic risks during surgical and nonsurgical procedures. Below are practical recommendations focused on the perioperative management of patients taking DOACs, based on a recent JAMA review article.

Elective Surgical or Nonsurgical Procedures

Classify Bleeding Risk of Procedures:

  1. Minimal Risk:
    • Minor dental procedures (e.g., cleaning, extractions)
    • Minor dermatologic procedures (e.g., skin lesion removal)
    • Cataract surgery
  2. Low to Moderate Risk:
    • Endoscopic procedures without high-risk interventions
    • Cholecystectomy
    • Inguinal hernia repair
  3. High Risk:
    • Major surgery (e.g., cancer surgery, joint replacement)
    • Procedures involving neuraxial anesthesia
    • Endoscopic procedures with high-risk interventions (e.g., large polyp removal)

DOAC Management Strategies:

  1. Minimal Bleeding Risk Procedures:
    • Option 1: Continue DOACs without interruption.
    • Option 2: For added safety, withhold the morning dose on the day of the procedure (especially for twice-daily DOACs like apixaban and dabigatran).
  2. Low to Moderate Bleeding Risk Procedures:
    • Preoperative:
      • Discontinue DOACs 1 day before the procedure.
      • This allows approximately 2 half-lives for drug clearance.
    • Postoperative:
      • Resume DOACs 1 day after the procedure, ensuring adequate hemostasis.
  3. High Bleeding Risk Procedures:
    • Preoperative:
      • Discontinue DOACs 2 days before the procedure.
      • This allows approximately 4-5 half-lives for drug clearance.
    • Postoperative:
      • Resume DOACs 2-3 days after the procedure, based on bleeding risk and hemostasis.

Evidence Supporting These Strategies:

  • The PAUSE study demonstrated that standardized interruption protocols without heparin bridging result in low rates of:
    • Thromboembolism: 0.2%–0.4%
    • Major Bleeding: 1%–2%

Postoperative DOAC Resumption:

  • Assess surgical-site hemostasis before resuming DOACs.
  • Delay resumption if there is ongoing bleeding or concerns about hemostasis.
  • For high bleeding risk procedures, consider a longer delay (2–3 days).

Perioperative Heparin Bridging:

  • Not recommended for patients on DOACs.
  • Bridging increases bleeding risk without reducing thromboembolism.
  • DOACs have rapid offset and onset, making bridging unnecessary.

Special Considerations

Patients with Impaired Renal Function:

  • For CrCl 30–50 mL/min:
    • Dabigatran: Extend preoperative discontinuation by an additional day.
  • For CrCl <30 mL/min:
    • Dabigatran is contraindicated.
    • For other DOACs, consider extending discontinuation to 3–4 days before surgery.

Patients Undergoing Neuraxial Anesthesia:

  • Discontinue DOACs for 3 days (apixaban, edoxaban, rivaroxaban) or 4 days (dabigatran) before the procedure.
  • Minimizes risk of spinal or epidural hematoma.

Dental Procedures:

  • Generally safe to continue DOACs.
  • For added safety:
    • Omit or delay the dose on the day of the procedure.
    • Employ local hemostatic measures (e.g., tranexamic acid mouthwash).

Endoscopic Procedures:

  • Low-risk procedures (e.g., diagnostic endoscopy without biopsy):
    • Follow standard DOAC interruption for low to moderate bleeding risk.
  • High-risk procedures (e.g., polypectomy of large polyps):
    • Extend DOAC discontinuation by an additional day pre- and post-procedure.

Patients Unable to Resume Oral Medications Postoperatively:

  • Use prophylactic low-molecular-weight heparin (LMWH) until oral intake is possible.
  • Avoid therapeutic-dose LMWH due to bleeding risk.

Emergent, Urgent, or Semiurgent Procedures

Risks:

  • Higher bleeding risk: Up to 23%
  • Thromboembolism risk: Up to 11%

Management Strategies:

  1. Assess Time Since Last DOAC Dose:
    • If within 48 hours, consider that significant anticoagulant effect may persist.
  2. Laboratory Testing (if available):
    • DOAC Level Testing:
      • ≥50 ng/mL: Consider using reversal agents.
      • <50 ng/mL: May proceed without reversal agents.
  3. Use of Reversal Agents:
    • For Dabigatran:
      • Idarucizumab (5 g IV)
    • For Factor Xa Inhibitors (apixaban, rivaroxaban, edoxaban):
      • Andexanet alfa (dosing based on last dose timing and amount)
      • Prothrombin Complex Concentrates (PCCs): If andexanet alfa is unavailable or contraindicated.
  4. Proceeding Without Testing:
    • If testing is unavailable and last DOAC dose was within 48 hours, consider reversal agents.
    • If >48 hours since last dose, may proceed without reversal.

Considerations:

  • Reversal agents are expensive and may carry thrombotic risks.
  • Use should be judicious, weighing risks and benefits.
  • Consult hematology or thrombosis experts when possible.

Key Takeaways

  • Elective Procedures:
    • Utilize standardized protocols based on procedural bleeding risk.
    • Routine preoperative DOAC level testing is unnecessary.
    • Avoid heparin bridging.
  • Emergent/Urgent Procedures:
    • Reversal agents may be appropriate when significant DOAC levels are present.
    • Decision to use reversal agents should consider bleeding risk, time since last dose, and availability of DOAC level testing.
  • Patient Communication:
    • Ensure patients understand the plan for DOAC interruption and resumption.
    • Provide clear instructions regarding timing and dosing.
  • Interdisciplinary Coordination:
    • Collaborate with surgical teams, anesthesiologists, and pharmacists.
    • Use electronic medical records and clinical decision support tools to enhance communication.

Conclusion

By applying standardized perioperative management protocols, clinicians can effectively balance the risks of bleeding and thromboembolism in patients taking DOACs who require surgical or nonsurgical procedures. These strategies simplify decision-making, avoid unnecessary interventions like heparin bridging, and promote patient safety.

Reference: Douketis JD, Spyropoulos AC. Perioperative Management of Patients Taking Direct Oral Anticoagulants: A Review. JAMA. 2024;332(10):825–834. doi:10.1001/jama.2024.12708

 

RCT: Edoxaban Monotherapy Reduces Bleeding Events in Atrial Fibrillation with Stable CAD Compared to Dual Therapy

7 Sep, 2024 | 13:03h | UTC

Study Design and Population: This multicenter, open-label, adjudicator-masked randomized trial enrolled 1,040 patients with atrial fibrillation (AF) and stable coronary artery disease (CAD) across 18 sites in South Korea. Patients were randomly assigned to receive either edoxaban monotherapy (n=524) or dual antithrombotic therapy (edoxaban plus a single antiplatelet agent; n=516). The mean age was 72.1 years, with a mean CHA2DS2-VASc score of 4.3, reflecting a moderate to high stroke risk.

Main Findings: At 12 months, the primary composite outcome occurred in fewer patients in the edoxaban monotherapy group (6.8%) than in the dual therapy group (16.2%) (HR, 0.44; 95% CI, 0.30–0.65; P<0.001). The reduction was largely driven by a significantly lower incidence of major bleeding or clinically relevant non-major bleeding (4.7% vs. 14.2%; HR, 0.34; 95% CI, 0.22–0.53). In contrast, the incidence of major ischemic events was similar between the two groups.

Implications for Practice: Edoxaban monotherapy provides a safer antithrombotic option for patients with AF and stable CAD by significantly reducing bleeding without increasing ischemic events compared to dual therapy. These findings suggest that monotherapy could be a preferable long-term treatment strategy in this population.

Reference: Cho, M.S., Kang, D.-Y., Ahn, J.-M., Yun, S.-C., Oh, Y.-S., Lee, C.H., Choi, E.-K., et al. (2024). Edoxaban Antithrombotic Therapy for Atrial Fibrillation and Stable Coronary Artery Disease. New England Journal of Medicine. http://doi.org/10.1056/NEJMoa2407362

 

RCT: Interruption of Oral Anticoagulation during TAVI Reduces Bleeding Without Increasing Thromboembolic Events

7 Sep, 2024 | 12:43h | UTC

Study Design and Population: This international, open-label, randomized noninferiority trial examined 858 patients undergoing transcatheter aortic-valve implantation (TAVI) who had an indication for oral anticoagulation due to concomitant diseases. Patients were randomized 1:1 to either continue or interrupt their oral anticoagulation during the procedure, with the primary outcome being a composite of cardiovascular death, stroke, myocardial infarction, major vascular complications, or major bleeding within 30 days.

Main Findings: Primary outcome events occurred in 16.5% of the continuation group and 14.8% of the interruption group, showing a non-significant risk difference of 1.7 percentage points (95% CI, -3.1 to 6.6). Thromboembolic events were similar between groups (8.8% in continuation vs. 8.2% in interruption). However, bleeding events were significantly higher in the continuation group (31.1% vs. 21.3%; risk difference, 9.8 percentage points; 95% CI, 3.9 to 15.6).

Implications for Practice: Interrupting oral anticoagulation during TAVI significantly reduces bleeding without increasing thromboembolic risks, suggesting it may be a safer strategy for patients undergoing TAVI. These findings could influence clinical decision-making regarding anticoagulation management in this population.

Reference: van Ginkel, D.J. et al. (2024). Continuation versus Interruption of Oral Anticoagulation during TAVI. The New England Journal of Medicine. https://doi.org/10.1056/NEJMoa2407794

 

RCT: Continuing Aspirin vs. Antiplatelet Cessation Before Surgery Did Not Reduce Ischemic Events in Patients With Coronary Stents Over 1 Year Post-Implantation

7 Sep, 2024 | 12:29h | UTC

Study Design and Population: This randomized controlled trial (ASSURE-DES) investigated the perioperative management of antiplatelet therapy in 926 patients with coronary drug-eluting stents (DES) undergoing low-to-intermediate-risk noncardiac surgery. The patients, at least one year post-stent implantation, were randomized to continue aspirin monotherapy or stop all antiplatelet therapy five days prior to surgery.

Main Findings: The study found no significant difference in the primary composite outcome (death, myocardial infarction, stent thrombosis, or stroke) between the aspirin monotherapy group (0.6%) and the no antiplatelet group (0.9%). However, minor bleeding was more frequent in the aspirin group (14.9% vs 10.1%, P=0.027), with no difference in major bleeding.

Implications for Practice: These results suggest that for stable patients with DES undergoing noncardiac surgery, temporarily discontinuing aspirin may be a safe option, as continuing aspirin did not reduce ischemic events but did increase minor bleeding risk. Further research is needed to assess outcomes in higher-risk surgical settings.

Reference: Kang, D.-Y. et al. (2024). Aspirin monotherapy vs no antiplatelet therapy in stable patients with coronary stents undergoing low-to-intermediate risk noncardiac surgery. Journal of the American College of Cardiology. https://doi.org/10.1016/j.jacc.2024.08.024

 

RCT: Vutrisiran Reduces Mortality and Cardiovascular Events in Patients with Transthyretin Amyloidosis Cardiomyopathy

6 Sep, 2024 | 21:57h | UTC

Study Design and Population: This double-blind, randomized clinical trial evaluated the efficacy of vutrisiran in 655 patients with transthyretin amyloidosis with cardiomyopathy (ATTR-CM). Participants were randomly assigned to receive either vutrisiran (25 mg) or placebo every 12 weeks for up to 36 months. The study population included patients both with and without baseline tafamidis treatment.

Main Findings: Vutrisiran treatment significantly reduced the risk of death from any cause and recurrent cardiovascular events compared to placebo (HR: 0.72, 95% CI: 0.56–0.93, p=0.01). In monotherapy patients (no tafamidis), the hazard ratio was 0.67 (95% CI: 0.49–0.93, p=0.02). Vutrisiran also preserved physical function, showing less decline in the 6-minute walk test distance (mean difference: 26.5 meters, p<0.001) and quality of life (mean KCCQ-OS difference: 5.8 points, p<0.001). Adverse events were comparable between groups.

Implications for Practice: Vutrisiran offers a promising treatment option for reducing mortality, cardiovascular events, and functional decline in ATTR-CM patients. Its favorable safety profile supports its potential use in long-term management.

Reference: Fontana M. et al. (2024). Vutrisiran in Patients with Transthyretin Amyloidosis with Cardiomyopathy. New England Journal of Medicine, Published August 30, 2024. http://doi.org/10.1056/NEJMoa2409134

 

Updated Guidelines on Perioperative Management of Anticoagulant and Antiplatelet Therapy for Interventional Techniques – Pain Physician

18 Aug, 2024 | 14:52h | UTC

Introduction: The American Society of Interventional Pain Physicians (ASIPP) has published updated guidelines for the perioperative management of patients undergoing interventional techniques while receiving antiplatelet and anticoagulant therapy. These guidelines are essential for clinicians to balance the risk of thromboembolism against the risk of bleeding during interventional procedures.

Key Points:

1 – Risk of Thromboembolic Events:

– Thromboembolic events have a higher risk of morbidity and mortality compared to the risk of epidural hematoma. Thus, interruption of antithrombotic therapy should be carefully considered.

2 – Risk Stratification of Procedures:

– Interventional techniques are classified into three categories based on risk: low, moderate, or high. For high-risk procedures, cessation of anticoagulant or antiplatelet therapy is recommended, whereas for low to moderate-risk procedures, therapy may continue under certain conditions.

3 – Management of Direct Oral Anticoagulants (DOACs):

– DOACs such as dabigatran, apixaban, rivaroxaban, and edoxaban should generally be discontinued for 2 days before high-risk procedures and one day for moderate-risk procedures. Adjustments are needed based on renal function, specially for dabigatran.

4 – Discontinuation of Aspirin:

– For high-risk interventional procedures, discontinuation of aspirin (81 or 325 mg) is recommended 6 days before the procedure. However, for low to moderate-risk procedures, aspirin therapy may be continued or stopped for 3 days depending on individual risk factors and clinical judgment.

5 – Discontinuation of Other Antiplatelet Agents:

– Clopidogrel (Plavix) and Prasugrel (Effient): These agents should be discontinued 6 days before high-risk procedures. For low-risk procedures, these medications can be continued.

– Ticagrelor (Brilinta): Discontinue for 5 days before high-risk procedures, with consideration of patient-specific risk factors.

6 – Timing for Restarting Therapy:

– Antithrombotic therapy should typically be resumed within 12-24 hours after low to moderate-risk procedures and within 24-48 hours after high-risk procedures, depending on bleeding risk and patient status.

7 – Shared Decision-Making:

– Decisions on whether to continue or discontinue antithrombotic therapy should involve shared decision-making between the patient, the interventional pain specialist, and other treating physicians, considering all associated risks.

Conclusion: These guidelines provide a comprehensive framework for managing the delicate balance between thromboembolic and bleeding risks in patients on anticoagulant or antiplatelet therapy undergoing interventional procedures. They emphasize the importance of personalized care and multidisciplinary collaboration.

Guideline Reference: Manchikanti, L., et al. (2024). Perioperative Management of Antiplatelet and Anticoagulant Therapy in Patients Undergoing Interventional Techniques: 2024 Updated Guidelines From The American Society Of Interventional Pain Physicians (ASIPP). Pain Physician, 27(S1-S94).

 

Meta-Analysis: 1-Month Dual Antiplatelet Therapy Reduces Major Bleeding Without Increasing Stent Thrombosis After PCI with DES – Am J Cardiol

17 Aug, 2024 | 19:29h | UTC

Main Findings: The analysis found that 1-month DAPT significantly reduced the risk of major bleeding (OR 0.66, 95% CI 0.45-0.97, p = 0.03) compared to >1-month DAPT. Additionally, there was no significant difference in stent thrombosis rates between the groups (OR 1.08, 95% CI 0.81-1.44, p = 0.60). Secondary outcomes, including all-cause mortality, cardiovascular death, myocardial infarction, stroke, and major adverse cardiovascular or cerebrovascular events were also similar between the groups.

Implications for Practice: The findings support the use of 1-month DAPT followed by aspirin or a P2Y12 receptor inhibitor as a safer alternative to longer-term DAPT in patients undergoing PCI with DES. This strategy may help reduce bleeding risks without increasing the likelihood of thrombotic events, making it a viable option for routine clinical practice, particularly in patients at high risk for bleeding.

Reference: Bajraktari G, Bytyçi I, Abdyli G, et al. (2024). One-Month Dual Antiplatelet Therapy Reduces Major Bleeding Compared With Longer-Term Treatment Without Excess Stent Thrombosis: A Systematic Review and Meta-Analysis of Randomized Clinical Trials. The American Journal of Cardiology, 227, 91-97. DOI: https://doi.org/10.1016/j.amjcard.2024.07.010.

 

Erythritol Ingestion Increases Platelet Reactivity and Thrombosis Potential in Healthy Adults – Arterioscler Thromb Vasc Biol

10 Aug, 2024 | 21:11h | UTC

Study Design and Population: This interventional study evaluated the effects of erythritol versus glucose on platelet reactivity and thrombosis potential in 20 healthy volunteers, with 10 participants in each group. Researchers measured erythritol plasma levels and assessed platelet function through aggregometry and granule marker analysis both before and after ingestion of 30 g of erythritol or glucose.

Main Findings: Erythritol ingestion resulted in a more than 1000-fold increase in plasma erythritol concentration and significantly enhanced stimulus-dependent platelet aggregation and release of serotonin and CXCL4, markers of platelet activation. In contrast, glucose ingestion did not significantly alter platelet reactivity or granule marker release, highlighting erythritol’s unique pro-thrombotic effects.

Implications for Practice: These findings raise concerns regarding the safety of erythritol as a non-nutritive sweetener, particularly its potential to enhance thrombosis risk. The results suggest a need to reevaluate erythritol’s safety status and consider its impact on cardiovascular health in regulatory guidelines.

Reference: Witkowski, M., Wilcox, J., Province, V., Wang, Z., Nemet, I., Tang, W. H. W., & Hazen, S. L. (2024). Ingestion of the non-nutritive sweetener erythritol, but not glucose, enhances platelet reactivity and thrombosis potential in healthy volunteers. Arteriosclerosis, Thrombosis, and Vascular Biology. https://doi.org/10.1161/ATVBAHA.124.321019

 

RCT: Liberal vs. Restrictive Transfusion Strategy Shows No Significant Difference in Neurologic Outcomes for Traumatic Brain Injury Patients – N Engl J Med

3 Aug, 2024 | 19:06h | UTC

Study Design and Population: This randomized clinical trial evaluated the effects of liberal versus restrictive red cell transfusion strategies in 742 adults with moderate to severe traumatic brain injury (TBI) and anemia. Participants were randomized to either a liberal transfusion strategy (initiated at hemoglobin ≤10 g/dL) or a restrictive strategy (initiated at hemoglobin ≤7 g/dL). The primary outcome was an unfavorable neurologic outcome at 6 months, assessed using the Glasgow Outcome Scale–Extended.

Main Findings: The study found that 68.4% of patients in the liberal-strategy group and 73.5% in the restrictive-strategy group experienced an unfavorable outcome (adjusted absolute difference of 5.4 percentage points; 95% CI, −2.9 to 13.7). No significant difference in mortality or depression was observed between the two groups. Although some functional independence and quality of life measures were better in the liberal group among survivors, venous thromboembolic events and acute respiratory distress syndrome rates were comparable.

Implications for Practice: The findings indicate that a liberal transfusion strategy does not significantly improve neurologic outcomes at 6 months in critically ill TBI patients compared to a restrictive strategy. Clinicians may consider maintaining a restrictive transfusion strategy, given the similar outcomes and potential for fewer transfusions. Further research is needed to explore specific subgroups that might benefit from different transfusion strategies.

Reference: Turgeon AF, Fergusson DA, Clayton L, et al. (2024). Liberal or Restrictive Transfusion Strategy in Patients with Traumatic Brain Injury. New England Journal of Medicine, 390(24), 1234-1245. DOI: 10.1056/NEJMoa2404360.

Randomized Controlled Trial: Mixed results with Andexanet Alfa for Factor Xa inhibitor-associated acute intracerebral hemorrhage – N Engl J Med

27 May, 2024 | 20:26h | UTC

Study Design and Population: This randomized controlled trial involved 530 patients with acute intracerebral hemorrhage who had taken factor Xa inhibitors within 15 hours before the event. They were randomly assigned to receive either andexanet alfa or usual care.

Main Findings: Hemostatic efficacy was achieved in 67% of patients receiving andexanet compared to 53.1% receiving usual care. Andexanet significantly reduced anti-factor Xa activity by 94.5%, compared to 26.9% with usual care. However, thrombotic events were more frequent in the andexanet group, including ischemic stroke.

Implications for Practice: Andexanet alfa is effective in controlling hematoma expansion in patients with factor Xa inhibitor-associated intracerebral hemorrhage but has an increased risk of thrombotic events. Further research is needed to balance efficacy and safety.

 

Reference (link to abstract – $ for full-text):

Connolly SJ, Sharma M, Cohen AT, et al. (2024). Andexanet for Factor Xa Inhibitor-Associated Acute Intracerebral Hemorrhage. New England Journal of Medicine, 390(19), 1745-1755. DOI: 10.1056/NEJMoa2313040.

 

Randomized Crossover Trial: Prophylactic recombinant ADAMTS13 prevents acute events in congenital thrombotic thrombocytopenic purpura – N Engl J Med

6 May, 2024 | 06:22h | UTC

This study evaluates the efficacy and safety of recombinant ADAMTS13 compared to standard plasma-derived therapy in managing congenital thrombotic thrombocytopenic purpura (TTP). In a phase 3, open-label, crossover trial involving 48 patients, each participant underwent two 6-month prophylaxis periods, receiving either recombinant ADAMTS13 or standard therapy, followed by a switch to the alternate treatment. Results indicate that recombinant ADAMTS13 prevented acute TTP events during prophylaxis, with no events recorded, versus one event under standard therapy. Furthermore, recombinant ADAMTS13 was associated with significantly lower rates of thrombocytopenia and adverse events compared to standard therapy. The treatment increased ADAMTS13 activity to approximately 100% of normal levels, with no development of neutralizing antibodies. Overall, recombinant ADAMTS13 was found to be safe and more effective than standard therapy in preventing TTP events and manifestations.

 

Reference (link to abstract – $ for full-text):

Marie Scully et al. (2024). Recombinant ADAMTS13 in Congenital Thrombotic Thrombocytopenic Purpura. N Engl J Med, 390(17), 1584-1596. DOI: 10.1056/NEJMoa2314793.

 

Cohort Study: Higher serious bleeding rates linked to diltiazem in elderly atrial fibrillation patients on anticoagulation

26 Apr, 2024 | 12:35h | UTC

Study Design and Population:
This retrospective cohort study analyzed data from 204,155 Medicare beneficiaries aged 65 years or older diagnosed with atrial fibrillation. The study focused on new users of the anticoagulants apixaban or rivaroxaban who commenced treatment with either diltiazem or metoprolol between January 2012 and November 2020, with follow-up extending up to 365 days.

 

Main Findings:
Patients treated with diltiazem exhibited a significantly increased risk of serious bleeding, including bleeding-related hospitalization and death, compared to those treated with metoprolol. The hazard ratio (HR) for serious bleeding events was 1.21, with a rate difference (RD) of 10.6 per 1000 person-years. Notably, the risk escalated with diltiazem doses exceeding 120 mg/day, indicating a dose-response relationship. Secondary outcomes, such as ischemic stroke or systemic embolism, did not show significant differences between the treatment groups.

 

Implications for Practice:
The findings suggest that in older adults with atrial fibrillation treated with apixaban or rivaroxaban, diltiazem increases the risk of serious bleeding, especially at higher doses. These results underscore the importance of cautious medication management and might influence clinical decisions regarding the choice of ventricular rate control in this population.

 

Reference (link to abstract – $ for full-text):

Ray, W. A., Chung, C. P., Stein, C. M., et al. (2024). Serious Bleeding in Patients With Atrial Fibrillation Using Diltiazem With Apixaban or Rivaroxaban. JAMA, Published online April 15, 2024. doi:10.1001/jama.2024.3867

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