A Review of the Incidence Diagnosis and Treatment of Spontaneous Hemorrhage in Patients Treated with Direct Oral Anticoagulants
Abstract
:1. Introduction
2. Indications for Modern Anticoagulants
3. Epidemiology
4. Bleeding
4.1. Bleeding Severity
4.2. Pathogenesis of Direct Oral Anticoagulant-Associated Bleeding
4.3. Risk Factors
4.4. Risk Reduction Strategies
5. Management
5.1. Diagnosis
5.2. Treatment
5.3. Reversal Agents
5.3.1. Drug-Specific Reversal Agents
5.3.2. Non-Specific Reversal Agents
5.3.3. Future Antidotes
5.4. Restitution of Anticoagulation
6. Summary
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
AF | Atrial fibrillation |
AF | Atrial Fibrillation |
Anti-Xa | drug-specific assays |
aPTT | Activated partial thromboplastin time |
COPD | Chronic Obstructive Pulmonary Disease |
CRNMB | Clinically relevant non-major bleeding |
CYP | Cytochromeombin time |
DOACs | Direct Oral Anticoagulants |
ECT | Ecarin clotting time |
GI | Gastrointestinal |
GI | Gastrointestinal |
ICH | Intracranial hemorrhage |
ICH | Intracranial Hemorrhage |
LMWH | Low Molecular Weight Heparin |
Nd | The total number of patients in the DOACs group |
Nk | the total number of patients in the vitamin K antagonist group |
NSAIDs | Nonsteroidal Anti-inflammatory Drugs |
PT | Prothrombin time |
UFH | Unfractionated Heparin |
VKA | Vitamin K Antagonist |
VTE | Venous Thromboembolism |
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Drugs | Dabigatran | Apixaban | Betrixaban | Edoxaban | Rivaroxaban |
---|---|---|---|---|---|
Mechanism of action | Direct IIa (Thrombin) Inhibitor | Factor Xa Inhibitor | Factor Xa Inhibitor | Factor Xa Inhibitor | Factor Xa Inhibitor |
Onset of action | Within 30 min | ~30 min | Within 30 min | Within 30 min | Within 30 min |
Duration of action (h) | 24–36 | At least 24 | At least 24 | 24 | 24 |
Baseline elimination half-life in hours | 12–17 | 9–14 | 19–27 | 10–14 | 5–9 (young)/11–13 (elderly) |
Dosage | |||||
Non-valvular AF | 150 mg twice daily | 5 mg twice daily ** | 60 mg once daily | 20 mg once daily with the evening meal | |
VTE treatment | Parenteral anticoagulation for 5–10 days; then dabigatran 150 mg twice daily | 10 mg twice daily for one week, then 5 mg twice daily | Parenteral anticoagulation for 5–10 days; then edoxaban 60 mg once daily | 15 mg twice daily with food for three weeks; then 20 mg once daily with food | |
VTE prophylaxis | 110 mg for the first day, then 220 mg once daily | 2.5 mg twice daily | 160 mg on the first day, followed by 80 mg once daily, with food | 10 mg once daily, with or without food | |
Best laboratory measurement | dTT, ECT | Anti-Xa | Anti-Xa | Anti-Xa | Anti-Xa |
Author (Year of Publication) | Study Inclusion | Fatal Bleeding | Major Bleeding | ICH | Major GI Bleeding | CRNMB |
---|---|---|---|---|---|---|
Van Der Hulle et al. (2014) | Five randomized controlled trials (2 evaluating rivaroxaban; 1, dabigatran; 1, apixaban; and 1, edoxaban) | 0.06% vs. 0.17% Nd = 12,197 Nk = 12,193 | 1.1% vs. 1.7% Nd = 12,197 Nk = 12,193 | 0.09% vs. 0.25% Nd = 12,197 Nk = 12,193 | 0.35% vs. 0.53% Nd = 12,197 Nk = 12,193 | 6.6% vs. 8.4% Nd = 12,197 Nk = 12,193 |
Chai-Adisaksopha et al. (2014) | Twelve randomized controlled trials (4 evaluating dabigatran; 4, rivaroxaban; 2, apixaban; and 2, edoxaban) | 0.30% vs. 0.52% Nd = 57,850 Nk = 44,757 | 4% vs. 4.64% Nd = 57,850 Nk = 44,757 | 0.51% vs. 1.08% Nd = 57,850 Nk = 44,757 | 2.09% vs. 1.70% Nd = 53,753 Nk = 40,650 | 10.24% vs. 11.05% Nd = 45,774 Nk = 38,750 |
BLEEDING COMPLICATIONS | |
---|---|
MAJOR BLEEDING | Intracranial bleeding (subarachnoid hemorrhage, epidural hemorrhage, subdural hemorrhage, and intraparenchymal hemorrhage) |
Intraspinal hemorrhage | |
Intraocular hemorrhage (retinal or vitreous hemorrhage) | |
Hemorrhagic cardiac tamponade/hemopericardium | |
Retroperitoneal hemorrhage | |
Gastrointestinal hemorrhage | |
Joint hematoma, traumatic or non-traumatic | |
Hemoperitoneum, atraumatic splenic rupture | |
CLINICALLY RELEVANT NON-MAJOR BLEEDING (CRNMB) | Genitourinary–Hematuria, vaginal bleeding, abnormal uterine bleeding |
Respiratory tract–hemoptysis, gingival bleeding, epistaxis | |
Intramuscular–Rectus sheath hematoma | |
Skin/subcutaneous–Bruising |
BARC Definitions | ||
Type 0 | No bleeding | |
Type 1 | Bleeding that is not actionable and does not cause the patient to seek unscheduled intervention. | |
Type 2 | Any overt, actionable sign of hemorrhage requiring non-surgical medical intervention by a healthcare professional. | |
Type 3 | a | Overt bleeding plus hemoglobin drop of 3 to <5 g/dL (provided hemoglobin drop is related to bleed) |
b | Overt bleeding plus hemoglobin drop ≥5 g/dL (provided hemoglobin drop is related to bleed) Cardiac tamponade Bleeding requiring surgical intervention for control or intravenous vasoactive agents | |
c | Intracranial hemorrhage confirmed by autopsy or imaging or lumbar puncture Intraocular bleed compromising vision | |
Type 4 | CABG-related or perioperative intracranial bleeding within 48 h | |
Type 5 | a | Probable fatal bleeding |
b | Definite fatal bleeding |
Patient-Related Risk Factors |
---|
Advanced age Low body mass Smoking Associated comorbidities like hypertension, chronic obstructive pulmonary disease, diabetes mellitus, renal failure, liver disease Previous gastrointestinal or intracranial bleeding Malignancies—tumor invasion Hematologic disorders Collagen vascular disorders Thrombocytopenia Concomitant use of other medications including steroids, nonsteroidal anti-inflammatory drugs, aspirin or clopidogrel |
COMMON BLEEDING SCORES |
---|
HAS-BLED score |
HEMORR2HAGES score |
ATRIA score |
ORBIT-AF score |
ABC bleeding score |
General Measures | Confirm DOAC intake history, the timing of the last dose, check for concomitant medicine, particularly antiplatelet drugs, assess for hemodynamic compromise, check the renal function, and oral activated charcoal (if the last dose within prior two hours) | |
Minor Bleeding | Stop therapy, local hemostatic measures, supportive care, and monitoring | |
Moderate Bleeding | All of the above and fluid resuscitation, blood transfusion, consider fresh frozen plasma transfusion, and consider hemodialysis for dabigatran | |
Major Bleeding | All of the above; consider massive transfusion protocol with packed red blood cells, platelets, fresh frozen plasma, and other procedures/surgeries to achieve hemostasis | |
Specific antidotes | Dabigatran–Idarazcizumab | |
Xa inhibitors (Apixaban, Rivaroxaban, Edoxaban)–Andexant alfa | ||
Non-specific reversal agents: 4 Prothrombin complex concentrates (PCC) [Factors II, VII, IX, and X], Tranexamic acid, epsilon- aminocaproic acid, Desmopressin | ||
Future antidotes | FXa(116L) for both factor Xa as well as direct thrombin inhibitors | |
PER977 (Arapazine/Chiraparantag) for factor Xa inhibitors |
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Gunasekaran, K.; Rajasurya, V.; Devasahayam, J.; Singh Rahi, M.; Chandran, A.; Elango, K.; Talari, G. A Review of the Incidence Diagnosis and Treatment of Spontaneous Hemorrhage in Patients Treated with Direct Oral Anticoagulants. J. Clin. Med. 2020, 9, 2984. https://doi.org/10.3390/jcm9092984
Gunasekaran K, Rajasurya V, Devasahayam J, Singh Rahi M, Chandran A, Elango K, Talari G. A Review of the Incidence Diagnosis and Treatment of Spontaneous Hemorrhage in Patients Treated with Direct Oral Anticoagulants. Journal of Clinical Medicine. 2020; 9(9):2984. https://doi.org/10.3390/jcm9092984
Chicago/Turabian StyleGunasekaran, Kulothungan, Venkat Rajasurya, Joe Devasahayam, Mandeep Singh Rahi, Arul Chandran, Kalaimani Elango, and Goutham Talari. 2020. "A Review of the Incidence Diagnosis and Treatment of Spontaneous Hemorrhage in Patients Treated with Direct Oral Anticoagulants" Journal of Clinical Medicine 9, no. 9: 2984. https://doi.org/10.3390/jcm9092984
APA StyleGunasekaran, K., Rajasurya, V., Devasahayam, J., Singh Rahi, M., Chandran, A., Elango, K., & Talari, G. (2020). A Review of the Incidence Diagnosis and Treatment of Spontaneous Hemorrhage in Patients Treated with Direct Oral Anticoagulants. Journal of Clinical Medicine, 9(9), 2984. https://doi.org/10.3390/jcm9092984