Minimizing bleeding risk in patients receiving direct oral anticoagulants for stroke prevention

Figures & data

Table 1 Key safety outcomes in the Phase III clinical trials comparing the use of DOACs with warfarin for stroke prevention in patients with nonvalvular atrial fibrillation

Parameter	Dabigatran (RE-LY)^Citation16,Citation19^–^Citation21		Rivaroxaban (ROCKET AF)^Citation15,Citation22,Citation70	Apixaban (ARISTOTLE)^Citation18	Edoxaban (ENGAGE AF-TIMI)^Citation17
Patients randomized	18,113		14,264	18,201	21,105
Comparator	Dose-adjusted warfarin (target INR 2.0–3.0)
Doses tested	110 mg bid	150 mg bid	20 mg oda	5 mg bidb	30 mg odc	60 mg odc
Patients eligible for reduced dose	NA	NA	2,950 (20.7%)	831 (4.6%)	5,330 (25.3%) at randomization; 7.1% after randomization
Major bleeding outcomes (DOAC vs warfarin; % per year)
Major bleeding	2.92 vs 3.61; P=0.003	3.40 vs 3.61; P=0.41	3.6 vs 3.4; P=0.58	2.13 vs 3.09; P<0.001	1.61 vs 3.43; P<0.001	2.75 vs 3.43; P<0.001
Fatal bleeding	0.19 vs 0.33; P=0.039	0.23 vs 0.33; P=0.15	0.2 vs 0.5; P=0.003	NR (34 vs 55 patients)	0.13 vs 0.38; P<0.001	0.21 vs 0.38; P=0.006
ICH	0.23 vs 0.76; P<0.001	0.32 vs 0.76; P<0.001	0.5 vs 0.7; P=0.02	0.33 vs 0.80; P<0.001	0.26 vs 0.85; P<0.001	0.39 vs 0.85; P<0.001
Major GI bleeding	1.15 vs 1.07; P=0.52	1.56 vs 1.07; P=0.001	2.00 vs 1.24; P<0.0001	0.76 vs 0.86; P=0.37	0.82 vs 1.23; P<0.001	1.51 vs 1.23; P=0.03

Notes:

a 15 mg od for patients with CrCl 30–49 mL/min at randomization;

b 2.5 mg bid for patients with ≥2 of: weight ≤60 kg, age ≥80 years, or serum creatinine ≥1.5 mg/dL at randomization; and

c dose was halved if any of the following characteristics were present at randomization or during study: CrCl 30–50 mL/min, weight ≤60 kg, or concomitant use of potent P-glycoprotein inhibitors (verapamil, quinidine, or dronedarone).

Abbreviations: bid, twice daily; CrCl, creatinine clearance; DOAC, direct oral anticoagulant; GI, gastrointestinal; ICH, intracranial hemorrhage; INR, international normalized ratio; NA, not applicable; NR, not reported; od, once daily.

Table 2 Bleeding risk scores validated for use in patients with nonvalvular atrial fibrillation

HAS-BLED^Citation33		ATRIA^Citation34		ORBIT^Citation35
Hypertension – uncontrolled (>160 mmHg systolic)	1	Anemiaa	3	Older age (≥75 years old)	1
Abnormal renal function (SCr ≥200 μmol/L or dialysis or transplantation) or abnormal hepatic functionb	1 or 2	Severe renal disease (eGFR <30 mL/min or dialysis)	3	Reduced hemoglobina, reduced hematocritc, or anemia	2
Stroke history	1	≥75 years old	2	Bleeding history	2
Bleeding history or predisposition to bleeding (eg, anemia and bleeding diathesis)	1	Any prior hemorrhage	1	Insufficient kidney function (eGFR <60 mg/dL/1.73 m^2)	1
Labile INRs	1	Diagnosed hypertension	1	Treatment with antiplatelets	1
Elderly (>65 years old)	1	–	–	–	–
Drugs or alcohol (antiplatelet agents or NSAIDs; alcohol ≥8 units per week)	1 or 2	–	–	–	–
Maximum score	9	Maximum score	10	Maximum score	7

Notes: Potentially modifiable bleeding risk factors are shown with green shading; criteria that may mandate the use of a reduced-dose DOAC to reduce bleeding risk are shown with orange shading; in the case of older patients, dose reductions may only be mandated in patients ≥80 years old on certain DOACs.

a Hemoglobin <13 g/dL in men and <12 g/dL in women;

b chronic hepatic disease (eg, cirrhosis) or biochemical evidence of significant hepatic derangement (eg, bilirubin >2× upper limit of normal, in association with aspartate aminotransferase/alanine aminotransferase/alkaline phosphatase >3× upper limit normal); and

c <40% for men and <36% for women.

Abbreviations: DOAC, direct oral anticoagulant; eGFR, estimated glomerular filtration rate; INR, international normalized ratio; NSAID, nonsteroidal anti-inflammatory drug; SCr, serum creatinine.

Table 3 Reversible risk factors and management strategies for bleeding in patients with AF receiving DOACs

Reversible risk factors for bleeding in patients with AF	Management
Hypertension
A systolic blood pressure of ≥140 mmHg is associated with an increase in the risk of both hemorrhagic and ischemic stroke among patients with AF^Citation40	• Regular monitoring for patients with a history of hypertension • Adequate control of blood pressure to the recommended level
Diabetes
Diabetes is associated with an increased risk of bleeding in patients with AF receiving anticoagulation therapy^Citation71	• Review medication and dosing regularly to ensure good glycemic control
Gastrointestinal bleeding
Risk of gastrointestinal bleeding is increased: • In patients with Helicobacter pylori infection and/or existing/previous stomach/peptic ulcers and/or dyspepsia • By ASA and NSAID use and alcohol consumption^Citation72	• Prescribe proton pump inhibitors • Treat for H. pylori • Manage diet and alcohol intake • Avoid concomitant use of NSAIDs and ASA unless indicated^Citation72
Polypharmacy
Concomitant use of P-gp and/or CYP3A4 inhibitors may lead to increased DOAC plasma concentrations Drug–drug interactions may increase the risk of falls^Citation40,Citation73	• Regular medicines management reviews should be performed to ensure no contraindications or unnecessary medicine usage and that the appropriate doses are being administered
Lifestyle
Poor adherence to anticoagulant therapy may increase the risk of bleeding (ie, if the patient overdoses) Drug and alcohol misuse may increase the risk of falls/trauma^Citation40	• Patient communication and education may improve treatment adherence • Reduce the risk of substance misuse; refer patient for alcohol/drug dependency counseling
Risk of falls
Postural hypotension, visual impairment, reduced mobility/frailty, and psychotropic medications (such as benzodiazepines, antidepressants, and antipsychotics) and drug–drug interactions may be associated with an increased risk of falls^Citation73,Citation74	• Check for low blood pressure to prevent dizziness and fainting • Correct visual impairment • Provide mobility aids such as walking sticks or handrails • Reconsider need for any psychotropic medications • Review medicine use regularly to optimize combinations

Abbreviations: AF, atrial fibrillation; ASA, acetylsalicylic acid; CYP3A4, cytochrome P450 3A4; DOAC, direct oral anticoagulant; NSAID, nonsteroidal anti-inflammatory drug; P-gp, P-glycoprotein.

Table 4 Recommendations for use and dosing regimens of the DOACs for stroke prevention in patients with nonvalvular atrial fibrillation according to patient characteristics and concomitant medications that may be associated with an increased risk of bleeding

Recommended use	Dabigatran^Citation45	Rivaroxaban^Citation43	Apixaban^Citation44	Edoxaban^Citation46
Standard dose	150 mg bid	20 mg od to be taken with food	5 mg bid	60 mg od
Patients with active bleeding
Contraindications	Active clinically significant bleeding or a lesion or condition considered to be a high risk for major bleeding (including current or recent GI ulceration, presence of malignant neoplasms at high risk of bleeding, recent CNS injury or surgery, recent ICH, known or suspected esophageal varices, arteriovenous malformations, vascular aneurysms, or major intracerebral or intraspinal abnormalities)
Patients with hepatic impairment
Contraindications	Hepatic impairment or liver disease expected to have an impact on survival	Hepatic disease associated with coagulopathy and clinically relevant bleeding risk, including cirrhotic patients with moderate-to-severe hepatic impairment (Child–Pugh B and C)	Hepatic disease associated with coagulopathy and clinically relevant bleeding risk		Hepatic disease associated with coagulopathy and clinically relevant bleeding risk
Not recommended	Elevated liver enzymes (>2× ULN)	NA	Severe hepatic impairment		Severe hepatic impairment
Use with caution	NA	NA	Mild or moderate hepatic impairment (Child–Pugh A or B) Elevated liver enzymes ALT/AST >2× ULN or total bilirubin ≥1.5× ULN		Mild-to-moderate hepatic impairment Elevated liver enzymes ALT/AST >2× ULN or total bilirubin ≥1.5× ULN
Patients with renal impairment
Dose adjustments	A dose reduction to 110 mg bid should be considered in patients with CrCl 30–49 mL/min and a high risk of bleeding	15 mg od in patients with CrCl 15–49 mL/min	2.5 mg bid in patients with ≥2 of the following criteria: age ≥80 years, body weight ≤60 kg, serum creatinine ≥1.5 mg/dL (133 μmol/L) 2.5 mg bid in patients with CrCl 15–29 mL/min		30 mg od in patients with CrCl 15–50 mL/min
Contraindications	CrCl <30 mL/min	NA	NA		NA
Not recommended	NA	Patients with CrCl <15 mL/min	Patients with CrCl <15 mL/min		Patients with CrCl <15 mL/min
Use with caution	NA	Patients with CrCl 15–29 mL/min	NA		NA
Elderly patients
Dose adjustments	Age ≥80 years: 110 mg bid In patients aged 75–80 years a dose reduction to 110 mg bid may be considered when thromboembolic risk is low and bleeding risk is high	No dose adjustment based on age alone	2.5 mg bid in patients with ≥2 of the following criteria: age ≥80 years, body weight ≤60 kg, serum creatinine ≥1.5 mg/dL (133 μmol/L)		No dose adjustment based on age alone
Patients receiving concomitant P-gp or CYP3A4 inhibitors that increase DOAC plasma concentrations
Dose adjustments	110 mg bid in patients receiving concomitant verapamil	No dose adjustment based on use of concomitant P-gp or CYP3A4 inhibitors alone	No dose adjustment based on use of concomitant P-gp or CYP3A4 inhibitors alone		30 mg od in patients receiving concomitant cyclosporine, dronedarone, erythromycin, or ketoconazole
Contraindications	Concomitant treatment with systemic ketoconazole, cyclosporine, itraconazole, and dronedarone	NA	NA		NA
Not recommended	Concomitant treatment with tacrolimus	Concomitant systemic treatment with azole antimycotics (eg, ketoconazole, itraconazole, voriconazole, and posaconazole) or HIV protease inhibitors (eg, ritonavir) Coadministration with dronedarone should be avoided	Concomitant systemic treatment with azole-antimycotics (eg, ketoconazole, itraconazole, voriconazole, and posaconazole) or HIV protease inhibitors (eg, ritonavir)		NA
Use with caution	Caution advised with concomitant treatment with amiodarone, quinidine, posaconazole, verapamil, clarithromycin, or ticagrelor, especially in patients with mild- to-moderate renal impairment	Caution advised in patients with renal impairment concomitantly receiving clarithromycin, erythromycin, or fluconazole	NA		NA
Patients receiving concomitant treatment with drugs affecting hemostasis
Dose reductions	Consider dose reduction to 110 mg bid in patients receiving concomitant treatment with clopidogrel, ASA, or NSAIDs, especially if patient is ≥75 years old	No dose adjustment based on use of drugs affecting hemostasis	No dose adjustment based on use of drugs affecting hemostasis		No dose adjustment based on use of drugs affecting hemostasis
Not recommended	NA	NA	Concomitant use of thienopyridines (eg, clopidogrel) or dipyridamole		Concomitant chronic use of high-dose ASA (325 mg/d) or NSAIDs
Use with caution	Concomitant administration with drugs affecting hemostasis by inhibition of platelet aggregation	Concomitant treatment with NSAIDs, ASA, or platelet aggregation inhibitors	Concomitant administration of NSAIDs or ASA		Concomitant administration of ASA in elderly patients
Other patients at increased risk of bleeding or elevated DOAC concentrations
Dose adjustments	Consider dose reduction to 110 mg bid in patients with gastritis, esophagitis, or gastroesophageal reflux and in other patients at increased risk of bleeding (eg, patients receiving concomitant treatment with SSRIs or SNRIs)	No dose adjustments based on bleeding risk alone	No dose adjustments based on bleeding risk alone		30 mg od in patients with low body weight (≤60 kg)

Abbreviations: ALT, alanine aminotransferase; ASA, acetylsalicylic acid; AST, aspartate aminotransferase; bid, twice daily; CNS, central nervous system; CrCl, creatinine clearance; CYP3A4, cytochrome P450 3A4; DOAC, direct oral anticoagulant; GI, gastrointestinal; HIV, human immunodeficiency virus; ICH, intracranial hemorrhage; NA, not applicable; NSAID, nonsteroidal anti-inflammatory drug; od, once daily; P-gp, P-glycoprotein; SNRI, serotonin–norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; ULN, upper limit of normal.

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