Gastrointestinal bleeding in patients on novel oral anticoagulants: Risk, prevention and management

Table 1 Characteristics of different novel oral anticoagulants

	Dabigatran	Rivaroxaban	Apixaban	Edoxaban
Mechanism of action	Anti-thrombin	Anti-factor Xa	Anti-factor Xa	Anti-factor Xa
Bioavailability	7%	66%	50%	60%
Tmax (h)	1.5	2.5	3	1-5
T½ (h)	9-17	6-13	12	12
Dosing	b.i.d	once daily	b.i.d	once daily
Renal excretion	High	Moderate	Moderate	Moderate
Hepatic metabolism	Low	Moderate	Moderate	Moderate
Reversal agents	Idarucizumab1	Andexanet alfa	Andexanet alfa	Andexanet alfa
	Aripazine	Aripazine	Aripazine	Aripazine

¹Idarucizumab is the only FDA-approved specific reversal agent currently. Tmax: Time to peak plasma level; T½: Half-life; GIB: Gastrointestinal bleeding.

Table 2 Dosing of different novel oral anticoagulants according to indications and renal function

	Dabigatran	Rivaroxaban	Apixaban	Edoxaban
Non-valvular AF
United States	150mg b.i.d	20 mg daily	5 mg b.i.d	60 mg daily
	75 mg b.i.d if CrCl 15-30 mL/min	15 mg daily if CrCl 15-50 mL/min	2.5 mg b.i.d if Cr 15-29 mL/min OR two out of the following:	30 mg daily if CrCl 15-50 mL/min
			age ≥ 80 years, BW ≤ 60 kg, Cr ≥ 1.5 mg/dL
	Avoid if CrCl < 15 mL/min	Avoid if CrCl < 15 mL/min	Avoid if CrCl < 25 mL/min or Cr > 2.5 mg/dL	Avoid if CrCl < 15 mL/min
Europe	150 mg b.i.d	20 mg daily	5 mg b.i.d	60 mg daily
	110 mg b.i.d if age ≥ 80 years	-	2.5 mg b.i.d if Cr 15-29 mL/min OR two out of the following:	30 mg daily if one out of the following: CrCl 15-50 mL/min, BW ≤ 60 kg, concomitant use of p-gp inhibitors
	(may consider 110 mg b.i.d also if increased risk of bleeding)		age ≥ 80 years, BW ≤ 60 kg, Cr ≥ 1.5 mg/dL
	Avoid if CrCl < 30 mL/min	Avoid if CrCl < 15 mL/min	Avoid if CrCl < 15 mL/min	Avoid if CrCl < 15 mL/min
Postoperative DVT / PE thromboprophylaxis (hip or knee replacement)
United States	Initial dose of 110 mg 1-4 h after operation, then 220 mg daily	Initial dose of 10 mg 6-10 h after operation, then 10 mg daily	Initial dose of 2.5 mg 12-24 h after operation, then 2.5 mg b.i.d	-
	-	-	-	-
	Avoid if CrCl < 30	Avoid if CrCl < 30 mL/min	Avoid if CrCl < 30 mL/min	-
Europe	Initial dose of 110 mg 1-4 h after operation, then 220 mg daily	Initial dose of 10 mg 6-10 h after operation, then 10 mg daily	Initial dose of 2.5 mg 12-24 h after operation, then 2.5 mg b.i.d	60 mg daily after 5 d of initial therapy with a parenteral anticoagulant
	Initial dose of 75 mg 1-4 h after operation, then 150 mg daily if CrCl 30-50 mL/min	-	-	30 mg daily after 5 d of initial therapy with a parenteral anticoagulant if one out of the following: CrCl 15-50 mL/min, BW ≤ 60 kg, concomitant use of p-gp inhibitors
	Avoid if CrCl < 30 mL/min	Avoid if CrCl < 15 mL/min	Avoid if CrCl < 15 mL/min	Avoid if CrCl < 15 mL/min
Treatment and prevention of recurrent DVT/PE
United States	150 mg b.i.d after 5-10 d of initial therapy with a parenteral anticoagulant	15 mg b.i.d for 3 wk, then 20 mg daily	10 mg b.i.d for 1 wk, then 5 mg b.i.d	60 mg daily after 5-10 d of initial therapy with a parenteral anticoagulant
	-	-	-	30 mg daily after 5-10 d of initial therapy with a parenteral anticoagulant if one out of the following: CrCl 15-50 mL/min, BW ≤ 60 kg, concomitant use of p-gp inhibitors
	Avoid if CrCl < 30 mL/min	Avoid if CrCl < 30 mL/min	Avoid if CrCl < 25 mL/min or Cr > 2.5 mg/dL	Avoid if CrCl < 15 mL/min
Europe	150 mg b.i.d after 5 d of initial therapy with a parenteral anticoagulant	15 mg b.i.d for 3 wk, then 20 mg daily	10 mg b.i.d for 1 wk, then 5 mg b.i.d	60 mg daily after 5 d of initial therapy with a parenteral anticoagulant
	110 mg b.i.d after 5 d of initial therapy with a parenteral anticoagulant if age ≥ 80 years	-	-	30 mg daily after 5 d of initial therapy with a parenteral anticoagulant if one out of the following: CrCl 15-50 mL/min, BW ≤ 60 kg, concomitant use of p-gp inhibitors
	(may consider 110 mg b.i.d also if increased risk of bleeding)
	Avoid if CrCl < 30 mL/min	Avoid if CrCl < 15 mL/min	Avoid if CrCl < 15 mL/min	Avoid if CrCl < 15 mL/min

NOACs: Novel oral anticoagulants; AF: Atrial fibrillation; CrCl: Creatinine clearance; BW: Body weight; Cr: Creatinine; DVT: Deep vein thrombosis; PE: Pulmonary embolism; p-gp inhibitors: p-glycoprotein inhibitors.

Table 3 Risk factors for novel oral anticoagulant-related gastrointestinal bleeding

Risk factors	Definition
Higher dose of dabigatran and edoxaban	Dabigatran: a dose of 150 mg b.i.d
	Edoxaban: a dose of 60 mg daily
Concomitant use of ulcerogenic agents	Antiplatelet agents, NSAIDs or steroid
Older age	Age ≥ 75 years
Renal impairment	Creatinine clearance < 50 mL/min
Prior history of peptic ulcers or GIB
Helicobacter pylori infection
Pre-existing GI tract lesions	Examples like diverticulosis, angiodysplasias
Ethnicity	Western population
HAS-BLED score	Score of ≥ 3
Protective factors	Definition
Gastroprotective agents	Proton pump inhibitors or histamine H2-receptor antagonists

NOAC: Novel oral anticoagulant; GIB: Gastrointestinal bleeding; NSAIDs: Non-steroidal anti-inflammatory drugs.

Table 4 Components of HAS-BLED bleeding risk score

Clinical characteristics	Definition	Points
Hypertension	Systolic blood pressure > 160 mmHg	1
Abnormal liver or renal function	Chronic liver disease (e.g., cirrhosis) or biochemical evidence of significantly impaired liver function (e.g., bilirubin > 2 times the ULN plus one or more liver enzymes > 3 times the ULN	1 or 2
	Chronic dialysis, renal transplantation, or serum creatinine ≥ 200 micromol/L
Stroke	Previous history of stroke	1
Bleeding tendency or predisposition	Bleeding disorder or previous bleeding episode requiring hospitalization or transfusion	1
Labile INRs	Labile INRs in patients taking warfarin	1
	(failure to maintain a therapeutic range at least 60% of the time)
Elderly	Age > 65 years	1
Drugs	Concomitant antiplatelet agents or NSAIDs	1 or 2
	Excessive alcohol use (≥ 8 units per week)

Maximum score is 9. ULN: Upper limit of normal; INR: International normalized ratio; NSAIDs: Non-steroidal anti-inflammatory drugs.