Evaluation of bleeding in patients receiving direct oral anticoagulants

Figures & data

Table 1 Bleeding outcomes in pivotal trials utilizing DOACs*

	Dabigatran				Rivaroxaban		Apixaban		Edoxaban
	HR (95% CI)	P	HR (95% CI)	P	HR (95% CI)	P	HR (95% CI)	P	HR (95% CI)	P	HR (95% CI)	P
Stroke prevention in NVAF
Trial	RE-LY^Citation4				ROCKET-AF^Citation5		ARISTOTLE^Citation6		ENGAGE-TIMI 48^Citation7
	110 mg		150 mg						30 mg		60 mg
Stroke or SE	0.91 (0.74–1.11)	<0.001 (for NI); 0.34 (for S)	0.66 (0.53–0.82)	<0.001 (for NI and for S)	0.88 (0.75–1.03)	<0.001 (for NI)	0.79 (0.66–0.95)	0.01	1.07 (0.87–1.31)	0.005 (for NI)	0.79 (0.63–0.99)	<0.001 (for NI)
Major or CRNM bleeding	0.78 (0.74–0.83)	<0.001	0.91 (0.86–0.97)	0.002	1.03 (0.96–1.11)	0.44	0.68 (0.61–0.75)	<0.001	0.62 (0.57–0.67)	<0.001	0.86 (0.80–0.92)	<0.001
Major bleeding	0.80 (0.69–0.93)	0.003	0.93 (0.81–1.07)	0.31	1.04 (0.90–1.20)	0.58	0.69 (0.60–0.80)	<0.001	0.47 (0.41–0.55)	<0.001	0.80 (0.71–0.91)	<0.001
Intracranial	0.31 (0.20–0.47)	<0.001	0.40 (0.27–0.60)	<0.001	0.67 (0.47–0.93)	0.02	0.42 (0.30–0.58)	<0.001	0.30 (0.21–0.43)	<0.001	0.47 (0.34–0.63)	<0.001
GI bleeding	1.10 (0.86–1.41)	0.43	1.50 (1.19–1.89)	<0.001	3.2% vs 2.2%	<0.001	0.89 (0.70–1.15)	0.37	0.67 (0.53–0.83)	<0.001	1.23 (1.02–1.50)	0.03
Acute VTE treatment
Trial	RE-COVER^Citation8				EINSTEIN DVT-PE^Citation11		AMPLIFY^Citation12		Hokusai-VTE^Citation13
	HR (95% CI)		P		HR (95% CI)	P	HR (95% CI)	P	HR (95% CI)		P
Recurrent VTE	1.10 (0.65–1.84)		NR		0.89 (0.66–1.19)	<0.001 (for NI)	0.84 (0.60–1.18)	<0.001 (for NI)	0.89 (0.70–1.13)		<0.001 (for NI)
Major or CRNM bleeding	0.63 (0.47–0.84)		NR		0.93 (0.81–1.06)	0.27	0.44 (0.36–0.55)	<0.001	0.81 (0.71–0.94)		0.004
Major bleeding	0.82 (0.45–1.48)		NR		0.54 (0.37–0.79)	0.002	0.31 (0.17–0.55)	<0.001	0.84 (0.59–1.21)		0.35
Intracranial	0 vs 3		NR		2 vs 4	NR	0.1% vs 0.2%	NR	NR		NR
GI bleeding	53 vs 35		NR		1 vs 3	NR	0.3% vs 0.7%	NR	NR		NR

Note:

* Comparator agent for each is warfarin, listed as HR, number of patients, or percentage of patients.

Abbreviations: CRNM, clinically relevant nonmajor; DOAC, direct oral anticoagulant; GI, gastrointestinal; HR, hazard ratio; NI, non-inferiority; NR, not reported; NVAF, nonvalvular atrial fibrillation; S, superiority; SE, systemic embolism; VTE, venous thromboembolism.

Table 2 Bleeding comparisons between DOACs and warfarin from international claims data

	Apixaban vs warfarin: HR (95% CI)	Rivaroxaban vs warfarin: HR (95% CI)	Dabigatran vs warfarin: HR (95% CI)	Apixaban vs rivaroxaban: HR (95% CI)	Apixaban vs dabigatran: HR (95% CI)	Rivaroxaban vs dabigatran: HR (95% CI)
Major bleeding
Larsen et al^Citation29 (n=61,678)	0.61 (0.49–0.75)	1.06 (0.91–1.23)	0.58 (0.47–0.71)	–	–	–
Halvorsen et al^Citation30 (n=32,675)	0.70 (0.61–0.80); P<0.001	1.05 (0.94–1.17); P=0.400	0.74 (0.66–0.84); P<0.001	–	–	–
Noseworthy et al^Citation31 (n=57,788)	–	–	–	0.39 (0.28–0.54); P<0.001	0.50 (0.36–0.70); P<0.001	1.30 (1.10–1.53); P<0.01
Lip et al^Citation32 (n=45,361)	0.53 (0.39–0.71)	0.98 (0.83–1.17)	0.69 (0.50–0.96)	1.82 (1.36–2.43) (R vs A)	1.41 (0.93–2.14) (D vs A)	1.05 (0.74–1.49) (D vs R)
Intracranial bleeding
Larsen et al^Citation29 (n=61,678)	0.72 (0.42–1.24)	0.56 (0.34–0.90)	0.40 (0.25–0.65)	–	–	–
Halvorsen et al^Citation30 (n=32,675)	0.56 (0.36–0.86); P=0.009	0.93 (0.67–1.29); P=0.656	0.46 (0.30–0.70); P<0.001	–	–	–
Noseworthy et al^Citation31 (n=57,788)	–	–	–	0.56 (0.21–1.45); P=0.23	0.65 (0.25–1.65); P=0.36	1.79 (1.12–2.86); P=0.02

Abbreviations: A, apixaban; D, dabigatran; DOAC, direct oral anticoagulants; HR, hazard ratio; R, rivaroxaban.

Table 3 Global registries of DOACs used for the treatment of VTE and prevention of SSE in NVAF

Name	Dates and location	Indication	Drug(s)	Target recruitment	National clinical trial identifier(s)	Outcomes
GARFIELD-AF	December 2009–July 2018; 35 countries	Newly diagnosed NVAF	Warfarin; DOAC; antiplatelet; no therapy	55,000	NCT01090362	Characterize treatment patterns and outcomes; rates of stroke and bleeding
GARFIELD-VTE	March 2014–December 2018; 20 countries	Acute, subacute, and extended duration VTE	Warfarin; DOAC	10,000	NCT02155491	Rate of recurrent VTE; bleeding events
GLORIA-AF	May 2011–January 2020; 50 countries	Newly diagnosed NVAF	Warfarin; DOAC; antiplatelet; no therapy	56,000	Phase I: NCT01428765; Phase II/III: NCT01937377, NCT01468701, NCT01671007	Characterize treatment patterns and outcomes; rates of stroke and bleeding
Dresden NOAC registry	November 2011–December 2018; Germany	Newly diagnosed NVAF or VTE	Warfarin; DOAC	3,500	NCT01588119	Characterize treatment patterns and outcomes; rates of stroke and bleeding
ORBIT-AF II	February 2013–February 2018; United States	Newly diagnosed NVAF or recent transition to DOAC	DOAC	15,000	NCT01701817	Major bleeding
RE-COVERY DVT/PE	November 2015–December 2018; multinational	Newly diagnosed DVT and/or PE	Dabigatran; warfarin	14,000	NCT02596230	Characterize DVT/PE patient population; safety and efficacy of dabigatran etexilate compared to VKA regimens
XANTUS	June 2012–March 2015; Canada, Europe, Israel	NVAF	Rivaroxaban	6,784	NCT01606995	Major bleeding; all-cause mortality; thromboembolic events; prescribing characteristics
XANTUS-EL	January 2013–June 2016; Eastern Europe, Middle East Africa	NVAF	Rivaroxaban	2,101	NCT01800006	Major bleeding; all-cause mortality; thromboembolic events; prescribing characteristics

Abbreviations: DOAC, direct oral anticoagulant; DVT, deep vein thrombosis; GARFIELD-AF, Global Anticoagulant Registry in the Field – Atrial Fibrillation; GARFIELD-VTE, Global Anticoagulant Registry in the Field – Venous Thromboembolic Events; GLORIA-AF, Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation; NOAC, novel oral anticoagulant; NVAF, nonvalvular atrial fibrillation; ORBIT-AF II, Outcomes Registry for Better Informed Treatment of Atrial Fibrillation II; PE, pulmonary embolism; RE-COVERY DVT/PE, Global Study on Treatment Secondary Prevention of Acute Venous Thromboembolism; SSE, stroke and systemic embolism; VKA, vitamin K antagonist; VTE, venous thromboembolism; XANTUS, Xarelto^® for Prevention of Stroke in Patients with Atrial Fibrillation; XANTUS-EL, Xarelto^® for Prevention of Stroke in Patients with Atrial Fibrillation in Latin America and EMEA (Eastern Europe, Middle East, Africa) Region.

Table 4 Pharmacologic and clinical trial comparisons between DOACs

	Dabigatran^Citation39	Rivaroxaban^Citation42	Apixaban^Citation50	Edoxaban^Citation43
Pharmacology
Mechanism of action	Direct thrombin inhibitor	Factor Xa inhibitor	Factor Xa inhibitor	Factor Xa inhibitor
Indication	VTE, NVAF	VTE, NVAF, postoperative DVT prevention	VTE, NVAF, postoperative DVT prevention	VTE, NVAF
Metabolism/elimination	Hepatic (pro-drug)/80% renal	CYP 3A4/5 and CYP 2J2/36% renal; 7% fecal	CYP 1A2, 2C8, 2C9, 2C19, 2J2, P-gp/~25% renal	CYP 3A4/50% renal
Oral bioavailability (F%)	3–7%	~66% (increased with food)	50%	62%
Half-life (h)	12–17	5–9	~12	10–14
Volume of distribution (L)	50–70	~50	~21	107

Landmark clinical trial comparisons
VTE (year)/NVAF (year)	RE-COVER I^Citation8 (2009)	RE-LY^Citation4 (2009)	EINSTEIN-DVT/PE^Citation9^–^Citation11 (2010/2012)	ROCKET-AF^Citation5 (2011)	AMPLIFY^Citation12 (2013)	ARISTOTLE^Citation6 (2011)	Hokusai-VTE^Citation13 (2013)	ENGAGE AF-TIMI 48^Citation7 (2013)
Study design	DB, DD, RCT	RCT	OL, RCT	DB, RCT	DB, RCT	DB, DD, RCT	DB, DD, RCT	DB, DD, RCT
Intervention	Dabigatran vs warfarin		Rivaroxaban vs warfarin		Apixaban vs warfarin		Edoxaban vs warfarin
N	2,539	18,113	4,832/3,449	14,264	5,395	18,201	8,240	21,105
Study population
Age (mean) (years)	~55	~72	~57	~73 (median)	~57	70 (median)	~55	72 (median)
Gender (%men)	68	64	51–57	60	58	65	57	62
Cancer (%)	57–64	–	4.5–6.8	–	–	–	~9	–
CHADS2 (score/majority%)	–	Even distribution (0–6)	–	3 (43%)	–	2 (36%)	–	<3 (72%)
Interventional drug regimen	150 mg bid*	110 mg bid or 150 mg bid	15 mg bid × 3 weeks; 20 mg daily	20 mg daily	10 mg bid × 7 days; 5 mg bid	5 mg bid	60 mg daily*	60 mg daily
Dosage adjustment	CrCl ≤30: NR	CrCl 15–30: 75 mg bid¥; CrCl ≤15: NR	CrCl<30: NR	CrCl 15–50: 15 mg daily; CrCl<15: NR	CrCl<25/SCr>2.5: NR	SCr≥1.5 and age≥80 years or weight ≤60 kg: 2.5 mg bid	CrCl 30: 30 mg daily, OR<60 kg	CrCl 30–50: 30 mg daily, or <60 kg or potent P-gp inhibitor; CrCl>95: NR
Mean TTR (INR 2–3)	60%	64%	62.7%	55%	68%	62%	63.5%	68% (median)
CrCl in landmark study	105 (mean)	50–79 (majority)	>80 (majority)	67 (median)	>80 (majority)	>50 (majority)	>50 (majority)	>50 (majority)
Key exclusion criteria
Renal dysfunction	CrCl<30	CrCl<30	CrCl<30	CrCl<30	CrCl<25; SCr>2.5	CrCl<25; SCr>2.5	CrCl<30	CrCl<30
Hepatic dysfunction	X	X	X	X	X	X	X	X
Stroke history	NS	<14 days or <6 months (severe)	NS	<14 days or <3 months (severe)	NS	<7 days	NS	<30 days
Hemodynamic instability	X	NS	SBP>180/DBP>110	SBP>180/DBP>110	SBP>180/DBP>110	SBP>180/DBP>110	SBP>170/DBP>110	SBP>170/DBP>110
Active/high risk for bleeding	X	X	X	X	X	X	X	X
Valvular disease	NS	X	NS	X	NS	X	NS	X
AP use	Indication for long-term AP	NS	NS	ASA>100 mg	ASA>165 mg; DAPT	ASA>165 mg; DAPT	ASA>100 mg;DAPT	DAPT
Drug interaction	NS	NS	Strong CYP 3A4 inhibitors/inducers	Strong CYP 3A4 inhibitors/inducers	Strong CYP 3A4 inhibitors/inducers	NS	Strong P-gp inhibitors/inducers	Cyclosporine use
Others	Symptoms >14 days; thrombolytic use; indication for VKA; life <6 months		IE; life<3 months; indication for VKA; thrombolytic exposure to AC	IE; LV thrombus; indication for VKA; thrombolytic	LMWH indication	IE; indication for VKA	LMWH indication; indication for VKA	LV thrombus; MI or planned PCI; active cancer

Notes:

* Patients received parental AC prior to starting oral drug therapy for VTE trials. RECOVER had an average of 9 days of parental AC and patients received 5 days of parental AC in Hokusai-VTE.

¥ Dosage adjustment as recommended in package insert, not studied in RE-LY. X, characteristic outlined in exclusion criteria.

Abbreviations: AC, anticoagulation; AP, antiplatelet; ASA, aspirin; CrCl, creatinine clearance (mL/min); DAPT, dual antiplatelet therapy; DB, double blind; DBP, diastolic blood pressure; DD, double dummy; DOACs, direct oral anticoagulants; DVT, deep vein thrombosis; IE, infectious endocarditis; INR, international normalized ratio; LMWH, low molecular weight heparin; NR, not recommended; LV thrombus, left ventricular thrombus; NS, not specified (in exclusion criteria); NVAF, nonvalvular atrial fibrillation; OL, open label; OR, odds ratio; P-gp, P-glycoprotein; RA, recommend against; RCT, randomized controlled trial; SBP, systolic blood pressure; TTR, time in therapeutic range; VKA, vitamin K antagonist; VTE, venous thromboembolism.

Table 5 Bleeding risk assessment tools

Atrial fibrillation			VTE
HEMORR2 HAGES^Citation51 (assigned points)	HAS-BLED^Citation52 (one point each)	ATRIA^Citation53 (assigned points)	RIETE^Citation55 (assigned points)	CHEST^Citation1 (one point each)
Liver/renal disease (1); age >75 years (1)	Abnormal liver or renal function; elderly	Severe renal disease/dialysis (3); age >75 years (2)	SCr>1.2 mL/dL (1.5); age >75 years (1)	Renal failure; age >65 years; age >75 years
Anemia (1); low platelets (1); history of bleeding (2); risk of re-bleeding (1)	History or risk of bleeding	Anemia (3); prior bleeding (1)	Anemia (1.5); recent bleeding (<15 days) (2)	Anemia; previous bleeding
Alcohol abuse (1)	Drug/alcohol use			Alcohol abuse Antiplatelet therapy; NSAID use
	Labile INR			Poor anticoagulant control
Uncontrolled hypertension (1)	Uncontrolled hypertension	Hypertension (1)
Risk of falls or stroke (1)	History of stroke			Previous stroke Frequent falls
Genetic factors (1)			Cancer (1); PE at baseline (1)	Cancer; metastatic cancer Diabetes Comorbidity and reduced functional capacity Recent surgery
Low risk: 0–1; intermediate risk: 2–3; high risk: ≥4	Low risk: <3; high risk: ≥3	Low risk: 0–3; intermediate risk: 4; high risk: ≥5	Low risk: 0; intermediate risk: 1–4; high risk: >4	Low risk: 0; intermediate: 1; high risk ≥2

Abbreviations: INR, international normalized ratio; NSAID, nonsteroidal anti-inflammatory drug; VTE, venous thromboembolism.

Table 6 Reversal agents for the DOACs⁵⁷

Agent	Idarucizumab	Andexanet alfa	Ciraparantag
Target	Dabigatran	Factor Xa inhibitors:	UFH
		Rivaroxaban	Enoxaparin
		Apixaban	Fondaparinux
		Edoxaban	Dabigatran
		Enoxaparin	Rivaroxaban
		Fondaparinux	Apixaban
			Edoxaban
Mechanism	Humanized antibody fragment; binds dabigatran with 350 times the affinity of thrombin	Recombinant modified human factor Xa decoy protein; directly binds target and restores activity of factor Xa	Small synthetic molecule; directly binds drug target to block binding to target site
Onset	<10 minutes	2–5 minutes	5–20 minutes
Approval status	FDA 2015 EMA 2015	Currently delayed by FDA until more data with edoxaban and enoxaparin	FDA granted fast track review in April 2015; currently in Phase III studies
Administration	Two consecutive IV infusions	Dose based on specific target anticoagulant; IV bolus with or without infusion	IV bolus; future studies may include infusion

Abbreviations: DOACs, direct oral anticoagulants; EMA, European Medicines Agency; FDA, US Food and Drug Administration; IV, intravenous; UFH, unfractionated heparin.

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