Direct oral anticoagulants in the treatment of venous thromboembolism, with a focus on patients with pulmonary embolism: an evidence-based review

Figures & data

Table 1 Pharmacological characteristics of the old and new anticoagulants used for treatment of VTE

Agent	Parenteral anticoagulants			Oral anticoagulants
	Heparin sodium	LMWH*	Fondaparinux	Vitamin K antagonists#	Dabigatran	Rivaroxaban	Apixaban	Edoxaban
Source	Pig intestinal mucosa	Pig intestinal mucosa	Synthetic	Synthetic	Synthetic	Synthetic	Synthetic	Synthetic
Molecular weight (Da)	12,000–15,000	3,600–6,500	1,728	≈1,000	628	436	460	548
Target	FXa=FIIa (1:1 ratio)	FXa > FIIa (2:1 to 9:1 ratio)	FXa only	FII, VII, IX, X	Thrombin	FXa	FXa	FXa
Type of inhibition	Indirect (bind to AT)	Indirect (bind to AT)	Indirect (bind to AT)	Indirect‡	Direct	Direct	Direct	Direct
Prodrug	No	No	No	No	Yes (as etexilate)	No	No	No
Bioavailability (%)	100 (IV), 60% (SC)	90–98 (SC)	≈100 (SC)	>60	6	80–100	50	62
Tmax	Few min (IV), 4–6 h (SC)	2–3 h	30–60 min	1–3 h	0.5–2 h	2–4 h	3–4 h	1.5 h
Protein binding (%)	High	Low	Low	≈99	35	92–95	87	40–60
Half life	0.5–1 h	3–6 h	17–21 h	8–11 h (acenocoumarol); 36–42 h (warfarin)	14–17 h	7–12 h	12 h	6–11 h
Metabolism	Depolymerization	Desulphation, depolymerization (<10%)	Negligible	CYP2C9/19 (acenocoumarol); CYP2C9/1A2/3A4 (warfarin)	Glucuronidation (<10%)	CYP3A4 > CYP2J2	CYP3A4/5 > CYP21A2, SC8, 2C9/19, 2J2	Hydrolysis > CYP3A4/5
Renal excretion (% of administered dose)	Medium	High	64–77 (unchanged)	92	5 (4 unchanged)	66 (33 unchanged)	27 (22 unchanged)	35 (24 unchanged)
Renal excretion (% of absorbed dose)	Medium	High	64–77 (unchanged)	92	85 (80 unchanged)	73 (37 unchanged)	54 (44 unchanged)	56 (39 unchanged)
Biliary–fecal excretion (% of administered dose)	Medium	Low	Negligible	8	95	34	56	62
Antidote	Protamine	Protamine (partial neutralization)	None	Vitamin K	None	None	None	None
Monitoring test	aPTT (1.5–2.5 times the control value) and/or ACT (≈250–500 secs)	Not required routinely Anti-Xa assay	Not required routinely. Anti-Xa assay	INR	Not required routinely. Diluted thrombin time	Not required routinely. Anti-Xa assay	Not required routinely. Anti-Xa assay	NA
Year of first marketing authorization (region)	1939 (EU, US)	1985 (EU)	2000 (US)	1941 (US)	2008 (EU)	2008 (EU)	2011 (EU)	2011 (Japan)

Notes:

* Dalteparin (first approved LMWH in 1985), ardeparin, bemiparin, certoparin, enoxaparin, nadroparin, parnaparin, reviparin, tinzaparin.

# Dicumarol (first approved VKA in 1941; no longer available), warfarin, acenocoumarol, phenprocoumon.

‡ Inhibition of vitamin K epoxide-reductase.

Abbreviations: ACT, activated coagulation time; anti-Xa, anti-activated Factor X activity; aPTT, activated partial thromboplastin time; AT, antithrombin; CYP, cytochrome P450; EU, European Union; h, hours; F, Factor; FIIa, activated Factor II; FXa, activated Factor X; INR, international normalized ratio; IV, intravenous; LMWH, low-molecular-weight heparin; min, minutes; NA, data not available; SC, subcutaneous; secs, seconds; T_max, time to maximum concentration; US, United States; VKA, vitamin K antagonist; VTE, venous thromboembolism.

Table 2 Clinical trials with DOAC in the treatment of VTE

Study (DOAC)	N (patients)	Age (yrs)	Male sex (%)	Index PE, n (%)	Anatomical extent of PE (%)*	Design	Experimental treatment	Control treatment	Planned duration	TTR (%)	Risk of bias
Acute treatment
RE-COVER I (Dabigatran)	2,564	55	58	786 (31)	NR	DBRCNI	Heparin ≥5 days followed by DAB 150 mg BID	Heparin ≥5 days + warfarin dose-adjusted (INR: 2.0–3.0)	6 months	60	Low
RE-COVER II (Dabigatran)	2,589	55	61	816 (32)	NR	DBRCNI	Heparin ≥5 days followed by DAB 150 mg BID	Heparin ≥5 days + warfarin dose-adjusted (INR: 2.0–3.0)	6 months	57	Low
EINSTEIN DVT (Rivaroxaban)	3,449	56	57	23 (1)	NA	OLRCNI	RIV 15 mg BID for the first 3 weeks, followed by RIV 20 mg OD	Heparin ≥5 days + warfarin dose-adjusted (INR: 2.0–3.0)	3, 6, or 12 months‡	57.7	Unclear
EINSTEIN PE (Rivaroxaban)	4,833	58	53	4,833 (100)	Extensive: 24; intermediate: 58; limited: 13; missing: 5	OLRCNI	RIV 15 mg BID for the first 3 weeks, followed by RIV 20 mg OD	Heparin ≥5 days + warfarin dose-adjusted (INR: 2.0–3.0)	3, 6, or 12 months‡	62.7	Unclear
AMPLIFY (Apixaban)	5,400	57	59	1,836 (35)	Extensive: 37; intermediate: 43; limited: 9; missing: 11	DBRCNI	API 10 mg BID 7 days, followed by API 5 mg BID	Enoxaparin ≥5 days + warfarin dose-adjusted (INR: 2.0–3.0)	6 months	61	Low
HOKUSAI-VTE (Edoxaban)	8,292	56	57	3,319 (40)	Extensive: 46; intermediate: 41; limited: 7; missing: 6	DBRCNI	Heparin ≥5 days followed by EDO 60 mg OD#	Heparin ≥5 days + warfarin dose-adjusted (INR: 2.0–3.0)	3 to 12 months‡	63.5	Low
Extended treatment
RE-MEDY (Dabigatran)	2,866	55	61	994 (35)	NR	DBRCNI	DAB 150 mg BID	Warfarin dose-adjusted (INR: 2.0–3.0)	18 months§	65	Low
RE-SONATE (Dabigatran)	1,343	56	55	443 (33)	NR	DBRCS	DAB 150 mg BID	Placebo	6 months§	NA	Low
EINSTEIN-EXTENSION (Rivaroxaban)	1,197	58	58	454 (38)	NR	DBRCS	RIV 20 mg OD	Placebo	6 or 12 months§	NA	Low
AMPLIFY-EXT (Apixaban)	2,486	57	57	34	NR	DBRCS	API 2.5 mg and 5 mg BID	Placebo	12 months§	NA	Low

Notes:

* Extensive: clots in ≥2 lobes and >25% of entire pulmonary vasculature (EINSTEIN-PE and HOKUSAI-VTE) or involving ≥50% or more of the vasculature for each lobe (AMPLIFY); intermediate: limited: clots in ≤25% of vasculature of a single lobe.

# Edoxaban 30 mg OD was administered to patients who had a CrCl of 30 to 50 mL/min or a body weight ≤60 kg, or who were receiving concomitant potent P-glycoprotein inhibitors.

‡ Physician’s criteria.

§ Patients had received at least 3 months of anticoagulant therapy before inclusion (RE-MEDY: 3–12 months; RE-SONATE: 6–18 months; EINSTEIN-EXTENSION and AMPLIFY-EXT: 6–12 months).

Abbreviations: AMPLIFY, Efficacy and Safety Study of Apixaban for the Treatment of Deep Vein Thrombosis or Pulmonary Embolism; AMPLIFY-EXT, Efficacy and Safety Study of Apixaban for Extended Treatment of Deep Vein; API, apixaban; BID, twice-daily; CrCl, creatine chloride; DAB, dabigatran; DBRCNI, double-blind randomized controlled non-inferiority trial; DBRCS, double-blind randomized controlled superiority trial; DOAC, direct oral anticoagulant; EDO, edoxaban; EINSTEIN DVT, Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients With Acute Symptomatic Deep Vein Thrombosis; EINSTEIN-EXTENSION, Once-Daily Oral Direct Factor Xa Inhibitor Rivaroxaban In The Long-Term Prevention Of Recurrent Symptomatic Venous Thromboembolism In Patients With Symptomatic Deep-Vein Thrombosis Or Pulmonary Embolism; EINSTEIN PE, Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients With Acute Symptomatic Pulmonary Embolism; HOKUSAI-VTE, Comparative Investigation of Low Molecular Weight (LMW) Heparin/Edoxaban Tosylate (DU176b) Versus (LMW) Heparin/Warfarin in the Treatment of Symptomatic Deep-Vein Blood Clots and/or Lung Blood Clots; INR, International Normalized Ratio; N, total patients in the trial; n, number of patients in the trial that have index PE; NA, not applicable; NR, not reported; OD, once-daily; OLRCNI, open-label randomized controlled non-inferiority trial; PE, pulmonary embolism; RE-COVER I, Efficacy and Safety of Dabigatran Compared to Warfarin for 6 Month Treatment of Acute Symptomatic Venous Thromboembolism; RE-COVER II, Phase III Study Testing Efficacy and Safety of Oral Dabigatran Etexilate versus Warfarin for 6 Month Treatment for Acute Symptomatic Venous Thromboembolism (VTE); RE-MEDY, Secondary Prevention of Venous Thrombo Embolism (VTE); RE-SONATE, Twice-daily Oral Direct Thrombin Inhibitor Dabigatran Etexilate in the Long Term Prevention of Recurrent Symptomatic VTE; RIV, rivaroxaban; TTR, time within therapeutic range; VKA, vitamin K antagonist (warfarin or acenocoumarol); VTE, venous thromboembolism; yrs, years.

Figure 1 Recurrent VTE in clinical trials with DOAC in the treatment of VTE.

Abbreviations: AMPLIFY, Efficacy and Safety Study of Apixaban for the Treatment of Deep Vein Thrombosis or Pulmonary Embolism; AMPLIFY-EXT, Efficacy and Safety Study of Apixaban for Extended Treatment of Deep Vein; CI, confidence interval; df, degrees of freedom; DOAC, direct oral anticoagulant; DVT, deep vein thrombosis; EINSTEIN DVT, Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients With Acute Symptomatic Deep Vein Thrombosis; EINSTEIN-EXTENSION, Once-Daily Oral Direct Factor Xa Inhibitor Rivaroxaban In The Long-Term Prevention Of Recurrent Symptomatic Venous Thromboembolism In Patients With Symptomatic Deep-Vein Thrombosis Or Pulmonary Embolism; EINSTEIN PE, Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients With Acute Symptomatic Pulmonary Embolism; HOKUSAI-VTE, Comparative Investigation of Low Molecular Weight (LMW) Heparin/Edoxaban Tosylate (DU176b) Versus (LMW) Heparin/Warfarin in the Treatment of Symptomatic Deep-Vein Blood Clots and/or Lung Blood Clots; M-H, Mantel–Haenszel; PE, pulmonary embolism; RE-COVER I, Efficacy and Safety of Dabigatran Compared to Warfarin for 6 Month Treatment of Acute Symptomatic Venous Thromboembolism; RE-COVER II, Phase III Study Testing Efficacy and Safety of Oral Dabigatran Etexilate versus Warfarin for 6 Month Treatment for Acute Symptomatic Venous Thromboembolism (VTE); RE-MEDY, Secondary Prevention of Venous Thrombo Embolism (VTE); RE-SONATE, Twice-daily Oral Direct Thrombin Inhibitor Dabigatran Etexilate in the Long Term Prevention of Recurrent Symptomatic VTE; VTE, venous thromboembolism.

Figure 2 Subgroup analysis of recurrent VTE depending on index event (PE or DVT) in clinical trials with DOAC in the treatment of VTE.

Notes: (A) Initial/long-term therapy versus standard treatment. (B) Extended therapy versus warfarin. (C) Extended therapy versus placebo.
Abbreviations: AMPLIFY, Efficacy and Safety Study of Apixaban for the Treatment of Deep Vein Thrombosis or Pulmonary Embolism; AMPLIFY-EXT, Efficacy and Safety Study of Apixaban for Extended Treatment of Deep Vein; CI, confidence interval; df, degrees of freedom; DOAC, direct oral anticoagulant; DVT, deep vein thrombosis; EINSTEIN DVT, Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients With Acute Symptomatic Deep Vein Thrombosis; EINSTEIN-EXTENSION, Once-Daily Oral Direct Factor Xa Inhibitor Rivaroxaban In The Long-Term Prevention Of Recurrent Symptomatic Venous Thromboembolism In Patients With Symptomatic Deep-Vein Thrombosis Or Pulmonary Embolism; EINSTEIN PE, Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients With Acute Symptomatic Pulmonary Embolism; HOKUSAI-VTE, Comparative Investigation of Low Molecular Weight (LMW) Heparin/Edoxaban Tosylate (DU176b) Versus (LMW) Heparin/Warfarin in the Treatment of Symptomatic Deep-Vein Blood Clots and/or Lung Blood Clots; M-H, Mantel–Haenszel; PE, pulmonary embolism; RE-COVER I, Efficacy and Safety of Dabigatran Compared to Warfarin for 6 Month Treatment of Acute Symptomatic Venous Thromboembolism; RE-COVER II, Phase III Study Testing Efficacy and Safety of Oral Dabigatran Etexilate versus Warfarin for 6 Month Treatment for Acute Symptomatic Venous Thromboembolism (VTE); RE-MEDY, Secondary Prevention of Venous Thrombo Embolism (VTE); RE-SONATE, Twice-daily Oral Direct Thrombin Inhibitor Dabigatran Etexilate in the Long Term Prevention of Recurrent Symptomatic VTE; VTE, venous thromboembolism.

Figure 3 Major and clinically relevant nonmajor bleeding in clinical trials with DOAC in the treatment of VTE.

Abbreviations: AMPLIFY, Efficacy and Safety Study of Apixaban for the Treatment of Deep Vein Thrombosis or Pulmonary Embolism; AMPLIFY-EXT, Efficacy and Safety Study of Apixaban for Extended Treatment of Deep Vein; CI, confidence interval; df, degrees of freedom; DOAC, direct oral anticoagulant; DVT, deep vein thrombosis; EINSTEIN DVT, Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients With Acute Symptomatic Deep Vein Thrombosis; EINSTEIN-EXTENSION, Once-Daily Oral Direct Factor Xa Inhibitor Rivaroxaban In The Long-Term Prevention Of Recurrent Symptomatic Venous Thromboembolism In Patients With Symptomatic Deep-Vein Thrombosis Or Pulmonary Embolism; EINSTEIN PE, Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients With Acute Symptomatic Pulmonary Embolism; HOKUSAI-VTE, Comparative Investigation of Low Molecular Weight (LMW) Heparin/Edoxaban Tosylate (DU176b) Versus (LMW) Heparin/Warfarin in the Treatment of Symptomatic Deep-Vein Blood Clots and/or Lung Blood Clots; M-H, Mantel–Haenszel; PE, pulmonary embolism; RE-COVER I, Efficacy and Safety of Dabigatran Compared to Warfarin for 6 Month Treatment of Acute Symptomatic Venous Thromboembolism; RE-COVER II, Phase III Study Testing Efficacy and Safety of Oral Dabigatran Etexilate versus Warfarin for 6 Month Treatment for Acute Symptomatic Venous Thromboembolism (VTE); RE-MEDY, Secondary Prevention of Venous Thrombo Embolism (VTE); RE-SONATE, Twice-daily Oral Direct Thrombin Inhibitor Dabigatran Etexilate in the Long Term Prevention of Recurrent Symptomatic VTE; VTE, venous thromboembolism.

Figure 4 Subgroup analysis of major and clinically relevant nonmajor bleeding events depending on index event (PE or DVT) in clinical trials with DOAC in the treatment of VTE.

Notes: (A) Initial/long-term therapy versus standard treatment. (B) Extended therapy versus placebo.
Abbreviations: AMPLIFY-EXT, Efficacy and Safety Study of Apixaban for Extended Treatment of Deep Vein; CI, confidence interval; df, degrees of freedom; DOAC, direct oral anticoagulant; DVT, deep vein thrombosis; EINSTEIN DVT, Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients With Acute Symptomatic Deep Vein Thrombosis; EINSTEIN PE, Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients With Acute Symptomatic Pulmonary Embolism; HOKUSAI-VTE, Comparative Investigation of Low Molecular Weight (LMW) Heparin/Edoxaban Tosylate (DU176b) Versus (LMW) Heparin/Warfarin in the Treatment of Symptomatic Deep-Vein Blood Clots and/or Lung Blood Clots; M-H, Mantel–Haenszel; PE, pulmonary embolism; VTE, venous thromboembolism.

Table 3 Pooled risks of recurrent VTE, CRB, and mortality by index event in patients receiving anticoagulant therapy (DOAC or heparin/warfarin)^*

Clinical setting	Outcome
	Index PE, % (n/N)	Index DVT, % (n/N)	% Absolute risk difference (95% CI)	Relative risk difference (95% CI)
Initial/long-term therapy^Citation36^–^Citation41
Recurrent VTE	2.5% (290/11589)	2.7% (412/15434)	−0.2 (−0.6 to 0.2)	0.94 (0.81 to 1.09)
CRB	10.7% (876/8151)	8.3% (696/8370)	2.4 (1.5 to 3.3)‡	1.29 (1.18 to 1.42)#
All-cause mortality‡	2.2% (108/4833)	2.5% (87/3449)	−0.3 (−1.04 to 3.7)	0.89 (0.67 to 1.17)
Extended therapy^Citation38,Citation42,Citation43
Recurrent VTE	3.0% (24/812)	3.0% (45/1522)	0.0 (−1.4 to 1.6)	1.00 (0.62 to 1.62)
Clinically relevant bleeding	4.6% (27/582)	3.3% (35/1069)	1.4 (−0.5 to 3.6)	1.42 (0.87 to 2.31)

Notes: Based on total events and patients with PE or DVT included in clinical trials in the initial/long-term and extended therapy of VTE.

# P<0.05

‡ Data only available from EINSTEIN PE and EINSTEIN DVT. Data shown in bold font signifies statistical significance, P<0.05.

Abbreviations: CI, confidence interval; CRB, clinically relevant bleeding; DOAC, direct oral anticoagulant; DVT, deep vein thrombosis; EINSTEIN DVT, Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients With Acute Symptomatic Deep Vein Thrombosis; EINSTEIN PE, Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients With Acute Symptomatic Pulmonary Embolism; N, total patients in the trial; n, number of events; PE, pulmonary embolism; VTE, venous thromboembolism.

Table 4 Summary of prescribing information of the DOAC in the treatment of VTE

Characteristic	Dabigatran etexilate (Pradaxa^®)	Rivaroxaban (Xarelto^®)	Apixaban (Eliquis^®)	Edoxaban (Lixiana^®)*
Dosing
Initial therapy	LMWH or fondaparinux for at least 5 days	Rivaroxaban 15 mg BID for 21 days (3 weeks)	Apixaban 10 mg BID for 7 days (1 week)	LMWH or fondaparinux for at least 5 days
Long-term therapy	Dabigatran 150 mg BID	Rivaroxaban 20 mg OD (15 mg OD in patients with CrCl 15–50 judged to be at high risk of bleeding) from day 22 onward	Apixaban 5 mg BID from day 8 onward	Edoxaban 60 mg OD (30 mg in patients with a CrCl 30–50 mL/min, a body weight ≤60 kg or concomitant treatment with potent Pg-p inhibitors)
Extended therapy#	Same posology as long-term therapy	Same posology as long-term therapy	Dose reduction to 2.5 mg BID is recommended following completion of at least 6 months of anticoagulation	Same as long-term therapy but no clinical experience is available beyond 12 months^‡
Intake with food	Not necessary	Mandatory (39% decrease in absorption when administered without food)	Not necessary	Not necessary
Absorption with proton pump inhibitors	30% decrease (no dose-adjustment necessary)	Not significantly altered	Not significantly altered	Not significantly altered
Relevant pharmacokinetic interactions	– Potent Pg-p inhibitors (contraindicated), – Potent Pg-p inducers (not recommended)	– Potent inhibitors of both P-gp and CYP3A4 (not recommended), – Potent inducers of both P-gp and CYP3A4 (use with caution)	– Potent inhibitors or inducers of both P-gp and CYP3A4 (use with caution)	– Potent Pg-p inhibitors (dose reduction) (see long-term therapy) – Potent Pg-p inducers (no specific recommendations available)
Relevant pharmacodynamic interactions	Drugs that alter hemostasis¶	Drugs that alter hemostasis¶	Drugs that alter hemostasis¶	Drugs that alter hemostasis¶
Use in renal insufficiency	Contraindicated in severe renal insufficiency (CrCl <30 mL/min)	Not recommended if CrCl <15 mL/min Dose-adjustment in some cases (see long-term therapy above)	Not recommended if CrCl <15 mL/min	Dose adjustment in some cases (see long-term therapy above). No data available in severe renal insufficiency)

Notes:

* Not approved yet (as of August 2014) in the European Union and other regions for the treatment of VTE.

# In selected patients at high risk of recurrence, according to clinical practice guidelines. ^‡Maximum treatment duration tested in HOKUSAI-VTE was 12 months. No experience beyond this period is available and no specific extended treatment studies with edoxaban have been conducted).

¶ Includes other anticoagulants (use contraindicated unless switching therapy), fibrinolytics, and antiplatelet drugs (use with caution unless formal contraindication). Grade 1–2, strong–weak evidence; Grade A–B–C, high–moderate–low quality of data.

Abbreviations: BID, twice-daily; BP, blood pressure; CrCl, creatine chloride; DOAC, direct oral anticoagulant; HOKUSAI-VTE, Comparative Investigation of Low Molecular Weight (LMW) Heparin/Edoxaban Tosylate (DU176b) Versus (LMW) Heparin/Warfarin in the Treatment of Symptomatic Deep-Vein Blood Clots and/or Lung Blood Clots; LMWH, low-molecular-weight heparin; min, minute; OD, once-daily; Pg-p, P-glycoprotein; VTE, venous thromboembolism.

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