Direct oral anticoagulants as alternative treatment options for the effective long-term treatment of patients with pulmonary embolism in primary care: a review

Figures & data

Figure 1. Risk stratification of PE and appropriate management, based on European Society of Cardiology 2008 guidelines (9). RV = right ventricular.

Table I. Variables used to calculate the Pulmonary Embolism Severity Index (PESI) score (original and simplified PESI) for the assessment of pulmonary embolism probability (X indicates the use of the variable in the respective scoring index) (29–31).

Variable	Original PESI	Simplified PESI
Age > 80 years	X	X
Male sex	X
History of cancer	X	X
History of heart failure	X	X^a
History of chronic lung disease	X
Pulse ≥ 110 beats/min	X	X
Systolic blood pressure < 100 mmHg	X	X
Respiratory rate ≥ 30 breaths/min	X
Temperature < 36°C	X
Altered mental status	X
Arterial oxyhaemoglobin saturation level < 90%	X	X

^aMerged into one category: chronic cardiopulmonary disease.

Table II. Pharmacokinetic and pharmacodynamic properties of the direct oral anticoagulants apixaban, dabigatran, edoxaban, and rivaroxaban compared with warfarin.

	Apixaban	Dabigatran	Edoxaban^a	Rivaroxaban	Warfarin (78)
Mechanism of action	Factor Xa inhibitor (80)	Thrombin inhibitor (32,81)	Factor Xa inhibitor (35)	Factor Xa inhibitor (36)	Vitamin K antagonist
Single drug use in acute VTE treatment	Yes (22,23)	No (19)	No (82)	Yes (58,59)	No
Prodrug	No	Yes (32)	No	No	No
Bioavailability, %	∼66 (83)	7.2 (84)	∼60 (42)	80–100^b (85)	∼100 (86)
Protein binding, %	87 (46)	34–35 (44)	40–59 (42)	92–95 (17,87)	∼99 (88)
Coagulation monitoring required	No (46)	No (44)	No (42)	No (89)	Yes
Tmax, h	1.5–3.3 (41)	1.25–1.5 (40)	1–2 (42)	2–4 (39,90)	Slow onset (peak anticoagulation effect may take up to 96 h after administration)
T½, h	∼11.5 (41)	7–17 (40)	6–11 (42)	5–9 in healthy young subjects (39,90); 11–13 in healthy elderly subjects (91)	∼40
Main mode of elimination	Renal/faecal (43)	Renal (84)	Renal/hepatobiliary (42,92)	Renal/hepatobiliary (45)	Renal
Drug interactions	Potent inhibitors of CYP3A4 and P-gp (46)	Potent inhibitors and inducers of P-gp (44)	CYP3A4 and P-gp (93,94)	Potent inhibitors of CYP3A4 and P-gp (95)	Multiple drugs, dietary vitamin K
Reversal agent	No (46)	No (44)	No	No (17)	Yes

CYP3A4 = cytochrome P450 3A4; P-gp = P-glycoprotein; T_max = time to maximum plasma concentration; T_½ = terminal half-life; VTE = venous thromboembolism.

^aSummary of Product Characteristics not currently available.

^bComplete absorption (100%) is only achieved at doses > 10 mg when taken with food.

Figure 2. Management of bleeding in patients receiving oral anticoagulants (17,44,46,78,79).

^aThere is currently no Summary of Product Characteristics for edoxaban; ^btests are not standardized, and results should be interpreted with caution; ^csome reversal agents may interfere with results from anticoagulation tests. aPCC, activated prothrombin complex concentrate; aPTT = activated partial thromboplastin time; dTT = diluted thrombin time; ECT = ecarin clotting time; INR = international normalized ratio; PCC = prothrombin complex concentrate; rFVIIa = recombinant activated factor VII.

Table III. Design of the clinical trial studies (19–24,58,59).

Trial name	n (ITT)	PE (with or without DVT) (%)	Design	Initial treatment with heparin/fondaparinux	Treatment duration (months)	Previous treatment duration (months)	Long-term treatment regimen	Active comparator
Rivaroxaban
EINSTEIN DVT	3449	0.7	Open label	No	3, 6, or 12	_	od	Enoxaparin/VKA
EINSTEIN PE	4832	100.0	Open label	No	3, 6, or 12	_	od	Enoxaparin/VKA
EINSTEIN EXT	1196	38.0	Double blind	No	6 or 12	6–12	od	Placebo
Dabigatran
RE-COVER	2539	31.0	Double blind	Yes^a	6	_	bid	Heparin/warfarin
RE-COVER II	2568	_	Double blind	Yes^b	6	_	bid	Heparin/warfarin
RE-MEDY	2856	34.8	Double blind	No	6–36	3–12	bid	Warfarin
RE-SONATE	1343	33.0	Double blind	No	6	6–18	bid	Placebo
Apixaban
AMPLIFY	5395	34.0	Double blind	No	6	_	bid	Enoxaparin/warfarin
AMPLIFY-EXT	2482	34.6	Double blind	No	12	6–12	bid	Placebo
Edoxaban
Hokusai-VTE	8240	40.3	Double blind	Yes^c	3–12	_	od^d	Heparin/warfarin

bid = twice daily; DVT = deep vein thrombosis; ITT = intention-to-treat; od = once daily; PE = pulmonary embolism; VKA = vitamin K antagonist.

^aMedian = 9 days; ^bMedian = 9.4 days in the dabigatran group and median = 9.6 days in the warfarin group; ^cmedian = 7 days; ^dtwo 30 mg tablets unless receiving the lower dose (one 30 mg tablet).

Table IV. Inclusion and exclusion criteria of the clinical trial studies (19–24,58,59).^a

Trial name	Inclusion criteria	Exclusion criteria
Rivaroxaban
EINSTEIN DVT	Legal age for consent; acute, symptomatic, objectively confirmed proximal DVT, without symptomatic PE	Received therapeutic doses of LMWH, fondaparinux, or UFH for > 48 h or > 1 dose of a VKA before randomization; treated with thrombectomy, a vena cava filter, or a fibrinolytic agent for the current episode of thrombosis; any contraindication listed in the labelling of enoxaparin, warfarin, or acenocoumarol Additional: another indication for a VKA; CrCl < 30 mL/min; clinically significant liver disease (e.g. acute hepatitis, chronic active hepatitis, or cirrhosis) or an ALT ≥ 3 × ULN; bacterial endocarditis; active bleeding or a high risk of bleeding contraindicating anticoagulant treatment; systolic blood pressure > 180 mmHg or diastolic blood pressure > 110 mmHg; child-bearing potential without proper contraceptive measures, pregnancy, or breast-feeding; concomitant use of strong cytochrome P450 3A4 inhibitors (e.g. human immunodeficiency virus protease inhibitors or systemic ketoconazole) or inducers (e.g. rifampicin, carbamazepine, or phenytoin); participation in another experimental pharmacotherapeutic programme within 30 days before screening; life expectancy of < 3 months
EINSTEIN PE	Legal age for consent; acute, symptomatic PE with objective confirmation, with or without symptomatic DVT	See exclusion criteria under EINSTEIN DVT
EINSTEIN EXT	Legal age for consent; objectively confirmed, symptomatic DVT or PE; treated for 6–12 months with acenocoumarol or warfarin (in the EINSTEIN studies or from routine care) or rivaroxaban (in the EINSTEIN studies); equipoise with respect to the need for continued anticoagulation	See additional exclusion criteria under EINSTEIN DVT
Dabigatran
RE-COVER	≥ 18 years of age; acute, symptomatic, objectively verified proximal DVT of the legs or PE; 6 months’ anticoagulant therapy considered to be an appropriate treatment	Duration of symptoms > 14 days; PE with haemodynamic instability or requiring thrombolytic therapy; another indication for warfarin therapy; recent unstable cardiovascular disease; a high risk of bleeding; liver disease with AST > 2 × ULN; an estimated CrCl < 30 mL/min; a life expectancy of < 6 months; contraindication to heparin or to radiographic contrast material; pregnancy or risk of becoming pregnant; requirement for long-term antiplatelet therapy (≤ 100 mg of acetylsalicylic acid daily was acceptable)
RE-COVER II	See inclusion criteria under RE-COVER	See exclusion criteria under RE-COVER
RE-MEDY	≥ 18 years of age; objectively confirmed, symptomatic, proximal DVT or PE that had already been treated with an approved anticoagulant or if they had received dabigatran in RE-COVER or RE-COVER II studies; initial treatment before trial enrolment of 3–12 months	Symptomatic DVT or PE at screening; patients with primary PE with suspected origin other than the legs; patients who are perceived to have an excessive risk of bleeding; actual or anticipated use of vena cava filter; ≥ 2 weeks interruption during the 3–6 months of prior treatment; known anaemia (haemoglobin < 100 g/L); anticoagulant treatment required for disorders other than VTE; recent unstable cardiovascular disease; liver disease with AST or ALT > 2 × ULN; liver disease expected to have any potential impact on survival (e.g. acute hepatitis, or possibly active hepatitis B, hepatitis C or cirrhosis, but not Gilbert's syndrome or hepatitis A with complete recovery); developed transaminase elevations upon exposure to ximelagatran; CrCl ≤ 30 mL/min; pregnancy or risk of becoming pregnant
RE-SONATE	≥ 18 years of age; objectively confirmed, symptomatic, proximal DVT or PE that had already been treated with an approved anticoagulant or if they had received dabigatran in RE-COVER or RE-COVER II studies; initial treatment before trial enrolment of 6–18 months	Indication for VKA other than DVT and/or PE; patients in whom anticoagulant treatment for VTE should be continued; active liver disease or liver disease decreasing survival (e.g. acute hepatitis, chronic active hepatitis, cirrhosis) or ALT > 3 × ULN; CrCl < 30 mL/min; acute bacterial endocarditis; active bleeding or high risk for bleeding; uncontrolled hypertension (investigator's judgement); intake of another experimental drug within the 30 days prior to randomization into the study; life expectancy < 6 months; pregnancy or risk of becoming pregnant
Apixaban
AMPLIFY	≥ 18 years of age; objectively confirmed, symptomatic proximal DVT or PE (with or without DVT)	Active bleeding; a high risk of bleeding; other contraindications to treatment with enoxaparin and warfarin; active cancer and planned long-term treatment with LMWH; DVT or PE provoked in the absence of a persistent risk factor for recurrence; planned anticoagulation treatment < 6 months; additional indication for long-term anticoagulation therapy, dual antiplatelet therapy, treatment with ASA > 165 mg daily, or treatment with potent inhibitors of cytochrome P450 3A4; > 2 doses of a once-daily LMWH regimen, fondaparinux, or a VKA; > 3 doses of a twice-daily LMWH regimen; > 36 hours of continuous intravenous heparin; a haemoglobin level of < 9 mg/dL; a platelet count of < 100,000/mm^3; serum creatinine level > 2.5 mg/dL (220 μmol/L), CrCl < 25 mL/min
AMPLIFY-EXT	≥ 18 years of age; objectively confirmed, symptomatic proximal DVT or PE (with or without DVT); 6–12 months’ prior treatment with standard anticoagulant therapy or with apixaban or enoxaparin and warfarin as participants in the AMPLIFY trial; no symptomatic recurrence during prior anticoagulant therapy; clinical equipoise about the continuation or cessation of anticoagulant therapy	Contraindication to continued anticoagulant therapy; ongoing anticoagulant therapy, dual antiplatelet therapy, or ASA > 165 mg daily; haemoglobin level < 9 mg/dL; platelet count of < 100,000/mm^3; serum creatinine level > 2.5 mg/dL (221 μmol/L); calculated CrCl < 25 mL/min; ALT or AST level > 2 × ULN; total bilirubin level > 1.5 × ULN
Edoxaban
Hokusai-VTE	≥ 18 years of age; objectively confirmed, acute, symptomatic DVT involving the popliteal, femoral, or iliac veins, or acute symptomatic PE (with or without DVT)	Contraindications to heparin or warfarin; treatment > 48 h with therapeutic doses of heparin or > 1 dose of a VKA; had cancer with planned long-term treatment with LMWH; another indication for warfarin; continued to receive treatment with ASA > 100 mg daily or dual antiplatelet therapy; CrCl < 30 mL/min

ALT = alanine aminotransferase; ASA = acetylsalicylic acid; AST = aspartate aminotransferase; CrCl = creatinine clearance; DVT = deep vein thrombosis; LMWH = low-molecular-weight heparin; PE = pulmonary embolism; UFH = unfractionated heparin; ULN = upper limit of normal; VKA = vitamin K antagonist; VTE = venous thromboembolism.

^aThe inclusion and exclusion criteria listed are not exhaustive.

Table V. Results from the acute VTE studies (19,21,22,24,58,59).

	EINSTEIN DVT		EINSTEIN PE		RE-COVER		RE-COVER II		AMPLIFY		Hokusai-VTE^a
Treatment arms	Rivaroxaban	Enoxaparin/ VKA	Rivaroxaban	Enoxaparin/ VKA	Heparin/ Dabigatran	Heparin/ Warfarin	Heparin/ Dabigatran	Heparin/ Warfarin	Apixaban	Enoxaparin/ Warfarin	Heparin/ Edoxaban	Heparin/ Warfarin
n (intention-to-treat)	1731	1718	2419	2413	1274	1265	1279	1289	2691	2704	4118	4122
n (safety)	1718	1711	2412	2405	1273	1266	1279	1289	2676	2689	NR	NR
Primary efficacy outcome
n (%)	36 (2.1)	51 (3.0)	50 (2.1)	44 (1.8)	30 (2.4)	27 (2.1)	30 (2.3)	28 (2.2)	59 (2.3)	71 (2.7)	130 (3.2)	146 (3.5)
HR/RR (95% CI)	HR = 0.68 (0.44–1.04)		HR = 1.12 (0.75–1.68)		HR = 1.1 (0.65–1.84)		HR = 1.08 (0.64–1.80)		RR = 0.84 (0.60–1.18)		HR = 0.89 (0.70–1.13)
P value	< 0.001		0.003		< 0.001		< 0.001		< 0.001		< 0.001
Major bleeding
n (%)	14 (0.8)	20 (1.2)	26 (1.1)	52 (2.2)	20 (1.6)	24 (1.9)	15 (1.2)	22 (1.7)	15 (0.6)	49 (1.8)	56 (1.4)	66 (1.6)
HR/RR (95% CI)	HR = 0.65 (0.33–1.30)		HR = 0.49 (0.31–0.79)		HR = 0.82 (0.45–1.48)		HR = 0.69 (0.36–1.32)		RR = 0.31 (0.17–0.55)		HR = 0.84 (0.59–1.21)
P value	0.21		0.003		NR		NR		< 0.001^b		0.35^b
Major or non-major clinically relevant bleeding
n (%)	139 (8.1)	138 (8.1)	249 (10.3)	274 (11.4)	71 (5.6)	111 (8.8)	64 (5.0)	102 (7.9)	115 (4.3)	261 (9.7)	349 (8.5)	423 (10.3)
HR/RR (95% CI)	HR = 0.97 (0.76–1.22)		HR = 0.90 (0.76–1.07)		HR = 0.63 (0.47–0.84)		HR = 0.62 (0.45–0.84)		RR = 0.44 (0.36–0.55)		HR = 0.81 (0.71–0.94)
P value	0.77		0.23		NR		NR		< 0.001		0.004^b

CI = confidence interval; HR = hazard ratio; NR = not reported; RR = relative risk; VKA = vitamin K antagonist.

^aModified intention-to-treat and safety analysis; ^bP value is for superiority.

Table VI. Results from the extended VTE studies (20,23,59).

	EINSTEIN EXT		RE-MEDY		RE-SONATE		AMPLIFY-EXT
Treatment arms	Rivaroxaban	Placebo	Dabigatran	Warfarin	Dabigatran	Placebo	Apixaban (2.5 mg)	Apixaban (5 mg)	Placebo
n (intention-to-treat)	602	594	1430	1426	681	662	840	813	829
n (safety)	598	590	1430	1426	684	659	840	811	826
Primary efficacy outcome
n (%)	8 (1.3)	42 (7.1)	26 (1.8)	18 (1.3)	3 (0.4)	37 (5.6)	32 (3.8)	34 (4.2)	96 (11.6)
HR/RR (95% CI)	HR = 0.18 (0.09–0.39)		HR = 1.44 (0.78–2.64)		HR = 0.08 (0.02–0.25)		RR = 0.33 (0.22–0.48)	RR = 0.36 (0.25–0.53)	_
P value	< 0.001^a		0.01		< 0.001^a		< 0.001^a	< 0.001^a	_
Major bleeding
n (%)	4 (0.7)	0	13 (0.9)	25 (1.8)	2 (0.3)	0	2 (0.2)	1 (0.1)	4 (0.5)
HR/RR (95% CI)	Not estimable		HR = 0.52 (0.27–1.02)		Not estimable		RR = 0.49 (0.09–2.64)	RR = 0.25 (0.03–2.24)	_
P value	0.11^a		0.06		1.0^a		NR	NR	_
Major or non-major clinically relevant bleeding
n (%)	36 (6.0)	7 (1.2)	80 (5.6)	145 (10.2)	36 (5.3)	12 (1.8)	27 (3.2)	35 (4.3)	22 (2.7)
HR/RR (95% CI)	HR = 5.19 (2.3–11.7)		HR = 0.54 (0.41–0.71)		HR = 2.92 (1.52–5.60)		RR = 1.2 (0.69–2.10)	RR = 1.62 (0.96–2.73)	_
P value	< 0.001^a		< 0.001		0.001^a		NR	NR	_

CI = confidence interval; HR = hazard ratio; NR = not reported; RR = relative risk.

^aP value is for superiority.

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