Effective management of venous thromboembolism in the community: non-vitamin K antagonist oral anticoagulants

Figures & data

Table 1 Key pharmacological properties of NOACs and VKAs (eg, warfarin)

	Dabigatran	Rivaroxaban	Apixaban	Edoxaban	Warfarin
Drug class/mechanism of action	Direct thrombin inhibitor	Direct factor Xa inhibitor	Direct factor Xa inhibitor	Direct factor Xa inhibitor	VKA
Time to maximum plasma concentration (hours)	0.5–2	2–4	3–4	1–2	∼90 minutes but requiring 5–6 days to achieve effective anticoagulation
Half-life (hours)	12–14	5–13	8–13	10–14	∼40 hours for warfarin
Proportion of unchanged drug excreted renally (%)	∼80	∼33	∼25	50	Minor only
Predictable anticoagulant effect	Yes	Yes	Yes	Yes	No
Fixed dosing regimen	Yes	Yes	Yes	Yes	No
Routine coagulation monitoring required	No	No	No	No	Yes
Food effect	No interaction; taken with or without food	No interaction but 15 mg and 20 mg doses should be taken with food for optimal bioavailability	No interaction; taken with or without food	No interaction; taken with or without food	Affected by many common foods containing high levels of vitamin K
Relevant drug interactions	Strong P-gp inhibitors: ketoconazole, cyclosporin, itraconazole, and dronedarone are contraindicated. P-gp inducer rifampicin should be avoided	Strong inhibitors of both CYP3A4 and P-gp: azole antimycotics (eg, ketoconazole) and HIV protease inhibitors (eg, ritonavir) are not recommended	Strong inhibitors of CYP3A4 and P-gp: azole antimycotics (eg, ketoconazole) and HIV protease inhibitors (eg, ritonavir) are not recommended	Concomitant use of P-gp inhibitors cyclosporin, dronedarone, erythromycin, or ketoconazole requires edoxaban dose reduction to 30 mg oda	Interaction with numerous drugs

Notes:

a Concomitant use of edoxaban with quinidine, verapamil, or amiodarone does not require dose reduction based on clinical data. The use of edoxaban with other P-gp inhibitors, including HIV protease inhibitors, has not been studied.⁹ Data from studies.^2,8–11,15

Abbreviations: CYP3A4, cytochrome P450 3A4; HIV, human immunodeficiency virus; NOAC, non-vitamin K antagonist oral anticoagulant; od, once daily; P-gp: P-glycoprotein; VKA, vitamin K antagonist.

Table 2 Efficacy and safety outcomes of NOACs vs standard therapy in Phase III clinical trials for the treatment of acute VTE

	Dabigatran		Rivaroxaban		Apixaban	Edoxaban
	RE-COVER^Citation20	RE-COVER II^Citation21	EINSTEIN DVT^Citation16	EINSTEIN PE^Citation17	AMPLIFY^Citation18	Hokusai-VTE^Citation19
Anticoagulant regimen	150 mg bid after parenteral agent for 8–11 days	150 mg bid after parenteral agent for 5–11 days	15 mg bid for 21 days followed by 20 mg od	15 mg bid for 21 days followed by 20 mg od	10 mg bid for 7 days followed by 5 mg bid	60 mg oda after heparin for a median of 7 days
Comparator arm	Parenteral agent/warfarin	Parenteral agent/warfarin	Enoxaparin/VKA	Enoxaparin/VKA	Enoxaparin/warfarin	Heparin/warfarin
Treatment duration (months)	6	6	3, 6, or 12	3, 6, or 12	6	3–12
Primary efficacy outcome
NOAC vs comparator (%)	2.4 vs 2.1	2.3 vs 2.2	2.1 vs 3.0	2.1 vs 1.8	2.3 vs 2.7	3.2 vs 3.5
HR/RR (95% CI)	HR 1.10 (0.65–1.84)	HR 1.08 (0.64–1.80)	HR 0.68 (0.44–1.04)	HR 1.12 (0.75–1.68)	RR 0.84 (0.60–1.18)	HR 0.89 (0.70–1.13)
P-value	P<0.001 for non-inferiority	P<0.001 for non-inferiority	P<0.001 for non-inferiority	P=0.003 for non-inferiority	P<0.001 for non-inferiority	P<0.001 for non-inferiority
Major bleeding
NOAC vs comparator (%)	1.6 vs 1.9	1.2 vs 1.7	0.8 vs 1.2	1.1 vs 2.2	0.6 vs 1.8	1.4 vs 1.6
HR/RR (95% CI)	HR 0.82 (0.45–1.48)	HR 0.69 (0.36–1.32)	HR 0.65 (0.33–1.30)	HR 0.49 (0.31–10.79)	RR 0.31 (0.17–0.55)	HR 0.84 (0.59–1.21)
P-value	NA	NA	P=0.21	P=0.003	P<0.001	P=0.35
Major or nonmajor clinically relevant bleeding
NOAC vs comparator (%)	5.6 vs 8.8	5.0 vs 7.9	8.1 vs 8.1	10.3 vs 11.4	4.3 vs 9.7	8.5 vs 10.3
HR/RR (95% CI)	HR 0.63 (0.47–0.84)	HR 0.62 (0.45–0.84)	HR 0.97 (0.76–1.22)	HR 0.90 (0.76–1.07)	RR 0.44 (0.36–0.55)	HR 0.81 (0.71–0.94)
P-value	P=0.002	NA	P=0.77	P=0.23	P<0.001	P=0.004

Notes:

a 30 mg od in patients with CrCl 30–50 mL/min, body weight ≤60 kg, or receiving concomitant treatment with a potent P-gp inhibitor.

Abbreviations: bid, twice daily; CI, confidence interval; CrCl, creatinine clearance; HR, hazard ratio; NA, not available; NOAC, non-vitamin K antagonist oral anticoagulant; od, once daily; P-gp, P-glycoprotein; RR, relative risk; VKA, vitamin K antagonist; VTE, venous thromboembolism.

Figure 1 Approved dose regimens of the NOACs (based on the EU labels) for the treatment of VTE.

Notes: Rivaroxaban, dabigatran, apixaban, and edoxaban are approved in the EU. ^aThe duration of therapy should be individualized after careful assessment of the treatment benefit against the risk of bleeding. Short duration of therapy (at least 3 months) should be based on transient risk factors (eg, recent surgery, trauma, immobilization) and longer durations should be based on permanent risk factors or idiopathic DVT/PE. ^bA reduction in the dose from 20 mg od to 15 mg od should be considered if the patient’s assessed risk of bleeding outweighs the risk of recurrent DVT/PE. Rivaroxaban should be used with caution in patients with CrCl 15–29 mL/min and is not recommended in patients with CrCl <15 mL/min.^{10 c}For the prevention of recurrent DVT or PE following completion of 6 months of treatment for DVT or PE, 2.5 mg bid is recommended. Apixaban should be used with caution in patients with CrCl 15–29 mL/min and is not recommended in patients with CrCl <15 mL/min.^{11 d}Dabigatran 110 mg bid is recommended in patients aged ≥80 years and those who receive concomitant verapamil. In the following patient groups, the dose (150 mg bid or 110 mg bid) should be selected based on individual assessment of the thromboembolic and bleeding risks: patients aged 75–80 years; patients with moderate renal impairment; those with gastritis, esophagitis, or gastroesophageal reflux; and other patients at increased risk of bleeding. Dabigatran is contraindicated in patients with severe renal impairment (CrCl <30 mL/min).^{8 e}Edoxaban 30 mg od is recommended in patients with one or more of the following clinical factors: moderate or severe renal impairment (CrCl 15–50 mL/min), low body weight (≤60 kg), or concomitant use of the following P-gp inhibitors: cyclosporin, dronedarone, erythromycin, or ketoconazole.⁹
Abbreviations: bid, twice daily; CrCl, creatinine clearance; DVT, deep-vein thrombosis; EU, European Union; od, once daily; NOAC, non-vitamin K antagonist oral anticoagulant; PE, pulmonary embolism; P-gp, P-glycoprotein; VTE, venous thromboembolism.

Table 3 Risk factors associated with recurrent VTE and anticoagulant-related bleeding

Recurrent VTE	Serious or fatal bleeding
Initial unprovoked VTE Initial proximal DVT or PE Residual venous thrombosis Cancer Elevated D-dimer concentrations when not receiving anticoagulation Male sex Post-thrombotic syndrome	Low platelet count Previous gastrointestinal bleeding Recent major bleeding Previous stroke Increasing age Hepatic failure Severe renal impairment Diabetes Thrombocytopenia Poor anticoagulant control

Note: Data from studies.^13,42–47

Abbreviations: DVT, deep-vein thrombosis; PE, pulmonary embolism; VTE, venous thromboembolism.

Lixiana^® (edoxaban) summary of product characteristicsMunichDaiichi Sankyo Europe GmbH2015

 Google Scholar

AgenoWGallusASWittkowskyAAmerican College of Chest PhysiciansOral anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelinesChest20121412 supple44Se88S22315269

 PubMed Web of Science ®Google Scholar

Pradaxa^® (dabigatran etexilate) summary of product characteristicsIngelheim am RheinBoehringer Ingelheim International GmbH2015

 Google Scholar

Eliquis^® (apixaban) summary of product characteristicsUxbridgeBristol-Myers Squibb, Pfizer2015

 Google Scholar

ErikssonBIQuinlanDJEikelboomJWNovel oral factor Xa and thrombin inhibitors in the management of thromboembolismAnnu Rev Med201162415721226611

 PubMed Web of Science ®Google Scholar

SchulmanSKearonCKakkarAKRE-COVER Study GroupDabigatran versus warfarin in the treatment of acute venous thromboembolismN Engl J Med2009361242342235219966341

 PubMed Web of Science ®Google Scholar

SchulmanSKakkarAKGoldhaberSZRE-COVER II Trial InvestigatorsTreatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysisCirculation2014129776477224344086

 PubMed Web of Science ®Google Scholar

The EINSTEIN InvestigatorsBauersachsRBerkowitzSDOral rivaroxaban for symptomatic venous thromboembolismN Engl J Med2010363262499251021128814

 PubMed Web of Science ®Google Scholar

The EINSTEIN–PE InvestigatorsBüllerHRPrinsMHOral rivaroxaban for the treatment of symptomatic pulmonary embolismN Engl J Med2012366141287129722449293

 PubMed Web of Science ®Google Scholar

AgnelliGBullerHRCohenAAMPLIFY InvestigatorsOral apixaban for the treatment of acute venous thromboembolismN Engl J Med2013369979980823808982

 PubMed Web of Science ®Google Scholar

The Hokusai-VTE InvestigatorsBüllerHRDécoususHEdoxaban versus warfarin for the treatment of symptomatic venous thromboembolismN Engl J Med2013369151406141523991658

 PubMed Web of Science ®Google Scholar

KearonCAklEAComerotaAJAmerican College of Chest PhysiciansAntithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelinesChest20121412 supple419Se494S22315268

 PubMed Web of Science ®Google Scholar

TorbickiAPerrierAKonstantinidesSESC Committee for Practice Guidelines (CPG)Guidelines on the diagnosis and management of acute pulmonary embolism: the Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC)Eur Heart J200829182276231518757870

 PubMed Web of Science ®Google Scholar

NijkeuterMSöhneMTickLWChristopher Study InvestigatorsThe natural course of hemodynamically stable pulmonary embolism: clinical outcome and risk factors in a large prospective cohort studyChest2007131251752317296656

 PubMed Web of Science ®Google Scholar