Considerations for long-term anticoagulant therapy in patients with venous thromboembolism in the novel oral anticoagulant era

Figures & data

Figure 1 The balance between the risk of recurrent venous thromboembolism and bleeding events.

Notes: Data from Konstantinides et al¹ and Kearon et al.²
Abbreviations: GI, gastrointestinal; VTE, venous thromboembolism.

Table 1 Thrombophilia and development of thromboembolism

Reference	Presentation	Underlying risk factor for recurrent thrombosis	Treatment	Outcome
Citro et al^Citation40	A 69-year-old woman who was a heterozygote carrier of Factor V Leiden mutation presented to the emergency room with the clinical scenario of massive pulmonary embolism	Factor V Leiden heterozygosity	• Unfractionated heparin • Surgical treatment consisting of complete excision of the thrombus • Long-term anticoagulation treatment (not specified)	At 1-year follow-up, the patient was on long-term anticoagulation treatment and free of thromboembolic events
Cook et al^Citation41	A 30-year-old, previously healthy woman diagnosed with acute, spontaneous, left-ovarian vein thrombosis with proximal extension into the renal vein	Factor V Leiden homozygosity	• Initial catheter-directed thrombolysis with tissue plasminogen activator, angioplasty of the left renal vein, heparinoid treatment • Long-term anticoagulation with rivaroxaban	Complete resolution of thrombosis at 3 months; no adverse effects or bleeding reported
Jukic et al^Citation42	A case of cerebral sinus thrombosis as a recurrent thrombotic event in a patient with heterozygous prothrombin G20210A genotype after discontinuation of oral anticoagulation therapy	Heterozygous prothrombin G20210A genotype	• Heparin and symptomatic therapy were started. On the fifth day, warfarin was included in the treatment (maintained at the international normalized ratio range of 2–3), and heparin was excluded after 8 days	Constantly improving condition of the patient and discharged after 6 weeks with recommendation for long-term use of warfarin
Kim et al^Citation43	A 35-year-old man who developed superior mesenteric venous thrombosis and portal vein thrombosis showed markedly decreased protein C and S levels	Protein C and S deficiency	• Heparin and total parenteral nutrition was given • 3 weeks after hospitalization, the patient was fed orally and heparin was replaced by warfarin	The patient was discharged 27 days after admission and had returned to work by the 9 month follow-up. Recent protein C level was 60% of control
Kshatriya et al^Citation44	A 55-year-old Caucasian man with history of hypertension, diabetes mellitus, protein C deficiency, and deep vein thrombosis presented with typical angina	Protein C deficiency	• Tomography and echocardiography presented a mobile mass in the left atrium • Cardiac catheterization and angiography indicated the presence of a myxoma rather than a thrombus • Cardiothoracic surgery was conducted for excision of the left atrial mass	Full recovery with outpatient cardiology follow-up. Angina symptoms were completely relieved, and the patient was started on anticoagulation with warfarin for the history of deep vein thrombosis

Table 2 The US and European guidelines on the duration of anticoagulant treatment for venous thromboembolism

Patient and disease type	Recommendations for duration of anticoagulant treatment
	ACCP 2012^Citation2	ESC 2014^Citation1
Patient with proximal DVT or hemodynamically stable PE associated with transient risk factors	VKA preferred over LMWH or NOAC Treat for 3 months	Anticoagulant treatment for 3 months
Patient with unprovoked proximal DVT or hemodynamically stable PE	VKA preferred over LMWH or NOAC First or subsequent unprovoked VTE with low/moderate bleeding risk: >3 months’ treatment	First or subsequent unprovoked PE with a low bleeding risk: >3 months to indefinite anticoagulant treatment
Patient with isolated distal DVT	Consider serial imaging rather than anticoagulation to monitor for any clot extension if symptoms are not severe or clot extension is considered unlikely. Provide anticoagulant treatment if symptoms are severe or clot extends (recommended therapy and durations as above)	Recommendations not provided
VTE in a patient with active cancer	LMWH preferred over VKA: >3 months	LMWH for 3–6 months, then consider indefinite anticoagulation or until cancer is in remission
VTE in a pregnant woman	LMWH preferred over UFH: continue for a minimum of 3 months and for at least 6 weeks postpartum	LMWH preferred over UFH Anticoagulation (VKA permitted after birth) to continue for at least 6 weeks postpartum for a minimum overall treatment duration of 3 months
VTE in a patient with severe renal impairment (CrCl <30 mL/min)	UFH preferred over LMWH, rivaroxaban, or dabigatran owing to lack of renal clearance	UFH preferred to LMWH owing to short half-life and rapid reversal by protamine
Patient with PTS secondary to DVT	Use of mechanical compression (stockings, venous foot pump)	Recommendations not provided
Patient with CTEPH secondary to PE	Extended anticoagulation; pulmonary thromboendarterectomy if expertise available	Pulmonary thromboendarterectomy if operable, or targeted medical therapy (riociguat) if not All patients should receive lifelong anticoagulation
Patient with inherited thrombophilia	Recommendations not provided	Consider indefinite anticoagulant treatment after a first unprovoked VTE

Note: Data from previous studies.^1,2,10

Abbreviations: ACCP, American College of Chest Physicians; CrCl, creatinine clearance; CTEPH, chronic thromboembolic pulmonary hypertension; DVT, deep vein thrombosis; ESC, European Society of Cardiology; LMWH, low-molecular-weight heparin; NOAC, novel oral anticoagulant; PE, pulmonary embolism; PTS, post-thrombotic syndrome; UFH, unfractionated heparin; VKA, vitamin K antagonist; VTE, venous thromboembolism.

Figure 2 Principal efficacy and safety results of Phase III clinical trials of novel oral anticoagulants for the acute treatment of venous thromboembolism and long-term prevention of recurrence.

Notes: Data from the acute treatment of VTE are presented for the (A) pooled EINSTEIN DVT and EINSTEIN PE,^11,12,20 (B) pooled RE-COVER I and RE-COVER II,^15,16 (C) AMPLIFY,¹³ and (D) Hokusai-VTE¹⁴ studies. Data from studies of extended treatment are also presented for the (A) EINSTEIN EXT,¹¹ (B) RE-SONATE,¹⁸ and (C) AMPLIFY-EXT¹⁷ studies. Patients in the extension studies did not necessarily complete the equivalent acute treatment study first. ^aEfficacy data were derived during the 6-month study period; ^bsafety data were obtained from the start of any study drug.
Abbreviations: bid, twice daily; CI, confidence interval; HR, hazard ratio; LMWH, low-molecular-weight heparin; NMCR, nonmajor clinically relevant; RR, relative risk; VKA, vitamin K antagonist; VTE, venous thromboembolism.

Table 3 Summary of pharmacological properties of novel oral anticoagulants

	Dabigatran	Rivaroxaban	Apixaban	Edoxaban
Mode of action	Direct thrombin inhibitor	Direct Factor Xa inhibitor	Direct Factor Xa inhibitor	Direct Factor Xa inhibitor
Approved for VTE treatment in Europe and the US?	Yes	Yes	Yes	Yes
VTE treatment regimen	Parenteral anticoagulant for 5–10 days, then 150 mg bid	15 mg bid for 21 days, then 20 mg od	10 mg bid for 7 days, then 5 mg bid	Parenteral anticoagulant, then 60 mg od
Dose adjustments for VTE treatment	None tested	None mandateda	None tested	30 mg od tested in patients who were expected to have an increased bleeding riskb
Food	Take with or without food	VTE treatment doses to be taken with food	Take with or without food	Take with or without food
Time to maximum concentration/anticoagulant effect (hours)	0.5–2	2–4	3–4	1–2
Half-life in healthy individuals (hours)	12–14	5–13	~12	8–10
Proportion of drug subject to renal clearancec (%)	85	33d	27	35
Co-medications contraindicated/not recommended	Strong P-gp inhibitors and inducers	Strong CYP3A4 and P-gp inhibitors	Strong CYP3A4 and P-gp inhibitors	Strong P-gp inhibitors

Notes:

a A reduced dose of rivaroxaban 15 mg od after the initial period of 15 mg bid dosing (ie, after 21 days) may be considered based on individual patient benefit–risk analysis (Europe only, not tested in Phase III treatment studies);

b creatinine clearance 30 mL/min –50 mL/min, body weight ≤60 kg, taking co-medications that are potent P-gp inhibitors;

c unchanged drug;

d 33% of the dose also undergoes renal excretion as inactive metabolites. Data from previous studies.^4,14,23–26

Abbreviations: bid, twice daily; CYP3A4, cytochrome P450 3A4; od, once daily; P-gp, P-glycoprotein; VTE, venous thromboembolism.

Table 4 Reversal strategies for patients experiencing severe bleeding while receiving a novel oral anticoagulant

Reference	Presentation	Cause of hemorrhage	NOAC and treatment	Outcome
Dumkow et al^Citation45	An 85-year-old man diagnosed with acute liver failure, acute kidney injury, and anemia	Hemorrhagic shock secondary to bleeding in his upper gastrointestinal tract	• Drug: dabigatran • Treatment: PCC, FFP	The patient’s hemoglobin concentration stabilized, and there were no further signs of overt bleeding
Javedani et al^Citation46	A 54-year-old man who experienced a new-onset stroke with a score of 9 on the National Institutes of Health stroke scale	Potential intracranial hemorrhage	• Drug: dabigatran • Treatment: PCC, rFVIIa	No evidence of intracranial hemorrhage was apparent on repeated computed tomography scans of the brain. The patient was discharged with ASA and warfarin and a stroke score of 8
Molina et al^Citation47	An 84-year-old woman with dementia, hypertension, diabetes, and chronic obstructive pulmonary disease who fell down some steps	Subarachnoid and intraventricular hemorrhage	• Drug: rivaroxaban • Treatment: FFP, vitamin K	Patient recovered previous neurological function, and warfarin was started 2 weeks–3 weeks later. The authors acknowledge that vitamin K was not appropriate for rivaroxaban reversal
Lakatos et al^Citation48	A 52-year-old Caucasian man with HIV receiving darunavir/ritonavir therapy	Gastrointestinal hemorrhage indicated by blood in stools; diarrhea, dehydration, and fever	• Drug: rivaroxaban • Treatment: interruption of anticoagulant; intravenous hydration and ciprofloxacin 500 mg twice daily	Resolution of bleeding shortly after interrupting rivaroxaban. Rivaroxaban should not be given concomitantly with HIV protease inhibitors because of a documented drug–drug interaction potential that can lead to elevated rivaroxaban concentrations
Gonzva et al^Citation49	A 67-year-old man with acute abdominal pain	Splenic rupture	• Drug: rivaroxaban • Treatment: packed red blood cells, FFP, and PCC	Hemorrhagic shock persisted for 12 hours until splenectomy. The patient developed multiorgan dysfunction 2 days later because of colic ischemia and required a colectomy

Abbreviations: ASA, acetylsalicylic acid; FFP, fresh frozen plasma; HIV, human immunodeficiency virus; NOAC, novel oral anticoagulant; PCC, prothrombin complex concentrate; rFVIIa, recombinant Factor VIIa.

Table 5 Warfarin drug interaction in cancer therapy

Reference	Presentation	Underlying risk factor for recurrent thrombosis	Treatment	Outcome
Onoda et al^Citation50	A 74-year-old female patient diagnosed with stage IV bronchioloalveolar carcinoma of the lung. The patient was on long-term warfarin therapy because of persistent atrial fibrillation	Cancer	• Gefitinib therapy was started • The daily warfarin dose was decreased from 4 mg to 3 mg, but the INR increased from 2.0 to 2.4 • Daily warfarin dose was decreased to 2.5 mg, which returned the INR to the therapeutic range	The patient’s dyspnea was promptly improved, and a chest X-ray taken 6 months after initiation of treatment revealed a considerable improvement of the disease
Saif et al^Citation51	A 70-year-old female patient newly diagnosed with pancreatic adenocarcinoma was started on anti-cancer treatment until an elevation of the INR was observed	Cancer	• Immediate cessation of capecitabine and cessation of docetaxel after cycle 9 • Gemcitabine was continued every 2 weeks with close monitoring of PT/INR • Second-line treatment was offered because of deterioration but was not administered	Elevated INR, progressive disease, and clinical deterioration

Abbreviations: INR, international normalized ratio; PT, prothrombin time.

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