Potential role of new anticoagulants for prevention and treatment of venous thromboembolism in cancer patients

Figures & data

Table 1 Summary of American College of Chest Physicians 2012 guideline recommendations for prophylaxis and treatment of venous thromboembolism in cancer patients

ACCP 2012	Treatment	Duration
Prophylaxis in surgery for cancer^Citation13	Pharmacologic prophylaxis with LMWH or UFH (Grade 1B) for general and abdominopelvic surgery patients at high risk for VTE (about 6.0%; Caprini score ≥ 5) who are not at high risk for major bleeding complications. Mechanical prophylaxis with elastic stockings or IPC should be added to pharmacological prophylaxis (Grade 2C). Mechanical thromboprophylaxis for general and abdominopelvic surgery patients at low risk for VTE (about 1.5%; Caprini score 1–2) or moderate risk for VTE (3.0%; 10, Caprini score 3–4) who are bleeding or are at high risk for major bleeding (Grade 2C).	Extended-duration (4 weeks), postoperative, pharmacological prophylaxis with LMWH for patients at high risk for VTE undergoing abdominal or pelvic surgery for cancer (Grade 1B). Limited-duration prophylaxis (approximately one week) in the remaining cases in which pharmacological prophylaxis is indicated (Grade 1B).
Prophylaxis in hospitalized medical patients with cancer^Citation14	Routine prophylaxis with LMWH, UFH, or fondaparinux in cancer patients with at least one additional risk factor for VTE in inpatients (Grade 1B). Mechanical thromboprophylaxis for cancer patients who are bleeding or are at high risk for major bleeding (Grade 2C).	During patient immobilization or acute hospital stay (Grade 1B). Recommendation against extending the duration of thromboprophylaxis beyond the period of patient immobilization or acute hospital stay (Grade 2B).
Ambulatory medical patients on chemotherapy^Citation14	Recommendation against routine prophylaxis with LMWH/UFH (Grade 2B) or VKA (Grade 1B) for ambulatory medical patients with cancer and no additional risk factors for VTE. Recommendation against routine prophylaxis with LMWH/UFH (Grade 2B) or VKA (Grade 2C) in cancer outpatients with indwelling CVC. LMWH or UFH prophylaxis in outpatients with solid tumors who have additional risk factors for VTE (previous VTE, immobilization, hormonal therapy, angiogenesis inhibitors, thalidomide, and lenalidomide) and who are at low risk of bleeding (Grade 2B).	Not established yet.
Initial/acute treatment^Citation15	Parenteral agent (preferably LMWH or fondaparinux, Grade 1B). Thrombolytic therapy for PE with hypotension (eg, systolic BP < 90 mmHg, Grade 2C).	Approximately one week.
Long-term treatment (from 7 days to 3 months)^Citation15	LMWH over VKA (Grade 2B for DVT and PE) and VKA over the new oral anticoagulants (Grade 2B for DVT and 2C for PE).	In upper DVT associated with CVC: long-term treatment (3 months) if the CVC is removed (Grade 2C).
Extended treatment (from 3 months to indefinite)^Citation15	LMWH over VKA (Grade 2B) and VKA over the new oral anticoagulants (Grade 2B).	Extended treatment over 3 months in VTE associated with active cancer if bleeding risk is not high (Grade 1B) or if it is high (Grade 2B) but exact duration not established yet. In upper DVT associated with CVC, long-term or extended treatment, as long as the CVC remains (Grade 1C).

Notes: Grade 1–2, strong-weak evidence; Grade A-B-C, high-moderate-low quality of data.

Abbreviations: BP, blood pressure; CVC, central venous catheters; DVT, deep vein thrombosis; LMWH, low molecular weight heparin; PE, pulmonary embolism; UFH, unfractionated heparin; VKA, vitamin K antagonists; VTE, venous thromboembolism.

Figure 1 New anticoagulants and their targets in the coagulation cascade.*

Note: *Continuous line indicates activation; dashed line indicates inhibition.

Table 2 Characteristics of old and new anticoagulants*

	Parenteral anticoagulants					Oral anticoagulants
Agent	Heparin sodium	LMWH†	Semuloparin	Fondaparinux	Idrabiotaparinux	Vitamin K antagonists‡	Dabigatran etexilate	Rivaroxaban	Apixaban	Edoxaban	Betrixaban
Source	Pig intestinal mucosa	Pig intestinal mucosa	Pig intestinal mucosa	Synthetic	Synthetic	Synthetic	Synthetic	Synthetic	Synthetic	Synthetic	Synthetic
Molecular weight (Da)	12,000–15,000	3600–6500	2000–3000	1728	1727 (idraparinux) + 244 (biotin)	About 1000	628	436	460	548	452
Target	FXa = FIIa (1 to 1 ratio)	FXa > FIIa (2 to 8:1 ratio)	FXa > FIIa (80:1 ratio)	FXa only	FXa only	FII, VII, IX, X, protein C, S	Thrombin	FXa	FXa	FXa	FXa
Type of inhibition	Indirect (bind to AT)	Indirect (bind to AT)	Indirect (bind to AT)	Indirect (bind to AT)	Indirect (bind to AT)	Indirect§	Direct	Direct	Direct	Direct	Direct
Bioavailability (%)	100 (IV)	90–98 (SC)	98% (SC)	About 100 (SC)	About 100 (SC)	>60	6.5	80–100	50	50%	34%
Tmax	Few minutes	2–3 hours	2–3 hours	30–60 minutes	4 hours	1–3 hours	0.5–2 hours	2–4 hours	3–4 hours	1.5 hours	2.5 hours
Drug interactions	¶	¶	¶	¶	¶	Dietary vitamin K, multiple drugs and foods	P-gp inh/ind, proton pump inh¶	Potent P-gp and CYP3A4 inh/ind¶	Potent P-gp and CYP3A4 inh/ind¶	Potent P-gp inh/ind¶	Potent P-gp inh/ind¶
Protein binding (%)	High	Low	Low	Low	Very low	About 99	35	92–95	87	40–60	60
Half-life	0.5–1 hour	3–6 hours	16–20 hours	17–21 hours	120 hours	8–11 hours (acenocoumarol); 36–42 hours (warfarin)	14–17 hours	7–12 hours	12 hours	6–11 hours	19 hours
Metabolism	Depolymerization	Desulfation, depolymerization (<10%)	Not reported	Negligible	Negligible	CYP2C9/19 (acenocoumarol); CYP2C9/1A2/3A4 (warfarin)	Glucuronidation(<10%)	CYP3A4 > CYP2J2	CYP3A4/5 > CYP21A2, SC8, 2C9/19, 2J2	Hydrolysis	Hydrolysis > demethylation
Renal excretion (%)	Medium	High	High	64–77 (unchanged)	High (unchanged)	92	85 (unchanged)	66	27	36–45	6–13
Biliary excretion (%)	Medium	Low	Low	Negligible	Negligible	8	6	28	25	NA	82–89
Antidote	Protamine	Protamine (partially)	None	None	Avidin	Vitamin K	None	None	None	None	None
Monitoring test	aPTT	Not required routinely Anti-Xa assay	Not required routinely Anti-Xa assay	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	NA
Approval date	1939 (EU, US)	1985 (EU, dalteparin) 1993 (US, enoxaparin)	Not yet approved	2000 (US) 2002 (EU)	Not yet approved	1941 (US, dicumarol) 1953 (EU, phenprocoumon)	2008 (EU) 2010 (US)	2008 (EU) 2011 (US)	2011 (EU) 2013 (US)	2011 (Japan)	Not yet approved

Notes:

† Ardeparin, bemiparin, certoparin, dalteparin, enoxaparin, nadroparin, parnaparin, reviparin, tinzaparin;

‡ dicumarol (no longer available), warfarin, acenocoumarol, phenprocoumon;

§ inhibition of vitamin K epoxide reductase;

¶ potential pharmacodynamic interactions with other drugs that alter haemostasis (eg, other anticoagulants, fibrinolytics, and antiplatelet drugs).

Abbreviations: ACT, activated coagulation time; aPTT, activated partial thromboplastin time; AT, antithrombin; inh/ind, inhibitors/inducers; CYP, cytochrome P450; EU, European Union; INR, international normalized ratio; IV, intravenous; LMWH, low molecular weight heparin; NA, data not available; PD, pharmacodynamics; P-gp, P-glycoprotein; PK, pharmacokinetics; SC, subcutaneous; T_max, time to maximum concentration; US, United States; VKA, vitamin K antagonist.

Table 3 Clinical trials with new parenteral indirect FXa anticoagulants for prophylaxis and treatment of venous thromboembolism

Drug, indication clinical trial	Randomized subjects	Cancer (56)	Comparators, dose, interval, route of administration, and treatment duration	Main results	Conclusion
Semuloparin
Chemotherapy
SAVE-ONCO^Citation35^–^Citation37	3212	100%	SEM 20 mg OD, 3.5 months (median) versus PBO, OD, 3.5 months (median)	Symptomatic VTE: 1.2% versus 3.4%; OR 0.36; 95% CI 0.21–0.60. CRB: 2.8% versus 2.0%; OR 1.40; 95% CI 0.89–2.21.	SEM superior to PBO for symptomatic VTE. Similar rates of CRB.
Abdominal surgery
SAVE-ABDO^Citation36^–^Citation38	4413	81%	SEM 20 mg OD, 7–10 days versus ENO 40 mg, OD, 7–10 days	All VTE or death: 6.3% versus 5.5%; OR 1.16; 95% CI 0.87–1.54. Major VTE or death: 2.2% versus 2.3%; OR 0.95; 95% CI 0.61–1.49. CRB: 2.9% versus 4.5%; OR 0.63; 95% CI 0.46–0.87.	Noninferiority of SEM versus ENO for VTE not shown. Less CRB with SEM than with ENO.
Idraparinux
Treatment of VTE
Van Gogh-DVT^Citation44	2904	15%	IDRA 2.5 mg OW, 3–6 months versus heparin + VKA dose-adjusted, 3–6 months	Recurrent VTE: 2.9% versus 3%; OR 0.98; 95% CI 0.63–1.50. CRB: 8.3% versus 8.1 %; P = 0.85.	IDRA noninferior to heparin + VKA Similar rates of CRB.
Van Gogh-PE^Citation44	2215	14%	IDRA 2.5 mg OW, 3–6 months versus heparin + VKA dose-adjusted, 3–6 months	Recurrent VTE: 3.4% versus 1.6%; OR 2.14; 95% CI 1.21–3.78. CRB: 7.7% versus 9.7%; P = 0.10.	IDRA inferior to heparin + VKA Similar rates of CRB.
Van-Gogh extension^Citation46	1215	9.9%	IDRA 2.5 mg OW, 6 months versus PBO, 6 months	Recurrent VTE: 3.4% versus 1.6%; OR 2.14; 95% CI 1.21–3.78. MB: 1.9% versus 0%; P < 0.001.	IDRA superior to PBO. More MB with IDRA than with PBO.
Idrabiotaparinx
Treatment of VTE
EQUINOX (DVT)^Citation45	757	5.2%	IDRAB 3 mg OW, 6 months versus IDR 2.5 mg OW, 6 months	Recurrent VTE: 2.3% versus 3.2%; ARD −0.9%; 95% CI −3.2 to 1.4. CRB: 5.2% versus 7.3%; ARD −2.1 %; 95% CI −5.6 to 1.4. MB: 0.8% versus 3.8%; P = 0.006	Similar rates of recurrent VTE and CRB to IDRAB and IDR. Less MB with IDRAB than with IDR.
CASSIOPEA (PE)^Citation50	3202	5.9%	ENO + IDRAB 3 mg OW, 3–6 months versus ENO + VKA dose-adjusted, 3–6 months	Recurrent VTE: 2% versus 3%; OR 0.79; 95% CI 0.50–1.25. CRB: 5% versus 7%; OR 0.67; 95% CI 0.49–0.91 ; P < 0.001.	ENO + IDRAB noninferior to ENO + VKA Less CRB with ENO + IDRAB than with ENO + VKA.

Abbreviations: ARD, absolute risk difference; BID, twice daily; CRB, clinically relevant bleeding; ENO, enoxaparin; HFR, hip fracture surgery; IDRA, idraparinux; IDRAB, idrabiotaparinux; MB, major bleeding; NA, not available; OD once daily; OR, odds ratio; OW, once-weekly; PBO, placebo; SEM, semuloparin; VTE, venous thromboembolism; VKA, vitamin K antagonist.

Table 4 Clinical trials with new oral anticoagulants for venous thromboembolism prophylaxis in nonsurgical patients

Drug, indication clinical trial	Randomized subjects	Cancer (%)	Comparators, dose, interval, and treatment duration	Main results	Conclusion
Rivaroxaban
Nonsurgical patients
MAGELLAN^Citation63^–^Citation65	8101	7%	RIV 10 mg OD, 35 days versus ENO 40 mg OD, 10 days + placebo, 25 days	Major VTE (day 10): 2.7% versus 2.7%; RR 0.97; 95% CI 0.71–1.33. Major VTE (day 35): 4.4% versus 5.7%; RR 0.77; 95% CI 0.62–0.96. CRB (day 10): 2.8% versus 1.2%; RR 2.3; 95% CI, NA; P < 0.0001. CRB (day 35): 4.1 % versus 1.7%; RR: 2.5; 95% CI, NA; P < 0.0001.	RIV noninferior to ENO on day 10 and superior to ENO + PBO on day 35 for major VTE. More CRB with RIV than with ENO on day 10 and 35.
Apixaban
Chemotherapy
ADVOCATE^Citation74	125	100%	API 5 mg and 10 mg and 20 mg, 84 days versus PBO, 84 days	CRB (primary outcome): 3.1% and 3.4% and 12.5% versus PBO 0%. Symptomatic VTE: API 0% and 0% and 0% versus PBO 10.3%.	API dose trend shown for CRB. No symptomatic VTE with API and no cases of CRB with PBO.
Nonsurgical patients
ADOPT^Citation75	6524	9.7%	API 2.5 mg BID, 30 days versus ENO 40 mg OD, 6–14 days + placebo, 16–24 days	Total VTE: 2.7% versus 3.1%; RR 0.87; 95% CI 0.62–1.23. MB: 0.5% versus 0.2%; RR 2.58; 95% CI 1.02–7.24.	API not superior to ENO + PBO for total VTE. More CRB with API than with ENO + PBO.
Betrixaban
Nonsurgical patients
APEX (ClinicalTrials.gov ID, NCTO1583218)	6850 (expected enrolment)	NA	BET 2.5 mg BID, 28–42 days versus ENO 40 mg OD, 6–14 days + placebo, 16–24 days	Ongoing study, results expected for December 2014.	–

Abbreviations: API, apixaban; ARD, absolute risk difference; BET, betrixaban; BID, twice-daily; CRB, clinically relevant bleeding; DAB, dabigatran; ENO, enoxaparin; MB, major bleeding; NA, not available; OD, once-daily; OR, Odds Ratio; PBO, placebo; R, rivaroxaban; RR, relative risk; THR, total hip replacement; TKA, total knee arthroplasty VTE, venous thromboembolism.

Table 5 Clinical trials with new oral anticoagulants for treatment of venous thromboembolism

Drug, indication clinical trial	Randomized subjects	Cancer subjects (%)	Comparators, dose, interval and treatment duration	Main results	Conclusions
Rivaroxaban
EINSTEIN-DVT^Citation61	3449	6%	RIV 15 mg BID, 3 weeks followed by RIV 20 mg OD 3–6–12 months versus ENO 1 mg/kg/12 hours (until INR 2–3) + WRF dose-adjusted (INR 2–3), 3–6–12 months	Recurrent VTE: 2.1 % versus 3%; HR 0.68; 95% CI 0.44–1.04. CRB: 8.1% versus 8.1%.	RIV noninferior to ENO + WRF for recurrent VTE. Similar rates of CRB.
EINSTEIN-PE^Citation62	4845	4.6%	RIV 15 mg BID, 3 weeks, followed by RIV 20 mg OD, 3–6–12 months versus ENO 1 mg/kg/12 hours (until INR 2–3) + WRF dose-adjusted (INR 2–3), 3–6–12 months	Recurrent VTE: 2.1% versus 1.8%; HR 1.12; 95% CI 0.75–1.68. CRB: 10.3% versus 11.4%.	RIV noninferior to ENO + WRF for recurrent VTE. Similar rates of CRB.
EINSTEIN-EXTENSION^Citation61	1196	4.5%	RIV 20 mg OD, 6–12 months versus PBO, 6–12 months	Recurrent VTE: 1.3% versus 7.1 %; HR 0.18; 95% CI 0.09–0.39. MB: 0.7% versus 0%; ARD 0.7%; P = 0.11. CRB: 6% versus 1.2%; HR 5.19; 95% CI 2.3–11.7.	RIV superior to PBO for recurrent VTE. Increase in CRB.
Apixaban
AMPLIFY (ClinicalTrials.gov ID: NCT00643201)	4816 (expected enrolment)	NA	API 10 mg BID, 7 days followed by API 5 mg BID, 6 months versus ENO 1 mg/kg/12 hours (until INR 2–3) + WRF dose-adjusted (INR 2–3), 6 months	Ongoing study, results expected for 2013.	–
AMPLIFY-EXT^Citation76	2486	1.7%	API 2.5 mg or 5 mg BID, 1 year versus PBO, 1 year	Recurrent VTE: API 2.5 mg 1.7% versus API 5 mg 1.7% versus ENO 8.8%. MB: API 2.5 mg 0.2% versus API 5 mg 0.1% versus PBO 0.5%. CRB: API 2.5 mg 3.2% versus API 5 mg 4.3% versus PBO 2.7%.	API (both doses) superior to PBO for recurrent VTE. Similar rates of MB and CRB in all groups.
Edoxaban
Edoxaban-Hokusai VTE [ClinicalTrials.gov ID: NCT00986154]		NA	EDO 60 mg OD, 3 months versus WRF dose-adjusted (INR 2–3), 3 months (both treatments administered after an initial treatment with ENO or UFH)	Ongoing study. Results expected for 2013.	–
Dabigatran
RE-COVER (about 70% DVT; about 30% PE)^Citation103	2564	4.8%	DAB 150 mg BID, 6 months versus WRF dose-adjusted (INR 2–3), 6 months (both treatments administered after an initial treatment with ENO or UFH)	Recurrent VTE: 2.4% versus 2.1%; HR 1.10; 95% CI 0.65–1.84. MB: 1.6% versus 1.9%: HR 0.82; 95% CI 0.45–1.48. CRB: 5.6% versus 8.8%; HR 0.63; 95% CI 0.47–0.84.	DAB noninferior to WRF for recurrent VTE. Less CRB with DAB than with WRF.
RE-COVER II^Citation104	2589	NA	DAB 150 mg BID, 6 months versus WRF dose-adjusted (INR 2–3), 6 months (both treatments administered after an initial treatment with ENO or UFH)	Recurrent VTE: 2.4% versus 2.2%; HR: 1.08; 95% CI 0.64–1.80. MB: 1.2% versus 1.7%: HR 0.69; 95% CI 0.36–1.32. Any bleed: 15.6% versus 22.1 %; HR 0.67; 95% CI 0.56–0.81.	DAB noninferior to WRF for recurrent VTE. Less bleeding with DAB than with WRF.
RE-MEDY^Citation105	2856	4.2%	DAB 150 mg BID, 16 months versus WRF dose-adjusted (INR 2–3), 16 months (patients who had completed 3–12 months of anticoagulant therapy)	Recurrent VTE: 1.8% versus 1.3%; HR: 1.44; 95% CI 0.78–2.64. CRB: 5.6% versus 10.2%; HR 0.54; 95% CI 0.41–0.71. ACS: 13 (0.9%) versus 3 (0.2%); P = 0.02.	DAB noninferior to WRF for recurrent VTE. Less bleeding with DAB than with WRF. More ACS with DAB than with WRF.
RE-SONATE^Citation105,Citation106	1343	< l%	DAB 150 mg BID, 6 months versus PBO, 6 months (patients who had completed 6–18 months of anticoagulant therapy)	Recurrent VTE: 0.4% versus 5.6%; HR 0.08; 95% CI 0.02–0.25. CRB: 5.3% versus 1.8%; HR 2.92; 95% CI 1.52–5.60. ACS: 3 (0.4%) versus 2 (0.3%).	DAB superior to PBO. More CRB with DAB than with PBO.

Abbreviations: ACS, acute coronary syndrome; API, apixaban; BID, twice daily; CI, confidence interval; CRB, clinically relevant bleeding; DAB, dabigatran; ENO, enoxaparin; ID, identifier; INR, international normalized ratio; NA, not available; OD, once daily; PBO, placebo; PE, pulmonary embolism; RIV, rivaroxaban; RR, relative risk; UFH, unfractionated heparin; VTE, venous thromboembolism; WRF, warfarin.

Figure 2 Pooled analysis of recurrent venous thromboembolism and clinically relevant bleeding in patients with cancer included in the EINSTEIN-DVT and EINSTEIN-PE studies.

Table 6 Summary of results with new oral anticoagulants for prophylaxis or treatment of venous thromboembolism in cancer patients*

Drug, indication, clinical trial	Data type	Cancer subjects n (%)	Comparators, dose, interval, and treatment duration	Main results in cancer patients	Conclusion in cancer patients
Semuloparin
Chemotherapy
SAVE-ONCO^Citation35^–^Citation37	Dedicated study	3172 (100%)	SEM 20 mg OD, 3.5 months (median) versus PBO, OD, 3.5 months (median)	Symptomatic VTE: 1.2% versus 3.4%; OR 0.36; 95% CI 0.21–0.60. CRB: 2.8% versus 2.0%; OR 1.40; 95% CI 0.89–2.21.	SEM superior to PBO for symptomatic VTE. Similar rates of CRB.
Abdominal surgery
SAVE-ABDO^Citation36^–^Citation38	Subgroup	3030 (81%)	SEM 20 mg OD, 7–10 days versus ENO 40 mg, OD, 7–10 days	All VTE or death: 7.1% versus 5.9%; OR 1.23; 95% CI 0.89–1.69. Bleeding: NA.	Nonsignificant trend towards less efficacy of SEM versus ENO in cancer patients.
Idraparinux
Treatment of VTE
Van Gogh-DVT^Citation45	Subgroup	421 (15%)	IDRA 2.5 mg OW, 3–6 months versus heparin + VKA dose-adjusted, 3–6 months	Recurrent VTE: 2.5% versus 6.4%; HR 0.39; 95% CI 0.14–1.11. CRB: 13.1% versus 14.4%; HR 0.89; 95% CI 0.50–1.59. Death: 22.7% versus 22.4%; HR 0.99; 95% CI 0.66–1.48.	IDRA noninferior to heparin + VKA. Similar rates of CRB and death.
Rivaroxaban
Treatment of VTE
EINSTEIN-DVT^Citation61	Subgroup	207 (6%)	RIV 15 mg BID, 3 weeks followed by RIV 20 mg OD 3–6–12 months versus ENO 1 mg/kg/12 hours (until INR 2–3) + WRF dose-adjusted (INR 2–3), 3–6–12 months	Recurrent VTE: 3.4% versus 5.6%; RR 0.60; 95% CI 0.17–2.18. CRB: 14.4% versus 15.9%; RR 0.91; 95% CI 0.47–1.74.	Similar rates of recurrent VTE and CRB.
EINSTEIN-PE^Citation62	Subgroup	223 (4.6%)	RIV 15 mg BID, 3 weeks, followed by RIV 20 mg OD, 3–6–12 months versus ENO 1 mg/kg/12 hours (until INR 2–3) + WRF dose-adjusted (INR 2–3), 3–6–12 months	Recurrent VTE: 1.8% versus 2.8%; RR 0.64; 95% CI 0.11–3.74. CRB: 12.3% versus 9.3%; RR 1.33; 95% CI 0.62–2.86.	Similar rates of recurrent VTE and CRB.
Nonsurgical patients
MAGELLAN^Citation63^–^Citation65	Subgroup	584 (7%)	RIV 10 mg OD, 35 days versus ENO 40 mg OD, 10 days + placebo, 25 days	Major VTE (day 35): 9.9% versus 7.4%; RR 1.34; 95% CI 0.71–2.54. CRB (day 35): 5.4% versus 1.7%; RR 3.16; 95% CI 1.17–8.50.	Extended RIV showed a nonsignificant trend towards less efficacy than short-term ENO and a significant increase in bleeding risk.
Apixaban
Chemotherapy
ADVOCATE^Citation74	Dedicated study	100%	API 5 mg and 10 mg and 20 mg, 84 days versus PBO, 84 days.	CRB (primary outcome): 3.1% and 3.4% and 12.5% versus PBO 0%. Symptomatic VTE: API 0% and 0% and 0% versus PBO 10.3%.	API dose trend shown for CRB. No symptomatic VTE with API and no cases of CRB with PBO.
Dabigatran
Treatment of VTE
RE-COVER (about 70% DVT; about 30% PE)^Citation103	Subgroup	121 (4.8%)	DAB 150 mg BID, 6 months versus WRF dose-adjusted (INR 2–3), 6 months (both treatments administered after an initial treatment with ENO or UFH).	Recurrent VTE: 3.1% versus 5.3%; RR 0.59; 95% CI 0.10–3.43. Bleeding: NA	Similar rates of recurrent VTE.
RE-MEDY^Citation105	Subgroup	119 (4.2%)	DAB 150 mg BID, 16 months versus WRF dose-adjusted (INR 2–3), 16 months (patients who had completed 3–12 months of anticoagulant therapy).	Recurrent VTE: 3.3% versus 1.7%; RR 1.97; 95% CI 0.18–21.11. Bleeding: NA.	Similar rates of recurrent VTE.

Abbreviations: API, apixaban; BID, twice daily; CI, confidence interval; CRB, clinically relevant bleeding; DAB, dabigatran; DVT, deep vein thrombosis; ENO, enoxaparin; HR, hazard ratio; IDRA, idraparinux; INR, international normalized ratio; NA, not available; OD, once daily; PBO, placebo; PE, pulmonary embolism; RIV, rivaroxaban; RR, relative risk; SEM, semuloparin; UFH, unfractionated heparin; VKA, vitamin K antagonist; VTE, venous thromboembolism; WRF, warfarin.

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