Improving prevention and treatment of venous thromboembolism: clinical trial results

Figures & data

Table 1.  The Joint Commission national hospital inpatient quality measures for venous thromboembolism17.

Set measure	Measure short name
VTE-1	Venous thromboembolism prophylaxis
VTE-2	Intensive care unit venous thromboembolism prophylaxis
VTE-3	Venous thromboembolism patients with anti-coagulant overlap therapy
VTE-4	Venous thromboembolism patients receiving unfractionated heparin therapy with dosage/platelet-count monitoring by protocol
VTE-5	Venous thromboembolism discharge instructions
VTE-6	Incidence of potentially preventable venous thromboembolism

Table 2.  Characteristics of rivaroxaban, dabigatran, and apixaban.

Drug features	Rivaroxaban	Apixaban	Dabigatran
Target	Factor Xa	Factor Xa	Factor IIa
Molecular weight (Daltons)	436	460	628 (prodrug) 472 (active)
Prodrug	No	No	Yes
Routine monitoring	No	No	No
Dosing frequency	Once or twice daily	Twice daily	Once or twice daily
Bioavailability (%)	80–100 (10 mg dose)	60	7.2
Half-life (h)	5–13	8–11 (twice daily) 12–15 (once daily)	12–17
Renal excretion (%)	66	25	80 (iv administration)
Drug interactions	Potent inhibitors or inducers of CYP3A4 or P-gp	Potent inhibitors or inducers of CYP3A4	Potent inhibitors or inducers of Pgp
Antidote	None developed yet	None developed yet	None developed yet
Populations being studied in	Medical and surgical VTE prophylaxis, AF, VTE treatment, and ACS	Medical and surgical VTE prophylaxis, AF, VTE treatment, and ACS	Medical and surgical VTE prophylaxis, AF, VTE treatment
Status	• Approved in more than 110 countries worldwide, including the EU, for prevention of VTE after elective hip or knee replacement surgery in adult patients • Approved in the US for the prevention of stroke and systemic embolism in atients with non-valvular AF • Approved in Europe for the treatment of DVT and for the long-term prevention of recurrent VTE	• Approved in many countries for the prevention of VTE in patients after elective hip or knee replacement surgery	• Approved in many countries for VTE prophylaxis after major orthopedic surgery • Approved in the US for the prevention of stroke and systemic embolism in patients with non-valvular AF

ACS, acute coronary syndrome; AF, atrial fibrillation; CYP3A4, cytochrome P450 3A4; DVT, deep vein thrombosis; iv, intravenous; P-gp, P-glycoprotein; VTE, venous thromboembolism.

Table 3.  Outcomes in the EINSTEIN acute DVT and continued treatment studies33.

End-points	Rivaroxaban	Enoxaparin/VKA	Placebo	HR (95% CI)	p-value
EINSTEIN DVT, n	1731	1718
Recurrent VTE, n (%)	36 (2.1)	51 (3.0)		0.68 (0.44–1.04)	<0.001*
Type of recurrent VTE, n
Fatal PE	1	0
PE could not be ruled out	3	6
Non-fatal PE	20	18
Recurrent DVT plus PE	1	0
Recurrent DVT	14	28
First major or non-major clinically relevant bleeding during treatment, n (%)	139 (8.1)	138 (8.1)		0.97 (0.76–1.22)	0.77
Major bleeding	14	20		0.65 (0.33–1.30)	0.21
Contributing to death	1	5
In a critical site	3	3
Non-major clinically relevant bleeding	126	119
EINSTEIN EXT, n	602		594
Recurrent VTE, n (%)	8 (1.3)		42 (7.1)^†	0.18 (0.09–0.39)	<0.001
Type of recurrent VTE, n
Fatal PE	0		1
PE could not be ruled out	1		0
Non-fatal PE	2		13
Recurrent DVT	5		31
First major or non-major clinically relevant bleeding during treatment, n (%)	36 (6.0)		7 (1.2)	5.19 (2.3–11.7)	<0.001
Major bleeding	4 (0.7)^‡		0	NA	0.11
Contributing to death	0		0
In a critical site	0		0
Non-major clinically relevant bleeding^†	32^‡		7

*The non-inferiority margin was 2.0.

^†Some patients had more than one event.

^‡All four patients with major bleeding (gastrointestinal in three patients; menorrhagic in one patient) discontinued treatment.

CI, confidence interval; DVT, deep vein thrombosis; HR, hazard ratio; NA, not applicable; PE, pulmonary embolism; VKA, vitamin K antagonist; VTE, venous thromboembolism.

Figure 1.  Phase III VTE treatment trial designs for apixaban: AMPLIFY (a) and AMPLIFY-EXT (b). DVT, deep vein thrombosis; INR, international normalized ratio; PE, pulmonary embolism; R, randomization; VTE, venous thromboembolism.

Figure 2.  Phase III VTE treatment trial designs for dabigatran etexilate: RE-COVER and RE-COVER II (a), RE-MEDY (b), and RE-SONATE (c). DVT, deep vein thrombosis; INR, international normalized ratio; PE, pulmonary embolism; R, randomization; VKA, vitamin K antagonist; VTE, venous thromboembolism.

Table 4.   Outcomes in the RE-COVER study40.

End-points	Dabigatran (n = 1274)	Warfarin (n = 1265)	HR (95% CI)
Primary end-point, n (%)
During the study period	30 (2.4)	27 (2.1)	1.10 (0.65–1.84)
During the study period plus 30-day follow-up	34 (2.7)	32 (2.5)	1.05 (0.65–1.70)
Secondary end-point, n (%)
Symptomatic DVT	16 (1.3)	18 (1.4)	0.87 (0.44–1.71)
Symptomatic non-fatal PE	13 (1.0)	7 (0.6)	1.85 (0.74–4.64)
Death related to VTE	1 (0.1)	3 (0.2)	0.33 (0.03–3.15)
All deaths	21 (1.6)	21 (1.7)	0.98 (0.53–1.79)
Major bleeding event, n (%)	20 (1.6)	24 (1.9)	0.82 (0.45–1.48)
Fatal event, n	1	1
Bleeding into critical organ, n	1	9
Major or non-major clinically relevant bleeding	71 (5.6)	111 (8.8)

CI, confidence interval; DVT, deep vein thrombosis; HR, hazard ratio; PE, pulmonary embolism; VTE, venous thromboembolism.

Rose AJ, Ozonoff A, Grant RW, et al. Epidemiology of subtherapeutic anticoagulation in the United States. Circ Cardiovasc Qual Outcomes 2009;2:591-7

 PubMed Web of Science ®Google Scholar

Kubitza D, Becka M, Mueck W, et al. Effects of renal impairment on the pharmacokinetics, pharmacodynamics and safety of rivaroxaban - an oral, direct Factor Xa inhibitor. Br J Clin Pharmacol 2010;70:703-12

 PubMed Web of Science ®Google Scholar

Cohen AT, Spiro TE, Büller HR, et al. Extended-duration rivaroxaban thromboprophylaxis in acutely ill medical patients: MAGELLAN study protocol. J Thromb Thrombolysis 2011;31:407-16

 PubMed Web of Science ®Google Scholar