Emergence of new oral antithrombotics: a critical appraisal of their clinical potential

Figures & data

Table 1 Limitations of current anticoagulants

Anticoagulant	Limitations	Consequences
UFH	Parenteral mode of administration	Inconvenient for long-term use
	Unpredictable anticoagulant effect due to unspecific binding	Regular monitoring of aPTT required
	Risk of HIT	Monitoring of platelet count required
LMWH	Parenteral mode of administration	Inconvenient and expensive for long-term use
	Risk of HIT	Monitoring of platelet count required
VKAs	Unpredictable anticoagulant effect	Regular monitoring and dose adjustment required to ensure patients stay within target INR (usually 2–3)
	Slow onset of action and narrow therapeutic window
	Food and drug interactions	Risk of adverse events (for example, bleeding)
Fondaparinux	Parenteral mode of administration	Inconvenient and expensive for long-term use

Abbreviations: UFH, unfractionated heparin; LMWH, low-molecular-weight heparin; VKAs, vitamin K antagonists; aPTT, activated partial thromboplastin time; HIT, heparin-induced thrombocytopenia; INR, international normalized ratio.

Figure 1 The coagulation cascade.

Abbreviations: VKAs, vitamin K antagonists; AT, antithrombin.

Table 2 Therapeutic target and pharmacologic properties of oral antithrombotic agents in clinical development

Drug	Manufacturer	Molecular weight	Therapeutic target	Half-life	Time to Cmax	Bioavailability	Mode of elimination
Dabigatran	Boehringer Ingelheim	628 (dabigatran etexilate), 471 (dabigatran)	Thrombin (Factor IIa)	14–17 h with multiple doses; 7–9 h with single doses	2 h	Approximately 6.5% in humans	Renal
Rivaroxaban	Bayer HealthCare AG and Johnson & Johnson Pharmaceutical Research and Development, L.L.C.	436	Factor Xa	Approximately 9 h in healthy subjects; approximately 12 h in elderly subjects (>75 yr)	2–4 h	Approximately 80% in humans	Renal/biliary-fecal
Apixaban	Bristol-Myers Squibb and Pfizer	460	Factor Xa	Approximately 12 h; terminal half-life 8–15 h	3 h	Chimps (51%); dogs (88%); rats (43%)	Renal/fecal

Table 3 Summary of clinical studies: prevention and treatment of venous thromboembolism (VTE)

Drug	Phase	Patient population	Dosing	Comparator(s)	Primary endpoint	Safety endpoint	Results summary (study drug vs comparator)
VTE prevention
Dabigatran etexilate
BISTRO II	II	THR/TKR	50–225 mg bid/300 mg od	Enoxaparin	Incidence of VTE (symptomatic or venographically detected DVT and/or PE)	Major bleeding	Primary endpoint: 28.5% (50 mg), 17.4% (150 mg), 13.1% (150 mg) and 16.6% (300 mg) vs 24%. Significant dose-dependent decrease in VTE with increasing doses of dabigatran etexilate
							Major bleeding: 0.3% vs 2.0%
RE-NOVATE	III	THR	220 and 150 mg od	Enoxaparin	Composite of VTE and all-cause mortality	Bleeding events (major, clinically relevant non-major, minor)	Primary endpoint: 8.6% (220 mg) and 6.0% (150 mg) vs 6.7%
							Major bleeding: 2.0% and 1.3% vs 1.6%
RE-MODEL	III	TKR	220 and 150 mg od	Enoxaparin	Composite of VTE and all-cause mortality	Major bleeding	Primary endpoint: 40.5% (150 mg) and 36.4% (220 mg) vs 37.7%
							Major bleeding: 1.3% (150 mg) and 1.5% (200 mg) vs 1.3%
RE-MOBILIZE	III	TKR	220 and 150 mg od	Enoxaparin	Composite of VTE and all-cause mortality	Major bleeding	Primary endpoint: 33.7% (150 mg), 31.1% (220 mg) vs 25.3%
							Major bleeding: 0.6% and 0.6% vs 1.4%
Rivaroxaban
ODIXa-HIP	II	THR	5–60 mg bid/od	Enoxaparina	Composite of objective DVT, symptomatic PE, and all-cause mortality	Major bleeding	No significant dose response for efficacy, total daily doses of 5–60 mg showed similar efficacy to enoxaparin.
ODIXa-HIP2	II	THR	5–60 mg bid
ODIXa-KNEE	II	TKR	5–60 mg bid
ODIXa-OD-HIP	II	THR	5–40 mg od
							Dose response for bleeding: total daily doses of 5–20 mg showed similar safety to enoxaparin
RECORD1	III	THR	10 mg od	Enoxaparin	Composite of DVT, PE and all-cause mortality	Major bleeding	Primary endpoint: 1.1% vs 3.7%; p < 0.001
							Major bleeding: 0.3% vs 0.1%
RECORD2	III	THR	10 mg od	Enoxaparin	Composite of DVT, PE and all-cause mortality	Major bleeding	Primary endpoint: 2.0% vs 9.3%; p < 0.001
							Major bleeding: 0.1% vs 0.1%
RECORD3	III	TKR	10 mg od	Enoxaparin	Composite of DVT, PE, and all-cause mortality	Major bleeding	Primary endpoint: 9.6% vs 18.9%; p < 0.001
							Major bleeding: 0.6% vs 0.5%
RECORD4	III	TKR	10 mg od	Enoxaparin	Composite of DVT, PE, and all-cause mortality	Major bleeding	Study completed; results not yet published
Apizaban
NCT-00097357	II	TKR	5–20 mg od	Enoxaparin or warfarin	Composite of DVT, PE and all-cause mortality	Major bleeding	No significant dose response for efficacy.
			2.5–10 mg bid				Significant dose-related increase in the incidence of total adjudicated bleeding events
VTE treatment
Rivaroxaban
ODIXa-DVT	II	–	10–30 mg bid/40 mg od	Enoxaparin and warfarin	Improvement in thrombotic burden at day 21 without recurrent symptomatic VTE or VTE-related death	Major bleeding	Primary endpoint: 53.0% (10 mg), 59.2% (20 mg), 56.9% (30 mg) and 43.8% (40 mg) vs 45.9%
							Major bleeding: 1.7%, 1.7%, 3.3% and 1.7% vs 0.0%
EINSTEIN-DVT	II	–	20–40 mg od	Enoxaparin/tinzaparin/UFH and warfarin	Composite of recurrent DVT/PE-related death, and reduced thrombotic burden	Composite of clinically relevant major and non-major bleeding	Primary endpoint: 6.1% (20 mg), 5.4% (30 mg), 6.6% (40 mg) vs 9.9%
							Major bleeding: 0.7%, 1.5% and 0.0% vs 1.5%
Apixaban
BOTICELLI-DVT	II	–	5 mg and 10 mg bid, 20 mg od	LMWH or fondaparinux and warfarin	Composite of recurrent VTE and reduced thrombotic burden	Composite of major and non-major bleeding	Primary endpoint: 6.0% (5 mg), 5.6% (10 mg) and 2.6% (20 mg) vs 4.2%
							Major bleeding: 0.8%, 0.0%, 0.8% vs 0.0%

a 30 mg bid or 40 mg od based on US or European requirements.

Abbreviations: THR, total hip replacement; TKR, total knee replacement; bid, twice daily; od, once daily; DVT, deep vein thrombosis; PE, pulmonary embolism.