Use of novel oral anticoagulants for the treatment of venous thromboembolism and its considerations in Asian patients

Figures & data

Table 1 Approval status of the novel oral anticoagulants (NOACs) for treatment and secondary prevention of venous thromboembolism

NOACs	USa	Europeb	Koreac	Japand
Dabigatran	Approved (2014/04)	Approved (2014/04)	Approved (2014/07)	–
Rivaroxaban	Approved (2012/11)	Approved (2011/09)	Approved (2012/06)	–
Apixaban	Approved (2014/08)	Approved (2014/06)	Approved (2014/09)	–
Edoxaban	–	–	–	–

Notes: Dash(–) represents that the drug has not yet been approved for the indication as of 2014/09

a from US Food and Drug Administration (www.accessdata.fda.gov/scripts/cder/drugsatfda/)

b from European Medicines Agency (www.ema.europa.eu/)

c from Korean Ministry of Food and Drug Safety (http://ezdrug.mfds.go.kr/)

d from Pharmaceuticals and Medical Devices Agency, Japan (http://www.pmda.go.jp/english/service/package.html).

Table 2 Study methods of Phase III trials with novel oral anticoagulants for the treatment and secondary prevention of venous thromboembolism (VTE)

Trial	Intervention	N	Treatment Duration	Primary efficacy end point	Primary safety end point
Treatment of VTE
RE-COVER^Citation26	Parenteral anticoagulation followed by dabigatran 150 mg bid Enoxaparin then VKAa	2,539	6 months	Recurrent VTE or VTE-related death	Major bleeding
RE-COVER II^Citation27	Parenteral anticoagulation followed by dabigatran 15 mg bid Enoxaparin then VKAa	2,589	6 months	Recurrent VTE or VTE-related death	Major bleeding
EINSTEIN-DVT^Citation28	Rivaroxaban 15 mg bid ×3 weeks, followed by 20 mg daily Parenteral anticoagulation followed by VKAa	3,449	3, 6, or 12 monthsb	Recurrent VTE	Major or clinically relevant nonmajor bleeding
EISTEIN-PE^Citation29	Rivaroxaban 15 mg bid ×3 weeks, followed by 20 mg daily Parenteral anticoagulation followed by VKAa	4,832	3, 6, or 12 monthsb	Recurrent VTE	Major or clinically relevant nonmajor bleeding
AMPLIFY^Citation30	Apixaban 10 mg bid ×7 days followed by 5 mg bid Parenteral anticoagulation followed by warfarina	5,395	6 months	Recurrent VTE or VTE-related death	Major bleeding
Hokusai-VTE^Citation31	Parenteral anticoagulation followed by edoxaban 60 mg daily Parenteral anticoagulation followed by warfarina	8,240	3–12 monthsb	Recurrent VTE	Major or clinically relevant nonmajor bleeding
Secondary prevention of VTE
RE-MEDY^Citation35	Dabigatran 150 mg bid Warfarina	2,856	6–36 months	Recurrent VTE or VTE-related death	Major bleeding
RE-SONATE^Citation35	Dabigatran 150 mg bid Placebo	1,343	6–18 months	Recurrent VTE or VTE-related death or unexplained death	Major bleeding
EINSTEIN-Extension^Citation28	Rivaroxaban 20 mg daily Placebo	1,196	6 or 12 months	Recurrent VTE	Major bleeding
AMPLIFY-EXT^Citation36	Apixaban 2.5 mg bid Apixaban 5 mg bid Placebo	2,482	12 months	Recurrent VTE or death from any cause	Major bleeding

Notes:

a VKA/warfarin treatment had a goal international normalized ratio of two to three

b treatment duration was determined by the physician.

Abbreviations: bid, twice daily; VKA, vitamin K antagonist.

Table 3 Results of the Phase III trials with novel oral anticoagulants for the treatment and secondary prevention of venous thromboembolism (VTE)

	Treatment	Primary efficacy end point	Major bleeding	Major or clinically relevant nonmajor bleeding
Treatment of VTE
RE-COVER^Citation26	Dabigatran vs conventional treatment	2.4% vs 2.1% HR 1.10 (0.65–1.84)	1.6% vs 1.9% HR 0.82 (0.45–1.48)	5.6% vs 8.8% HR 0.63 (0.47–0.84)
RE-COVER II^Citation27	Dabigatran vs conventional treatment	2.3% vs 2.2% HR 1.08 (0.64–1.80)	1.2% vs 1.7% HR 0.69 (0.36–1.32)	5.0% vs 7.9% HR 0.62 (0.45–0.84)
EINSTEIN-DVT^Citation28	Rivaroxaban vs conventional treatment	2.1% vs 3.0% HR 0.68 (0.44–1.04)	0.8% vs 1.2% HR 0.65 (0.33–1.30)	8.1% vs 8.1% HR 0.97 (0.76–1.22)
EISTEIN-PE^Citation29	Rivaroxaban vs conventional treatment	2.1% vs 1.8% HR 1.12 (0.75–1.68)	1.1% vs 2.2% HR 0.49 (0.31–0.79)	10.3% vs 11.4% HR 0.90 (0.76–1.07)
AMPLIFY^Citation30	Apixaban vs conventional treatment	2.3% vs 2.7% RR 0.84 (0.60–1.18)	0.6% vs 1.8% RR 0.31 (0.17–0.55)	4.3% vs 9.7% RR 0.44 (0.36–0.55)
Hokusai-VTE^Citation31	Edoxaban vs conventional treatment	3.2% vs 3.5% HR 0.89 (0.70–1.13)	1.4% vs 1.6% HR 0.84 (0.59–1.21)	8.5% vs 10.3% HR 0.81 (0.71–0.94)
Secondary prevention of VTE
RE-MEDY^Citation35	Dabigatran vs warfarin	1.8% vs 1.3% HR 1.44 (0.78–2.64)	0.9% vs 1.9% HR 0.52 (0.27–1.02)	5.6% vs 10.2% HR 0.54 (0.41–0.71)
RE-SONATE^Citation35	Dabigatran vs placebo	0.4% vs 5.6% HR 0.08 (0.02–0.25)	0.3% vs 0%	5.3% vs 1.8% HR 2.92 (1.52–5.60)
EINSTEIN-Extension^Citation28	Rivaroxaban vs placebo	1.3% vs 7.1% HR 0.18 (0.09–0.39)	0.7% vs 0%	6.0% vs 1.2% HR 5.19 (2.3–11.7)
AMPLIFY-EXT^Citation36	Apixaban 2.5 mg vs apixaban 5 mg vs placebo	3.8% vs 4.2% vs 11.6% Apixaban 2.5 mg vs placebo HR 0.33 (0.22–0.48) Apixaban 5 mg vs placebo HR 0.36 (0.25–0.53) Apixaban 2.5 mg vs 5 mg Not reported	0.2% vs 0.1% vs 0.5% Apixaban 2.5 mg vs placebo HR 0.49 (0.09–2.64) Apixaban 5 mg vs placebo HR 0.25 (0.03–2.24) Apixaban 2.5 mg vs 5 mg HR 1.93 (0.18–21.25)	3.2% vs 4.3% vs 2.7% Apixaban 2.5 mg vs placebo HR 1.20 (0.69–2.10) Apixaban 5 mg vs placebo HR 1.62 (0.96–2.73) Apixaban 2.5 mg vs 5 mg HR 0.74 (0.46–1.22)

Abbreviations: HR, hazard ratio; RR, relative risk.

Table 4 Efficacy and safety outcomes in Asian subgroup

	Treatment	Number of Asians	Efficacy	Safety
Treatment of VTE
RE-COVER^Citation26	Dabigatran vs conventional treatment	65	4.0% vs 2.5% P-value for interaction =0.96	NR
RE-COVER II^Citation27	Dabigatran vs conventional treatment	537	2.4% vs 1.0%a P-value for interaction =0.44a	NR
EINSTEIN-DVT^Citation28	Rivaroxaban vs conventional treatment	494	1.4% vs 3.8% P-value for interaction >0.05	8.4% vs 11.5% P-value for interaction >0.05
EISTEIN-PE^Citation29	Rivaroxaban vs conventional treatment	287	4.1% vs 2.1% P-value for interaction >0.05	7.7% vs 9.3% P-value for interaction >0.05
AMPLIFY^Citation30	Apixaban vs conventional treatment	NR	NR	NR
Hokusai-VTE^Citation31	Edoxaban vs conventional treatment	1,727	3.1% vs 3.9% P-value for interaction =0.8264	8.7% vs 14.5% P-value for interaction =0.0266
Secondary prevention of VTE
RE-MEDY^Citation35	Dabigatran vs warfarin	227	0.9% vs 0.9% P-value for interaction =0.978	NR
RE-SONATE^Citation35	Dabigatran vs placebo	118	1.4% vs 2.6%b P-value for interaction =0.102	NR
EINSTEIN-Extension^Citation28	Rivaroxaban vs placebo	NR	NR	NR
AMPLIFY-EXT^Citation36	Apixaban 2.5 mg vs apixaban 5 mg vs placebo	NR	NR	NR

Notes: All P-values for interaction reported in this trial are on the racial subgroup

a pooled data from RE-COVER and RE-COVER II

b composite data of Asian and Black patients.

Abbreviations: VTE, venous thromboembolism; NR, not reported.

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