Direct oral anticoagulants for extended thromboprophylaxis in medically ill patients: meta-analysis and risk/benefit assessment

Figures & data

Table 1 Study design and outcomes

	ADOPT^Citation5	MAGELLAN^Citation6	APEX^Citation7
Sample size	6758	8101	6850
Design	Randomized double-blind	Randomized double-blind	Randomized double-blind
Intervention	Apixaban for 30 days	Rivaroxaban for 35±4 days	Betrixaban for 35–42 days
Control	Enoxaparin for 6–14 days	Enoxaparin for 10±4 days	Enoxaparin for 6–14 days
Type of analysis	Superiority analysis	Superiority analysis	Superiority analysis
Primary efficacy outcomes	Composite of fatal or non-fatal PE, symptomatic DVT, asymptomatic proximal leg DVT, death related to VTE	Composite of asymptomatic proximal DVT, symptomatic proximal or distal DVT, symptomatic non-fatal PE, death related to VTE	Composite of asymptomatic proximal DVT, symptomatic proximal or distal DVT, symptomatic non-fatal PE, death from VTE
Rate of the primary efficacy outcomes during extended-duration thromboprophylaxis	Day 30:	Day 35:	Cohort 1: Betrixaban 6.9% Enoxaparin/placebo 8.5%
	Apixaban 2.7% Enoxaparin/placebo 3.1%	Rivaroxaban 4.4% Enoxaparin/placebo 5.7%	Cohort 2: Betrixaban 5.6% Enoxaparin/placebo 7.1% Cohort 3: Betrixaban 5.3% Enoxaparin/placebo 7.0%
Rate of the primary efficacy outcomes during short-duration thromboprophylaxis Safety outcomes	Apixaban 1.7% Enoxaparin 1.6% Major bleeding, clinically relevant non-major bleeding, and all bleeding reported by investigators	Rivaroxaban 2.7%	Enoxaparin 2.7% Composite of major bleeding or clinically relevant non-major bleeding events observed no later than 2 days after administration of the last dose of double-blind study medication Betrixaban 0.27% Enoxaparin 0.34% Major bleeding at any point until 7 days after the discontinuation of all study medications
Rate of the safety outcomes during extended-duration thromboprophylaxis	Major bleeding: Apixaban 0.47% Enoxaparin/placebo 0.19% Major bleeding plus clinically-relevant non-major bleeding:	Rivaroxaban 4.1% Enoxaparin/placebo 1.7%	Cohort 1: Betrixaban 0.6% Enoxaparin/placebo 0.7% Cohorts 2 and 3:
	Apixaban 2.67% Enoxaparin/placebo 2.08% All bleeding: Apixaban 7.73% Enoxaparin/placebo 6.81%		Betrixaban 0.7% Enoxaparin/placebo 0.6%
Rate of the safety outcomes during short-duration thromboprophylaxis	Major bleeding: Apixaban 0.25% Enoxaparin 0.12% Major bleeding plus clinically-relevant non-major bleeding: Apixaban 1.82% Enoxaparin 1.37%	Rivaroxaban 2.8% Enoxaparin 1.2%	Cohort 3: Betrixaban 1.37% Enoxaparin/placebo 2.86%
	All bleeding: Apixaban 5.34% Enoxaparin 4.86%

Abbreviations: DVT, deep vein thrombosis; PE, pulmonary embolism; VTE, venous thrombo-embolism.

Table 2 Patient demographics and clinical status

	ADOPT		MAGELLAN		APEX		Combined
	Apixaban (N=3255)	Enoxaparin (N=3273)	Rivaroxaban (N=4050)	Enoxaparin (N=4051)	Betrixaban (N=3759)	Enoxaparin (N=3754)	DOAC (N=11,064)	Enoxaparin (N=11,078)
Age, mean (SD) years	66.8 (12.0)	66.7 (12.0)	71*	71*	76.6 (8.46)	76.2 (8.31)	NR	NR
Women (%)	50.0	51.80	44.40	47.30	54.60	54.20	49.67	51.10
Main disease on admission
Heart failure (%)	39.0	38.10	32.30	32.40	44.60	44.50	38.63	38.33
Respiratory failure (%)	37.10	37.10	27.30	28.70	11.90	12.60	25.43	26.13
Infection (%)	21.50	22.80	45.80	45.10	29.60	28.20	32.30	32.03
Ischemic stroke (%)	NA	NA	17.30	17.30	10.90	11.50	14.10	14.40
Risk factors for VTE
History of cancer (%)	9.60	9.80	17.30	16.70	12.40	11.80	13.10	12.77
History of VTE (%)	4.30	3.80	5.0	4.40	8.30	7.90	5.87	5.37
Age ≥75 years (%)	29.60	29.90	38.30	38.60	68.50	67.0	45.47	45.17
Hormonal replacement therapy (%)	1.50	0.80	1.20	1.20	1.10	0.80	1.27	0.93

Notes:

* Median reported only. NR, means age could not be calculated as one study reported age as median.

Abbreviations: DOAC, direct oral anti-coagulant; NA, not available; NR, not reported; VTE, venous thrombo-embolism.

Figure 1 Meta-analysis results: efficacy outcomes.

Notes: Weights are from random effects analysis. risk ratio refers to the efficacy benefit of averting a VTE event when prophylacting with either DOACs or enoxaparin. risk ratio <1.00 with 95% CI <1.00 denotes that DOACs are prophylactically more efficacious, whereas risk ratio >1.00 with 95% CI >1.00 denotes that enoxaparin is prophylactically more efficacious than DOACs in averting a VTE. risk ratio with 95% CI limits 0.00< risk ratio estimate >1.00 denotes relative equivalence of DOAC and enoxaparin prophylaxis in averting VTE.
Abbreviations: DOAC, direct oral anti-coagulant; DVT, deep vein thrombosis; PE, pulmonary embolism; VTE, venous thromboembolism.

Figure 2 Meta-analysis results: safety outcomes.

Notes: Weights are from random effects analysis. risk ratio refers to the safety benefit of averting a bleeding event when prophylacting with either DOACs or enoxaparin. risk ratio <1.00 with 95% CI <1.00 denotes that DOACs are prophylactically more efficacious, whereas risk ratio>1.00 with 95% CI >1.00 denotes that enoxaparin is prophylactically more efficacious than DOACs in averting bleeding event. risk ratio with 95% CI limits 0.00< risk ratio estimate >1.00 denotes relative equivalence of DOAC and enoxaparin prophylaxis in averting bleeding events.
Abbreviation: DOAC, direct oral anti-coagulant.

Table 3 Risk/benefit assessment for clinical outcomes with statistically significant results in the meta-analysis

Benefit (thromboprophylaxis) of DOACs over enoxaparin	Clinical outcome rates		Absolute risk reduction by DOACs (clinical outcomes)			Number-needed-to-treat
	Enoxaparin	DOAC	ARR	95% CI		NNT	95% CI
Symptomatic VTE	0.010	0.006	0.004	0.001	0.006	276	165	1016
Total VTE	0.047	0.037	0.010	0.004	0.015	105	66	253
Harm (bleeding) of DOACs over enoxaparin	Adverse event rates		Absolute risk increase by DOACs (adverse events)			Number-needed-to-harm
	Enoxaparin	DOAC	ARI	95% CI		NNH	95% CI
Major bleeding	0.004	0.008	0.004	0.002	0.006	268	180	598
Clinically-relevant non-major bleeding	0.014	0.026	0.012	0.008	0.015	86	66	126
Clinically-relevant bleeding	0.018	0.033	0.015	0.011 0.015	0.015	66	53	91
Risk–benefit assessment (NNH/NNT) of DOACs over enoxaparin	Major bleeding	Clinically-relevant non-major bleeding		Clinically-relevant bleeding
Symptomatic VTE	0.97	0.31		0.24
Total VTE	2.56	0.82		0.63

Notes: The absolute risk reduction is the difference in the event rates for a given clinical outcome attributable to prophylaxis with DOACs versus enoxaparin; that is, the incremental benefit of DOAC over enoxaparin prophylaxis. The NNT is the number of patients to be prophylacted with DOACs to avoid a given clinical outcome in 1 patient (lower = better). The ARI refers to the difference in event rates for a given adverse event attributable to prophylaxis with DOACs versus enoxaparin; that is, the incremental harm of DOAC over enoxaparin prophylaxis. The NNH is the number of patients to be prophylacted with DOACs for 1 patient to experience the AE (higher = better). ARR, ARI, NNT, and NNH were calculated using www.statpages.info/ctab2x2.html. The risk/benefit ratio is the ratio of NNH to NNT. A value <1 indicates that the harm from a given AE exceeds the clinical benefit of a given outcome; a value >1 indicates that the clinical benefit of a given outcome exceeds the harm from a given AE.

Abbreviations: AE, adverse event; ARI, absolute risk increase; ARR, absolute risk reduction; DOAC, direct oral anti-coagulant; DVT, deep vein thrombosis; NNH, number-needed-to-harm; NNT, number-needed-to-treat; PE, pulmonary embolism; VTE, venous thromboembolism.

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