Direct oral anticoagulants versus warfarin for preventing stroke and systemic embolic events among atrial fibrillation patients with chronic kidney disease

Miho Kimachi; Toshi A Furukawa; Kimihiko Kimachi; Yoshihito Goto; Shingo Fukuma; Shunichi Fukuhara

doi:10.1002/14651858.CD011373.pub2

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Figure 1

Study flow diagram.

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Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Analysis 1.1

Comparison 1 Direct oral anticoagulants versus warfarin, Outcome 1 All strokes and systemic embolic events.

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Analysis 1.2

Comparison 1 Direct oral anticoagulants versus warfarin, Outcome 2 Ischaemic stroke.

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Analysis 1.3

Comparison 1 Direct oral anticoagulants versus warfarin, Outcome 3 Haemorrhagic stroke.

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Analysis 1.4

Comparison 1 Direct oral anticoagulants versus warfarin, Outcome 4 Major bleeding.

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Analysis 1.5

Comparison 1 Direct oral anticoagulants versus warfarin, Outcome 5 Myocardial infarction.

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Analysis 1.6

Comparison 1 Direct oral anticoagulants versus warfarin, Outcome 6 Minor bleeding.

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Analysis 1.7

Comparison 1 Direct oral anticoagulants versus warfarin, Outcome 7 Gastrointestinal bleeding.

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Analysis 1.8

Comparison 1 Direct oral anticoagulants versus warfarin, Outcome 8 Intracranial haemorrhage.

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Analysis 1.9

Comparison 1 Direct oral anticoagulants versus warfarin, Outcome 9 All‐cause mortality.

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Analysis 2.1

Comparison 2 Direct oral anticoagulants versus warfarin: subgroup analysis for participants with CrCl 30 to 50 mL/min, Outcome 1 All strokes and systemic embolic events.

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Analysis 2.2

Comparison 2 Direct oral anticoagulants versus warfarin: subgroup analysis for participants with CrCl 30 to 50 mL/min, Outcome 2 Major bleeding.

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Analysis 3.1

Comparison 3 Direct oral anticoagulants versus warfarin: subgroup analysis for participants with CrCl 15 to 30 mL/min, Outcome 1 All strokes and systemic embolic events.

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Analysis 3.2

Comparison 3 Direct oral anticoagulants versus warfarin: subgroup analysis for participants with CrCl 15 to 30 mL/min, Outcome 2 Major bleeding.

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Analysis 4.1

Comparison 4 Direct oral anticoagulants versus warfarin: subgroup analysis for different doses of DOAC, Outcome 1 All strokes and systemic embolic events.

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Analysis 4.2

Comparison 4 Direct oral anticoagulants versus warfarin: subgroup analysis for different doses of DOAC, Outcome 2 Major bleeding.

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Analysis 4.3

Comparison 4 Direct oral anticoagulants versus warfarin: subgroup analysis for different doses of DOAC, Outcome 3 All‐cause mortality.

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Analysis 5.1

Comparison 5 Direct oral anticoagulants versus warfarin: adverse events, Outcome 1 Epistaxis.

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Analysis 5.2

Comparison 5 Direct oral anticoagulants versus warfarin: adverse events, Outcome 2 Nasopharyngitis.

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Analysis 5.3

Comparison 5 Direct oral anticoagulants versus warfarin: adverse events, Outcome 3 Diarrhoea.

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Analysis 5.4

Comparison 5 Direct oral anticoagulants versus warfarin: adverse events, Outcome 4 Upper respiratory tract inflammation.

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Analysis 5.5

Comparison 5 Direct oral anticoagulants versus warfarin: adverse events, Outcome 5 Back pain.

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Analysis 5.6

Comparison 5 Direct oral anticoagulants versus warfarin: adverse events, Outcome 6 Cardiac failure.

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Analysis 6.1

Comparison 6 Direct oral anticoagulants versus warfarin: fixed‐effect model, Outcome 1 All strokes and systemic embolic events.

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Analysis 6.2

Comparison 6 Direct oral anticoagulants versus warfarin: fixed‐effect model, Outcome 2 Major bleeding.

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Summary of findings for the main comparison. Direct oral anticoagulants (DOAC) versus warfarin for preventing stroke and systemic embolic events among atrial fibrillation patients with chronic kidney disease (CKD)

DOAC versus warfarin for preventing stroke and systemic embolic events among atrial fibrillation patients with CKD
Patient or population: atrial fibrillation patients with CKD Setting: Hospital‐based setting Intervention: DOAC Comparison: Dose‐adjusted warfarin
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No. of participants (studies)	Quality of the evidence (GRADE)
	Assumed risk	Corresponding risk
	Warfarin	DOAC
All strokes and systemic embolic events Follow up: 1.8 years to 2.8 years	29 per 1,000	23 per 1,000 (19 to 29)	RR 0.81 (0.65 to 1.00)	12,545 (5)	⊕⊕⊕⊝¹ MODERATE
Major bleeding Follow up: 1.8 years to 2.8 years	55 per 1,000	43 per 1,000 (32 to 57)	RR 0.79 (0.59 to 1.04)	12,521 (5)	⊕⊕⊝⊝¹ ² LOW
Myocardial infarction Follow up: 2.8 years	11 per 1,000	10 per 1,000 (5 to 21)	RR 0.92 (0.45 to 1.90)	2,740 (1)	‐
Minor bleeding Follow up: 2.5 years to 2.8 years	74 per 1,000	72 per 1,000 (43 to 119)	RR 0.97 (0.58 to 1.61)	3,012 (2)	⊕⊕⊝⊝¹ ² LOW
Gastrointestinal bleeding Follow up: 1.9 years to 2.8 years	17 per 1,000	24 per 1,000 (17 to 35)	RR 1.40 (0.97 to 2.01)	5,678 (2)	⊕⊕⊕⊝¹ MODERATE
Intracranial haemorrhage Follow up: 1.8 years to 2.8 years	14 per 1,000	6 per 1,000 (4 to 9)	RR 0.43 (0.27 to 0.69)	12,521 (5)	⊕⊕⊕⊝¹ MODERATE
All‐cause mortality Follow up: 1.8 years to 2.8 years	78 per 1,000	71 per 1,000 (61 to 82)	RR 0.91 (0.78 to 1.05)	9,595 (4)	⊕⊕⊕⊝¹ MODERATE
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). AF: atrial fibrillation; CI: confidence interval; DOAC: direct oral anticoagulants; RR: risk ratio
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹ Some concerns with imprecision because of the uncertain effect estimate ² Some concerns with inconsistency because of medium heterogeneity

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Table 1. Recommendation of major regulatory agencies

	Dabigatran	Apixaban	Rivaroxaban	Edoxaban
EMA 2014	150 mg twice daily for CKD stage G3 (CrCl 30 to 50 mL/min) No recommendation for CKD stage G4	2.5 mg twice daily in patients with at least two of the following characteristics: ‐ age ≥ 80 years ‐ body weight ≤ 60 kg ‐ SCr > 1.5 mg/dL	15 mg daily for CKD stage G3 and G4 (CrCl 15 to 50 mL/min)	30 mg once daily for CKD stage G3 and G4 (CrCl 15 to 50 mL/min)
FDA 2014	150 mg twice daily for CKD stage G3 (CrCl > 30 mL/min) 75 mg twice daily for CKD stage G4 (CrCl 15 to 30 mL/min)	2.5 mg twice daily in patients with at least two of the following characteristics: ‐ age ≥ 80 years ‐ body weight ≤ 60 kg ‐ SCr > 1.5 mg/dL	15 mg daily for CKD stage G3 and G4 (CrCl 15 to 50 mL/min)	30 mg once daily for CKD stage G3 and G4 (CrCl 15 to 50 mL/min)
Health Canada 2017	110 or 150 mg twice daily for CKD stage G3 (CrCl 30 to 50 mL/min) No recommendation for CKD stage G4	2.5 mg twice daily in patients with at least two of the following characteristics: ‐ age ≥ 80 years ‐ body weight ≤ 60 kg ‐ SCr > 1.5 mg/dL	15 mg daily for CKD stage G3 (CrCl 30 to 50 mL/min) No recommendation for CKD stage G4	30 mg once daily for CKD stage G3 (CrCl 30 to 50 mL/min)
CKD ‐ chronic kidney disease; CrCl ‐ creatinine clearance; SCr ‐ serum creatinine

Table 1. Recommendation of major regulatory agencies

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Comparison 1. Direct oral anticoagulants versus warfarin

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 All strokes and systemic embolic events Show forest plot	5	12545	Risk Ratio (M‐H, Random, 95% CI)	0.81 [0.65, 1.00]

2 Ischaemic stroke Show forest plot	4	8991	Risk Ratio (M‐H, Random, 95% CI)	1.01 [0.75, 1.36]

3 Haemorrhagic stroke Show forest plot	4	8991	Risk Ratio (M‐H, Random, 95% CI)	0.52 [0.28, 0.97]

4 Major bleeding Show forest plot	5	12521	Risk Ratio (M‐H, Random, 95% CI)	0.79 [0.59, 1.04]

5 Myocardial infarction Show forest plot	1	2740	Risk Ratio (M‐H, Random, 95% CI)	0.92 [0.45, 1.90]

6 Minor bleeding Show forest plot	2	3012	Risk Ratio (M‐H, Random, 95% CI)	0.97 [0.58, 1.61]

7 Gastrointestinal bleeding Show forest plot	2	5678	Risk Ratio (M‐H, Random, 95% CI)	1.40 [0.97, 2.01]

8 Intracranial haemorrhage Show forest plot	5	12521	Risk Ratio (M‐H, Random, 95% CI)	0.43 [0.27, 0.69]

9 All‐cause mortality Show forest plot	4	9595	Risk Ratio (M‐H, Random, 95% CI)	0.91 [0.78, 1.05]

Comparison 1. Direct oral anticoagulants versus warfarin

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Comparison 2. Direct oral anticoagulants versus warfarin: subgroup analysis for participants with CrCl 30 to 50 mL/min

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 All strokes and systemic embolic events Show forest plot	5	12155	Risk Ratio (M‐H, Random, 95% CI)	0.82 [0.66, 1.02]

2 Major bleeding Show forest plot	5	12132	Risk Ratio (M‐H, Random, 95% CI)	0.80 [0.62, 1.03]

Comparison 2. Direct oral anticoagulants versus warfarin: subgroup analysis for participants with CrCl 30 to 50 mL/min

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Comparison 3. Direct oral anticoagulants versus warfarin: subgroup analysis for participants with CrCl 15 to 30 mL/min

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 All strokes and systemic embolic events Show forest plot	2	390	Risk Ratio (M‐H, Random, 95% CI)	0.68 [0.23, 2.00]

2 Major bleeding Show forest plot	1	268	Risk Ratio (M‐H, Random, 95% CI)	0.30 [0.11, 0.80]

Comparison 3. Direct oral anticoagulants versus warfarin: subgroup analysis for participants with CrCl 15 to 30 mL/min

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Comparison 4. Direct oral anticoagulants versus warfarin: subgroup analysis for different doses of DOAC

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 All strokes and systemic embolic events Show forest plot	5	12545	Risk Ratio (M‐H, Random, 95% CI)	0.81 [0.65, 1.00]

2 Major bleeding Show forest plot	5	12521	Risk Ratio (M‐H, Random, 95% CI)	0.81 [0.63, 1.03]

3 All‐cause mortality Show forest plot	4	9595	Risk Ratio (M‐H, Random, 95% CI)	0.91 [0.78, 1.05]

Comparison 4. Direct oral anticoagulants versus warfarin: subgroup analysis for different doses of DOAC

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Comparison 5. Direct oral anticoagulants versus warfarin: adverse events

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Epistaxis Show forest plot	2	3234	Risk Difference (M‐H, Random, 95% CI)	‐0.05 [‐0.22, 0.11]

2 Nasopharyngitis Show forest plot	2	3234	Risk Difference (M‐H, Random, 95% CI)	0.03 [‐0.06, 0.11]

3 Diarrhoea Show forest plot	2	3234	Risk Difference (M‐H, Random, 95% CI)	0.01 [‐0.04, 0.06]

4 Upper respiratory tract inflammation Show forest plot	2	3234	Risk Difference (M‐H, Random, 95% CI)	‐0.01 [‐0.02, 0.01]

5 Back pain Show forest plot	2	3234	Risk Difference (M‐H, Random, 95% CI)	‐0.02 [‐0.05, 0.01]

6 Cardiac failure Show forest plot	2	3234	Risk Difference (M‐H, Random, 95% CI)	‐0.01 [‐0.03, 0.01]

Comparison 5. Direct oral anticoagulants versus warfarin: adverse events

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Comparison 6. Direct oral anticoagulants versus warfarin: fixed‐effect model

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 All strokes and systemic embolic events Show forest plot	5	12545	Risk Ratio (M‐H, Fixed, 95% CI)	0.81 [0.65, 1.01]

2 Major bleeding Show forest plot	5	12521	Risk Ratio (M‐H, Fixed, 95% CI)	0.79 [0.67, 0.92]

Comparison 6. Direct oral anticoagulants versus warfarin: fixed‐effect model

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