Vitamin K for reversal of excessive vitamin K antagonist anticoagulation: a systematic review and meta-analysis

Rasha Khatib, Maja Ludwikowska, Daniel M. Witt, Jack Ansell, Nathan P. Clark, Anne Holbrook, Wojtek Wiercioch, Holger Schünemann and Robby Nieuwlaat

Data supplements

Article Figures & Data



  • Table 1.

    Characteristics of included studies

    ReferenceCountryNo. of randomized patientsBaseline INRType of VKAVKA indicationTreatment*Follow-up duration, d
    Fondevila 200122Argentina109Treatment, 8.4 (6.0-19.6); control, 8.1 (6.0-14.1)ANRIntervention, 1 mg oral vitamin K; comparison: observation7
    Crowther 200020Canada92Treatment, 5.4 (4.5-9.8); control, 5.9 (4.5-9.8)WNRIntervention, 1 mg oral vitamin K; comparison: placebo30
    Patel 200017United States30Treatment, 7.2 (6.0-9.2); control, 7.0 (6.1-9.5)WVTE, 27%; AF, 44%; CVD, 7%; LVD, 13%; other, 10%Intervention, 2.5 mg oral vitamin K; comparison: placeboNot specified
    Ageno 200219Italy, Canada60Treatment, 6.2; control, 6.0AVTE, 32%; AF, 67%; stroke prophylaxis, 1%Intervention, 1 mg oral vitamin K; comparison: observation30
    Ageno 200518Italy, United States59Treatment, 7.2; control, 7.7WMechanical heart value, 100%Intervention, 1 mg oral vitamin K; comparison: observation30
    Crowther 200921Canada, United States, Italy724Treatment, 6.0 (4.5-9.9); control, 5.8 (4.5-9.5)WThromboembolism treatment or prevention, AF, or artificial heart valveIntervention, 1.25 mg oral vitamin K; comparison: placebo90
    • A, acenocoumarol; AF, atrial fibrillation; CVD, cardiovascular disease; LVD, left ventricular dysfunction; NR, not reported; W, warfarin.

    • * All included studies withheld vitamin K antagonist administration in the treatment and control groups.

    • Study fulfilled the inclusion criteria but reported 0 events and was therefore not included in the meta-analysis.

    • Patients may have more than 1 indication for VKA.

  • Table 2.

    GRADE evidence table

    Quality assessmentSummary of findings
    No. of participants (studies)Risk biasInconsistencyIndirectnessImprecisionPublication biasOverall quality of evidenceStudy event rates (%)RE (95% CI)Anticipated absolute effects
    Temporary cessation of VKA aloneTemporary cessation of VKA + vitamin K administrationRisk with temporary cessation of VKA aloneRisk difference with temporary cessation of VKA + vitamin K administration (range)
    Mortality (follow-up: 30-90 d; assessed with all-cause mortality)
     860 (3 RCTs)NSNSNSS*None⊕⊕⊕○ Moderate13/439 (3.0)16/421 (3.8)RR = 1.24 (0.62-2.47)30 per 10007 more per 1000 (11 fewer-44 more)
    Major bleeding (follow-up: mean, 90 d; assessed with fatal bleeding or bleeding requiring blood transfusion or admission)
     801 (2 RCTs)NSNSNSS*None⊕⊕⊕○ Moderate4/409 (1.0)10/392 (2.6)RR = 2.43 (0.81-7.27)10 per 100014 more per 1000 (2 fewer-61 more)
    Any thromboembolism (follow-up: mean, 90 d; assessed with venous or arterial thromboembolism)
     801 (2 RCTs)NSNSNSS*None⊕⊕⊕○ Moderate4/409 (1.0)5/392 (1.3)RR = 1.29 (0.35-4.78)10 per 10003 more per 1000 (6 fewer-37 more)
    Proportion reaching goal INR (follow-up: mean, 1 d; assessed with INR goal ranges: INR, 1.8-3.2; INR, 2.3-4.5; and INR, 2.0-4.0)
     1025 (5 RCTs)SSNSS*None⊕○○○ Very low90/518 (17.4)218/507 (43.0)RR = 1.95 (0.88-4.33)174 per 1000165 more per 1000 (21 fewer-579 more)
    • Overall quality of evidence measured according to GRADE criteria.

    • RE, relative effect; NS, not serious; S, serious.

    • * Lower and upper bounds of 95% CI may lead to different recommendations.

    • Four of the 5 studies did not blind patients and personnel, or outcome assessors.

    • I2 = 93%.