Venous thromboembolism is the presence of a blood clot that blocks a blood vessel within the venous system; it includes deep vein thrombosis (DVT) and pulmonary embolism (PE), which can be fatal. Venous thromboembolism occurs in 40% to 60% of patients after major orthopedic surgery.
Venous thromboembolism is usually treated for a minimum of five days with an anticoagulant administered by injection－either unfractionated heparin or low molecular weight heparin－together with warfarin dose titration. Achieving a therapeutic international normalized ratio (INR) as soon as possible while taking warfarin is important because this minimizes the duration of medication given via injections, infusions, etc, necessary to attain immediate anticoagulation and potentially decreases costs and inconvenience. Although a 5-mg loading-dose nomogram tends to prevent excessive anticoagulation, a 10-mg loading-dose nomogram may achieve a therapeutic INR more quickly.
Study characteristics and key results
This review of four studies with a total of 494 participants (current until June 2015) found that in patients with acute thromboembolism aged 18 years or older, considerable uncertainty surrounds the use of a 10-mg or a 5-mg loading dose for initiation of warfarin to achieve an INR of 2.0 to 3.0 on the fifth day of therapy. A benefit of 10-mg warfarin compared with 5-mg warfarin was observed for the proportion of patients with VTE who had achieved a therapeutic INR by day five but the quality of the evidence was moderate due to the differences among analyzed studies. In addition, no differences were observed between 5-mg and 10-mg nomograms for recurrent venous thromboembolism, major and minor bleeding, and length of hospital stay. Studies with high-quality evidence regarding the efficacy of 5-mg and 10-mg warfarin nomograms are needed.
Quality of the evidence
The quality of the evidence was moderate for therapeutic INR and major bleeding, low for recurrent VTE and length of hospital stay, and very low for minor bleeding. The main reason for downgrading the quality of the evidence was differences between the studies in types of study participants and length of follow-up.
In patients with acute thromboembolism (DVT or PE) aged 18 years or older, considerable uncertainty surrounds the use of a 10-mg or a 5-mg loading dose for initiation of warfarin to achieve an INR of 2.0 to 3.0 on the fifth day of therapy. Heterogeneity among analyzed studies, mainly caused by differences in types of study participants and length of follow-up, limits certainty surrounding optimal warfarin initiation nomograms.
Venous thromboembolism (VTE) is a common condition in hospital patients. Considerable controversy is ongoing regarding optimal initial warfarin dosing for patients with acute deep venous thrombosis (DVT) and pulmonary embolism (PE). Achieving a therapeutic international normalized ratio (INR) with warfarin as soon as possible is important because this minimizes the duration of parenteral medication necessary to attain immediate anticoagulation, and it potentially decreases the cost and inconvenience of treatment. Although a 5-mg loading-dose nomogram tends to prevent excessive anticoagulation, a 10-mg loading-dose nomogram may achieve a therapeutic INR more quickly. This is an update of a review first published in 2013.
To evaluate the efficacy of a 10-mg warfarin nomogram compared with a 5-mg warfarin nomogram among patients with VTE.
For this update the Cochrane Vascular Trials Search Co-ordinator searched the Specialised Register (last searched September 2015) and the Cochrane Register of Studies (CENTRAL (2015, Issue 8). Clinical trials databases were also searched. The review authors searched PubMed (last searched 11 June 2015) and LILACS (last searched 11 June 2015). In addition, the review authors contacted pharmaceutical companies.
Randomized controlled studies comparing warfarin initiation nomograms of 10 and 5 mg in patients with VTE.
Two review authors independently assessed trial quality and extracted data. The review authors contacted study authors for additional information.
Four trials involving 494 participants were included. Three studies involving 383 participants provided data on the proportion of participants who had achieved a therapeutic INR by day five. Significant benefit of a 10-mg warfarin nomogram was observed (risk ratio (RR) 1.27, 95% confidence interval (CI) 1.05 to 1.54; moderate quality evidence), although with substantial heterogeneity (I2 = 90%). The review authors analyzed each study separately because it was not possible to perform a subgroup analysis by inpatient or outpatient status. One study showed significant benefit of a 10-mg warfarin nomogram for the proportion of outpatients with VTE who had achieved a therapeutic INR by day five (RR 1.78, 95% CI 1.41 to 2.25), with the number needed to treat for an additional beneficial outcome (NNTB = 3, 95% CI 2 to 4); another study showed significant benefit of a 5-mg warfarin nomogram in outpatients with VTE (RR 0.58, 95% CI 0.36 to 0.93) with NNTB = 5 (95% CI 3 to 28); a third study, consisting of both inpatients and outpatients, showed no difference (RR 1.08, 95% CI 0.65 to 1.80).
No difference was observed in recurrent venous thromboembolism at 90 days when the warfarin nomogram of 10 mg was compared with the warfarin nomogram of 5 mg (RR 1.48, 95% CI 0.39 to 5.56; 3 studies, 362 participants, low quality evidence); no difference was observed in major bleeding at 14 to 90 days (RR 0.97, 95% CI 0.27 to 3.51; 4 studies, 494 participants, moderate quality evidence). No difference was observed in minor bleeding at 14 to 90 days (RR 0.52, 95% CI 0.15 to 1.83; 2 studies, 243 participants, very low quality evidence) or in length of hospital stay (mean difference (MD) -2.3 days, 95% CI -7.96 to 3.36; 1 study, 111 participants, low quality evidence).