Warfarin initiation nomograms for venous thromboembolism

Abstract

Background: 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. Objectives: To evaluate the efficacy of a 10-mg warfarin nomogram compared with a 5-mg warfarin nomogram among patients with VTE. Search methods: 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. Selection criteria: Randomized controlled studies comparing warfarin initiation nomograms of 10 and 5 mg in patients with VTE. Data collection and analysis: Two review authors independently assessed trial quality and extracted data. The review authors contacted study authors for additional information. Main results: 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 (I-2 = 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 inmajor 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). Authors' conclusions 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.