Subcutaneous unfractionated heparin for the initial treatment of venous thromboembolism

Lindsay Robertson, James Strachan

Venous thromboembolism (VTE) is a prevalent and serious condition. Its medical treatment requires anticoagulation, usually with either unfractionated or low molecular weight heparin (LMWH). Administration of unfractionated heparin (UFH) is usually intravenous (IV) but can be subcutaneous as well. This is an update of a review first published in 2009. To assess the effects of subcutaneous UFH versus intravenous UFH, subcutaneous LMWH or any other anticoagulant drug for the initial treatment of venous thromboembolism. For this update, the Cochrane Vascular Information Specialist searched the Specialised Register (last searched 30 November 2016) and CENTRAL (2016, Issue 10). The Cochrane Vascular Information Specialist also searched trials registries for details of ongoing or unpublished studies. Randomised controlled trials comparing subcutaneous UFH to control, such as subcutaneous LMWH, continuous intravenous UFH or other anticoagulant drugs in participants with acute venous thromboembolism. Two review authors (JS and LR) independently extracted data and assessed the risk of bias in the trials. We used meta-analyses when we considered heterogeneity low. The primary outcomes were symptomatic recurrent venous thromboembolism (deep vein thrombosis and/or pulmonary embolism), VTE-related mortality, adverse effects of treatment including major bleeding, and all-cause mortality. We calculated all outcomes using an odds ratio (OR) with a 95% confidence interval (CI). We included one additional study in this update, bringing the total number of studies in the review to 16 randomised controlled trials, with a total of 3593 participants (1745 participants in the intervention group and 1848 participants in the control group). Eight trials used intravenous UFH as the control treatment, seven trials used LMWH, and one trial had three arms with both drugs as the controls. We did not identify trials comparing subcutaneous UFH with other anticoagulant drugs. We downgraded the quality of the evidence to low due to lack of blinding in studies, which led to a risk of performance bias, and also for imprecision, as reflected by the wide confidence intervals.When comparing subcutaneous versus IV UFH, there was no difference in the incidence of symptomatic recurrent VTE at three months (odds ratio (OR) 1.66, 95% confidence interval (CI) 0.89 to 3.10; 8 studies; N = 965; low-quality evidence), symptomatic recurrent deep vein thrombosis (DVT) at three months (OR 3.29, 95% CI 0.64 to 17.06; 1 study; N = 115; low-quality evidence), pulmonary embolism (PE) at three months (OR 1.44, 95% CI 0.73 to 2.84; 9 studies; N = 1161; low-quality evidence), VTE-related mortality at three months (OR 0.98, 95% CI 0.20 to 4.88; 9 studies; N = 1168; low-quality evidence), major bleeding (OR 0.91, 95% CI 0.42 to 1.97; 4 studies; N = 583; low-quality evidence) or all-cause mortality (OR 1.74, 95% CI 0.67 to 4.51; 8 studies; N = 972; low-quality evidence). There were no episodes of asymptomatic VTE occurring within three months of the commencement of treatment.When comparing subcutaneous UFH versus LMWH, there was no difference in the incidence of recurrent VTE at three months (OR 1.01, 95% CI 0.63 to 1.63; 5 studies; N = 2156; low-quality evidence), recurrent DVT at three months (OR 1.38, 95% CI 0.73 to 2.63; 3 studies; N = 1566; low-quality evidence), PE (OR 0.84, 95% CI 0.36 to 1.96; 5 studies, N = 1819; low-quality evidence), VTE-related mortality (OR 0.53, 95% CI 0.17 to 1.67; 8 studies; N = 2469; low-quality evidence), major bleeding (OR 0.72, 95% CI 0.43 to 1.20; 5 studies; N = 2300; low-quality evidence) or all-cause mortality (OR 0.73, 95% CI 0.50 to 1.07; 7 studies; N = 2272; low-quality evidence). There were no episodes of asymptomatic VTE occurring within three months of the commencement of treatment. There is no evidence of a difference between subcutaneous versus intravenous UFH for preventing VTE recurrence, VTE-related or all-cause mortality, and major bleeding. According to GRADE criteria, the quality of the evidence was low. There is also no evidence of a difference between subcutaneous UFH and LMWH for preventing VTE recurrence, VTE-related or all-cause mortality or major bleeding.