Treatment of deep vein thrombosis and risk of recurrent venous thromboembolism

Abstract: A cute deep vein thrombosis (DVT) and pulmonary embolism (PE) are different clinical presentations of the same underlying disease, namely venous thromboembolism (VTE), which is a common and potentially fatal condition. Risk factors associated with the first and probably also subsequent events of VTE are hereditary or acquired. Regarding recurrent VTE the risk persists for many years after the first episode and is increased approximately 50 times compared with the risk of the first event in the general population. The traditional treatment of VTE has for decades been unfractionated. heparin (UFH) given intravenously (i.v.) or subcutaneously (s.c.). Low-molecular-mass hepatitis (LMMHs) have been developed and are characterized by the following pharmacokinetic benefits compared with UFH: higher bioavailability; longer half-life in plasma and an improved dose response after s.c. administration. The aims of our studies (Paper I-III) were to investigate the efficacy and safety in the treatment of acute DVT with a LMMH (dalteparin) administered s.c. once daily in the dose of 200 U per kg bodyweight compared with UFH i.v., and secondly, whether this new regimen could be utilized in an outpatient setting. We have demonstrated that the efficacy, assessed as changes of venograms between inclusion, after initial treatment and 6 months later, were similar in dalteparin (n=101) and UFH (n=103) treated patients (Paper I and III). The safety defined as frequency of bleeding events was also comparable. In a safety assessment and health economy outpatient study (Paper II) using this dalteparin regimen the combined frequency of major bleeding and recurrent VTE was 0.92% (95% confidence interval 0.25-2.35%), which is lower than in in-hospital trials. Deficiencies of the coagulation inhibitors antithrombin, protein C and protein S, as well as the mutations G1691->A and G20210->A in the coagulation factor V (FV) and prothrombin (FII) genes, respectively, are important risk factors for the first episode of VTE. Impaired fibrinolysis and the presence of antibodies against cardiolipin have also been associated with VTE. In a prospective open study (Paper IV) we intervened with recommendations of a changed lifestyle (low-fat diet, weight reduction, physical exercise, cessation of smoking) in patients with VTE and impaired fibrinolysis, defined as increased level of plasminogen activator inhibitor-1 (PAI-1) in plasma. In 65% of 144 patients at least one of four life-style improvements was achieved and the more improvements the greater reduction in PAI-1 levels. However, the frequency of recurrent VTE episodes during 6 years of follow-up did not correlate with these improvements. In an open randomized multicenter trial (DURAC-1) 902 patients with objectively verified VTE received oral anti- vitamin K therapy for 6 weeks or for 6 months after the acute event. We followed 534 of these patients aged <70 years at inclusion, for 48 months after their index event and obtained blood samples retrospectively for analyses of the G1691A and G20210A allele in the FV and FII genes, respectively (Paper V). The aim was to investigate the risk of recurrent VIE in carriers of these mutations. This risk in heterozygotes for the G1691A allele was not different from that in non-carriers (15.4% vs 13.0%). Homozygotes had an increased risk (p=0.036) of recurrent VTE. The risk of recurrent VTE for G20210A carriers was not different from that in non-carriers. However, this risk was significantly increased in patients with an idiopathic cause or a proximal extension of DVT or with PE at the index event, independent of the mutations discussed here. Of the patients in DURAC-1 trial with a first episode of DVT initially (n=790) 175 and 43 experienced recurrent DVT and PE, respectively (Paper VI). A recurrent thrombosis in the contra- and ipsilateral leg was diagnosed in 95 and 80 patients, respectively. No variable was associated with the side of recurrent event, except that ipsilateral DVT was significantly more frequent within 6 months only among those randomized to 6 weeks of oral anti-vitamin K therapy. In conclusion, the dalteparin regimen used in our studies is well tolerated and effective in defined patient categories in an outpatient setting and allows for substantial cost savings. Our studies emphasize the persistent and continuous risk of recurrent VTE in a long-term perspective for many patients. An increased risk of recurrent VTE has been documented in patients with an idiopathic cause, proximal DVT or PE at the index event and for homozygotes of the G1691A mutation. The risk of recurrent ipsi- and contralateral DVT was similar.