Institutionen för medicin / Department of Medicine
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