Rosuvastatin use to improve the coagulation profile in patients with venous thrombosis: The STAtins Reduce Thrombophilia (START) Study

Venous thrombosis affects 2-3 per thousand inhabitants per year, has a 2.6%
immediate death rate and recurrence rates of 25% within 5 years. Recurrence
usually leads to life-long anticoagulant treatment, which has serious potential
side effects, most notably major bleeding. Moreover, epidemiological studies
have shown a 2-3 fold increased long-term risk of arterial cardiovascular
disease after venous thrombosis, most predominant in the first year following
initial venous thrombosis. The results of recent observational studies that
showed 40-50% risk reductions for first venous thrombosis occurrence when using
a statin are in this aspect promising. However, these results are primarily
obtained from non randomised studies, and therefore leave open the possibility
of confounding issues. The results are also somewhat surprising, because the
mechanism behind this effect is unclear. Dyslipidaemia may be the most
plausible explanation to be considered. However, as dyslipidaemia is not
related to an increased risk of venous thrombosis, it is unlikely that statins
decrease venous thrombosis risk by lipid lowering activities. Recent
observations indicated that coagulation can activate the initial formation of
atherosclerosis. Our hypothesis is therefore that the coagulation profile in
persons with venous thrombosis is improved when using a statin, ultimately
leading to less atherosclerosis: another well known property of statin use.
Such a causal relation makes the observation that statins decrease venous
thrombosis risk biologically plausible. A confirmation of our hypothesis will
be an important step towards a rationale for conducting randomised clinical
trials of statin/placebo with recurrent venous thrombosis as outcome event.

To understand why statins are able to decrease the risk of developing venous
thrombosis, by analyzing whether statins can influence pathways that inhibit
coagulation.

Prospective randomised controlled, open label, clinical trial.

After informed consent, participants will be screened on acquired risk factors
for thrombosis through a questionnaire and tested on blood parameters that may
exclude a particpant from taking rosuvastatin (baseline visit). After a time
window of four weeks (to allow a wear off of anticoagulant drugs), a blood
sample (approximately 25 mL) will be drawn at randomisation visit. At
randomisation, participants will be allocated to receive either rosuvastatin 20
mg/day or no study medication. The study will be continued for 28 days. After
stopping rosuvastatin one month later, a final blood sample will be drawn.
Blood will be sampled for the measurement of specific inflammatory, endothelial
and coagulation factors (of which high or low levels are known to increase the
risk). The study is powered on coagulation factor VIII, as a high factor VIII
level is well associated with recurrent venous thrombosis. With an amount of
2*125=250 participants, we should be able to find a mean difference of 17 IU/dL
with alpha=0.05/beta=0.80. The expected inclusion time is 1.5 years.

The risks that are related to this study are related to risks of blood
withdrawal and rosuvastatin use. A maximum of 60 ml of blood will be drawn per
participant. The use of riosuvastatin leads very rarely to side effects
(0.01-0.1% of cases). Most frequuent side effects are muscle ache and
gastrointestinal side effects.