Risk factor profiling for future arterial cardiovascular events in patients wih unprovoked pulmonary embolism

Acute pulmonary embolism (PE) is a frequent problem occurring in around 0.7 *
1.0 per 1000 inhabitants per year in the Netherlands. Several studies have
observed an increased risk of arterial cardiovascular events occurring during
follow-up after PE. One prospective study demonstrated a higher incidence of
arterial cardiovascular events in patients with unprovoked pulmonary embolism
(PE) than in those with PE
associated with transient risk factors (e.g. post surgery, immobilization,
pregnancy, etcetera; relative risk [RR] 7.2; 95%CI, 1.71-30.45).[1] In a second
study, the incidence of fatal and non-fatal arterial cardiovascular events was
15% in patients with unprovoked VTE and 8.5% in patients with provoked VTE
(adjusted hazard ratio [HR] 1.6; 95%CI, 1.2*2.0).[2] Importantly, in neither of
the studies individualised patient data explaining
the increased risk for arterial cardiovascular events were available.
Identification of patients at high risk for arterial cardiovascular events is
very relevant since these patients may benefit from modified treatment regimens
including preventive use of antiplatelet and cholesterol synthesis inhibiting
treatment. Thus, the identification of risk factors that predict the occurrence
of arterial cardiovascular events would be an important
step forward in the prevention of arterial cardiovascular events.
Several common, well established risk factors for both venous thromboembolism
and arterial cardiovascular events which could contribute to the association
between both disease entities have been identified. These include thrombogenic
factors (platelet function and markers of thrombogenesis); atherogenic risk
factors (classical atherogenic risk factors, inflammation and vessel wall
abnormalities).[3] These risk factors can be assessed by blood tests
(thrombogenic and atherogenic risk factors), determination of the Systematic
Coronary Risk Evaluation -score (SCORE-score) [4], and radiologic examination
for atherosclerotic vessel wall changes (Agatston calcium score by CT scan and
intima media thickness- plaque assessment of the carotid artery by
ultrasonography).[5,6] These risk factors have never been systematically and
prospectively assessed at baseline in a PE population.
In a recent retrospective study we have shown that 20% of patients with
unprovoked PE developed arterial cardiovascular events during 4 years of
follow-up; patients with provoked PE and patients without PE were shown to have
a risk of 5.0-7.0% (HR 2.18; 95% CI 1.1-4.5) .[7]

References
1. Becattini C, et al. Prospective study on cardiovascular events after acute
pulmonary embolism. Eur Heart J. 2005; 26:77-83.
2. Prandoni P, et al. Venous thromboembolism and the risk of subsequent
symptomatic atherosclerosis. J Thromb Haemost. 2006; 4:1891-6.
3. Ageno W, et al. Cardiovascular Risk Factors and Venous Thromboembolism: A
Meta-Analysis. Circulation 2008; 117; 93-102.
4. Conroy, Estimation of ten-year risk of fatal cardiovascular disease in
Europe. Euro Heart J. 2003; 24:987-1003.
5. Taylor, Coronary calcium independently predicts incident premature coronary
heart disease over measured cardiovascular risk factors: mean three-year
outcomes in the Prospective Army Coronary Calcium (PACC) project. JACC 2005;
46:807-14.
6. Bots M et al. Common carotid intima-media thickness and risk of stroke and
myocardial infarction: the Rotterdam Study. Circulation 1997; 96:1432-7.
7. Klok FA, Risk of arterial cardiovascular events in patients after pulmonary
embolism. Blood 2009; 114:1484-8.

Currently, no established risk factor profile for developing arterial
cardiovascular events after an acute unprovoked PE exists and is carried out in
general practice. The aim of our project is to prospectively study the relation
between presence and levels of risk factors for developing arterial
cardiovascular events after unprovoked PE and occurrence of arterial events
during follow-up.

Our objectives are:
1. to prospectively assess the presence of risk factors at baseline in patients
with unprovoked PE
2. to assess all arterial cardiovascular events during long term follow-up in
patients with unprovoked PE
3. to compare the presence and level of risk factors assessed at baseline in
patients with unprovoked PE who get arterial events during follow-up with those
in patients who do not get an arterial event during follow-up.

This is a prospective cohort-follow-up study in patients with unprovoked PE.

The burden of this study are 3 extra hospital visits.

Visit 1 is within one week of inclusion. In this visit carotid
initma-media-thickness will be measured by ultrasound and a coronary calcium
score will be calculated by CT. The radiation dose will be around 1.5mSv.

Visit 2 will be at 7 months (6 months vitamin K antagonists treatment and 1
month wash-out) from inclusion. During this visit blood will be drawn to assess
thrombogenic and endothelial risk factors for venous and arterial thrombosis,
which can not be measured at baseline due its unreliability during an acute
pulmonary embolism and the treatment phase.

Visit 3 will be the end-of-study visit.

Every year all patients are called in order to evaluate whether they reached a
study endpoint (arterial cardiovascular event)