Statin Use in Patients With Acute VTE

VTE is a potentially life-threatening disease, with an estimated incidence of 1-2 per 1000.
Despite anticoagulation as standard of care, many patients still suffer from its
complications: 30% will have VTE recurrence after an unprovoked VTE, and 25-50% will develop
post-thrombotic syndrome. Therefore, there is an urgent need for effective therapies to
reduce long-term VTE morbidities. Limitations in our understanding of the underlying
pathophysiology of VTE and the absence of accurate biomarkers are significant problems.
Without this knowledge, improvement in treatment is unlikely. Therefore, the overall
objective of the study is to determine important biomarker changes in acute VTE and the
actions of innovative adjunct therapy on those biomarkers. The rationale of the study is
that, once the biomarker changes following acute VTE and the actions of therapies are
established, treatment for acute VTE could be improved.

Statins are effective in the prevention of arterial thrombosis. Recently, arterial and venous
thromboses are shown to share common pathophysiological mechanisms, and effective therapies
for arterial thrombosis could provide benefits in VTE. Several observational studies and the
JUPITER trial, a large, randomized, placebo-controlled study, have demonstrated that statins
significantly reduce the risk of first VTE by 40%. Additionally, as few as 3 days of
atorvastatin increase plasma fibrin clot permeability and susceptibility to lysis. Statins
have been commonly prescribed for many other medical conditions such as coronary artery
diseases and hyperlipidemia, and have demonstrated good safety profiles. These promising
results, as well as their safety profiles, make statins an attractive potential addition to
the standard anticoagulation for treating acute VTE, in an effort to reduce long-term
morbidity. The effects of statins on thrombin generation in patients with acute VTE have not
been studied. A study in patients with atrial fibrillation on warfarin showed a 40% reduction
in endogenous thrombin potential with only three months of intensive cholesterol-lowering
treatment including statins. Similar effects could be seen in patients with acute VTE. In
addition, previous studies evaluating the effects of statins on the reduction of D-dimer or
inflammatory cytokines revealed promising results but were not focused on patients with acute
VTE. Therefore, this study will generate important information for acute VTE patients. This
is a pilot, randomized, open-labelled study. Eligible patients will be enrolled and
randomized 1:1 into "anticoagulation" arm or "anticoagulation plus atorvastatin" arm, with
atorvastatin given at 40 mg orally daily for 3 months. The targeted total accrual is 80
patients, with 40 in each arm. Patients will be recruited from the hospitals and clinics at
The Ohio State University Wexner Medical Center. Follow up visits are planned at enrollment,
3 months, and 9 months after randomization. At each follow up, blood will be obtained and
assessments will include structured interviews of signs and symptoms of recurrent venous
thromboembolism (VTE), bleeding, post thrombotic syndrome, and adverse events from study
drugs. The primary objective of the study is to determine the reduction of thrombin peak
concentration and/or endogenous thrombin potential measured by Thrombin Generation Assay
(TGA) at 3 months in the "anticoagulation +atorvastatin" arm as compared to the
"anticoagulation" arm. The secondary objectives are to determine the chronological changes of
hemostatic, inflammatory, and lipidomic biomarker profiles in patients with acute VTE
receiving anticoagulation as standard of care, with and without statins. The biomarker
profile of interest, in addition to thrombin generation, include: D-dimer, IL-6, IL-8, TNF-α,
high sensitivity C-reactive protein, free fatty acids, lipoprotein-associated phospholipase
A2 , pro- inflammatory eicosanoids. The ultimate goal is to study the mechanisms of VTE and
use of statin in VTE patients. Other secondary objectives include determination of relevant
clinical outcomes such as VTE recurrence, VTE related mortality, arterial thrombosis,
hemorrhage, post thrombotic syndrome, and residual vein obstruction in patients receiving
standard of care versus standard of care plus statins.

Inclusion Criteria:

- At least 18 years old

- A diagnosis of proximal DVT (proximal to and including popliteal vein), with or
without PE, confirmed by objective imaging studies, such as Doppler ultrasound,
venograms (for DVT) and/or computer tomography, angiograms, ventilation-perfusion scan
(for PE)

- Treated with warfarin as anticoagulation (short-term bridging with heparin or lovenox
is allowed)

Exclusion Criteria:

- Thrombolysis within 6 weeks prior to enrollment

- Patients with statin use within 6 weeks of enrollment

- Patients with known allergy or intolerance to statins or statins are contraindicated
for any other reasons

- Patients with baseline aspartate aminotransferase (AST), alanine aminotransferase
(ALT), or total bilirubin ≥2.0 x ULN (upper limit of normal)

- Pregnant or breastfeeding females are excluded

- Any malignancy diagnosed within the preceding 2 years, except for squamous cell
carcinoma or basal cell carcinoma of skin treated with local resection only, or
carcinoma in situ of the cervix

- Incarcerated patients are excluded from the study due to the inherent difficulties in
maintaining close follow-up for study purposes in patients who are incarcerated.