Clinical trial NCT02331095: Statin Use in Patients With Acute VTE
Official title: A Pilot Study of Using Statins in Patients With Acute Venous Thromboembolism (VTE)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: EARLY_PHASE1
Conditions: Venous Thromboembolism
Lead sponsor: Ohio State University
Sponsor class: OTHER
First posted: 2015-01-06
Enrollment: 21
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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, Interleukin- 6 (IL-6), Interleukin-8 (IL-8), tumor necrosis factor (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.

Eligibility criteria: 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 upper limit of normal (ULN)
* 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.

Primary outcomes:
measure: The Reduction of Endogenous Thrombin Potential
timeFrame: 3 Months
measure: The Reduction of Peak Thrombin Concentration
timeFrame: 3 Months
Secondary outcomes:
measure: The Composite Rate of Recurrent Venous Thromboembolism (VTE) and VTE Related Mortality
timeFrame: 3 months and 9 months
measure: The Rate of Arterial Thrombotic Events
timeFrame: 3 months and 9 months
measure: The Rate of Residual (Chronic) Vein Obstruction by Doppler Ultrasound
timeFrame: 3 Months
measure: The Reduction of Clinical Post-thrombotic Syndrome (PTS), as Objectively Evaluated With Villalta Scoring System
timeFrame: 3 Months
measure: The Rate of Major, Non-major, and All Hemorrhages Defined by the International Society on Thrombosis and Haemostasis (ISTH) Criteria
timeFrame: 3 months and 9 months
measure: Change in the Levels of D-Dimer at 3 Months
timeFrame: 3 Months
measure: Change in the Levels of C-Reactive Protein at 3 Months
timeFrame: 3 Months
measure: Change in Low-Density Lipoproteins (LDL) at 3 Months
timeFrame: 3 Months
measure: Change in Triglyceride Levels at 3 Months
timeFrame: 3 Months
Other outcomes:
Locations:
city: Columbus
country: United States
facility: The Ohio State University Medical Center
state: Ohio
Study officials:
affiliation: Ohio State University
name: Tzu-Fei Wang, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Wang TF, Waller AP, Lin E, Wei L, Bartosic A, Riedl K, Kerlin BA. A pilot randomized trial of atorvastatin as adjunct therapy in patients with acute venous thromboembolism. Blood Coagul Fibrinolysis. 2021 Jan 1;32(1):16-22. doi: 10.1097/MBC.0000000000000968.