Statin Use in Patients With Acute VTE

NCT ID: NCT02331095

Last Updated: 2020-10-19

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: EARLY_PHASE1
• Total Enrollment: 21 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-01-31
• Study Completion Date: 2020-05-20

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.

Conditions

Venous Thromboembolism

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Anticoagulation

Patients will be treated with warfarin with dose adjusted to goal International Normalized Ratio (INR) of 2-3 or rivaroxaban standard dose (15 mg twice daily for 3 weeks then 20 mg daily)

Group Type: ACTIVE_COMPARATOR

Anticoagulation Therapy

Intervention Type: DRUG

Warfarin is a standard anticoagulation in the treatment for venous thromboembolism. The dose will be adjusted to goal INR of 2-3.

Atorvastatin + anticoagulation

In addition to standard anticoagulation, patients will be given concurrent atorvastatin 40 mg daily for the study period of 9 months, starting from the time of enrollment

Group Type: EXPERIMENTAL

Atorvastatin

Intervention Type: DRUG

Atorvastatin belongs to the "statin" class of drugs, and is routinely used for prevention of cardiovascular diseases and/or reduction of cholesterol levels. It has been shown to decrease the risk of first venous thromboembolism in an otherwise healthy population with elevated high-sensitivity C-reactive protein (hs-CRP).

Anticoagulation Therapy

Intervention Type: DRUG

Warfarin is a standard anticoagulation in the treatment for venous thromboembolism. The dose will be adjusted to goal INR of 2-3.

Interventions

Atorvastatin

Atorvastatin belongs to the "statin" class of drugs, and is routinely used for prevention of cardiovascular diseases and/or reduction of cholesterol levels. It has been shown to decrease the risk of first venous thromboembolism in an otherwise healthy population with elevated high-sensitivity C-reactive protein (hs-CRP).

Intervention Type: DRUG

Anticoagulation Therapy

Warfarin is a standard anticoagulation in the treatment for venous thromboembolism. The dose will be adjusted to goal INR of 2-3.

Intervention Type: DRUG

Other Intervention Names

Lipitor; warfarin or rivaroxaban

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Ohio State University

OTHER

Sponsor Role: lead

Responsible Party

Tzu-Fei Wang

Associate professor of Internal Medicine

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Tzu-Fei Wang, MD

Role: PRINCIPAL_INVESTIGATOR

Ohio State University

Locations

The Ohio State University Medical Center

Columbus, Ohio, United States

Countries

United States

References

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.

Reference Type: DERIVED

PMID: 33196511 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

2014H0262

Identifier Type: -

Identifier Source: org_study_id