Statins for Venous Event Reduction in Patients With Venous Thromboembolism (SAVER)

The standard or usual treatment for patients diagnosed with deep vein thrombosis or pulmonary embolism is treatment with blood thinners (called anticoagulants).

While treatment of blood clots with blood thinners is effective, some research has shown that adding a statin (medication used to lower cholesterol) may give extra protection. It is thought that statins can improve how cells along the walls of the vein control inflammation, which can prevent new blood clots from forming.

The medication in this study, rosuvastatin, is approved in Canada for use as a cholesterol-lowering medication. The use of rosuvastatin in this study is considered investigational. This means that Health Canada has not approved the use of rosuvastatin as a treatment for blood clots. However, it has been approved for use in this research study.

The purpose of this study is to examine if adding a statin (rosuvastatin) to the usual blood thinner treatment will decrease the risk of another blood clot forming. The investigators also hope to discover if taking a statin reduces damage to your veins. To do this, some of the participants in this study will get rosuvastatin and others will receive a placebo (a substance that looks like the study rosuvastatin but does not have any active or medicinal ingredients). The placebo in this study is not intended to have any effect on your blood clot. A placebo is used to make the results of the study more reliable.

Study Overview

• Status: Recruiting
• Conditions: Venous Thromboembolism; Post Thrombotic Syndrome; Blood Clot
• Intervention / Treatment: Drug: Rosuvastatin Calcium; Drug: Placebo Oral Tablet

Detailed Description

Recent research has demonstrated that it is plausible that statins have additive, and potentially even synergistic effects, in reducing recurrent VTE in patients managed with anticoagulant-based strategies. Furthermore, it is plausible that statins may reduce the risk of recurrent VTE in those not on anticoagulants and therefore offer an alternative in patients with contraindications to anticoagulants (e.g. after major intracranial bleed), who refuse to take anticoagulants long-term (e.g. due to lifestyle modifications or fear of bleeding) or who cannot afford anticoagulants (e.g. vulnerable or impoverished populations). Finally, statins may also provide protection from recurrent VTE in patients who are not fully compliant with anticoagulant therapy. However, no known RCTs have been done to explore these possibilities.

This study aims to determine if generic rosuvastatin reduces the risk of recurrent VTE compared to placebo in patients with symptomatic major VTE.

Primary Objectives

- To determine the primary outcome event rate (i.e. symptomatic recurrent major VTE [proximal DVT or segmental or larger PE]) in patients taking generic rosuvastatin compared to placebo.

Secondary Objectives

• To determine the major bleeding event rate in patients taking generic rosuvastatin compared to placebo.
• To explore if rosuvastatin reduces the incidence of PTS, as measured by the Villalta scale at end of study.

• Study Type: Interventional
• Enrollment (Estimated): 2700
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Jennifer Brinkhurst; Phone Number: 71068 +16137378899; Email: jbrinkhurst@ohri.ca

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 2T9
      • Recruiting
      • Foothills Medical Centre
      • Contact: Jill Baxter
      • Principal Investigator: Leslie Skeith, MD
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 2Y9
      • Recruiting
      • Queen Elizabeth II Hospital
      • Principal Investigator: Sudeep Shivakumar, MD
  • Ontario
    • Hamilton, Ontario, Canada, L8L 2X2
      • Recruiting
      • Hamilton General Hospital
      • Principal Investigator: Sam Schulman, MD
    • Hamilton, Ontario, Canada, L8N 4A6
      • Not yet recruiting
      • St. Joseph's Healthcare
      • Principal Investigator: Jim Douketis, MD
    • Hamilton, Ontario, Canada, L8V 1C3
      • Recruiting
      • Juravinski Hospital
      • Principal Investigator: Peter Gross, MD
    • Ottawa, Ontario, Canada, K1H 8L6
      • Recruiting
      • The Ottawa Hospital
      • Contact: Jennifer Brinkhurst; Phone Number: 71068 6137378899; Email: jbrinkhurst@ohri.ca
      • Principal Investigator: Aurélien Delluc, MD
    • Ottawa, Ontario, Canada, K1K 0T2
      • Recruiting
      • Hopital Montfort
      • Contact: Melanie Potvin
      • Principal Investigator: Miriam Kimpton, MD
    • St. Catharines, Ontario, Canada, L2S 0A9
      • Recruiting
      • Niagara Health - St. Catharines Site
      • Contact: Kailee Morrison
      • Principal Investigator: Blair Leonard, MD
    • Toronto, Ontario, Canada, M4N 3M5
      • Not yet recruiting
      • Sunnybrook Hospital
      • Principal Investigator: Jean-Philippe Galanaud, MD
    • Toronto, Ontario, Canada, M5G 2C4
      • Not yet recruiting
      • University Health Network
      • Principal Investigator: Erik Yeo, MD
  • Quebec
    • Montreal, Quebec, Canada, H3T 1E2
      • Recruiting
      • Jewish General Hospital
      • Principal Investigator: Susan Kahn, MD
    • Montreal, Quebec, Canada, H4A 3J1
      • Recruiting
      • McGill Univeristy Health Centre
      • Principal Investigator: Véronique Naessens, MD
    • Quebec City, Quebec, Canada, G1V 4G2
      • Recruiting
      • CHU de Quebec-Universite Laval
      • Principal Investigator: Guillaume Roberge, MD
• France
  • Brest, France
    • Not yet recruiting
    • Brest University Hospital Centre
    • Principal Investigator: Raphael Le Mao, MD
• Ireland
  • Dublin, Ireland
    • Not yet recruiting
    • Mater Misericordiae University Hospital
    • Principal Investigator: Fionnuala Ní Áinle, MD
• Italy
  • Varese, Italy
    • Not yet recruiting
    • University of Insubria
    • Principal Investigator: Walter Ageno, MD
• Netherlands
  • Holland
    • Amsterdam, Holland, Netherlands, 1098XH
      • Not yet recruiting
      • Amsterdam University
      • Principal Investigator: Michiel Coppens, MD
• Norway
  • Sarpsborg, Norway
    • Not yet recruiting
    • Ostfold Hopsital
    • Principal Investigator: Waleed Ghanima, MD
    • Contact: Sven Arne Sogn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Symptomatic objectively confirmed proximal leg DVT (above the trifurcation of the popliteal vein) and/or PE (segmental or greater) diagnosed in the last 30 days.

Exclusion criteria

1. Unable or unwilling to provide written informed consent;
2. ≤ 18 years of age;
3. Women of childbearing potential unwilling to use appropriate contraception;
4. Currently prescribed a statin;

5. A known medical history or current diagnosis of any of the following for which statins are indicated in secondary prevention:

   1. Diabetes;
   2. Abdominal aortic aneurysm;
   3. Peripheral arterial disease;
   4. Stroke;
   5. Transient ischemic attack (TIA);
   6. Myocardial infarction (MI);
   7. Acute coronary syndromes;
   8. Stable/unstable angina;
   9. Coronary or other arterial revascularization;
6. Known diagnosis of hypercholesterolemia or dyslipidemia;

7. Contraindication to rosuvastatin;

   1. Known hypersensitivity or intolerance to statins;
   2. History of muscle disorders or statin-related muscle pain;
   3. Known liver disease (active liver disease, e.g. Hepatitis A, B, C, non-alcoholic fatty liver);
   4. Chronic kidney disease (creatinine clearance < 30ml/min);
   5. Currently pregnant or breast feeding;
   6. Taking cyclosporine;
   7. Taking atazanavir/ritonavir;
   8. Taking darolutamide;
   9. Taking regorafenib;
8. Unstable medical or psychological condition that would interfere with trial participation.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Rosuvastatin; Participants randomized to the experimental arm will take one rosuvastatin 20 mg tablet by mouth every day for the duration of their participation in the study.	Drug: Rosuvastatin Calcium; Each participant will receive the usual treatment for their newly diagnosed blood clot in addition to the intervention they are randomized to.; Other Names: Rosuvastatin
Placebo Comparator: Placebo; Participants randomized to the control arm will take one placebo tablet by mouth every day for the duration of their participation in the study.	Drug: Placebo Oral Tablet; Each participant will receive the usual treatment for their newly diagnosed blood clot in addition to the intervention they are randomized to.; Other Names: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Recurrent Major VTE	Symptomatic recurrent major VTE (proximal DVT or segmental or larger PE) occurring between randomization and the end of follow-up (i.e. completion of the trial) in patients taking generic rosuvastatin as compared with placebo.	Up to 60 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Post Thrombotic Syndrome	Post-thrombotic syndrome as measured by the Villalta scale throughout the follow-up period in patients taking generic rosuvastatin as compared with placebo. The Villalta PTS scale has been adopted by the International Society on Thrombosis and Haemostasis (ISTH) as a standard to diagnose and grade the severity of PTS in clinical studies. Points are summed to yield total score: 0-4: No PTS; 5-9: Mild PTS; 10-14: Moderate PTS; 15 or more, or presence of ulcer: Severe PTS.	Up to 60 months
Number of participants diagnosed with non-major VTE during follow-up	Symptomatic non-major VTE (see below) occurring between randomization and the end of follow-up (i.e. completion of the trial) in patients taking generic rosuvastatin as compared with placebo. Non-major VTE: Distal DVT (distal to the trifurcation of the popliteal vein);; Isolated sub-segmental PE;; Upper extremity DVT;; Superficial phlebitis > 5 cm;; Superficial phlebitis ≤ 5 cm.	Up to 60 months
Number of participants diagnosed with an arterial vascular event during follow-up	Components of composite arterial vascular events (see below) occurring between randomization and the end of follow-up (i.e. completion of the trial) in patients taking generic rosuvastatin as compared with placebo. Components of composite arterial vascular events: Fatal myocardial infarction;; Non-fatal myocardial infarction;; Hospitalization for unstable angina;; Coronary artery revascularization;; Sudden cardiac death;; Ischemic stroke.	Up to 60 months
Number of deaths during study participation	All-cause mortality occurring between randomization and the end of follow-up (i.e. completion of the trial) in patients taking generic rosuvastatin as compared with placebo.	Up to 60 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants who have a bleeding event during follow-up	Bleeding event (major, clinically relevant non-major, minor) occurring between randomization and the end of follow-up (i.e. completion of the trial) in patients taking generic rosuvastatin as compared with placebo.	Up to 60 months

Collaborators and Investigators

• Sponsor: Ottawa Hospital Research Institute
• Investigators: Principal Investigator: Aurélien Delluc, MD, Ottawa Hospital Research Institute

Study record dates

Study Major Dates

• Study Start (Actual): February 10, 2021
• Primary Completion (Estimated): January 1, 2026
• Study Completion (Estimated): January 1, 2027

Study Registration Dates

• First Submitted: March 20, 2020
• First Submitted That Met QC Criteria: March 23, 2020
• First Posted (Actual): March 24, 2020

Study Record Updates

• Last Update Posted (Actual): May 31, 2023
• Last Update Submitted That Met QC Criteria: May 30, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: Statin; Rosuvastatin; VTE; PTS
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Embolism and Thrombosis; Venous Thrombosis; Peripheral Vascular Diseases; Venous Insufficiency; Phlebitis; Thrombosis; Thromboembolism; Venous Thromboembolism; Postthrombotic Syndrome; Postphlebitic Syndrome; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Calcium-Regulating Hormones and Agents; Rosuvastatin Calcium; Calcium
• Other Study ID Numbers: SAVER Trial

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No