Microvascular and Antiinflammatory Effects of Rivaroxaban Compared to Aspirin in Type-2 Diabetic Patients With Subclinical Inflammation and High Cardiovascular Risk (MicroVasc-DIVA)

Microvascular and Antiinflammatory Effects of Rivaroxaban Compared to Low Dose Aspirin in Type-2 Diabetic Patients With Very High Cardiovascular Risk and Subclinical Inflammation

Study to investigate microvascular and antiinflammatory effects of Rivaroxaban compared to low dose aspirin in type 2 diabetic patients.

Especially patients with cardiovascular disease and subclinical inflammation are in the focus of interest.

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetic Patients
• Intervention / Treatment: Drug: Aspirin; Drug: Rivaroxaban

• Study Type: Interventional
• Enrollment (Actual): 179
• Phase: Phase 3

Contacts and Locations

Study Locations

• Germany
  • Berlin, Germany, 13125
    • Universitätsmedizin Berlin / Charité Campus Buch
  • Dresden, Germany, 01307
    • GWT-TUD GmbH / Studienzentrum Hanefeld
  • Dresden, Germany, 01279
    • Gemeinschaftspraxis Dr. Schaper/ Dr. Faulmann
  • Pirna, Germany, 01796
    • Cardiologicum Prina
  • Sachsen
    • Dresden, Sachsen, Germany, 01067
      • Krankenhaus Dresden-Friedrichstadt

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Type 2 diabetes duration between 2 and 20 years

• Two or more components of metabolic syndrome:

  • HDL-cholesterol < 1.0 mmol/L (in males) or < 1.3 mmol/L (in females)
  • Elevated triglycerides (> 1.7 mmol/L)
  • Elevated blood pressure (> 130 mmHg systolic and/or >85 mmHg diastolic or antihypertensive treatment)
  • Elevated waist circumference (> 102 cm in males, > 85 cm in females)

• Or at least one of the following

  • Carotid ultrasound showing an IMT > 1 mm and plaque of carotid artery or
  • Left ventricular hypertrophy or
  • Increased UACR in the absence of other renal diseases than diabetic nephropathy
• Increased hsCRP (> 2 mg/l but < 10 mg/l) at or within 6 months prior to screening and/or increased PAI 1 (> 15 ng/ml) at or within 6 months prior to screening (the historical hsCRP or PAI 1 value can be used only if the patient was in stable conditions regarding the concomitant diseases and statin therapy since the time point of measurement)
• Stable treatment with statins (if tolerated/clinically indicated)
• Age 40 - 75 years

Exclusion Criteria:

• Major cardiovascular (CV) event with need for oral anticoagulation or platelet inhibitor therapy or acute coronary syndrome < 12 month before study entry
• Sustained uncontrolled hypertension: systolic blood pressure > 180 mmHg or diastolic blood pressure > 100 mmHg
• Hypersensitivity to the active substance or to any of the excipients
• Active clinically significant bleeding
• Lesion or condition, if considered to be a significant risk for major bleeding
• Concomitant treatment of acute coronary syndrome (ACS) with antiplatelet therapy in patients with a prior stroke or a transient ischemic attack (TIA)
• Hepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhotic patients with Child Pugh B and C
• Chronic renal failure with eGFR < 15 ml/min (MDRD formula)
• Pregnant or breast-feeding woman and woman without adequate method of contraception.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Rivaroxaban; 5mg b.i.d. for 20 weeks (primary phase) + additional 32 weeks (extension phase)	Drug: Rivaroxaban
Active Comparator: Aspirin; 100mg once daily for 20 weeks (primary phase) + additional 32 weeks (extension phase)	Drug: Aspirin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Post-ischemic Forearm Blood Flow	Change of maximal postischemic forearm blood flow during reactive hyperaemia after 5 min of forearm ischemia (FBF max. ml/100ml). Difference of change in post-ischemic forearm blood flow measured by venous occlusion plethysmography at baseline and after 20 weeks treatment with rivaroxaban or aspirin.	Baseline and week 20
Change in Pulse Wave Velocity	Change in pulse wave velocity as a marker of arterial stiffness (measured by IEM Mobil-O-Graph)	Baseline and week 52

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Post-ischemic Forearm Blood Flow	Difference of change in post-ischemic forearm blood flow measured by venous occlusion plethysmography at baseline and after 52 weeks treatment with rivaroxaban or aspirin.	Baseline and week 52
Change in Pulse Wave Velocity	Change in pulse wave velocity as a marker for arterial stiffness (measured by IEM Mobil-O-Graph)	Baseline to week 20
Change in Skin Blood Flow	Change in skin blood flow for assessment of peripheral skin microcirculatory function (measured by laserdopplerfluxmetry; LDF)	Baseline to week 20
Change in Skin Blood Flow	Change in skin blood flow for assessment of peripheral skin microcirculatory function (measured by laserdopplerfluxmetry; LDF)	Baseline to week 52
Major Bleeding	Major bleeding defined as clinically overt and associated with one of the following: 1) reduction of hemoglobin level of 2 g/L or 2) required transfusion of at least 2 units of red cells or, involved a critical organ or was fatal, in accordance with the recommendation of the International Society on Thrombosis and Hemostasis (ISTH).	Week 1 to week 20
Major Bleeding	Major bleeding defined as clinically overt and associated with one of the following: 1) reduction of hemoglobin level of 2 g/L or 2) required transfusion of at least 2 units of red cells or, involved a critical organ or was fatal, in accordance with the recommendation of the International Society on Thrombosis and Hemostasis (ISTH).	Week 1 to week 52
Clinically Relevant Non-major (CRNM) Bleeding	Clinically relevant non-major (CRNM) bleeding defined as at least one of the following: spontaneous skin hematoma of at least 25 cm; spontaneous nose bleeding of more than 5 minutes duration; macroscopic hematuria, either spontaneous or, if associated with an intervention, lasting more than 24 hours; spontaneous rectal bleeding (more than spotting on toilet paper); gingival bleeding for more than 5 minutes; bleeding leading to hospitalization and/or requiring surgical treatment; bleeding leading to a transfusion of less than 2 units of whole blood or red cells; any other bleeding event considered clinically relevant by the investigator	Week 1 to week 20
Clinically Relevant Non-major (CRNM) Bleeding	Clinically relevant non-major (CRNM) bleeding defined as at least one of the following: spontaneous skin hematoma of at least 25 cm; spontaneous nose bleeding of more than 5 minutes duration; macroscopic hematuria, either spontaneous or, if associated with an intervention, lasting more than 24 hours; spontaneous rectal bleeding (more than spotting on toilet paper); gingival bleeding for more than 5 minutes; bleeding leading to hospitalization and/or requiring surgical treatment; bleeding leading to a transfusion of less than 2 units of whole blood or red cells; any other bleeding event considered clinically relevant by the investigator	Week 1 to week 52

Collaborators and Investigators

• Sponsor: GWT-TUD GmbH
• Investigators: Principal Investigator: Frank Pistrosch, Dr. med., GWT-TUD GmbH

Publications and helpful links

General Publications

• Pistrosch F, Matschke JB, Schipp D, Schipp B, Henkel E, Weigmann I, Sradnick J, Bornstein SR, Birkenfeld AL, Hanefeld M. Rivaroxaban compared with low-dose aspirin in individuals with type 2 diabetes and high cardiovascular risk: a randomised trial to assess effects on endothelial function, platelet activation and vascular biomarkers. Diabetologia. 2021 Dec;64(12):2701-2712. doi: 10.1007/s00125-021-05562-9. Epub 2021 Sep 8.

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2015
• Primary Completion (Actual): December 12, 2018
• Study Completion (Actual): April 30, 2020

Study Registration Dates

• First Submitted: June 12, 2014
• First Submitted That Met QC Criteria: June 13, 2014
• First Posted (Estimated): June 16, 2014

Study Record Updates

• Last Update Posted (Actual): November 7, 2023
• Last Update Submitted That Met QC Criteria: January 26, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Inflammation; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Antipyretics; Protease Inhibitors; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Aspirin; Rivaroxaban
• Other Study ID Numbers: MicroVasc-DIVA