Study of Ticagrelor Versus Aspirin Treatment in Patients With Myocardial Injury Post Major Non-cardiac Surgery (INTREPID)

An Open Label, Randomized Study to Determine the Rate of Cardiovascular Events at 1 yr for Patients With Elevated Troponins Post Major Non-cardiac Surgery and the Impact of Ticagrelor vs Aspirin on the Occurrence of Cardiovascular Events

The purpose of this pilot study is to establish the rate of cardiovascular events in patients with elevated troponins levels after major, non-cardiac surgery and to evaluate the efficacy and safety of FDA approved study drug (ticagrelor) compared to aspirin in these patients.

Data from current studies suggest that myocardial injury detected by minor elevations in troponin levels within 3 days after non-cardiac surgery may occur in 10-24% of patients and is associated with an increased risk of mortality at 30 days and 1 year. There are no current guidelines for care of patients with elevated troponin levels in the absence of acute coronary syndrome. This study will assess if the increased risk of these patients is modifiable by an anti-platelet medication and evaluate the safety of this medication.

Patients will be randomized in an open label fashion to receive ticagrelor (anti-platelet medication) or 81 mg. aspirin. Patients will be followed on study treatment for 12 months, with the last contact at one month post treatment discontinuation.

Study Overview

• Status: Terminated
• Conditions: Myocardial Injury
• Intervention / Treatment: Drug: ticagrelor; Drug: aspirin

Detailed Description

The objective of this pilot study is to establish the rate of cardiovascular events in patients with elevated troponins levels post major, non-cardiac surgery and to evaluate the efficacy and safety of ticagrelor treatment compared to aspirin in these patients.

Data from current studies suggest that myocardial injury detected by minor elevations in troponin levels within 3 days after non-cardiac surgery may occur in 10-24% of patients and is associated with an increased risk of mortality at 30 days and 1 year. There are no current guidelines for care of patients with elevated troponin levels in the absence of acute coronary syndrome (ACS) and it is not certain if this is a modifiable disease process. Ticagrelor is a direct, reversible inhibitor of the platelet P2Y12ADP-receptor. It has been shown to be superior to clopidogrel in the setting of ACS. The clinical benefit of treating patients with port-operative troponin elevation with antiplatelet agents remains unexplored. The short half-life of ticagrelor makes it favorable to use in this setting.

This is an open label, randomized, parallel group study comparing ticagrelor to aspirin in patients who experience troponin elevations post major non-cardiac surgery. Patients will be randomized in an open-label fashion to receive either ticagrelor 90 mg twice daily or aspirin 81 mg once daily. Patients will be followed for 13 months post randomization (12 months of treatment and a phone call 30 days after study drug discontinuation). The maximum duration of treatment will be 12 months.

Follow-up visits will occur at Month 1, Month 6, and Month 12. Phone calls will be made at Month 3, Month 9, and at 30 days after study drug discontinuation.

Up to 1000 patients with post-operative troponin elevation ≥2x ULN within first 7 postoperative days, will be enrolled in the study.

• Study Type: Interventional
• Enrollment (Actual): 6
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Mobile, Alabama, United States, 36617
      • University of South Alabama Health System
  • Arkansas
    • Little Rock, Arkansas, United States, 72211
      • Arkansas Site Management Service, LLC
  • Florida
    • Jacksonville, Florida, United States, 32209
      • University of Florida College of Medicine - Jacksonville
    • Orlando, Florida, United States, 32804
      • Florida Hospital Orthopaedic Institute and Fracture Care Center
    • Tampa, Florida, United States, 33060
      • University of South Florida
  • Georgia
    • Macon, Georgia, United States, 31201
      • Central Georgia Heart Center
  • Indiana
    • Indianapolis, Indiana, United States, 46260
      • Saint Vincent Medical Group
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • University of Kentucky
  • Maryland
    • Baltimore, Maryland, United States, 21215
      • Sinai Hospital of Baltimore
  • Michigan
    • Bay City, Michigan, United States, 48708
      • McLaren Bay Region
    • Detroit, Michigan, United States, 48202
      • Henry Ford Hospital
    • Mount Clemens, Michigan, United States, 48043
      • McLaren Macomb
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota
  • New York
    • New York, New York, United States, 10016
      • New York University School of Medicine
  • Ohio
    • Cincinnati, Ohio, United States, 45220
      • Cincinnati VA Medical Center
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
    • Cleveland, Ohio, United States, 44109
      • MetroHealth Medical Center
    • Cleveland, Ohio, United States, 44106
      • VA Medical Center - Cleveland Louis Stokes
    • Dayton, Ohio, United States, 45409
      • Miami Valley Hospital
  • Oklahoma
    • Tulsa, Oklahoma, United States, 74104
      • Oklahoma Heart Institute
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health and Science University
  • Texas
    • Dallas, Texas, United States, 75216
      • VA North Texas Health Care System
    • Houston, Texas, United States, 77030
      • University of Texas Health Science Center at Houston
  • Washington
    • Bellevue, Washington, United States, 98004
      • Overlake Hospital Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Written informed consent before any study related procedures are performed.
2. A qualifying post-operative T or I troponin elevation (≥2x ULN of assay within 7 days of index surgery and during the index hospitalization).
3. Men and women ≥40 years of age if troponin elevation was identified as part of routine post-operative clinical care OR
4. Men and women ≥55 years of age if troponin elevation was identified post-operatively as part of screening for the study.
5. Undergone non-cardiac surgery requiring an overnight hospital stay.
6. Women of childbearing potential who are sexually active must have a negative pregnancy test at enrollment and agree to use adequate contraception from screening until 30 days after receiving the last dose of study drug.
7. Able to be randomized within 35 days following the index surgery.

Exclusion Criteria:

1. Post-operative ST-elevation Myocardial Infarction (STEMI).

2. Post-operative high-risk non-STEMI, defined as patients with elevated troponin with either:

   1. active Ischemic EKG changes (≥2 mm of ST-segment depression in at least 2 adjacent leads)
   2. ongoing hemodynamic instability thought to be ischemia mediated or
   3. persistent anginal symptoms.
3. Planned or urgent coronary angiography/revascularization.
4. A current or ongoing indication for dual antiplatelet therapy (DAPT) as determined by the patient's physician.
5. History of intracranial hemorrhage
6. Bleeding disorder or active bleeding that prevents ticagrelor or aspirin administration.
7. Taking any of the following medications at the time of randomization: vitamin K antagonists, dabigatran, rivaroxaban, apixaban, edoxaban , fondaparinux, cilostazol, vorapaxar or LMWHs.
8. Renal dialysis.
9. Hepatic impairment with transaminase ≥3x ULN at time of randomization.
10. Known contra-indication for use of ticagrelor.
11. Estimated life expectancy of <1 year.
12. Enrolled in another ongoing drug or device research protocol
13. A definite non-ischemic explanation for troponin elevation, such as myocarditis or pulmonary embolism.
14. A documented hypersensitivity to aspirin.
15. Hypersensitivity to ticagrelor or any component of the product.
16. Neurological or ophthalmic surgery during the index hospitalization.
17. Patients taking strong CYP3A inhibitors and/or CYP3A inducers that cannot be stopped for the course of the study.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ticagrelor; ticagrelor 90mg bid	Drug: ticagrelor; ticagrelor 90 mg bid; Other Names: Brilinta
Active Comparator: aspirin; Patients in the aspirin arm will receive aspirin 81 mg daily orally	Drug: aspirin; aspirin 81 mg daily; Other Names: Bayer, ASA

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Major Adverse Cardiovascular Events	Time to first occurence of the composite of Cardiovascular Death, Non-fatal Myocardial Infarction, Coronary Revascularization or Non-fatal Stroke. The number of patients with events is reported.	up to 6 months. The planned duration of treatment was one year but the study was terminated after 6 months.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cardiovascular Death	Time to first occurence of Cardiovascular death. The number of patients with events was reported.	Up to 6 months. The planned duration of treatment was one year but the study was terminated after 6 months.
Non-fatal Myocardial Infarction or Coronary Revascularization	Time to first occurence of Non-fatal myocardial infarction or coronary revascularization. The number of participants with events was reported.	up to 6 months. The planned duration of treatment was one year but the study was terminated after 6 months.
All-cause Death	Time to first occurence of All-cause death. The number of participants with events was reported.	up to 6 months. The planned duration of treatment was one year but the study was terminated after 6 months.
Non-fatal Stroke	Time to first occurence of Non-fatal stroke. The number of participants with events was reported.	up to 6 months. The planned duration of treatment was one year but the study was terminated after 6 months.

Other Outcome Measures

Outcome Measure	Time Frame
The Number of Participants With Bleeding According to Bleeding Academic Research Consortium (BARC) Definitions	up to 6 months. The planned duration of treatment was one year but the study was terminated after 6 months.

Collaborators and Investigators

• Sponsor: The Cleveland Clinic
• Collaborators: AstraZeneca
• Investigators: Principal Investigator: Venu Menon, MD, The Cleveland Clinic

Publications and helpful links

General Publications

• Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, Horrow J, Husted S, James S, Katus H, Mahaffey KW, Scirica BM, Skene A, Steg PG, Storey RF, Harrington RA; PLATO Investigators; Freij A, Thorsen M. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009 Sep 10;361(11):1045-57. doi: 10.1056/NEJMoa0904327. Epub 2009 Aug 30.
• Vascular Events In Noncardiac Surgery Patients Cohort Evaluation (VISION) Study Investigators; Devereaux PJ, Chan MT, Alonso-Coello P, Walsh M, Berwanger O, Villar JC, Wang CY, Garutti RI, Jacka MJ, Sigamani A, Srinathan S, Biccard BM, Chow CK, Abraham V, Tiboni M, Pettit S, Szczeklik W, Lurati Buse G, Botto F, Guyatt G, Heels-Ansdell D, Sessler DI, Thorlund K, Garg AX, Mrkobrada M, Thomas S, Rodseth RN, Pearse RM, Thabane L, McQueen MJ, VanHelder T, Bhandari M, Bosch J, Kurz A, Polanczyk C, Malaga G, Nagele P, Le Manach Y, Leuwer M, Yusuf S. Association between postoperative troponin levels and 30-day mortality among patients undergoing noncardiac surgery. JAMA. 2012 Jun 6;307(21):2295-304. doi: 10.1001/jama.2012.5502. Erratum In: JAMA. 2012 Jun 27;307(24):2590.
• POISE Study Group; Devereaux PJ, Yang H, Yusuf S, Guyatt G, Leslie K, Villar JC, Xavier D, Chrolavicius S, Greenspan L, Pogue J, Pais P, Liu L, Xu S, Malaga G, Avezum A, Chan M, Montori VM, Jacka M, Choi P. Effects of extended-release metoprolol succinate in patients undergoing non-cardiac surgery (POISE trial): a randomised controlled trial. Lancet. 2008 May 31;371(9627):1839-47. doi: 10.1016/S0140-6736(08)60601-7. Epub 2008 May 12.
• Horr S, Reed G, Menon V. Troponin elevation after noncardiac surgery: Significance and management. Cleve Clin J Med. 2015 Sep;82(9):595-602. doi: 10.3949/ccjm.82a.15076.

Study record dates

Study Major Dates

• Study Start: July 1, 2015
• Primary Completion (Actual): June 1, 2016
• Study Completion (Actual): June 1, 2016

Study Registration Dates

• First Submitted: November 5, 2014
• First Submitted That Met QC Criteria: November 13, 2014
• First Posted (Estimate): November 14, 2014

Study Record Updates

• Last Update Posted (Estimate): February 9, 2017
• Last Update Submitted That Met QC Criteria: February 8, 2017
• Last Verified: February 1, 2017

More Information

Terms related to this study

• Keywords: myocardial injury; ticagrelor; non-cardiac surgery; elevated troponin
• Additional Relevant MeSH Terms: Wounds and Injuries; Physiological Effects of Drugs; Neurotransmitter Agents; 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; Purinergic P2Y Receptor Antagonists; Purinergic P2 Receptor Antagonists; Purinergic Antagonists; Purinergic Agents; Aspirin; Ticagrelor
• Other Study ID Numbers: CCAZ-2014

Plan for Individual participant data (IPD)

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