Clinical trial NCT02291419: Study of Ticagrelor Versus Aspirin Treatment in Patients With Myocardial Injury Post Major Non-cardiac Surgery
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE4
Conditions: Myocardial Injury
Keywords: ticagrelor
non-cardiac surgery
elevated troponin
myocardial injury
Lead sponsor: The Cleveland Clinic
Sponsor class: OTHER
Collaborators: name: AstraZeneca
First posted: 2014-11-14
Enrollment: 6
Sex: ALL
Minimum age (years): 40
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Major Adverse Cardiovascular Events
timeFrame: up to 6 months. The planned duration of treatment was one year but the study was terminated after 6 months.
Secondary outcomes:
measure: Cardiovascular Death
timeFrame: Up to 6 months. The planned duration of treatment was one year but the study was terminated after 6 months.
measure: Non-fatal Myocardial Infarction or Coronary Revascularization
timeFrame: up to 6 months. The planned duration of treatment was one year but the study was terminated after 6 months.
measure: All-cause Death
timeFrame: up to 6 months. The planned duration of treatment was one year but the study was terminated after 6 months.
measure: Non-fatal Stroke
timeFrame: up to 6 months. The planned duration of treatment was one year but the study was terminated after 6 months.
Other outcomes:
measure: The Number of Participants With Bleeding According to Bleeding Academic Research Consortium (BARC) Definitions
timeFrame: up to 6 months. The planned duration of treatment was one year but the study was terminated after 6 months.
Locations:
city: Mobile
country: United States
facility: University of South Alabama Health System
state: Alabama
city: Little Rock
country: United States
facility: Arkansas Site Management Service, LLC
state: Arkansas
city: Jacksonville
country: United States
facility: University of Florida College of Medicine - Jacksonville
state: Florida
city: Orlando
country: United States
facility: Florida Hospital Orthopaedic Institute and Fracture Care Center
state: Florida
city: Tampa
country: United States
facility: University of South Florida
state: Florida
city: Macon
country: United States
facility: Central Georgia Heart Center
state: Georgia
city: Indianapolis
country: United States
facility: Saint Vincent Medical Group
state: Indiana
city: Lexington
country: United States
facility: University of Kentucky
state: Kentucky
city: Baltimore
country: United States
facility: Sinai Hospital of Baltimore
state: Maryland
city: Bay City
country: United States
facility: McLaren Bay Region
state: Michigan
city: Detroit
country: United States
facility: Henry Ford Hospital
state: Michigan
city: Mount Clemens
country: United States
facility: McLaren Macomb
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: New York
country: United States
facility: New York University School of Medicine
state: New York
city: Cincinnati
country: United States
facility: Cincinnati VA Medical Center
state: Ohio
city: Cleveland
country: United States
facility: VA Medical Center - Cleveland Louis Stokes
state: Ohio
city: Cleveland
country: United States
facility: MetroHealth Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Dayton
country: United States
facility: Miami Valley Hospital
state: Ohio
city: Tulsa
country: United States
facility: Oklahoma Heart Institute
state: Oklahoma
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Dallas
country: United States
facility: VA North Texas Health Care System
state: Texas
city: Houston
country: United States
facility: University of Texas Health Science Center at Houston
state: Texas
city: Bellevue
country: United States
facility: Overlake Hospital Medical Center
state: Washington
Study officials:
affiliation: The Cleveland Clinic
name: Venu Menon, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.