Effect of Modifying Anti-platelet Treatment to Ticagrelor in Patients With Diabetes and Low Response to Clopidogrel

NCT01643031 | Unknown Phase 4 DMC

• 1 other identifier: 6793
• Study Type: interventional
• Target: 500
• Locations: 1 country
• Sites: 1

Brief Summary

In recent years numerous studies have shown that the response of patients to the anti-platelet drug clopidogrel is widely variable. Furthermore, patients who do not respond well to the drug ("resistant") have been shown to be at increased risk to develop cardiac events, including myocardial infarction and mortality. It thus seems reasonable to test the efficacy of the drug (by platelet function tests) and modify treatment accordingly. However, a large study that examined a strategy of routine testing of clopidogrel response in thousands of patients (GRAVITAS study) did not show any clinical benefit. This study was limited, however, by a very low event rate (2.3%), and by the strategy employed to treat patients with low response (increasing the clopidogrel dose), which is currently known to be ineffective in many patients with low response. To overcome these limitations the investigators plan to examine a high risk population - patients with diabetes planned to undergo coronary angiography - and to treat clopidogrel low responders by switching their treatment to the potent anti-platelet drug ticagrelor, which has been shown to overcome clopidogrel low response. The investigators hypothesize that patients with diabetes and low response to clopidogrel will benefit clinically from switching therapy to ticagrelor. The main endpoint of the study will be the risk of myocardial enzyme elevation following percutaneous coronary intervention (PCI); a marker which has been strongly associated with poor clinical outcome. The aim of the study is, therefore, to assess whether a strategy of monitoring platelet function during clopidogrel treatment in patients with diabetes undergoing PCI, and modifying treatment to ticagrelor in patients with low response, will be associated with reduced risk of myocardial enzyme release. The investigators plan to enroll patients with treated diabetes, planned to undergo coronary angiography. Patients with acute or recent myocardial infarction will be excluded. They will be tested for response to clopidogrel by the VerifyNow P2Y12 assay (either on chronic clopidogrel treatment or 12-24 hours after receiving 300 mg clopidogrel). Patients with low response to clopidogrel (≥ 208 PRU) will be randomized to either continued treatment with clopidogrel (75 mg/day), or switching of treatment to ticagrelor (90 mg twice a day) for 30 days (followed by continued clopidogrel therapy). The primary endpoint will be the rate of troponin of CK-MB (cardiac enzymes) measured 20-24 hours after the PCI. Secondary endpoints will be the occurrence of adverse clinical endpoints - myocardial infarction, need for urgent revascularization or mortality at 30 days. The investigators aim to enroll 100 patients in each study group (ticagrelor vs. continued clopidogrel). Assuming a clopidogrel low response rate of 40% among patients with diabetes, about 500 patients would have to be screened to identify 200 patients with low response.

Conditions

Diabetes Mellitus; Coronary Disease

Keywords

Diabetes; Platelets aggregation inhibitors; Platelet function tests

Outcome Measures

Primary Outcomes (1)

• Rate of elevation of troponin or CK-MB (above the upper limit of normal, and above 3 times the upper limit of normal) measured 20-24 hours after the PCI.

  Rate of elevation of troponin or CK-MB (above the upper limit of normal, and above 3 times the upper limit of normal) measured 20-24 hours after the PCI.

  20-24 hours after the PCI

Secondary Outcomes (1)

• Rate of major adverse cardiovascular endpoints including death, myocardial infarction or urgent target vessel revascularization at 30 days

  30 days

Study Arms (2)

Ticagrelor

EXPERIMENTAL

Patients randomized to the ticagrelor group will receive ticagrelor at a dose of 180 mg given 1-2 hours before the coronary angiography, followed by 90 mg twice a day for 30 days after the PCI. After 30 days the patient will be invited to a special research clinic in the hospital and his treatment will be switched back to clopidogrel (to complete 1 year of treatment).

Drug: Ticagrelor

Continued Clopidogrel

ACTIVE COMPARATOR

Patients randomized to continued clopidogrel treatment will be given an additional 300 mg of clopidogrel loading 1-2 hours before coronary angiography (in addition to the previous 300 mg load or chronic clopidogrel therapy the patient received), followed by 75 mg a day for 1 year after the PCI

Drug: Continued clopidogrel

Interventions

Ticagrelor DRUG

Ticagrelor will be given (to patients with low response to clopidogrel randomized to the Ticagrelor group) at a dose of 180 mg given 1-2 hours before the coronary angiography, followed by 90 mg twice a day for 30 days after the PCI. After 30 days the patient's treatment will be switched back to clopidogrel (to complete 1 year of treatment).

Also known as: Brilinta

Ticagrelor

Continued clopidogrel DRUG

Patients with low response to clopidogrel randomized to continued clopidogrel treatment will be given an additional 300 mg of clopidogrel loading 1-2 hours before coronary angiography (in addition to the previous 300 mg load or chronic clopidogrel therapy the patient received), followed by 75 mg a day for 1 year after the PCI

Also known as: Plavix

Continued Clopidogrel

Eligibility Criteria

• Age: 30 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients with diabetes treated with oral hypoglycemic medications and/or insulin.
• Aged 30-80 years.
• Patients with stable angina and a positive non-invasive test, or patients with unstable angina, all planned to undergo coronary angiography.
• Treated with aspirin 75-100 mg per day.

You may not qualify if:

• Any myocardial infarction (STEMI or non-STEMI) as the indication for the cardiac catheterization. Thus, only troponin-negative and CK-MB negative patients will be included.
• Any contraindications to ticagrelor or clopidogrel.
• Anemia (Hg\<10 g/dL) or thrombocytopenia (\<100,000 / mm3)
• Chronic renal failure (Cr ≥ 2.5 mg/dL)

Sponsors & Collaborators

• Rabin Medical Center: lead
• Tel Aviv Medical Center: collaborator
• Sheba Medical Center: collaborator
• Meir Medical Center: collaborator
• Rambam Health Care Campus: collaborator

Study Sites (1)

Rabin Medical Center

Petah Tikva, 49100, Israel

Location

Related Publications (12)

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• Price MJ, Berger PB, Teirstein PS, Tanguay JF, Angiolillo DJ, Spriggs D, Puri S, Robbins M, Garratt KN, Bertrand OF, Stillabower ME, Aragon JR, Kandzari DE, Stinis CT, Lee MS, Manoukian SV, Cannon CP, Schork NJ, Topol EJ; GRAVITAS Investigators. Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial. JAMA. 2011 Mar 16;305(11):1097-105. doi: 10.1001/jama.2011.290.

  PMID: 21406646 BACKGROUND

• Oestreich JH, Holt J, Dunn SP, Smyth SS, Campbell CL, Charnigo R, Akers WS, Steinhubl SR. Considerable variability in platelet activity among patients with coronary artery disease in response to an increased maintenance dose of clopidogrel. Coron Artery Dis. 2009 May;20(3):207-13. doi: 10.1097/MCA.0b013e328329924b.

  PMID: 19318928 BACKGROUND

• Gladding P, Webster M, Zeng I, Farrell H, Stewart J, Ruygrok P, Ormiston J, El-Jack S, Armstrong G, Kay P, Scott D, Gunes A, Dahl ML. The antiplatelet effect of higher loading and maintenance dose regimens of clopidogrel: the PRINC (Plavix Response in Coronary Intervention) trial. JACC Cardiovasc Interv. 2008 Dec;1(6):612-9. doi: 10.1016/j.jcin.2008.09.005.

  PMID: 19463374 BACKGROUND

• Gurbel PA, Bliden KP, Butler K, Antonino MJ, Wei C, Teng R, Rasmussen L, Storey RF, Nielsen T, Eikelboom JW, Sabe-Affaki G, Husted S, Kereiakes DJ, Henderson D, Patel DV, Tantry US. Response to ticagrelor in clopidogrel nonresponders and responders and effect of switching therapies: the RESPOND study. Circulation. 2010 Mar 16;121(10):1188-99. doi: 10.1161/CIRCULATIONAHA.109.919456. Epub 2010 Mar 1.

  PMID: 20194878 BACKGROUND

• BARI 2D Study Group; Frye RL, August P, Brooks MM, Hardison RM, Kelsey SF, MacGregor JM, Orchard TJ, Chaitman BR, Genuth SM, Goldberg SH, Hlatky MA, Jones TL, Molitch ME, Nesto RW, Sako EY, Sobel BE. A randomized trial of therapies for type 2 diabetes and coronary artery disease. N Engl J Med. 2009 Jun 11;360(24):2503-15. doi: 10.1056/NEJMoa0805796. Epub 2009 Jun 7.

  PMID: 19502645 BACKGROUND

• Feldman DN, Kim L, Rene AG, Minutello RM, Bergman G, Wong SC. Prognostic value of cardiac troponin-I or troponin-T elevation following nonemergent percutaneous coronary intervention: a meta-analysis. Catheter Cardiovasc Interv. 2011 Jun 1;77(7):1020-30. doi: 10.1002/ccd.22962. Epub 2011 May 13.

  PMID: 21574239 BACKGROUND

• Nienhuis MB, Ottervanger JP, Bilo HJ, Dikkeschei BD, Zijlstra F. Prognostic value of troponin after elective percutaneous coronary intervention: A meta-analysis. Catheter Cardiovasc Interv. 2008 Feb 15;71(3):318-24. doi: 10.1002/ccd.21345.

  PMID: 18288753 BACKGROUND

• Lev EI, Patel RT, Maresh KJ, Guthikonda S, Granada J, DeLao T, Bray PF, Kleiman NS. Aspirin and clopidogrel drug response in patients undergoing percutaneous coronary intervention: the role of dual drug resistance. J Am Coll Cardiol. 2006 Jan 3;47(1):27-33. doi: 10.1016/j.jacc.2005.08.058. Epub 2005 Dec 9.

  PMID: 16386660 BACKGROUND

• Price MJ, Angiolillo DJ, Teirstein PS, Lillie E, Manoukian SV, Berger PB, Tanguay JF, Cannon CP, Topol EJ. Platelet reactivity and cardiovascular outcomes after percutaneous coronary intervention: a time-dependent analysis of the Gauging Responsiveness with a VerifyNow P2Y12 assay: Impact on Thrombosis and Safety (GRAVITAS) trial. Circulation. 2011 Sep 6;124(10):1132-7. doi: 10.1161/CIRCULATIONAHA.111.029165. Epub 2011 Aug 29.

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  PMID: 12796140 BACKGROUND

MeSH Terms

Conditions

Diabetes Mellitus; Coronary Disease

Interventions

Ticagrelor; Clopidogrel

Condition Hierarchy (Ancestors)

Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases

Intervention Hierarchy (Ancestors)

Adenosine; Purine Nucleosides; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides; Ticlopidine; Thienopyridines; Thiophenes; Sulfur Compounds; Organic Chemicals; Pyridines; Heterocyclic Compounds, 1-Ring

Study Officials

• Eli I Lev, MD

  Rabin Medical Center

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Hagar Medan

CONTACT

972-3-9376442; hagarme@clalit.org.il

Ofira Yehoshua

CONTACT

972-3-9376441; ofiray@clalit.org.il

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prof. Eli Lev, Director, Cardiac catheterization laboratory, Hasharon Hospital, Rabin Medical Center, Israel

Study Record Dates

• First Submitted: July 15, 2012
• First Posted: July 17, 2012
• Study Start: August 1, 2012
• Primary Completion: September 1, 2014
• Study Completion: October 1, 2014
• Last Updated: June 17, 2013

Record last verified: 2013-06

Locations

IL (1)