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Optimal Anti-platelet Treatment for Patients With Clopidogrel Low Response

Information source: The First Hospital of Nanjing Medical University
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Coronary Artery Disease

Intervention: Ticagrelor (Drug); Clopidogrel (Drug); Cilostazol (Drug); Clopidogrel (Drug); Clopidogrel (Drug)

Phase: Phase 4

Status: Not yet recruiting

Sponsored by: The First Hospital of Nanjing Medical University

Official(s) and/or principal investigator(s):
Chunjian Li, Ph.D, Principal Investigator, Affiliation: The First Hospital of Nanjing Medical University

Overall contact:
Chunjian Li, Ph.D, Phone: +86-25-83718836, Ext: 6018, Email: lijay@njmu.edu.cn

Summary

The purpose of this study is to determine that for patients who received stent implantation but present low response to regular anti-platelet treatment, whether 1-month intensified anti-platelet treatment by replacing clopidogrel with ticagrelor (TCL) is superior to double dose clopidogrel or adding cilostazol.

Clinical Details

Official title: Optimal Anti-Platelet Treatment for Patients With Stent IMplantation And Clopidogrel Low Response: OPTIMAL Study

Study design: Allocation: Randomized, Endpoint Classification: Pharmacodynamics Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: Inhibition of platelet aggregation (IPA)

Secondary outcome: Clinical efficacy

Detailed description: Optimal anti-Platelet Treatment for patients with stent IMplantation And clopidogrel Low response: OPTIMAL study Previous studies showed that dual anti-platelet treatment (DAPT) with aspirin and clopidogrel provided 20% risk reduction for cardiovascular death, myocardial infarction and stroke compared with aspirin alone in patients with acute coronary syndrome (ACS)1-4. However, about 5~40% patients were reported being low response to clopidogrel, which is associated with higher risk of cardiovascular events5. Thus, it is of great clinical value to explore an intensified anti-platelet regimen to improve the inhibition of platelet function for the clopidogrel low responders. Several intensified anti-platelet protocols have been evaluated in the non-selected ACS patients. OASIS-7 showed that 600mg loading dose and 1-week double dose clopidogrel was associated with a 42% risk reduction of the definite stent thrombosis compared with regular DAPT6; our meta-analysis has demonstrated that cilostazol based triple anti-platelet treatment (TAPT) reduces the risk of late loss of minimal lumen diameter (MLD) and binary angiographic restenosis as well as target lesion revascularization(TLR) and target vessel revascularization (TVR) compared to regular DAPT in patients undergoing coronary stent implantation; PLATO study showed that ticagrelor (TCL) based DAPT was associated with a significantly lower incidence of myocardial infarction and cardiovascular death compared with clopidogrel based DAPT, and the difference mainly appeared in the first 30 days7. However, there is still no study to investigate which of the mentioned methods is the optimal one to improve the anti-platelet effect as well as clinical outcome for the clopidogrel low responders. The investigators hypotheses that for patients who received stent implantation but present clopidogrel low response, 1-month intensified anti-platelet treatment by replacing clopidogrel with ticagrelor (TCL) is superior to double dose clopidogrel or adding cilostazol regarding the inhibition of platelet aggregation in response to adenosine diphosphate (ADP). Inclusion criteria: 1. Successively recruit all patients who receive stent implantation; 2. Patient aged >18 years and ≦80 years old; 3. Signed inform consent. Exclusion criteria: 1. Allergy or intolerance to ASA, clopidogrel or TCL; 2. Subjects at a high risk of bleeding (e. g. platelet count< 80*109/L, known bleeding diathesis , active peptic ulcer ); 3. Patients who are planning to take warfarin or drugs that potentially could interfere with the anti-platelet effects of ASA (e. g. non-steroidal anti-inflammatory drugs ) , clopidogrel or TCL (e. g. strong CYP3A inhibitors or CYP3A inducers). Randomization: All patients take 300mg loading dose clopidogrel plus 100mg daily ASA and 75mg daily clopidogrel after admission. Patients are recruited after percutaneous coronary intervention (PCI). Light transmittancy aggregation (LTA) in response to 5μM ADP is to measured 5 days after taking the loading dose clopidogrel. Patients are randomized into the following 4 groups receiving either regular DAPT or different intensified anti-platelet treatments for 1 month if the inhibition of platelet aggregation (IPA) is no more than 60%. All patients return to regular DAPT (ASA 100mg daily, clopidogrel 75mg daily) for 11 month after 1-month intensified treatment. Patients with IPA > 60% receive regular DAPT as the 5th group. 1. Intensified anti-platelet treatment-1: ASA 100mg daily + Ticagrelor 90mg Bid 2. Intensified anti-platelet treatment-2: ASA 100mg daily + Clopidogrel 150mg daily 3. Intensified anti-platelet treatment-3: ASA 100mg daily + Clopidogrel 75mg daily + cilostazol 150mg Bid 4. Regular DAPT (IPA≦60%): ASA 100mg daily + Clopidogrel 75mg daily 5. Regular DAPT (IPA>60%): ASA 100mg daily + Clopidogrel 75mg daily Sample size calculation: The IPA of ticagrelor in response to ADP was reported to be 88±15%, with a 5% 2-side alpha, 30 patients in each group would offer 80% power to demonstrate that the result of ticagrelor is superior to any of the other groups. According to previous study, we assume the ratio of clopidogrel low response is 10%, then 1200 patients is required to reach the statistical significance. To avoid some drop-out, our sample size is set as 1350 patients. Tests: 1. ADP-induced platelet aggregation: Light transmittancy aggregation (LTA) in response to 5μM ADP. 2. Arachidonic acid(AA)-induced platelet aggregation: Light transmittancy aggregation (LTA) in response to 1mM AA. 3. Blood sample points: baseline (5 days after taking the loading dose clopidogrel), 1month after randomization. Clinical follow-up: Time points: 1month, 6month, and 1year after randomization. Primary endpoints: 1. Inhibition of platelet aggregation (IPA) in response to 5μM ADP determined by light transmittancy aggregometer (LTA) 1-month after intensified anti-platelet treatment. Secondary endpoints: 1. Clinical efficacy: death, non-fatal myocardial infarction, ischemic stroke, revascularization, and stent thrombosis (ARC definition); 2. Safety: minor, moderate, and major bleeding.

Eligibility

Minimum age: 18 Years. Maximum age: 80 Years. Gender(s): Both.

Criteria:

Inclusion Criteria: 1. Successively recruit all patients who receive stent implantation; 2. Patient aged >18 years and ≦80 years old; 3. Signed inform consent. Exclusion Criteria: 1. Allergy or intolerance to ASA, clopidogrel or TCL; 2. Subjects at a high risk of bleeding (e. g. platelet count< 80*109/L, known bleeding diathesis , active peptic ulcer ); 3. Patients who are planning to take warfarin or drugs that potentially could interfere with the anti-platelet effects of ASA (e. g. non-steroidal anti-inflammatory drugs ) , clopidogrel or TCL (e. g. strong CYP3A inhibitors or CYP3A inducers).

Locations and Contacts

Chunjian Li, Ph.D, Phone: +86-25-83718836, Ext: 6018, Email: lijay@njmu.edu.cn

First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China; Not yet recruiting
Fuming Zhang, M.D., Phone: +86-25-83718836, Ext: 6360, Email: jsphkj@163.com
Yi Chai, M.D., Phone: +86-25-83718836, Ext: 6360, Email: jsphkj@163.com
Dingguo Zhang, Ph.D, Sub-Investigator
Additional Information

Related publications:

Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK; Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001 Aug 16;345(7):494-502. Erratum in: N Engl J Med 2001 Dec 6;345(23):1716. N Engl J Med 2001 Nov 15;345(20):1506.

Main C, Palmer S, Griffin S, Jones L, Orton V, Sculpher M, Henderson R, Sudlow C, Hawkins N, Riemsma R. Clopidogrel used in combination with aspirin compared with aspirin alone in the treatment of non-ST-segment-elevation acute coronary syndromes: a systematic review and economic evaluation. Health Technol Assess. 2004 Oct;8(40):iii-iv, xv-xvi, 1-141. Review.

Bhatt DL, Fox KA, Hacke W, Berger PB, Black HR, Boden WE, Cacoub P, Cohen EA, Creager MA, Easton JD, Flather MD, Haffner SM, Hamm CW, Hankey GJ, Johnston SC, Mak KH, Mas JL, Montalescot G, Pearson TA, Steg PG, Steinhubl SR, Weber MA, Brennan DM, Fabry-Ribaudo L, Booth J, Topol EJ; CHARISMA Investigators. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med. 2006 Apr 20;354(16):1706-17. Epub 2006 Mar 12.

Kronzon I, Feit F. Clopidogrel plus aspirin was effective but increased bleeding in acute coronary syndromes without ST-segment elevation. ACP J Club. 2002 Mar-Apr;136(2):45.

De Miguel A, Ibanez B, Badimón JJ. Clinical implications of clopidogrel resistance. Thromb Haemost. 2008 Aug;100(2):196-203. Review.

Mehta SR, Tanguay JF, Eikelboom JW, Jolly SS, Joyner CD, Granger CB, Faxon DP, Rupprecht HJ, Budaj A, Avezum A, Widimsky P, Steg PG, Bassand JP, Montalescot G, Macaya C, Di Pasquale G, Niemela K, Ajani AE, White HD, Chrolavicius S, Gao P, Fox KA, Yusuf S; CURRENT-OASIS 7 trial investigators. Double-dose versus standard-dose clopidogrel and high-dose versus low-dose aspirin in individuals undergoing percutaneous coronary intervention for acute coronary syndromes (CURRENT-OASIS 7): a randomised factorial trial. Lancet. 2010 Oct 9;376(9748):1233-43. doi: 10.1016/S0140-6736(10)61088-4.

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, Thorsén 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.

Starting date: October 2013
Last updated: October 4, 2013

Page last updated: August 23, 2015

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