OPTImal Management of Antithrombotic Agents: OPTIMA-2 Trial

Coronary Artery Disease Clinical Trial

— OPTIMA-2  

Official title:

Intensified Antiplatelet Therapy in Post-PCI Patients With High On-treatment Platelet Reactivity: the OPTIMA-2 Trial

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01955200
• Other study ID #: 001
• Status: Completed
• Phase: Phase 4
• Start date: October 5, 2013
• Est. completion date: November 28, 2017

Study information

• Verified date: August 2020
• Source: The First Affiliated Hospital with Nanjing Medical University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

High on-treatment platelet reactivity (HOPR) is associated with increased risk of cardiovascular events in patients undergoing percutaneous coronary intervention (PCI). We sought to investigate the efficacy and safety of 1-month intensified antiplatelet therapies in post-PCI patients with HOPR.

Description:

OPTImal Management of Antithrombotic agents: OPTIMA-2 trial

Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor inhibitor is the foundation antiplatelet therapy in patients undergoing percutaneous coronary intervention (PCI). Clopidogrel is the most commonly used P2Y12 receptor inhibitor worldwide because it is effective and inexpensive1. High on-treatment platelet reactivity (HOPR) occurs in as many as one-third of patients treated with standard dose clopidogrel (75mg once daily), and is associated with an increased risk of major adverse cardiovascular events (MACE).

Various approaches have been tested to overcome HOPR in patients treated with aspirin and clopidogrel, including higher doses of clopidogrel; the addition of cilostazol; and replacement of clopidogrel with prasugrel; however, the results of these intensified treatments were controversial, and a more potent P2Y12 receptor inhibitor, ticagrelor has never been studied in this scenario.

TOPIC study showed that short-term (i.e. 1-month) intensification of antiplatelet treatment might be sufficient to achieve optimal outcomes. Similarly, TROPICAL ACS showed that guided de-escalation of antiplatelet treatment with clopidogrel was non-inferior to the treatment with prasugrel at 1 year after PCI in terms of net clinical benefit, which suggests that routinely long-term intensification of antiplatelet treatment is not required for all PCI patients.

Accordingly we performed a randomized trial to test the hypothesis that in patients with HOPR intensification of antiplatelet therapy with double dose clopidogrel, the addition of cilostazol, or replacement of clopidogrel with ticagrelor for 1 month followed by resumption of conventional DAPT with aspirin and clopidogrel for 11 months would be superior to conventional DAPT for 12 months in reducing the prevalence of HOPR and MACE without increasing bleeding.

Inclusion criteria:

1. Successively recruit all patients who receive stent implantation;

2. Intended use of conventional DAPT with the combination of aspirin 100mg once daily and clopidogrel 75mg once daily for at least 12 months;

3. Patient aged over 18 years;

4. Signed inform consent.

Exclusion criteria:

1. Allergy or intolerance to study drugs;

2. History of gastrointestinal or intracranial bleeding;

3. Need for anticoagulant therapy;

4. High risk of bleeding (e.g., myelodysplasia, baseline platelet count < 80 × 109/L);

5. Hemoglobin < 90g/L;

6. Active malignancy or life expectancy < 1 year;

7. Patients with other conditions made them unsuitable to be recruited at the discretion of the investigators.

Study procedures:

Following treatment for at least 5 days with the combination of aspirin 100mg once daily and clopidogrel 75mg once daily irrespective of a loading dose we measured platelet aggregation in response to adenosine diphosphate (ADP) (PLADP) using light transmittance aggregometry (LTA). HOPR was defined as PLADP > 40%. Patients with HOPR were continued on aspirin 100mg once daily and were randomly assigned to one of the following 4 groups:

1. clopidogrel 150mg once daily (CLOP-150);

2. clopidogrel 75mg once daily plus cilostazol 100mg twice daily (CLOP+CILOST);

3. ticagrelor 90mg twice daily (TICAG);

4. clopidogrel 75mg once daily (conventional DAPT, CON). At 1 month, platelet aggregation testing was repeated after which all patients were switched back to conventional DAPT for a further 11 months.

All patients without HOPR were treated with conventional DAPT and followed to 12 months (Non-HOPR).

Sample size calculation:

Based on the published literature, we assumed a 38% rate of persistent HOPR in patients randomized to intensified treatment and 60% in those randomized to CON therapy. With a sample size of 81 per group, we calculated that we would have 80% power to detect this difference with a 2-sided P value of 0.05. After allowing for 20% study drug discontinuation rate at 1 month, we planned a sample size of 405 patients with HOPR.

Platelet Reactivity Assay

1. ADP-induced platelet aggregation: Light transmittancy aggregation (LTA) in response to 5μM ADP.

2. Blood sample collection time: baseline (more than 5 days after taking clopidogrel 75mg daily and aspirin 100mg daily), 1month after randomization.

Clinical follow-up:

Time points: 1month, 6month, and 1year after randomization.

The study endpoints:

The primary outcome was the proportion of patients with persistent HOPR at 1 month.

The secondary outcomes included a composite of MACE including cardiovascular death, nonfatal myocardial infarction (MI), ischemic stroke, target vessel revascularization (TVR), stent thrombosis (ST) and cardiac readmission during 12-month follow-up, and any bleeding defined by the Thrombolysis in Myocardial Infarction (TIMI) criteria.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1724
• Est. completion date: November 28, 2017
• Est. primary completion date: December 26, 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion criteria:

1. Successively recruit all patients who receive stent implantation;

2. Intended use of standard DAPT with the combination of aspirin 100mg once daily and clopidogrel 75mg once daily for at least 12 months;

3. Patient aged >18 years and ?80 years old;

4. Signed inform consent.

Exclusion criteria:

1. Allergy or intolerance to study drugs;

2. History of gastrointestinal or intracranial bleeding;

3. Need for anticoagulant therapy;

4. High risk of bleeding (e.g., myelodysplasia, baseline platelet count < 80 × 109/L);

5. Hemoglobin < 90g/L;

6. Active malignancy or life expectancy < 1 year;

7. Patients with other conditions made them unsuitable to be recruited at the discretion of the investigators.

Related Conditions & MeSH terms

• Coronary Artery Disease

Intervention

Drug:
• Clopidogrel
(ASA 100mg daily + Clopidogrel 150mg daily) x 1 month; (ASA 100mg daily + Clopidogrel 75mg daily) x 11 month.
• Cilostazol
(ASA 100mg daily + Clopidogrel 75mg daily + Cilostazol 150mg Bid) x 1 month; (ASA 100mg daily + Clopidogrel 75mg daily) x 11 month.
• Ticagrelor
(ASA 100mg daily + Ticagrelor 90mg Bid) x 1 month; (ASA 100mg daily + Clopidogrel 75mg daily) x 11 month.
• Clopidogrel
(ASA 100mg daily + Clopidogrel 75mg daily) x 12 month.
• Clopidogrel
(ASA 100mg daily + Clopidogrel 75mg daily) x 12 month.

Locations

Country	Name	City	State
China	First Affiliated Hospital of Nanjing Medical University	Nanjing	Jiangsu

Sponsors (2)

Lead Sponsor	Collaborator
The First Affiliated Hospital with Nanjing Medical University	National Natural Science Foundation of China

Country where clinical trial is conducted

China, 

References & Publications (10)

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. — View Citation

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

Deharo P, Quilici J, Camoin-Jau L, Johnson TW, Bassez C, Bonnet G, Fernandez M, Ibrahim M, Suchon P, Verdier V, Fourcade L, Morange PE, Bonnet JL, Alessi MC, Cuisset T. Benefit of Switching Dual Antiplatelet Therapy After Acute Coronary Syndrome According to On-Treatment Platelet Reactivity: The TOPIC-VASP Pre-Specified Analysis of the TOPIC Randomized Study. JACC Cardiovasc Interv. 2017 Dec 26;10(24):2560-2570. doi: 10.1016/j.jcin.2017.08.044. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. Erratum in: JAMA. 2011 Jun 1;305(21);2174. Stillablower, Michael E [corrected to Stillabower, Michael E]. — View Citation

Sibbing D, Aradi D, Jacobshagen C, Gross L, Trenk D, Geisler T, Orban M, Hadamitzky M, Merkely B, Kiss RG, Komócsi A, Dézsi CA, Holdt L, Felix SB, Parma R, Klopotowski M, Schwinger RHG, Rieber J, Huber K, Neumann FJ, Koltowski L, Mehilli J, Huczek Z, Massberg S; TROPICAL-ACS Investigators. Guided de-escalation of antiplatelet treatment in patients with acute coronary syndrome undergoing percutaneous coronary intervention (TROPICAL-ACS): a randomised, open-label, multicentre trial. Lancet. 2017 Oct 14;390(10104):1747-1757. doi: 10.1016/S0140-6736(17)32155-4. Epub 2017 Aug 28. — View 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, 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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Bleeding	any bleeding defined by the Thrombolysis in Myocardial Infarction (TIMI) criteria	1-year after randomization
Primary	the proportion of patients with persistent HOPR at 1 month	platelet aggregation in response to 5µM adenosine diphosphate (PLADP) measured by light transmittancy aggregometer (LTA) ; HOPR was defined as PLADP > 40%.	1-month after randomization
Secondary	MACE	a composite of MACE including cardiovascular death, nonfatal myocardial infarction (MI), ischemic stroke, target vessel revascularization (TVR), stent thrombosis (ST) and cardiac readmission during 12-month follow-up,revascularization, and stent thrombosis (ARC definition)	1-year after randomization