Cost-effectiveness of Genotype Guided Treatment With Antiplatelet Drugs in STEMI Patients: Optimization of Treatment (POPular Genetics)

Myocardial Infarction Clinical Trial

Official title:

Cost-effectiveness of CYP2C19 Genotype Guided Treatment With Antiplatelet Drugs in Patients With ST-segment-elevation Myocardial Infarction Undergoing Immediate PCI With Stent Implantation: Optimization of Treatment (POPular Genetics).

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01761786
• Other study ID #: PGxSTEMI08
• Status: Completed
• Phase: Phase 4
• Start date: June 2011
• Est. completion date: April 4, 2019

Study information

• Verified date: May 2019
• Source: St. Antonius Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Rationale: the use of antiplatelet drugs (i.e. clopidogrel, ticagrelor or prasugrel) is crucial in the treatment of patients undergoing percutaneous coronary intervention (PCI) with stent implantation to prevent atherothrombotic events. Ticagrelor and prasugrel are more effective in preventing atherothrombotic events, but with a higher risk of bleeding complications, compared to clopidogrel. Clopidogrel is converted into its active metabolite by CYP2C19. Carriers of the non functional CYP2C19*2 and *3 alleles have an impaired CYP2C19 capacity, making clopidogrel less effective. For these subjects ticagrelor or prasugrel is an alternative.

Objective: to assess the efficacy, safety and cost-effectiveness of the CYP2C19 genotype guided antiplatelet treatment strategy, using clopidogrel in non-carriers of a CYP2C19*2 or *3 allele and ticagrelor or prasugrel in carriers of a CYP2C19*2 or *3 allele in STEMI patients.

Intervention: the intervention group will be genotyped for CYP2C19*2 and *3 allele variants within 48 hours after primary PCI. Carriers will receive either ticagrelor (90 mg twice daily) or prasugrel (10 mg once daily or 5 mg once daily if the patient is older than age 75 or has a body weight less than 60 kg), according to local standards. Non-carriers will be treated with clopidogrel (75 mg once daily). The control group receives either ticagrelor or prasugrel, according to local standards at the same dosage as the CYP2C19*2 or *3 carriers in the intervention group. The antiplatelet drug will be continued for one year after PCI. The follow-up duration will be one year using follow-up questionnaires.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 2700
• Est. completion date: April 4, 2019
• Est. primary completion date: April 4, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 22 Years and older

Eligibility

Inclusion Criteria:

• more than 21 years of age with symptoms of acute myocardial infarction of more than 30 minutes but less than 12 hours

• performed primary PCI with stenting for STEMI

Exclusion Criteria:

• unable to give informed consent or have a life expectancy of less than one year

• active malignancy with increase in bleeding risk, in the investigator's opinion

• women who are known to be pregnant or who have given birth within the past 90 days or who are breastfeeding

• having received thrombolytic therapy within the previous 24 hours or oral anticoagulants during the previous 7 days

• severe renal function impairment needing dialysis

• confirmed or persistent severe hypertension (Systolic Blood Pressure (SBP) > 180 mmHg and/or Diastolic Blood Pressure (DBP) >110 mmHg) at randomization

• contraindication to anticoagulation or at increased bleeding risk, at the investigator's opinion

• cardiogenic shock (SBP = 80mmHg for >30 mins) or Intra-Aortic Balloon Pump (IABP) placed

• history of major surgery, severe trauma, fracture or organ biopsy within 90 days prior to randomisation

• clinically significant out of range values for platelet count or haemoglobin level at screening, in the investigator's opinion.

Related Conditions & MeSH terms

• Infarction
• Myocardial Infarction
• ST Elevation Myocardial Infarction
• STEMI

Intervention

Genetic:
• CYP2C19 genotyping
CYP2C19 genotyping will be performed in the intervention group. In patients with *1/*1 genotype (Extensive Metabolizer) clopidogrel will be prescribed. All patients who are carrier of a loss-to-function (*2 or *3) gene allel and all patients randomized to the control group will be prescribed prasugrel or ticagrelor, according to local protocol.

Locations

Country	Name	City	State
Belgium	OLV Hospital	Aalst
Italy	University of Naples Federico II	Naples
Netherlands	Meander Medisch Centrum	Amersfoort
Netherlands	OLVG	Amsterdam
Netherlands	Rijnstate Hospital	Arnhem
Netherlands	Amphia Hospital	Breda
Netherlands	University Medical Center Groningen	Groningen
Netherlands	St. Antonius Hospital	Nieuwegein
Netherlands	University Medical Center	Utrecht
Netherlands	Isala Klinieken	Zwolle

Sponsors (11)

Lead Sponsor	Collaborator
Vera HM Deneer	Amphia Hospital, Federico II University, Isala, Meander Medical Center, OLVG, Onze Lieve Vrouw Hospital, Rijnstate Hospital, UMC Utrecht, University Medical Center Groningen, ZonMw: The Netherlands Organisation for Health Research and Development

Countries where clinical trial is conducted

Belgium,  Italy,  Netherlands, 

References & Publications (10)

Bergmeijer TO, Janssen PW, Schipper JC, Qaderdan K, Ishak M, Ruitenbeek RS, Asselbergs FW, van 't Hof AW, Dewilde WJ, Spanó F, Herrman JP, Kelder JC, Postma MJ, de Boer A, Deneer VH, ten Berg JM. CYP2C19 genotype-guided antiplatelet therapy in ST-segment elevation myocardial infarction patients-Rationale and design of the Patient Outcome after primary PCI (POPular) Genetics study. Am Heart J. 2014 Jul;168(1):16-22.e1. doi: 10.1016/j.ahj.2014.03.006. Epub 2014 Mar 21. — View Citation

Brandt JT, Close SL, Iturria SJ, Payne CD, Farid NA, Ernest CS 2nd, Lachno DR, Salazar D, Winters KJ. Common polymorphisms of CYP2C19 and CYP2C9 affect the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel. J Thromb Haemost. 2007 Dec;5(12):2429-36. Epub 2007 Sep 26. — View Citation

Collet JP, Hulot JS, Pena A, Villard E, Esteve JB, Silvain J, Payot L, Brugier D, Cayla G, Beygui F, Bensimon G, Funck-Brentano C, Montalescot G. Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study. Lancet. 2009 Jan 24;373(9660):309-17. doi: 10.1016/S0140-6736(08)61845-0. Epub 2008 Dec 26. — View Citation

Harmsze A, van Werkum JW, Bouman HJ, Ruven HJ, Breet NJ, Ten Berg JM, Hackeng CM, Tjoeng MM, Klungel OH, de Boer A, Deneer VH. Besides CYP2C19*2, the variant allele CYP2C9*3 is associated with higher on-clopidogrel platelet reactivity in patients on dual antiplatelet therapy undergoing elective coronary stent implantation. Pharmacogenet Genomics. 2010 Jan;20(1):18-25. doi: 10.1097/FPC.0b013e328333dafe. — View Citation

Harmsze AM, van Werkum JW, Ten Berg JM, Zwart B, Bouman HJ, Breet NJ, van 't Hof AW, Ruven HJ, Hackeng CM, Klungel OH, de Boer A, Deneer VH. CYP2C19*2 and CYP2C9*3 alleles are associated with stent thrombosis: a case-control study. Eur Heart J. 2010 Dec;31(24):3046-53. doi: 10.1093/eurheartj/ehq321. Epub 2010 Sep 10. — View Citation

Mega JL, Close SL, Wiviott SD, Shen L, Hockett RD, Brandt JT, Walker JR, Antman EM, Macias W, Braunwald E, Sabatine MS. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med. 2009 Jan 22;360(4):354-62. doi: 10.1056/NEJMoa0809171. Epub 2008 Dec 22. — View Citation

Mega JL, Simon T, Collet JP, Anderson JL, Antman EM, Bliden K, Cannon CP, Danchin N, Giusti B, Gurbel P, Horne BD, Hulot JS, Kastrati A, Montalescot G, Neumann FJ, Shen L, Sibbing D, Steg PG, Trenk D, Wiviott SD, Sabatine MS. Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis. JAMA. 2010 Oct 27;304(16):1821-30. doi: 10.1001/jama.2010.1543. — View Citation

Montalescot G, Wiviott SD, Braunwald E, Murphy SA, Gibson CM, McCabe CH, Antman EM; TRITON-TIMI 38 investigators. Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for ST-elevation myocardial infarction (TRITON-TIMI 38): double-blind, randomised controlled trial. Lancet. 2009 Feb 28;373(9665):723-31. doi: 10.1016/S0140-6736(09)60441-4. — View Citation

Peters BJ, Harmsze AM, ten Berg JM, Maitland-van der Zee AH, Tjoeng MM, de Boer A, Deneer VH. CYP2C19 and ABCB1 genes and individualized treatment with clopidogrel. Pharmacogenomics. 2011 Feb;12(2):141-4. doi: 10.2217/pgs.10.211. — View Citation

Wallentin L, James S, Storey RF, Armstrong M, Barratt BJ, Horrow J, Husted S, Katus H, Steg PG, Shah SH, Becker RC; PLATO investigators. Effect of CYP2C19 and ABCB1 single nucleotide polymorphisms on outcomes of treatment with ticagrelor versus clopidogrel for acute coronary syndromes: a genetic substudy of the PLATO trial. Lancet. 2010 Oct 16;376(9749):1320-8. doi: 10.1016/S0140-6736(10)61274-3. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Net clinical benefit	The primary endpoint is the number of patients who either died, developed a recurrent myocardial infarction (MI), developed definite stent thrombosis, stroke or PLATO major bleeding at 1 year after PCI.	1 year
Primary	Safety endpoint	The primary safety endpoint is the number of patients with PLATO major or minor bleeding at 1 year after PCI.	1 year
Primary	Pharmacoeconomics endpoint	The primary endpoints in terms of pharmacoeconomics are quality of life, direct medical costs e.g. costs for blood transfusions, drugs, hospitalization and non-medical costs e.g. costs incurred due to sickness absence.	1 year
Secondary	Net clinical benefit at 30 days	The number of patients who either died, developed a recurrent myocardial infarction (MI), developed definite stent thrombosis, stroke or PLATO major bleeding at 30 days after PCI.	30 days
Secondary	Secondary efficacy and safety endpoint	both efficacy and safety will be studied in more detail, using the items of the primary endpoint (death, recurrent myocardial infarction, stentthrombosis, stroke, PLATO major bleeding) as separate parameters and in different combinations, adding cardiovascular and cerebrovascular death, probable and possible stent thrombosis, urgent target vessel revascularization (uTVR) and hospital admission for acute coronary syndrome (ACS) to the efficacy analysis, and (non-)CABG-related bleeding, major-, minor-, life threatening-, fatal-, intracranial and bleeding requiring transfusion to the bleeding analysis, both for 30 days and 1 year follow-up	30 days and 1 year
Secondary	Secondary safety endpoint	Number of patients with bleeding events in 1 year follow up, not only using PLATO bleeding classification, but also, TIMI and BARC bleeding classifications to make the study comparable to previous and future publications	30 days and 1 year
Secondary	Drug endpoint	Comparing the number of patients switching from the recommended P2Y12 inhibitor to a different P2Y12 inhibitor and the number of patients who discontinue the P2Y12 inhibitor early in both the control and genotype group	30 days and 1 year