Clopidogrel in noncarriers of CYP2C19 loss-of-function alleles versus ticagrelor in elderly patients with acute coronary syndrome: A pre-specified sub analysis from the POPular Genetics and POPular Age trials CYP2C19 alleles in elderly patients

Daniel M.F. Claassens; Marieke E. Gimbel; Thomas O. Bergmeijer; Gerrit J.A. Vos; Renicus S. Hermanides; Pim van der Harst; Emanuele Barbato; Carmine Morisco; Richard M. Tjon Joe Gin; Evelyn A. de Vrey; Ton A.C.M. Heestermans; J. Wouter Jukema; Clemens von Birgelen; Reinier A. Waalewijn; Sjoerd H. Hofma; Frank R. den Hartog; Michiel Voskuil; Arnoud W.J. van't Hof; Folkert W. Asselbergs; A. Mosterd; Jean Paul R. Herrman; Willem Dewilde; Bakhtawar K. Mahmoodi; Vera H.M. Deneer; Jurriën M. ten Berg

doi:10.1016/j.ijcard.2021.04.029

Clopidogrel in noncarriers of CYP2C19 loss-of-function alleles versus ticagrelor in elderly patients with acute coronary syndrome: A pre-specified sub analysis from the POPular Genetics and POPular Age trials CYP2C19 alleles in elderly patients

Daniel M.F. Claassens, Marieke E. Gimbel, Thomas O. Bergmeijer, Gerrit J.A. Vos, Renicus S. Hermanides, Pim van der Harst, Emanuele Barbato, Carmine Morisco, Richard M. Tjon Joe Gin, Evelyn A. de Vrey, Ton A.C.M. Heestermans, J. Wouter Jukema, Clemens von Birgelen, Reinier A. Waalewijn, Sjoerd H. Hofma, Frank R. den Hartog, Michiel Voskuil, Arnoud W.J. van't Hof, Folkert W. Asselbergs, A. MosterdJean Paul R. Herrman, Willem Dewilde, Bakhtawar K. Mahmoodi, Vera H.M. Deneer, Jurriën M. ten Berg^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Background: Patients with acute coronary syndrome (ACS) who are carrying CYP2C19 loss-of-function alleles derive less benefit from clopidogrel treatment. Despite this, in elderly patients, clopidogrel might be preferred over more potent P2Y₁₂ inhibitors due to a lower bleeding risk. Whether CYP2C19 genotype-guided antiplatelet treatment in the elderly could be of benefit has not been studied specifically. Methods: Patients aged 70 years and older with known CYP2C19*2 and *3 genotype were identified from the POPular Genetics and POPular Age trials. Noncarriers of loss-of-function alleles treated with clopidogrel were compared to patients, irrespective of CYP2C19 genotype, treated with ticagrelor and to clopidogrel treated carriers of loss-of-function alleles. We assessed net clinical benefit (all-cause death, myocardial infarction, stroke and Platelet Inhibition and Patient Outcomes (PLATO) major bleeding), atherothrombotic outcomes (cardiovascular death, myocardial infarction, stroke) and bleeding outcomes (PLATO major and minor bleeding). Results: A total of 991 patients were assessed. There was no significant difference in net clinical benefit (17.2% vs. 15.1%, adjusted hazard ratio (adjHR) 1.05, 95% confidence interval (CI) 0.77–1.44), atherothrombotic outcomes (9.7% vs. 9.2%, adjHR 1.00, 95%CI 0.66–1.50), and bleeding outcomes (17.7% vs. 19.8%, adjHR 0.80, 95%CI 0.62–1.12) between clopidogrel in noncarriers of loss-of-function alleles and ticagrelor respectively. Conclusion: In ACS patients aged 70 years and older, there was no significant difference in net clinical benefit and atherothrombotic outcomes between noncarriers of a loss-of-function allele treated with clopidogrel and patients treated with ticagrelor. The bleeding rate was numerically; though not statistically significant, lower in patients using clopidogrel.

Original language	English
Pages (from-to)	10-17
Number of pages	8
Journal	International Journal of Cardiology
Volume	334
DOIs	https://doi.org/10.1016/j.ijcard.2021.04.029
Publication status	Published - 1 Jul 2021

Bibliographical note

Funding Information:
AvtH reports grants from Medtronic, Astra Zeneca and Sanofi and personal fees from Astra Zeneca and AMGEN; CvB reports institutional research grants provided by the research department of Thoraxcentrum Twente, from Abbott Vascular, Biotronik, Boston Scientific, and Medtronic, outside the submitted work; EB reports personal fees from BOSTON SCIENTIFIC, ABBOTT VASCULAR and GE; JtB reports grants from Astra Zeneca and personal fees from AstraZeneca, Daiichi Sankyo, Eli Lilly, the Medicines Company, Accumetrics, Boehringer-Ingelheim, Bayer, BMS, Pfizer and Ferrer; WJ and his department have received research grants from Amgen, Athera, AstraZeneca, Biotronik, Boston Scientific, Daiichi Sankyo, Lilly, Medtronic, Merck-Schering-Plough, Pfizer, Roche, Sanofi Aventis, The Medicine Company, the Netherlands Heart Foundation, Netherlands CardioVascular Research, the Netherlands Heart Institute, and the European Community Framework KP7 Programme; and was a speaker (with and without lecture fees) on amongst others (Continuing Medical Education accredited) meetings sponsored by Amgen, Athera, AstraZeneca, Biotronik, Boston Scientific, Daiichi Sankyo, Lilly, Medtronic, Merck-Schering-Plough, Pfizer, Roche, Sanofi Aventis, The Medicine Company, the Netherlands Heart Foundation, CardioVascular Research the Netherlands, the Netherlands Heart Institute, and the European Community Framework KP7 Programme, during the conduct of the study. All other authors declare no conflicts of interests.

Funding Information:
Dr. Asselbergs is supported by the University College London Hospitals National Institute for Health Research Biomedical Research Centre .

Funding Information:
The POPular Genetics and POPular Age trial were both funded by ZonMw , a Dutch Governmental agency promoting research in healthcare. In the POPular Genetics trial, a portion of the patients was tested using point-of-care tests supplied by Spartan Bioscience Inc. for free.

Publisher Copyright:
© 2021

Funding

AvtH reports grants from Medtronic, Astra Zeneca and Sanofi and personal fees from Astra Zeneca and AMGEN; CvB reports institutional research grants provided by the research department of Thoraxcentrum Twente, from Abbott Vascular, Biotronik, Boston Scientific, and Medtronic, outside the submitted work; EB reports personal fees from BOSTON SCIENTIFIC, ABBOTT VASCULAR and GE; JtB reports grants from Astra Zeneca and personal fees from AstraZeneca, Daiichi Sankyo, Eli Lilly, the Medicines Company, Accumetrics, Boehringer-Ingelheim, Bayer, BMS, Pfizer and Ferrer; WJ and his department have received research grants from Amgen, Athera, AstraZeneca, Biotronik, Boston Scientific, Daiichi Sankyo, Lilly, Medtronic, Merck-Schering-Plough, Pfizer, Roche, Sanofi Aventis, The Medicine Company, the Netherlands Heart Foundation, Netherlands CardioVascular Research, the Netherlands Heart Institute, and the European Community Framework KP7 Programme; and was a speaker (with and without lecture fees) on amongst others (Continuing Medical Education accredited) meetings sponsored by Amgen, Athera, AstraZeneca, Biotronik, Boston Scientific, Daiichi Sankyo, Lilly, Medtronic, Merck-Schering-Plough, Pfizer, Roche, Sanofi Aventis, The Medicine Company, the Netherlands Heart Foundation, CardioVascular Research the Netherlands, the Netherlands Heart Institute, and the European Community Framework KP7 Programme, during the conduct of the study. All other authors declare no conflicts of interests. Dr. Asselbergs is supported by the University College London Hospitals National Institute for Health Research Biomedical Research Centre . The POPular Genetics and POPular Age trial were both funded by ZonMw , a Dutch Governmental agency promoting research in healthcare. In the POPular Genetics trial, a portion of the patients was tested using point-of-care tests supplied by Spartan Bioscience Inc. for free.

Keywords

CYP2C19
Genotyping
Myocardial infarction
Older
P2Y12
Pharmacogenetics

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Claassens, D. M. F., Gimbel, M. E., Bergmeijer, T. O., Vos, G. J. A., Hermanides, R. S., van der Harst, P., Barbato, E., Morisco, C., Tjon Joe Gin, R. M., de Vrey, E. A., Heestermans, T. A. C. M., Jukema, J. W., von Birgelen, C., Waalewijn, R. A., Hofma, S. H., den Hartog, F. R., Voskuil, M., van't Hof, A. W. J., Asselbergs, F. W., ... ten Berg, J. M. (2021). Clopidogrel in noncarriers of CYP2C19 loss-of-function alleles versus ticagrelor in elderly patients with acute coronary syndrome: A pre-specified sub analysis from the POPular Genetics and POPular Age trials CYP2C19 alleles in elderly patients. International Journal of Cardiology, 334, 10-17. https://doi.org/10.1016/j.ijcard.2021.04.029

Claassens, Daniel M.F. ; Gimbel, Marieke E. ; Bergmeijer, Thomas O. et al. / Clopidogrel in noncarriers of CYP2C19 loss-of-function alleles versus ticagrelor in elderly patients with acute coronary syndrome : A pre-specified sub analysis from the POPular Genetics and POPular Age trials CYP2C19 alleles in elderly patients. In: International Journal of Cardiology. 2021 ; Vol. 334. pp. 10-17.

@article{60b72ea50f6042359a6927dc0209e578,

title = "Clopidogrel in noncarriers of CYP2C19 loss-of-function alleles versus ticagrelor in elderly patients with acute coronary syndrome: A pre-specified sub analysis from the POPular Genetics and POPular Age trials CYP2C19 alleles in elderly patients",

abstract = "Background: Patients with acute coronary syndrome (ACS) who are carrying CYP2C19 loss-of-function alleles derive less benefit from clopidogrel treatment. Despite this, in elderly patients, clopidogrel might be preferred over more potent P2Y12 inhibitors due to a lower bleeding risk. Whether CYP2C19 genotype-guided antiplatelet treatment in the elderly could be of benefit has not been studied specifically. Methods: Patients aged 70 years and older with known CYP2C19*2 and *3 genotype were identified from the POPular Genetics and POPular Age trials. Noncarriers of loss-of-function alleles treated with clopidogrel were compared to patients, irrespective of CYP2C19 genotype, treated with ticagrelor and to clopidogrel treated carriers of loss-of-function alleles. We assessed net clinical benefit (all-cause death, myocardial infarction, stroke and Platelet Inhibition and Patient Outcomes (PLATO) major bleeding), atherothrombotic outcomes (cardiovascular death, myocardial infarction, stroke) and bleeding outcomes (PLATO major and minor bleeding). Results: A total of 991 patients were assessed. There was no significant difference in net clinical benefit (17.2% vs. 15.1%, adjusted hazard ratio (adjHR) 1.05, 95% confidence interval (CI) 0.77–1.44), atherothrombotic outcomes (9.7% vs. 9.2%, adjHR 1.00, 95%CI 0.66–1.50), and bleeding outcomes (17.7% vs. 19.8%, adjHR 0.80, 95%CI 0.62–1.12) between clopidogrel in noncarriers of loss-of-function alleles and ticagrelor respectively. Conclusion: In ACS patients aged 70 years and older, there was no significant difference in net clinical benefit and atherothrombotic outcomes between noncarriers of a loss-of-function allele treated with clopidogrel and patients treated with ticagrelor. The bleeding rate was numerically; though not statistically significant, lower in patients using clopidogrel.",

keywords = "CYP2C19, Genotyping, Myocardial infarction, Older, P2Y12, Pharmacogenetics",

author = "Claassens, {Daniel M.F.} and Gimbel, {Marieke E.} and Bergmeijer, {Thomas O.} and Vos, {Gerrit J.A.} and Hermanides, {Renicus S.} and {van der Harst}, Pim and Emanuele Barbato and Carmine Morisco and {Tjon Joe Gin}, {Richard M.} and {de Vrey}, {Evelyn A.} and Heestermans, {Ton A.C.M.} and Jukema, {J. Wouter} and {von Birgelen}, Clemens and Waalewijn, {Reinier A.} and Hofma, {Sjoerd H.} and {den Hartog}, {Frank R.} and Michiel Voskuil and {van't Hof}, {Arnoud W.J.} and Asselbergs, {Folkert W.} and A. Mosterd and Herrman, {Jean Paul R.} and Willem Dewilde and Mahmoodi, {Bakhtawar K.} and Deneer, {Vera H.M.} and {ten Berg}, {Jurri{\"e}n M.}",

note = "Funding Information: AvtH reports grants from Medtronic, Astra Zeneca and Sanofi and personal fees from Astra Zeneca and AMGEN; CvB reports institutional research grants provided by the research department of Thoraxcentrum Twente, from Abbott Vascular, Biotronik, Boston Scientific, and Medtronic, outside the submitted work; EB reports personal fees from BOSTON SCIENTIFIC, ABBOTT VASCULAR and GE; JtB reports grants from Astra Zeneca and personal fees from AstraZeneca, Daiichi Sankyo, Eli Lilly, the Medicines Company, Accumetrics, Boehringer-Ingelheim, Bayer, BMS, Pfizer and Ferrer; WJ and his department have received research grants from Amgen, Athera, AstraZeneca, Biotronik, Boston Scientific, Daiichi Sankyo, Lilly, Medtronic, Merck-Schering-Plough, Pfizer, Roche, Sanofi Aventis, The Medicine Company, the Netherlands Heart Foundation, Netherlands CardioVascular Research, the Netherlands Heart Institute, and the European Community Framework KP7 Programme; and was a speaker (with and without lecture fees) on amongst others (Continuing Medical Education accredited) meetings sponsored by Amgen, Athera, AstraZeneca, Biotronik, Boston Scientific, Daiichi Sankyo, Lilly, Medtronic, Merck-Schering-Plough, Pfizer, Roche, Sanofi Aventis, The Medicine Company, the Netherlands Heart Foundation, CardioVascular Research the Netherlands, the Netherlands Heart Institute, and the European Community Framework KP7 Programme, during the conduct of the study. All other authors declare no conflicts of interests. Funding Information: Dr. Asselbergs is supported by the University College London Hospitals National Institute for Health Research Biomedical Research Centre . Funding Information: The POPular Genetics and POPular Age trial were both funded by ZonMw , a Dutch Governmental agency promoting research in healthcare. In the POPular Genetics trial, a portion of the patients was tested using point-of-care tests supplied by Spartan Bioscience Inc. for free. Publisher Copyright: {\textcopyright} 2021",

year = "2021",

month = jul,

day = "1",

doi = "10.1016/j.ijcard.2021.04.029",

language = "English",

volume = "334",

pages = "10--17",

journal = "International Journal of Cardiology",

issn = "0167-5273",

publisher = "Elsevier Ireland Ltd.",

}

Claassens, DMF, Gimbel, ME, Bergmeijer, TO, Vos, GJA, Hermanides, RS, van der Harst, P, Barbato, E, Morisco, C, Tjon Joe Gin, RM, de Vrey, EA, Heestermans, TACM, Jukema, JW, von Birgelen, C, Waalewijn, RA, Hofma, SH, den Hartog, FR, Voskuil, M, van't Hof, AWJ, Asselbergs, FW, Mosterd, A, Herrman, JPR, Dewilde, W, Mahmoodi, BK, Deneer, VHM & ten Berg, JM 2021, 'Clopidogrel in noncarriers of CYP2C19 loss-of-function alleles versus ticagrelor in elderly patients with acute coronary syndrome: A pre-specified sub analysis from the POPular Genetics and POPular Age trials CYP2C19 alleles in elderly patients', International Journal of Cardiology, vol. 334, pp. 10-17. https://doi.org/10.1016/j.ijcard.2021.04.029

Clopidogrel in noncarriers of CYP2C19 loss-of-function alleles versus ticagrelor in elderly patients with acute coronary syndrome: A pre-specified sub analysis from the POPular Genetics and POPular Age trials CYP2C19 alleles in elderly patients. / Claassens, Daniel M.F.; Gimbel, Marieke E.; Bergmeijer, Thomas O. et al.
In: International Journal of Cardiology, Vol. 334, 01.07.2021, p. 10-17.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - Clopidogrel in noncarriers of CYP2C19 loss-of-function alleles versus ticagrelor in elderly patients with acute coronary syndrome

T2 - A pre-specified sub analysis from the POPular Genetics and POPular Age trials CYP2C19 alleles in elderly patients

AU - Claassens, Daniel M.F.

AU - Gimbel, Marieke E.

AU - Bergmeijer, Thomas O.

AU - Vos, Gerrit J.A.

AU - Hermanides, Renicus S.

AU - van der Harst, Pim

AU - Barbato, Emanuele

AU - Morisco, Carmine

AU - Tjon Joe Gin, Richard M.

AU - de Vrey, Evelyn A.

AU - Heestermans, Ton A.C.M.

AU - Jukema, J. Wouter

AU - von Birgelen, Clemens

AU - Waalewijn, Reinier A.

AU - Hofma, Sjoerd H.

AU - den Hartog, Frank R.

AU - Voskuil, Michiel

AU - van't Hof, Arnoud W.J.

AU - Asselbergs, Folkert W.

AU - Mosterd, A.

AU - Herrman, Jean Paul R.

AU - Dewilde, Willem

AU - Mahmoodi, Bakhtawar K.

AU - Deneer, Vera H.M.

AU - ten Berg, Jurriën M.

N1 - Funding Information: AvtH reports grants from Medtronic, Astra Zeneca and Sanofi and personal fees from Astra Zeneca and AMGEN; CvB reports institutional research grants provided by the research department of Thoraxcentrum Twente, from Abbott Vascular, Biotronik, Boston Scientific, and Medtronic, outside the submitted work; EB reports personal fees from BOSTON SCIENTIFIC, ABBOTT VASCULAR and GE; JtB reports grants from Astra Zeneca and personal fees from AstraZeneca, Daiichi Sankyo, Eli Lilly, the Medicines Company, Accumetrics, Boehringer-Ingelheim, Bayer, BMS, Pfizer and Ferrer; WJ and his department have received research grants from Amgen, Athera, AstraZeneca, Biotronik, Boston Scientific, Daiichi Sankyo, Lilly, Medtronic, Merck-Schering-Plough, Pfizer, Roche, Sanofi Aventis, The Medicine Company, the Netherlands Heart Foundation, Netherlands CardioVascular Research, the Netherlands Heart Institute, and the European Community Framework KP7 Programme; and was a speaker (with and without lecture fees) on amongst others (Continuing Medical Education accredited) meetings sponsored by Amgen, Athera, AstraZeneca, Biotronik, Boston Scientific, Daiichi Sankyo, Lilly, Medtronic, Merck-Schering-Plough, Pfizer, Roche, Sanofi Aventis, The Medicine Company, the Netherlands Heart Foundation, CardioVascular Research the Netherlands, the Netherlands Heart Institute, and the European Community Framework KP7 Programme, during the conduct of the study. All other authors declare no conflicts of interests. Funding Information: Dr. Asselbergs is supported by the University College London Hospitals National Institute for Health Research Biomedical Research Centre . Funding Information: The POPular Genetics and POPular Age trial were both funded by ZonMw , a Dutch Governmental agency promoting research in healthcare. In the POPular Genetics trial, a portion of the patients was tested using point-of-care tests supplied by Spartan Bioscience Inc. for free. Publisher Copyright: © 2021

PY - 2021/7/1

Y1 - 2021/7/1

N2 - Background: Patients with acute coronary syndrome (ACS) who are carrying CYP2C19 loss-of-function alleles derive less benefit from clopidogrel treatment. Despite this, in elderly patients, clopidogrel might be preferred over more potent P2Y12 inhibitors due to a lower bleeding risk. Whether CYP2C19 genotype-guided antiplatelet treatment in the elderly could be of benefit has not been studied specifically. Methods: Patients aged 70 years and older with known CYP2C19*2 and *3 genotype were identified from the POPular Genetics and POPular Age trials. Noncarriers of loss-of-function alleles treated with clopidogrel were compared to patients, irrespective of CYP2C19 genotype, treated with ticagrelor and to clopidogrel treated carriers of loss-of-function alleles. We assessed net clinical benefit (all-cause death, myocardial infarction, stroke and Platelet Inhibition and Patient Outcomes (PLATO) major bleeding), atherothrombotic outcomes (cardiovascular death, myocardial infarction, stroke) and bleeding outcomes (PLATO major and minor bleeding). Results: A total of 991 patients were assessed. There was no significant difference in net clinical benefit (17.2% vs. 15.1%, adjusted hazard ratio (adjHR) 1.05, 95% confidence interval (CI) 0.77–1.44), atherothrombotic outcomes (9.7% vs. 9.2%, adjHR 1.00, 95%CI 0.66–1.50), and bleeding outcomes (17.7% vs. 19.8%, adjHR 0.80, 95%CI 0.62–1.12) between clopidogrel in noncarriers of loss-of-function alleles and ticagrelor respectively. Conclusion: In ACS patients aged 70 years and older, there was no significant difference in net clinical benefit and atherothrombotic outcomes between noncarriers of a loss-of-function allele treated with clopidogrel and patients treated with ticagrelor. The bleeding rate was numerically; though not statistically significant, lower in patients using clopidogrel.

AB - Background: Patients with acute coronary syndrome (ACS) who are carrying CYP2C19 loss-of-function alleles derive less benefit from clopidogrel treatment. Despite this, in elderly patients, clopidogrel might be preferred over more potent P2Y12 inhibitors due to a lower bleeding risk. Whether CYP2C19 genotype-guided antiplatelet treatment in the elderly could be of benefit has not been studied specifically. Methods: Patients aged 70 years and older with known CYP2C19*2 and *3 genotype were identified from the POPular Genetics and POPular Age trials. Noncarriers of loss-of-function alleles treated with clopidogrel were compared to patients, irrespective of CYP2C19 genotype, treated with ticagrelor and to clopidogrel treated carriers of loss-of-function alleles. We assessed net clinical benefit (all-cause death, myocardial infarction, stroke and Platelet Inhibition and Patient Outcomes (PLATO) major bleeding), atherothrombotic outcomes (cardiovascular death, myocardial infarction, stroke) and bleeding outcomes (PLATO major and minor bleeding). Results: A total of 991 patients were assessed. There was no significant difference in net clinical benefit (17.2% vs. 15.1%, adjusted hazard ratio (adjHR) 1.05, 95% confidence interval (CI) 0.77–1.44), atherothrombotic outcomes (9.7% vs. 9.2%, adjHR 1.00, 95%CI 0.66–1.50), and bleeding outcomes (17.7% vs. 19.8%, adjHR 0.80, 95%CI 0.62–1.12) between clopidogrel in noncarriers of loss-of-function alleles and ticagrelor respectively. Conclusion: In ACS patients aged 70 years and older, there was no significant difference in net clinical benefit and atherothrombotic outcomes between noncarriers of a loss-of-function allele treated with clopidogrel and patients treated with ticagrelor. The bleeding rate was numerically; though not statistically significant, lower in patients using clopidogrel.

KW - CYP2C19

KW - Genotyping

KW - Myocardial infarction

KW - Older

KW - P2Y12

KW - Pharmacogenetics

UR - http://www.scopus.com/inward/record.url?scp=85106259701&partnerID=8YFLogxK

U2 - 10.1016/j.ijcard.2021.04.029

DO - 10.1016/j.ijcard.2021.04.029

M3 - Article

C2 - 33887342

AN - SCOPUS:85106259701

SN - 0167-5273

VL - 334

SP - 10

EP - 17

JO - International Journal of Cardiology

JF - International Journal of Cardiology

ER -

Claassens DMF, Gimbel ME, Bergmeijer TO, Vos GJA, Hermanides RS, van der Harst P et al. Clopidogrel in noncarriers of CYP2C19 loss-of-function alleles versus ticagrelor in elderly patients with acute coronary syndrome: A pre-specified sub analysis from the POPular Genetics and POPular Age trials CYP2C19 alleles in elderly patients. International Journal of Cardiology. 2021 Jul 1;334:10-17. doi: 10.1016/j.ijcard.2021.04.029

Clopidogrel in noncarriers of CYP2C19 loss-of-function alleles versus ticagrelor in elderly patients with acute coronary syndrome: A pre-specified sub analysis from the POPular Genetics and POPular Age trials CYP2C19 alleles in elderly patients

Abstract

Bibliographical note

Funding

Keywords

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