- Email: [email protected]
ANTARCTIC: platelet function testing to adjust therapy
Correspondence
Alexandre Hideo-Kajita, Ron Waksman, *Hector M Garcia-Garcia [email protected] MedStar Washington Hospital Center, Section of Interventional Cardiology, Washington DC 20010, USA 1
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Cayla G, Cuisset T, Silvain J, et al, for the ANTARCTIC Investigators. Platelet function monitoring to adjust antiplatelet therapy in elderly patients stented for an acute coronary syndrome (ANTARCTIC): an open-label, blinded-endpoint, randomised controlled superiority trial. Lancet 2016; 388: 2015–22. Wiviott SD, Braunwald E, McCabe CH, et al, TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357: 2001–15. Bittl JA, Baber U, Bradley SM, Wijeysundera DN. Duration of dual antiplatelet therapy: a systematic review for the 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2016; 68: 1116–39. Windecker S, Kolh P, Alfonso F, et al. 2014 ESC/EACTS guidelines on myocardial revascularization. EuroIntervention 2015; 10: 1024–94.
We read the ANTARCTIC study by Guillaume Cayla and colleagues1 with interest. The authors interpreted that platelet function monitoring with treatment adjustment did not improve the clinical outcome of elderly patients treated with coronary stenting for an acute coronary syndrome. We think that the following granular conclusion is more appropriate: elderly patients with acute coronary syndrome given low-dose prasugrel who had low ontreatment reactivity identified by platelet function testing did not have reduced bleeding after switching to clopidogrel therapy. With low-dose prasugrel, the monitoring group— ie, the group given dose or drug adjustments in case of inadequate response—had scarce need to intensify therapy for high platelet reactivity (about 4% of patients). Rather, almost all of the adjustment www.thelancet.com Vol 389 March 25, 2017
in ANTARCTIC was de-intensification to clopidogrel in an attempt to reduce bleeding. In the GENERATIONS2 and TRILOGY ACS3 trials, the bleeding rates were the same between the prasugrel 5 mg and clopidogrel 75 mg groups. Therefore, the ANTARCTIC results were unsurprisingly unsupportive of personalisation. Given these important limitations, the study is insufficient to refute the utility of personalising antiplatelet therapy, and therefore the authors are overreaching with their generalised statements in the interpretation about how the study results should influence guideline recommendations. PAG reports grants from Haemonetics, Duke Clinical Research Institute, National Institutes of Health, Merck, MedImmune, Coramed, and New Haven Pharmaceuticals; personal fees from AstraZeneca, Boehringer, Merck, Janssen, Bayer, and New Haven Pharmaceuticals outside the submitted work; and he has a patent for platelet function testing issued. MJP reports personal fees from AstraZeneca, Medtronic, Boston Scientific, Abbott Vascular, Terumo, Chiesi USA, The Medicines Company, and ACIST Medical outside the submitted work. JRD reports personal fees from Aggredyne, Fujimori Kogyo, and Accriva outside the submitted work. UST declares no competing interests.
*Paul A Gurbel, Matthew J Price, Jeffrey R Dahlen, Udaya S Tantry [email protected] Inova Center for Thrombosis Research and Drug Development, Inova Heart and Vascular Institute, Falls Church, VA 22042, USA (PAG, UST); Scripps Clinic, La Jolla, CA, USA (MJP); and Hikari Dx, San Diego, CA, USA (JRD) 1
2
3
Cayla G, Cuisset T, Silvain J, et al, for the ANTARCTIC Investigators. Platelet function monitoring to adjust antiplatelet therapy in elderly patients stented for an acute coronary syndrome (ANTARCTIC): an open-label, blinded-endpoint, randomised controlled superiority trial. Lancet 2016; 388: 2015–22. Erlinge D, Gurbel PA, James S, et al. Prasugrel 5 mg in the very elderly attenuates platelet inhibition but maintains noninferiority to prasugrel 10 mg in nonelderly patients: the GENERATIONS trial, a pharmacodynamic and pharmacokinetic study in stable coronary artery disease patients. J Am Coll Cardiol 2013; 62: 577–83. Gurbel PA, Erlinge D, Ohman EM, et al, for the TRILOGY ACS Platelet Function Substudy Investigators. Platelet function during extended prasugrel and clopidogrel therapy for patients with ACS treated without revascularization: the TRILOGY ACS platelet function substudy. JAMA 2012; 308: 1785–94.
Authors’ reply
We thank Paul Gurbel and colleagues for their interest in our randomised ANTARCTIC study,1 but we think they have wrongly interpreted both the design and the results of the study. Their statement corresponds neither to the hypothesis nor to the primary endpoint of the study. We wish to underscore that the ANTARCTIC study was not a comparison between prasugrel and clopidogrel, that bleeding was not the primary endpoint, that the study never tested switching from prasugrel to clopidogrel, and that 5 mg is not a low dose but the approved dose of prasugrel for the elderly. When patients were randomised to platelet function testing in our study, drug and dose adjustments could occur in both directions: more intense platelet inhibition (higher dose of prasugrel) for the patients exposed to ischaemic events because of their high platelet reactivity, or less intense platelet inhibition (clopidogrel) when they were exposed to bleeding because of their low platelet reactivity. No adjustment was the third possibility when the patients had reached the optimal platelet reactivity target. Notably, Gurbel and colleagues refer us to their own paper, the GENERATIONS trial,2 which showed a significant difference (p<0·001) in platelet reactivity in the elderly between those who took clopidogrel 75 mg (41% of patients had high platelet reactivity—defined as >235 platelet reactivity units) and those who took prasugrel 5 mg (14% of patients had high platelet reactivity). On this basis, we and Gurbel and colleagues, all thought that better individual control of platelet reactivity would lead to better outcomes—not only for bleeding, but also for ischaemic events. Better control of platelet reactivity was obtained after platelet function testing and drug adjustment in ANTARCTIC, but it had no effect on bleeding and ischaemic events. Gurbel and colleagues think that the negative results of ANTARCTIC are insufficient to refute the utility of personalising
Science Photo
Biosensors International; is a member of the speakers, bureau for AstraZeneca, Boston Scientific, and Merck; and has received grants from AstraZeneca, Biotronik, Boston Scientific, Biosensors International, The Medicines Company, and Edwards Lifesciences. All other authors declare no competing interests.
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Alexandre Hideo-Kajita, Ron Waksman, *Hector M Garcia-Garcia [email protected] MedStar Washington Hospital Center, Section of Interventional Cardiology, Washington DC 20010, USA 1
2
3
4
Cayla G, Cuisset T, Silvain J, et al, for the ANTARCTIC Investigators. Platelet function monitoring to adjust antiplatelet therapy in elderly patients stented for an acute coronary syndrome (ANTARCTIC): an open-label, blinded-endpoint, randomised controlled superiority trial. Lancet 2016; 388: 2015–22. Wiviott SD, Braunwald E, McCabe CH, et al, TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357: 2001–15. Bittl JA, Baber U, Bradley SM, Wijeysundera DN. Duration of dual antiplatelet therapy: a systematic review for the 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2016; 68: 1116–39. Windecker S, Kolh P, Alfonso F, et al. 2014 ESC/EACTS guidelines on myocardial revascularization. EuroIntervention 2015; 10: 1024–94.
We read the ANTARCTIC study by Guillaume Cayla and colleagues1 with interest. The authors interpreted that platelet function monitoring with treatment adjustment did not improve the clinical outcome of elderly patients treated with coronary stenting for an acute coronary syndrome. We think that the following granular conclusion is more appropriate: elderly patients with acute coronary syndrome given low-dose prasugrel who had low ontreatment reactivity identified by platelet function testing did not have reduced bleeding after switching to clopidogrel therapy. With low-dose prasugrel, the monitoring group— ie, the group given dose or drug adjustments in case of inadequate response—had scarce need to intensify therapy for high platelet reactivity (about 4% of patients). Rather, almost all of the adjustment www.thelancet.com Vol 389 March 25, 2017
in ANTARCTIC was de-intensification to clopidogrel in an attempt to reduce bleeding. In the GENERATIONS2 and TRILOGY ACS3 trials, the bleeding rates were the same between the prasugrel 5 mg and clopidogrel 75 mg groups. Therefore, the ANTARCTIC results were unsurprisingly unsupportive of personalisation. Given these important limitations, the study is insufficient to refute the utility of personalising antiplatelet therapy, and therefore the authors are overreaching with their generalised statements in the interpretation about how the study results should influence guideline recommendations. PAG reports grants from Haemonetics, Duke Clinical Research Institute, National Institutes of Health, Merck, MedImmune, Coramed, and New Haven Pharmaceuticals; personal fees from AstraZeneca, Boehringer, Merck, Janssen, Bayer, and New Haven Pharmaceuticals outside the submitted work; and he has a patent for platelet function testing issued. MJP reports personal fees from AstraZeneca, Medtronic, Boston Scientific, Abbott Vascular, Terumo, Chiesi USA, The Medicines Company, and ACIST Medical outside the submitted work. JRD reports personal fees from Aggredyne, Fujimori Kogyo, and Accriva outside the submitted work. UST declares no competing interests.
*Paul A Gurbel, Matthew J Price, Jeffrey R Dahlen, Udaya S Tantry [email protected] Inova Center for Thrombosis Research and Drug Development, Inova Heart and Vascular Institute, Falls Church, VA 22042, USA (PAG, UST); Scripps Clinic, La Jolla, CA, USA (MJP); and Hikari Dx, San Diego, CA, USA (JRD) 1
2
3
Cayla G, Cuisset T, Silvain J, et al, for the ANTARCTIC Investigators. Platelet function monitoring to adjust antiplatelet therapy in elderly patients stented for an acute coronary syndrome (ANTARCTIC): an open-label, blinded-endpoint, randomised controlled superiority trial. Lancet 2016; 388: 2015–22. Erlinge D, Gurbel PA, James S, et al. Prasugrel 5 mg in the very elderly attenuates platelet inhibition but maintains noninferiority to prasugrel 10 mg in nonelderly patients: the GENERATIONS trial, a pharmacodynamic and pharmacokinetic study in stable coronary artery disease patients. J Am Coll Cardiol 2013; 62: 577–83. Gurbel PA, Erlinge D, Ohman EM, et al, for the TRILOGY ACS Platelet Function Substudy Investigators. Platelet function during extended prasugrel and clopidogrel therapy for patients with ACS treated without revascularization: the TRILOGY ACS platelet function substudy. JAMA 2012; 308: 1785–94.
Authors’ reply
We thank Paul Gurbel and colleagues for their interest in our randomised ANTARCTIC study,1 but we think they have wrongly interpreted both the design and the results of the study. Their statement corresponds neither to the hypothesis nor to the primary endpoint of the study. We wish to underscore that the ANTARCTIC study was not a comparison between prasugrel and clopidogrel, that bleeding was not the primary endpoint, that the study never tested switching from prasugrel to clopidogrel, and that 5 mg is not a low dose but the approved dose of prasugrel for the elderly. When patients were randomised to platelet function testing in our study, drug and dose adjustments could occur in both directions: more intense platelet inhibition (higher dose of prasugrel) for the patients exposed to ischaemic events because of their high platelet reactivity, or less intense platelet inhibition (clopidogrel) when they were exposed to bleeding because of their low platelet reactivity. No adjustment was the third possibility when the patients had reached the optimal platelet reactivity target. Notably, Gurbel and colleagues refer us to their own paper, the GENERATIONS trial,2 which showed a significant difference (p<0·001) in platelet reactivity in the elderly between those who took clopidogrel 75 mg (41% of patients had high platelet reactivity—defined as >235 platelet reactivity units) and those who took prasugrel 5 mg (14% of patients had high platelet reactivity). On this basis, we and Gurbel and colleagues, all thought that better individual control of platelet reactivity would lead to better outcomes—not only for bleeding, but also for ischaemic events. Better control of platelet reactivity was obtained after platelet function testing and drug adjustment in ANTARCTIC, but it had no effect on bleeding and ischaemic events. Gurbel and colleagues think that the negative results of ANTARCTIC are insufficient to refute the utility of personalising
Science Photo
Biosensors International; is a member of the speakers, bureau for AstraZeneca, Boston Scientific, and Merck; and has received grants from AstraZeneca, Biotronik, Boston Scientific, Biosensors International, The Medicines Company, and Edwards Lifesciences. All other authors declare no competing interests.
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