Canadian Journal of Cardiology 30 (2014) 1396e1399
Brief Rapid Report
Superiority of Ticagrelor Over Clopidogrel in Patients After Cardiac Arrest Undergoing Therapeutic Hypothermia Rohit Moudgil, MD, PhD, Haytham Al-Turbak, MD, Christina Osborne, BSc, Benjamin Hibbert, MD, PhD, Derek Y.F. So, MD, and Michel R. Le May, MD; on behalf of the CAPITAL Investigators Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, Ottawa, Ontario, Canada
ABSTRACT
RESUM E
Current guidelines suggest that patients undergoing percutaneous coronary intervention (PCI) receive dual-antiplatelet therapy. There are limited data on the pharmacodynamics of P2Y12 inhibitors in patients with cardiac arrest and return of spontaneous circulation (ROSC) undergoing PCI and therapeutic hypothermia (TH). Accordingly, we compared inhibition of platelet reactivity in patients undergoing TH receiving clopidogrel or ticagrelor. Notably, clopidogrel was ineffective in lowering platelet reactivity, with ticagrelor providing a more rapid (within 4 hours) and sustained reduction (6 days) in platelet reactivity. Pending outcome-based studies, ticagrelor should be used preferentially in patients who have ROSC and are undergoing PCI and TH.
Les lignes directrices actuelles suggèrent que les patients qui sue (ICP) reçoivent une bissent une intervention coronarienne percutane rapie antiplaquettaire. Il existe peu de donne es sur la pharmacobithe cepteurs P2Y12 chez les patients dynamique des inhibiteurs des re e ayant eu un arrêt cardiaque suivi d’un retour de la circulation spontane rapeutique (HT). Par (RCS) qui subissent une ICP et une hypothermie the quent, nous avons compare l’inhibition de la re activite plaquetconse taire chez les patients subissant une HT qui reçoivent le clopidogrel ou le lor. Notamment, le clopidogrel s’est ave re inefficace pour ticagre activite plaquettaire, tandis que le ticagre lor a montre une diminuer la re diminution plus rapide (en 4 heures) et soutenue (6 jours) de la activite plaquettaire. Dans l’attente d’e tudes fonde es sur les re sultats, re lor devrait être utilise pre fe rentiellement chez les patients qui le ticagre ont un RCS, et qui subissent une ICP et une HT.
Dual antiplatelet therapy (DAPT) consisting of aspirin and a P2Y12 inhibitor is the standard of care for patients after percutaneous coronary intervention (PCI).1 Accordingly, DAPT has been integrated into the management of patients after cardiac arrest who are undergoing PCI and are subsequently treated with therapeutic hypothermia (TH). However, some studies have suggested that clopidogrel efficacy may be markedly reduced at lower body temperatures, exposing patients to an increased risk of stent thrombosis.2-5 A novel oral P2Y12 inhibitor, ticagrelor, exhibits superior platelet inhibition compared with clopidogrel.6 However, there are currently no data available on the impact of TH on the pharmacodynamics of ticagrelor. Thus as a high-volume regional cardiac arrest center, we conducted a pilot study to compare the pharmacodynamic efficacy of clopidogrel and
ticagrelor in patients with return of spontaneous circulation (ROSC) treated with PCI and TH.7,8
Received for publication June 16, 2014. Accepted July 30, 2014. Corresponding author: Dr Michel R. Le May, University of Ottawa Heart Institute, Department of Medicine, 40 Ruskin Street, Ottawa, Ontario K1Y 4W7, Canada. Tel.: þ1-613-761-4223; fax: þ1-613-761-4690. E-mail: [email protected] See page 1398 for disclosure information.
Methods This study was a prospective single-centre nonrandomized open-label design with ticagrelor or clopidogrel use left to the discretion of the treating interventional cardiologist. Inclusion required out-of-hospital cardiac arrest caused by ventricular fibrillation or ventricular tachycardia with ROSC. Patients had to be > 18 years of age, have undergone PCI to a culprit artery with implantation of a coronary stent, and have ROSC within 60 minutes of the cardiac arrest. Patients were excluded if they had a known coagulopathy or intractable arrhythmias or were already taking clopidogrel or ticagrelor. The study was approved by the University of Ottawa Heart Institute Human Research Ethics Board. Patients were recruited between April 2011 and November 2012. During the study period, patients received aspirin and either clopidogrel or ticagrelor. At the time of admission, aspirin was given as 162 mg and then 81 mg daily; clopidogrel was administered as a 600-mg loading dose followed by 75 mg
http://dx.doi.org/10.1016/j.cjca.2014.07.745 0828-282X/Ó 2014 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.
Moudgil et al. Ticagrelor in Therapeutic Hypothermia
1397
Table 1. Baseline characteristics between clopidogrel- and ticagrelor-treated patients undergoing therapeutic hypothermia after return of spontaneous circulation Characteristics Age, y Male sex, no. (%) Initial rhythm ventricular fibrillation, no. (%) Hypertension, no. (%) Hyperlipidemia, no. (%) Diabetes mellitus, no. (%) History of peripheral artery disease, no. (%) History of congestive heart failure, no. (%) Previous myocardial infarction, no. (%) Previous PCI, no. (%) Previous coronary bypass grafting, no. (%) Patients who underwent PCI, no. (%) Critical time intervals (min) Arrest to return of spontaneous circulation, median (IQR) Hospital arrival to antiplatelet loading, median (IQR) Hospital arrival to cardiac catheterization laboratory, median (IQR) Hospital arrival to first balloon angioplasty, median (IQR) Hospital arrival to initiation of cooling, median (IQR)
Clopidogrel (n ¼ 8)
Ticagrelor (n ¼ 7)
P value
59 5.2 7 (87.5) 8 (100) 4 (50) 3 (37.5) 2 (25) 1 (12.5) 0 2 (25) 1 (12.5) 1 (12.5) 7 (87.5)
53 3.8 6 (85.7) 7 (100) 2 (29) 2 (29) 0 1 (14) 0 1 (14) 0 1 (14) 7 (100)
0.38 1.00 1.00 0.66 1.00 0.49 1.00 1.00 1.00 1.00 1.00 1.00
17 13 32 36 79
(10-29) (2-28) (10-52) (11-71) (40-148)
18 40 60 85 165
(13-29) (2-60) (22-133) (47-144) (67-195)
0.77 0.33 0.15 0.05 0.42
IQR, interquartile range; PCI, percutaneous coronary intervention.
daily, and ticagrelor was given as a 180-mg loading dose followed by 90 mg twice daily. Antiplatelet agents were given through a nasogastric tube. TH was achieved by the use of an endovascular cooling device (Zoll Medical, Chelmsford, MA) or with external cooling pads (Arctic Sun Medivance, Louisville, CO) to a target temperature of 33 , which was maintained for 24 hours.7,8 Subsequently, rewarming was performed at a rate of 0.25 C . Platelet reactivity was measured in a core laboratory using the VerifyNow point-ofcare device (Accumetrics, San Diego, CA).9 The primary end point was the difference in mean platelet reactivity between clopidogrel and ticagrelor expressed as platelet reactivity units (PRUs) measured at various time points. Secondary end points included death, Thrombolysis in Myocardial Infarction (TIMI) major bleeding, and stent thrombosis as previously described.10 Continuous variables are reported as means standard deviation or medians and interquartile ranges as appropriate. The Student t test and a mixed-effects model with the assumption of linear equation were used to determine significance between PRU levels in each group. Categorical variables are described as number and percent and were compared using the c2 or Fisher exact test as appropriate. All analyses were completed using SAS software, version 9.2 (SAS Institute, Cary, NC). A P value < 0.05 was considered significant in all comparisons.
Results In total, 8 patients in the clopidogrel group and 7 patients in the ticagrelor group were recruited. All patients included in the study presented with ventricular fibrillation from which they had ROSC. Baseline characteristics of the patients in the clopidogrel group were similar to those in the ticagrelor group: age, male sex, and cardiac risk factors, including diabetes mellitus. Moreover, critical time intervals between clopidogrel and ticagrelor measured in minutes were also comparable between the 2 groups (Table 1).
In terms of platelet reactivity, there was no difference in mean PRUs between the 2 groups at baseline. At 4 hours and all subsequent time points, platelet reactivity was dramatically lower in the ticagrelor-treated patients compared with the clopidogrel-treated patients (Fig. 1). Notably, in clopidogreltreated patients, no effect was observed between baseline values and those throughout the treatment period (P ¼ 0.85), suggesting a lack of effect in patients who undergo TH. However, the mixed-effects model showed a significant difference between ticagrelor and clopidogrel with respect to time and treatment group (P ¼ 0.005). Regarding clinical outcomes, no cases of stent thrombosis occurred in either cohort. Two patients died in the clopidogrel arm because of anoxic brain injury, with no deaths in the ticagrelor cohort. Finally, 1 patient in each cohort experienced a TIMI major bleeding event with an overt source of blood
Figure 1. Measurement of platelet reactivity (PRU) units in patients receiving either clopidogrel or ticagrelor. Differences in mean PRU levels were noted at 4 hours, and the antiplatelet effect in the ticagrelor group persisted throughout the whole study. Mixed-effects model analysis suggests significant difference with respect to time and treatment group (P ¼ 0.005). A PRU cutoff of 240, as shown, suggests an increased risk of adverse cardiovascular outcomes.
1398
loss, and transfusions were necessary in 1 patient in the clopidogrel arm and 2 patients in the ticagrelor arm.
Discussion The current study makes 2 important observations with implications for treating patients undergoing TH after PCI. First, clopidogrel is ineffective in lowering platelet reactivity in comparison to baseline PRU values, suggesting that decreased generation of the active metabolite occurred in this clinical scenario. Second, we observed a more rapid and profound inhibition of platelet reactivity when ticagrelor was used, irrespective of TH. Accordingly, pending further data, ticagrelor should be used preferentially in patients treated with TH for effective P2Y12 inhibition. Concern has been expressed that TH may alter the pharmacodynamic profile of clopidogrel,5 potentially exposing patients undergoing cooling to an increased risk of stent thrombosis.4 Penela et al.3 reported that patients receiving clopidogrel and undergoing PCI and TH had a 31.2% rate of stent thrombosis, significantly higher than seen in their cohort who did not undergo TH (0.44%-0.7%). Indeed, there are several potential explanations for the reduction in clopidogrel efficacy in TH. First, it has been demonstrated that hypothermia induces hypercoagulability by augmenting adenosine diphosphate (ADP)-induced platelet aggregationdeven after clopidogrel treatment.11 Second, hypothermia also results in decreased activity of enzymes involved in converting clopi dogrel to its active metabolite,12 namely, at 32 C, CYP3A, CYP2C9, and CYP2C19 activity is reduced to 69%, 49%, and 65%, respectively, from basal levels.13,14 Finally, alterations in gastric emptying, the impact of nasogastric suction, and altered drug absorption during TH induction and maintenance all contribute to impaired efficacy. Thus, lack of platelet inhibition with clopidogrel during TH is likely caused by each of these factors rather than any single mechanism. In contrast, ticagrelor is a direct inhibitor of the P2Y12 receptor and does not require metabolic transformation. Moreover, it demonstrates a superior pharmacodynamic profile compared with clopidogrel in patients undergoing PCI and has been shown to reduce ST elevation in patients with ST-elevation myocardial infarction.9,15,16 Although onset of platelet inhibition is delayed compared with patients with acute coronary syndromes, our data show that in patients undergoing TH who are treated with PCI, ticagrelor affords more rapid and profound platelet inhibition than does clopidogrel, potentially affording greater protection from stent thrombosis. Certainly, our study is not without limitations. First, it is a relatively small cohort of patients, and treatment was not randomized, leading to the potential that confounding factors could impact the PRU outcomes. Second, our study was designed to test the pharmacodynamic profiles of clopidogrel and ticagrelor in patients undergoing TH, and recent studies have failed to demonstrate benefit of using platelet function testing to guide treatment in patients after PCI.17,18 Thus, although adequately powered studies of clinical outcomes in patients undergoing TH are unlikely to be performed, we cannot be certain that the large differences in PRU values observed translate into improved clinical outcomes.
Canadian Journal of Cardiology Volume 30 2014
Nonetheless, pending further studies, ticagrelor should be preferentially used to achieve adequate P2Y12 inhibition. Funding Sources Supported by The University of Ottawa Heart Institute STEMI fund. Disclosures The authors have no conflicts of interest to disclose. References 1. Tanguay JF, Bell AD, Ackman ML, et al. Focused 2012 update of the Canadian Cardiovascular Society guidelines for the use of antiplatelet therapy. Can J Cardiol 2013;29:1334-45. 2. Simard T, Hibbert B, Ramirez FD, et al. The evolution of coronary stents: a brief review. Can J Cardiol 2014;30:35-45. 3. Penela D, Magaldi M, Fontanals J, et al. Hypothermia in acute coronary syndrome: brain salvage versus stent thrombosis? J Am Coll Cardiol 2013;61:686-7. 4. Sambu N, Radhakrishnan A, Dent H, et al. Personalised antiplatelet therapy in stent thrombosis: observations from the Clopidogrel Resistance in Stent Thrombosis (CREST) registry. Heart 2012;98:706-11. 5. Bjelland TW, Hjertner O, Klepstad P, et al. Antiplatelet effect of clopidogrel is reduced in patients treated with therapeutic hypothermia after cardiac arrest. Resuscitation 2010;81:1627-31. 6. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009;361:1045-57. 7. Maze R, Le May MR, Froeschl M, et al. Endovascular cooling catheter related thrombosis in patients undergoing therapeutic hypothermia for out of hospital cardiac arrest. Resuscitation 2014 Oct;85(10):1354-8. 8. Maze R, Le May MR, Hibbert B, et al. The impact of therapeutic hypothermia as adjunctive therapy in a regional primary PCI program. Resuscitation 2013;84:460-4. 9. Hibbert B, Maze R, Pourdjabbar A, et al. A comparative pharmacodynamic study of ticagrelor versus clopidogrel and ticagrelor in patients undergoing primary percutaneous coronary intervention: the CAPITAL RELOAD study. PLoS One 2014;9:e92078. 10. Hibbert B, MacDougall A, Labinaz M, et al. Bivalirudin for primary percutaneous coronary interventions: outcome assessment in the Ottawa STEMI registry. Circ Cardiovasc Interv 2012;5:805-12. 11. Hogberg C, Erlinge D, Braun OO. Mild hypothermia does not attenuate platelet aggregation and may even increase ADP-stimulated platelet aggregation after clopidogrel treatment. Thromb J 2009;7:2. 12. Zhou J, Poloyac SM. The effect of therapeutic hypothermia on drug metabolism and response: cellular mechanisms to organ function. Expert Opin Drug Metab Toxicol 2011;7:803-16. 13. Fritz HG, Holzmayr M, Walter B, et al. The effect of mild hypothermia on plasma fentanyl concentration and biotransformation in juvenile pigs. Anesth Analg 2005;100:996-1002. 14. Vandenbranden M, Wrighton SA, Ekins S, et al. Alterations of the catalytic activities of drug-metabolizing enzymes in cultures of human liver slices. Drug Metab Dispos 1998;26:1063-8. 15. Alexopoulos D, Galati A, Xanthopoulou I, et al. Ticagrelor versus prasugrel in acute coronary syndrome patients with high on-clopidogrel
Moudgil et al. Ticagrelor in Therapeutic Hypothermia platelet reactivity following percutaneous coronary intervention: a pharmacodynamic study. J Am Coll Cardiol 2012;60:193-9. 16. Steg PG, James S, Harrington RA, et al. Ticagrelor versus clopidogrel in patients with ST-elevation acute coronary syndromes intended for reperfusion with primary percutaneous coronary intervention: a Platelet Inhibition and Patient Outcomes (PLATO) trial subgroup analysis. Circulation 2010;122:2131-41.
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17. Price MJ, Berger PB, Teirstein PS, et al. Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial. JAMA 2011;305: 1097-105. 18. Collet JP, Cuisset T, Range G, et al. Bedside monitoring to adjust antiplatelet therapy for coronary stenting. N Engl J Med 2012;367: 2100-9.
Brief Rapid Report
Superiority of Ticagrelor Over Clopidogrel in Patients After Cardiac Arrest Undergoing Therapeutic Hypothermia Rohit Moudgil, MD, PhD, Haytham Al-Turbak, MD, Christina Osborne, BSc, Benjamin Hibbert, MD, PhD, Derek Y.F. So, MD, and Michel R. Le May, MD; on behalf of the CAPITAL Investigators Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, Ottawa, Ontario, Canada
ABSTRACT
RESUM E
Current guidelines suggest that patients undergoing percutaneous coronary intervention (PCI) receive dual-antiplatelet therapy. There are limited data on the pharmacodynamics of P2Y12 inhibitors in patients with cardiac arrest and return of spontaneous circulation (ROSC) undergoing PCI and therapeutic hypothermia (TH). Accordingly, we compared inhibition of platelet reactivity in patients undergoing TH receiving clopidogrel or ticagrelor. Notably, clopidogrel was ineffective in lowering platelet reactivity, with ticagrelor providing a more rapid (within 4 hours) and sustained reduction (6 days) in platelet reactivity. Pending outcome-based studies, ticagrelor should be used preferentially in patients who have ROSC and are undergoing PCI and TH.
Les lignes directrices actuelles suggèrent que les patients qui sue (ICP) reçoivent une bissent une intervention coronarienne percutane rapie antiplaquettaire. Il existe peu de donne es sur la pharmacobithe cepteurs P2Y12 chez les patients dynamique des inhibiteurs des re e ayant eu un arrêt cardiaque suivi d’un retour de la circulation spontane rapeutique (HT). Par (RCS) qui subissent une ICP et une hypothermie the quent, nous avons compare l’inhibition de la re activite plaquetconse taire chez les patients subissant une HT qui reçoivent le clopidogrel ou le lor. Notamment, le clopidogrel s’est ave re inefficace pour ticagre activite plaquettaire, tandis que le ticagre lor a montre une diminuer la re diminution plus rapide (en 4 heures) et soutenue (6 jours) de la activite plaquettaire. Dans l’attente d’e tudes fonde es sur les re sultats, re lor devrait être utilise pre fe rentiellement chez les patients qui le ticagre ont un RCS, et qui subissent une ICP et une HT.
Dual antiplatelet therapy (DAPT) consisting of aspirin and a P2Y12 inhibitor is the standard of care for patients after percutaneous coronary intervention (PCI).1 Accordingly, DAPT has been integrated into the management of patients after cardiac arrest who are undergoing PCI and are subsequently treated with therapeutic hypothermia (TH). However, some studies have suggested that clopidogrel efficacy may be markedly reduced at lower body temperatures, exposing patients to an increased risk of stent thrombosis.2-5 A novel oral P2Y12 inhibitor, ticagrelor, exhibits superior platelet inhibition compared with clopidogrel.6 However, there are currently no data available on the impact of TH on the pharmacodynamics of ticagrelor. Thus as a high-volume regional cardiac arrest center, we conducted a pilot study to compare the pharmacodynamic efficacy of clopidogrel and
ticagrelor in patients with return of spontaneous circulation (ROSC) treated with PCI and TH.7,8
Received for publication June 16, 2014. Accepted July 30, 2014. Corresponding author: Dr Michel R. Le May, University of Ottawa Heart Institute, Department of Medicine, 40 Ruskin Street, Ottawa, Ontario K1Y 4W7, Canada. Tel.: þ1-613-761-4223; fax: þ1-613-761-4690. E-mail: [email protected] See page 1398 for disclosure information.
Methods This study was a prospective single-centre nonrandomized open-label design with ticagrelor or clopidogrel use left to the discretion of the treating interventional cardiologist. Inclusion required out-of-hospital cardiac arrest caused by ventricular fibrillation or ventricular tachycardia with ROSC. Patients had to be > 18 years of age, have undergone PCI to a culprit artery with implantation of a coronary stent, and have ROSC within 60 minutes of the cardiac arrest. Patients were excluded if they had a known coagulopathy or intractable arrhythmias or were already taking clopidogrel or ticagrelor. The study was approved by the University of Ottawa Heart Institute Human Research Ethics Board. Patients were recruited between April 2011 and November 2012. During the study period, patients received aspirin and either clopidogrel or ticagrelor. At the time of admission, aspirin was given as 162 mg and then 81 mg daily; clopidogrel was administered as a 600-mg loading dose followed by 75 mg
http://dx.doi.org/10.1016/j.cjca.2014.07.745 0828-282X/Ó 2014 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.
Moudgil et al. Ticagrelor in Therapeutic Hypothermia
1397
Table 1. Baseline characteristics between clopidogrel- and ticagrelor-treated patients undergoing therapeutic hypothermia after return of spontaneous circulation Characteristics Age, y Male sex, no. (%) Initial rhythm ventricular fibrillation, no. (%) Hypertension, no. (%) Hyperlipidemia, no. (%) Diabetes mellitus, no. (%) History of peripheral artery disease, no. (%) History of congestive heart failure, no. (%) Previous myocardial infarction, no. (%) Previous PCI, no. (%) Previous coronary bypass grafting, no. (%) Patients who underwent PCI, no. (%) Critical time intervals (min) Arrest to return of spontaneous circulation, median (IQR) Hospital arrival to antiplatelet loading, median (IQR) Hospital arrival to cardiac catheterization laboratory, median (IQR) Hospital arrival to first balloon angioplasty, median (IQR) Hospital arrival to initiation of cooling, median (IQR)
Clopidogrel (n ¼ 8)
Ticagrelor (n ¼ 7)
P value
59 5.2 7 (87.5) 8 (100) 4 (50) 3 (37.5) 2 (25) 1 (12.5) 0 2 (25) 1 (12.5) 1 (12.5) 7 (87.5)
53 3.8 6 (85.7) 7 (100) 2 (29) 2 (29) 0 1 (14) 0 1 (14) 0 1 (14) 7 (100)
0.38 1.00 1.00 0.66 1.00 0.49 1.00 1.00 1.00 1.00 1.00 1.00
17 13 32 36 79
(10-29) (2-28) (10-52) (11-71) (40-148)
18 40 60 85 165
(13-29) (2-60) (22-133) (47-144) (67-195)
0.77 0.33 0.15 0.05 0.42
IQR, interquartile range; PCI, percutaneous coronary intervention.
daily, and ticagrelor was given as a 180-mg loading dose followed by 90 mg twice daily. Antiplatelet agents were given through a nasogastric tube. TH was achieved by the use of an endovascular cooling device (Zoll Medical, Chelmsford, MA) or with external cooling pads (Arctic Sun Medivance, Louisville, CO) to a target temperature of 33 , which was maintained for 24 hours.7,8 Subsequently, rewarming was performed at a rate of 0.25 C . Platelet reactivity was measured in a core laboratory using the VerifyNow point-ofcare device (Accumetrics, San Diego, CA).9 The primary end point was the difference in mean platelet reactivity between clopidogrel and ticagrelor expressed as platelet reactivity units (PRUs) measured at various time points. Secondary end points included death, Thrombolysis in Myocardial Infarction (TIMI) major bleeding, and stent thrombosis as previously described.10 Continuous variables are reported as means standard deviation or medians and interquartile ranges as appropriate. The Student t test and a mixed-effects model with the assumption of linear equation were used to determine significance between PRU levels in each group. Categorical variables are described as number and percent and were compared using the c2 or Fisher exact test as appropriate. All analyses were completed using SAS software, version 9.2 (SAS Institute, Cary, NC). A P value < 0.05 was considered significant in all comparisons.
Results In total, 8 patients in the clopidogrel group and 7 patients in the ticagrelor group were recruited. All patients included in the study presented with ventricular fibrillation from which they had ROSC. Baseline characteristics of the patients in the clopidogrel group were similar to those in the ticagrelor group: age, male sex, and cardiac risk factors, including diabetes mellitus. Moreover, critical time intervals between clopidogrel and ticagrelor measured in minutes were also comparable between the 2 groups (Table 1).
In terms of platelet reactivity, there was no difference in mean PRUs between the 2 groups at baseline. At 4 hours and all subsequent time points, platelet reactivity was dramatically lower in the ticagrelor-treated patients compared with the clopidogrel-treated patients (Fig. 1). Notably, in clopidogreltreated patients, no effect was observed between baseline values and those throughout the treatment period (P ¼ 0.85), suggesting a lack of effect in patients who undergo TH. However, the mixed-effects model showed a significant difference between ticagrelor and clopidogrel with respect to time and treatment group (P ¼ 0.005). Regarding clinical outcomes, no cases of stent thrombosis occurred in either cohort. Two patients died in the clopidogrel arm because of anoxic brain injury, with no deaths in the ticagrelor cohort. Finally, 1 patient in each cohort experienced a TIMI major bleeding event with an overt source of blood
Figure 1. Measurement of platelet reactivity (PRU) units in patients receiving either clopidogrel or ticagrelor. Differences in mean PRU levels were noted at 4 hours, and the antiplatelet effect in the ticagrelor group persisted throughout the whole study. Mixed-effects model analysis suggests significant difference with respect to time and treatment group (P ¼ 0.005). A PRU cutoff of 240, as shown, suggests an increased risk of adverse cardiovascular outcomes.
1398
loss, and transfusions were necessary in 1 patient in the clopidogrel arm and 2 patients in the ticagrelor arm.
Discussion The current study makes 2 important observations with implications for treating patients undergoing TH after PCI. First, clopidogrel is ineffective in lowering platelet reactivity in comparison to baseline PRU values, suggesting that decreased generation of the active metabolite occurred in this clinical scenario. Second, we observed a more rapid and profound inhibition of platelet reactivity when ticagrelor was used, irrespective of TH. Accordingly, pending further data, ticagrelor should be used preferentially in patients treated with TH for effective P2Y12 inhibition. Concern has been expressed that TH may alter the pharmacodynamic profile of clopidogrel,5 potentially exposing patients undergoing cooling to an increased risk of stent thrombosis.4 Penela et al.3 reported that patients receiving clopidogrel and undergoing PCI and TH had a 31.2% rate of stent thrombosis, significantly higher than seen in their cohort who did not undergo TH (0.44%-0.7%). Indeed, there are several potential explanations for the reduction in clopidogrel efficacy in TH. First, it has been demonstrated that hypothermia induces hypercoagulability by augmenting adenosine diphosphate (ADP)-induced platelet aggregationdeven after clopidogrel treatment.11 Second, hypothermia also results in decreased activity of enzymes involved in converting clopi dogrel to its active metabolite,12 namely, at 32 C, CYP3A, CYP2C9, and CYP2C19 activity is reduced to 69%, 49%, and 65%, respectively, from basal levels.13,14 Finally, alterations in gastric emptying, the impact of nasogastric suction, and altered drug absorption during TH induction and maintenance all contribute to impaired efficacy. Thus, lack of platelet inhibition with clopidogrel during TH is likely caused by each of these factors rather than any single mechanism. In contrast, ticagrelor is a direct inhibitor of the P2Y12 receptor and does not require metabolic transformation. Moreover, it demonstrates a superior pharmacodynamic profile compared with clopidogrel in patients undergoing PCI and has been shown to reduce ST elevation in patients with ST-elevation myocardial infarction.9,15,16 Although onset of platelet inhibition is delayed compared with patients with acute coronary syndromes, our data show that in patients undergoing TH who are treated with PCI, ticagrelor affords more rapid and profound platelet inhibition than does clopidogrel, potentially affording greater protection from stent thrombosis. Certainly, our study is not without limitations. First, it is a relatively small cohort of patients, and treatment was not randomized, leading to the potential that confounding factors could impact the PRU outcomes. Second, our study was designed to test the pharmacodynamic profiles of clopidogrel and ticagrelor in patients undergoing TH, and recent studies have failed to demonstrate benefit of using platelet function testing to guide treatment in patients after PCI.17,18 Thus, although adequately powered studies of clinical outcomes in patients undergoing TH are unlikely to be performed, we cannot be certain that the large differences in PRU values observed translate into improved clinical outcomes.
Canadian Journal of Cardiology Volume 30 2014
Nonetheless, pending further studies, ticagrelor should be preferentially used to achieve adequate P2Y12 inhibition. Funding Sources Supported by The University of Ottawa Heart Institute STEMI fund. Disclosures The authors have no conflicts of interest to disclose. References 1. Tanguay JF, Bell AD, Ackman ML, et al. Focused 2012 update of the Canadian Cardiovascular Society guidelines for the use of antiplatelet therapy. Can J Cardiol 2013;29:1334-45. 2. Simard T, Hibbert B, Ramirez FD, et al. The evolution of coronary stents: a brief review. Can J Cardiol 2014;30:35-45. 3. Penela D, Magaldi M, Fontanals J, et al. Hypothermia in acute coronary syndrome: brain salvage versus stent thrombosis? J Am Coll Cardiol 2013;61:686-7. 4. Sambu N, Radhakrishnan A, Dent H, et al. Personalised antiplatelet therapy in stent thrombosis: observations from the Clopidogrel Resistance in Stent Thrombosis (CREST) registry. Heart 2012;98:706-11. 5. Bjelland TW, Hjertner O, Klepstad P, et al. Antiplatelet effect of clopidogrel is reduced in patients treated with therapeutic hypothermia after cardiac arrest. Resuscitation 2010;81:1627-31. 6. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009;361:1045-57. 7. Maze R, Le May MR, Froeschl M, et al. Endovascular cooling catheter related thrombosis in patients undergoing therapeutic hypothermia for out of hospital cardiac arrest. Resuscitation 2014 Oct;85(10):1354-8. 8. Maze R, Le May MR, Hibbert B, et al. The impact of therapeutic hypothermia as adjunctive therapy in a regional primary PCI program. Resuscitation 2013;84:460-4. 9. Hibbert B, Maze R, Pourdjabbar A, et al. A comparative pharmacodynamic study of ticagrelor versus clopidogrel and ticagrelor in patients undergoing primary percutaneous coronary intervention: the CAPITAL RELOAD study. PLoS One 2014;9:e92078. 10. Hibbert B, MacDougall A, Labinaz M, et al. Bivalirudin for primary percutaneous coronary interventions: outcome assessment in the Ottawa STEMI registry. Circ Cardiovasc Interv 2012;5:805-12. 11. Hogberg C, Erlinge D, Braun OO. Mild hypothermia does not attenuate platelet aggregation and may even increase ADP-stimulated platelet aggregation after clopidogrel treatment. Thromb J 2009;7:2. 12. Zhou J, Poloyac SM. The effect of therapeutic hypothermia on drug metabolism and response: cellular mechanisms to organ function. Expert Opin Drug Metab Toxicol 2011;7:803-16. 13. Fritz HG, Holzmayr M, Walter B, et al. The effect of mild hypothermia on plasma fentanyl concentration and biotransformation in juvenile pigs. Anesth Analg 2005;100:996-1002. 14. Vandenbranden M, Wrighton SA, Ekins S, et al. Alterations of the catalytic activities of drug-metabolizing enzymes in cultures of human liver slices. Drug Metab Dispos 1998;26:1063-8. 15. Alexopoulos D, Galati A, Xanthopoulou I, et al. Ticagrelor versus prasugrel in acute coronary syndrome patients with high on-clopidogrel
Moudgil et al. Ticagrelor in Therapeutic Hypothermia platelet reactivity following percutaneous coronary intervention: a pharmacodynamic study. J Am Coll Cardiol 2012;60:193-9. 16. Steg PG, James S, Harrington RA, et al. Ticagrelor versus clopidogrel in patients with ST-elevation acute coronary syndromes intended for reperfusion with primary percutaneous coronary intervention: a Platelet Inhibition and Patient Outcomes (PLATO) trial subgroup analysis. Circulation 2010;122:2131-41.
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