Letters to the Editor
1069
Ticagrelor reduces thrombus formation more than clopidogrel, even when co-administered with bivalirudin M. Urooj Zafar; David A. Vorchheimer; Mita Patel Tewar; Chiara Giannarelli; Matteo Crippa; Samantha Sartori; David Rodriguez; Usman Baber; Roxana Mehran; Juan J. Badimon Cardiovascular Institute, Icahn School of Medicine at Mount Sinai New York, New York, USA
Dear Sirs, Bivalirudin has been shown to lower adverse events in patients undergoing percutaneous coronary intervention (PCI) more than heparin+GPIIb/IIIa inhibitors in the HORIZONS-AMI trial, but it was also associated with a higher rate of acute stent thrombosis (AST) (1). Given the role of high post-treatment platelet reactivity in stent thrombosis (2), use of a stronger platelet inhibitor with bivalirudin during PCI would help reduce the rate of AST. In the HORIZONS study stent thrombosis was lower with the more potent 600 mg dose of clopidogrel than with 300 mg (3). Ticagrelor is a stronger platelet inhibitor than clopidogrel (4) and may prove be a better treatment option with bivalirudin during PCI. However, anti-platelet properties do not always translate into equivalent antithrombotic action and at times agents of lower antithrombotic potency fail to demonstrate their full effect in the presence of a stronger compound (for e. g. effects of aspirin have been reported to vary with the degree of P2Y12 blockade [5] and its antithrombotic effects seem attenuated with higher dose of factor Xa inhibition [6]). Bi-
Correspondence to: Juan J. Badimon Cardiovascular Institute Icahn School of Medicine at Mount Sinai One Gustave L. Levy Place, Box 1030 New York, NY 10029, USA Tel.: +1 212 241 8484, Fax: +1 212 426 6962 E-mail: [email protected] Financial support: The study was funded in part by Astra-Zeneca. Received: March 25, 2014 Accepted after major revision: June 20, 2014 Epub ahead of print: August 7, 2014 http://dx.doi.org/10.1160/TH14-03-0269 Thromb Haemost 2014; 112: 1069–1070
© Schattauer 2014
valirudin has been shown to exert strong antithrombotic effects via its direct-thrombin inhibition (7) and has the potential to diminish ticagrelor’s anti-thrombotic advantage over clopidogrel without affecting the P2Y12 inhibitors’ anti-platelet properties in the peri-procedural period. We investigated the acute antithrombotic effects of ticagrelor (180 mg + 90 mg) versus clopidogrel (600 mg), when coadministered with aspirin (81 mg) and bivalirudin (weight-adjusted clinical dose, given as bolus plus 1 hour [h] infusion) using a randomised, two-treatment, two-period, cross-over design in healthy volunteers. Comparisons were made between the two treatments in their ability to reduce thrombus formation (high-shear rate Badimon chamber) (8) and platelet aggregation (VerifyNow P2Y12), and prolong coagulation time (CT – ThromboElastoMetry, ROTEM Gamma). All assessments were made at baseline, and after 1 h and 24 h of treatment administration. Statistical analyses were performed using a linear mixed model to compare differences between treatments as this allows specific settings for the treatment, carryover and sequence variables. Significance was set at the nominal p < 0.05 level and data are presented as mean (95 % confidence interval) unless specified otherwise. The mean age of study subjects (n=15) was 31.2 years (26.8–35.6) with 60 % males and a body mass index (BMI) of 27.0 kg/m2 (24.9–29.1). In both groups, thrombus formation was significantly lower after treatment compared with baseline (▶ Figure 1). Reduction in thrombus size from baseline was significantly greater after treatment with ticagrelor than with clopidogrel at both 1 (56.3 % vs 35.2 %) and 24 h (34.1 % vs 18.5 %), p< 0.001 and =0.012, respectively.
Although thrombus formation varied between the two groups, CT showed no differences between the groups at any time; 53.1 vs 51.1 seconds (s) at baseline; 163.1 vs 174.0 s at 1 h and 56.1 vs 54.3 s at 24 h for ticagrelor vs clopidogrel, respectively (p=NS between treatments for all timepoints). The identical pattern of CT changes in both groups (i. e. significant prolongation at 1 h that reverts to baseline values by 24 h) fit the short acting profile of bivalirudin. Platelet-specific effects of treatment, performed as a quality check, produced results that confirmed previous findings. Both treatments significantly lowered P2Y12-mediated platelet aggregation from baseline values, but as expected, the inhibitory effects of ticagrelor were substantially stronger than clopidogrel at both post-dose time-points (69.4 % vs 20.1 % at 1 h, p< 0.001; 67.4 % vs 53.4 % at 24 h, p=0.049). Our data show that ticagrelor’s known advantage over clopidogrel in inhibiting platelets is maintained even in the presence of a potent thrombin inhibitor like bivalirudin. More importantly, the stronger anti-platelet activity translates successfully into a significantly greater anti-thrombotic effect. The change in thrombus formation at 1 h reflects the combined effects of platelet inhibition by ticagrelor/clopidogrel and thrombin inhibition by bivalirudin. Since both treatment groups showed nearidentical changes in CT, a parameter not influenced by P2Y12 inhibitors, it is evident that effects of bivalirudin are equivalent in the two groups. The greater thrombus reduction at 1 h can therefore be attributed solely to ticagrelor. After 4 h when the effects of bivalirudin are completely dissipated, ticagrelor still maintains its significant anti-thrombotic advantage over clopidogrel. Our findings are of importance in ACS patients undergoing stent implantation with bivalirudin therapy, where acute stent thrombosis would be a concern. As we demonstrate, ticagrelor provides a stronger antithrombotic milieu to compliment the effect of bivalirudin than does clopidogrel. The earlier and more potent antithrombotic effects could play a critical role in reducing intra-procedural and acute stent Thrombosis and Haemostasis 112.5/2014
Downloaded from www.thrombosis-online.com on 2014-11-21 | ID: 1000471267 | IP: 132.206.27.24 For personal or educational use only. No other uses without permission. All rights reserved.
Letters to the Editor
1070
Figure 1: Effects of ticagrelor vs clopidogrel on thrombus formation (top) and coagulation time (bottom) when coadministered with bivalirudin and aspirin. Thrombus formation was reduced in both treatment groups from baseline values at 1 h (p< 0.001 for both) and 24 h (p≤ 0.003 for both), but the antithrombotic effects were significantly greater with ticagrelor than clopidogrel at both time-points. Coagulation times were prolonged equally in both groups at 1 h (p< 0.05 for both) and returned to baseline values by 24 h (p=NS for both).
thrombosis, known to be predictive of subsequent adverse events. In conclusion, dual antiplatelet therapy with bivalirudin exerts faster and stronger antithrombotic effects if ticagrelor is used instead of clopidogrel. Our results, taken in light of the findings from recent clinical trials suggest that with ticagrelor use during intracoronary stenting, the risk of acute stent thrombosis could potentially be lower than with clopidogrel. Replacing clopidogrel with ticagrelor during stenting may significantly reduce the risk of acute instent thrombosis. Conflicts of interest
J. J. Badimon has received Institutional Research Grant Support from AstraZeneca. R. Mehran has received Institutional Research Grant Support from The Medicines Company, Bristol-Myers Squibb/Sanofi-Aventis/Daiichi Sankyo,
Regado Biosciences and STENTYS, she has served as a consultant for Abbott Vascular, AstraZeneca, Boston Scientific, Covidien, CSL Behring, Janssen (JNJ), Maya Medical, Merck, and has served on the Advisory Board for Covidien, Janssen Pharmaceuticals and Sanofi-Aventis. She holds 25,000 shares for Endothelix Inc. None of the other authors declares any conflicts of interest.
References 1. Stone GW, Witzenbichler B, Guagliumi G, et al. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med 2008; 358: 2218–2230. 2. Gurbel PA, Bliden KP, Samara W, et al. Clopidogrel effect on platelet reactivity in patients with stent thrombosis: results of the CREST Study. J Am Coll Cardiol 2005; 46: 1827–1832. 3. Dangas G, Mehran R, Guagliumi G, et al. Role of clopidogrel loading dose in patients with ST-segment elevation myocardial infarction undergoing primary angioplasty: results from the HORIZONS-AMI (harmonizing outcomes with revas-
4.
5.
6.
7.
8.
cularization and stents in acute myocardial infarction) trial. J Am Coll Cardiol 2009; 54: 1438–1446. Gurbel PA, Bliden KP, Butler K, et al. Randomized double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease: the ONSET/OFFSET study. Circulation 2009; 120: 2577–2585. Kirkby NS, Leadbeater PD, Chan MV, et al. Antiplatelet effects of aspirin vary with level of P2Y(1)(2) receptor blockade supplied by either ticagrelor or prasugrel. J Thromb Haemost 2011; 9: 2103–2105. Shimbo D, Osende J, Chen J, et al. Antithrombotic effects of DX-9065a, a direct factor Xa inhibitor: a comparative study in humans versus low molecular weight heparin. Thromb Haemost 2002; 88: 733–738. Lev EI, Patel R, Karim A, et al. Anti-thrombotic effect of bivalirudin compared with eptifibatide and unfractionated heparin in diabetic patients: an ex vivo human study. Thromb Haemost 2006; 95: 441–446. Zafar MU, Ibanez B, Choi BG, et al. A new oral antiplatelet agent with potent antithrombotic properties: comparison of DZ-697b with clopidogrel a randomised phase I study. Thromb Haemost 2010; 103: 205–212.
Thrombosis and Haemostasis 112.5/2014 Downloaded from www.thrombosis-online.com on 2014-11-21 | ID: 1000471267 | IP: 132.206.27.24 For personal or educational use only. No other uses without permission. All rights reserved.
© Schattauer 2014
1069
Ticagrelor reduces thrombus formation more than clopidogrel, even when co-administered with bivalirudin M. Urooj Zafar; David A. Vorchheimer; Mita Patel Tewar; Chiara Giannarelli; Matteo Crippa; Samantha Sartori; David Rodriguez; Usman Baber; Roxana Mehran; Juan J. Badimon Cardiovascular Institute, Icahn School of Medicine at Mount Sinai New York, New York, USA
Dear Sirs, Bivalirudin has been shown to lower adverse events in patients undergoing percutaneous coronary intervention (PCI) more than heparin+GPIIb/IIIa inhibitors in the HORIZONS-AMI trial, but it was also associated with a higher rate of acute stent thrombosis (AST) (1). Given the role of high post-treatment platelet reactivity in stent thrombosis (2), use of a stronger platelet inhibitor with bivalirudin during PCI would help reduce the rate of AST. In the HORIZONS study stent thrombosis was lower with the more potent 600 mg dose of clopidogrel than with 300 mg (3). Ticagrelor is a stronger platelet inhibitor than clopidogrel (4) and may prove be a better treatment option with bivalirudin during PCI. However, anti-platelet properties do not always translate into equivalent antithrombotic action and at times agents of lower antithrombotic potency fail to demonstrate their full effect in the presence of a stronger compound (for e. g. effects of aspirin have been reported to vary with the degree of P2Y12 blockade [5] and its antithrombotic effects seem attenuated with higher dose of factor Xa inhibition [6]). Bi-
Correspondence to: Juan J. Badimon Cardiovascular Institute Icahn School of Medicine at Mount Sinai One Gustave L. Levy Place, Box 1030 New York, NY 10029, USA Tel.: +1 212 241 8484, Fax: +1 212 426 6962 E-mail: [email protected] Financial support: The study was funded in part by Astra-Zeneca. Received: March 25, 2014 Accepted after major revision: June 20, 2014 Epub ahead of print: August 7, 2014 http://dx.doi.org/10.1160/TH14-03-0269 Thromb Haemost 2014; 112: 1069–1070
© Schattauer 2014
valirudin has been shown to exert strong antithrombotic effects via its direct-thrombin inhibition (7) and has the potential to diminish ticagrelor’s anti-thrombotic advantage over clopidogrel without affecting the P2Y12 inhibitors’ anti-platelet properties in the peri-procedural period. We investigated the acute antithrombotic effects of ticagrelor (180 mg + 90 mg) versus clopidogrel (600 mg), when coadministered with aspirin (81 mg) and bivalirudin (weight-adjusted clinical dose, given as bolus plus 1 hour [h] infusion) using a randomised, two-treatment, two-period, cross-over design in healthy volunteers. Comparisons were made between the two treatments in their ability to reduce thrombus formation (high-shear rate Badimon chamber) (8) and platelet aggregation (VerifyNow P2Y12), and prolong coagulation time (CT – ThromboElastoMetry, ROTEM Gamma). All assessments were made at baseline, and after 1 h and 24 h of treatment administration. Statistical analyses were performed using a linear mixed model to compare differences between treatments as this allows specific settings for the treatment, carryover and sequence variables. Significance was set at the nominal p < 0.05 level and data are presented as mean (95 % confidence interval) unless specified otherwise. The mean age of study subjects (n=15) was 31.2 years (26.8–35.6) with 60 % males and a body mass index (BMI) of 27.0 kg/m2 (24.9–29.1). In both groups, thrombus formation was significantly lower after treatment compared with baseline (▶ Figure 1). Reduction in thrombus size from baseline was significantly greater after treatment with ticagrelor than with clopidogrel at both 1 (56.3 % vs 35.2 %) and 24 h (34.1 % vs 18.5 %), p< 0.001 and =0.012, respectively.
Although thrombus formation varied between the two groups, CT showed no differences between the groups at any time; 53.1 vs 51.1 seconds (s) at baseline; 163.1 vs 174.0 s at 1 h and 56.1 vs 54.3 s at 24 h for ticagrelor vs clopidogrel, respectively (p=NS between treatments for all timepoints). The identical pattern of CT changes in both groups (i. e. significant prolongation at 1 h that reverts to baseline values by 24 h) fit the short acting profile of bivalirudin. Platelet-specific effects of treatment, performed as a quality check, produced results that confirmed previous findings. Both treatments significantly lowered P2Y12-mediated platelet aggregation from baseline values, but as expected, the inhibitory effects of ticagrelor were substantially stronger than clopidogrel at both post-dose time-points (69.4 % vs 20.1 % at 1 h, p< 0.001; 67.4 % vs 53.4 % at 24 h, p=0.049). Our data show that ticagrelor’s known advantage over clopidogrel in inhibiting platelets is maintained even in the presence of a potent thrombin inhibitor like bivalirudin. More importantly, the stronger anti-platelet activity translates successfully into a significantly greater anti-thrombotic effect. The change in thrombus formation at 1 h reflects the combined effects of platelet inhibition by ticagrelor/clopidogrel and thrombin inhibition by bivalirudin. Since both treatment groups showed nearidentical changes in CT, a parameter not influenced by P2Y12 inhibitors, it is evident that effects of bivalirudin are equivalent in the two groups. The greater thrombus reduction at 1 h can therefore be attributed solely to ticagrelor. After 4 h when the effects of bivalirudin are completely dissipated, ticagrelor still maintains its significant anti-thrombotic advantage over clopidogrel. Our findings are of importance in ACS patients undergoing stent implantation with bivalirudin therapy, where acute stent thrombosis would be a concern. As we demonstrate, ticagrelor provides a stronger antithrombotic milieu to compliment the effect of bivalirudin than does clopidogrel. The earlier and more potent antithrombotic effects could play a critical role in reducing intra-procedural and acute stent Thrombosis and Haemostasis 112.5/2014
Downloaded from www.thrombosis-online.com on 2014-11-21 | ID: 1000471267 | IP: 132.206.27.24 For personal or educational use only. No other uses without permission. All rights reserved.
Letters to the Editor
1070
Figure 1: Effects of ticagrelor vs clopidogrel on thrombus formation (top) and coagulation time (bottom) when coadministered with bivalirudin and aspirin. Thrombus formation was reduced in both treatment groups from baseline values at 1 h (p< 0.001 for both) and 24 h (p≤ 0.003 for both), but the antithrombotic effects were significantly greater with ticagrelor than clopidogrel at both time-points. Coagulation times were prolonged equally in both groups at 1 h (p< 0.05 for both) and returned to baseline values by 24 h (p=NS for both).
thrombosis, known to be predictive of subsequent adverse events. In conclusion, dual antiplatelet therapy with bivalirudin exerts faster and stronger antithrombotic effects if ticagrelor is used instead of clopidogrel. Our results, taken in light of the findings from recent clinical trials suggest that with ticagrelor use during intracoronary stenting, the risk of acute stent thrombosis could potentially be lower than with clopidogrel. Replacing clopidogrel with ticagrelor during stenting may significantly reduce the risk of acute instent thrombosis. Conflicts of interest
J. J. Badimon has received Institutional Research Grant Support from AstraZeneca. R. Mehran has received Institutional Research Grant Support from The Medicines Company, Bristol-Myers Squibb/Sanofi-Aventis/Daiichi Sankyo,
Regado Biosciences and STENTYS, she has served as a consultant for Abbott Vascular, AstraZeneca, Boston Scientific, Covidien, CSL Behring, Janssen (JNJ), Maya Medical, Merck, and has served on the Advisory Board for Covidien, Janssen Pharmaceuticals and Sanofi-Aventis. She holds 25,000 shares for Endothelix Inc. None of the other authors declares any conflicts of interest.
References 1. Stone GW, Witzenbichler B, Guagliumi G, et al. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med 2008; 358: 2218–2230. 2. Gurbel PA, Bliden KP, Samara W, et al. Clopidogrel effect on platelet reactivity in patients with stent thrombosis: results of the CREST Study. J Am Coll Cardiol 2005; 46: 1827–1832. 3. Dangas G, Mehran R, Guagliumi G, et al. Role of clopidogrel loading dose in patients with ST-segment elevation myocardial infarction undergoing primary angioplasty: results from the HORIZONS-AMI (harmonizing outcomes with revas-
4.
5.
6.
7.
8.
cularization and stents in acute myocardial infarction) trial. J Am Coll Cardiol 2009; 54: 1438–1446. Gurbel PA, Bliden KP, Butler K, et al. Randomized double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease: the ONSET/OFFSET study. Circulation 2009; 120: 2577–2585. Kirkby NS, Leadbeater PD, Chan MV, et al. Antiplatelet effects of aspirin vary with level of P2Y(1)(2) receptor blockade supplied by either ticagrelor or prasugrel. J Thromb Haemost 2011; 9: 2103–2105. Shimbo D, Osende J, Chen J, et al. Antithrombotic effects of DX-9065a, a direct factor Xa inhibitor: a comparative study in humans versus low molecular weight heparin. Thromb Haemost 2002; 88: 733–738. Lev EI, Patel R, Karim A, et al. Anti-thrombotic effect of bivalirudin compared with eptifibatide and unfractionated heparin in diabetic patients: an ex vivo human study. Thromb Haemost 2006; 95: 441–446. Zafar MU, Ibanez B, Choi BG, et al. A new oral antiplatelet agent with potent antithrombotic properties: comparison of DZ-697b with clopidogrel a randomised phase I study. Thromb Haemost 2010; 103: 205–212.
Thrombosis and Haemostasis 112.5/2014 Downloaded from www.thrombosis-online.com on 2014-11-21 | ID: 1000471267 | IP: 132.206.27.24 For personal or educational use only. No other uses without permission. All rights reserved.
© Schattauer 2014
