1077
Invited Editorial Focus
Can we improve the efficacy of low-dose aspirin? Erik L. Grove1; Robert F. Storey2; Steen D. Kristensen1 1Department
of Cardiology, Aarhus University Hospital, Aarhus, Denmark; 2Department of Cardiovascular Science, University of Sheffield, Sheffield, UK
Platelets provide primary haemostasis, but also play important roles in the development of atherothrombosis, resulting in stroke and acute coronary syndromes. Cardiovascular events remain the number one cause of death worldwide, and antiplatelet therapy is a cornerstone in the prevention and treatment of cardiovascular disease. At the turn of its 115th anniversary, aspirin remains one of the most widely used antiplatelet drugs. Still, treatment with aspirin continues to spark debate on well-known topics such as optimal dosing to optimise the benefit-risk ratio, the suggested presence of aspirin “low-responders” and its role in combination antithrombotic therapy after coronary stenting. An interesting study presented by Bonten et al. (1) in this issue of Thrombosis and Haemostasis highlights another important, but so far unexplored topic: the optimal timing of oncedaily aspirin intake. Aspirin has a short plasma half-life of only 20 minutes, yet once daily intake of aspirin doses as low as 40 mg prevents atherothrombotic events through cumulative inhibition of platelet aggregation (2). Accordingly, daily low-dose aspirin (75–150 mg) is recommended in patients at risk of first-time or recurrent cardiovascular events (3, 4). Aspirin is usually taken on awakening, although evidence regarding the optimal timing of intake is lacking. Platelet aggregation shows some circadian rhythm with a morning peak that coincides with the well-known morning peak Correspondence to: Erik L. Grove, MD, PhD Department of Cardiology Aarhus University Hospital Brendstrupgaardsvej 100 8200 Aarhus, Denmark Tel.: +45 7845 2029, Fax: +45 7845 2260 E-mail: [email protected] Received: August 5, 2014 Accepted: August 25, 2014 Epub ahead of print: September 11, 2014 http://dx.doi.org/10.1160/TH14-08-0702 Thromb Haemost 2014; 112: 1077–1078
of myocardial infarction (5, 6). Consequently, there is an interest in this biological variation both to explain the phenomenon and to develop new therapeutic strategies. Due to its short half-life, only platelets circulating at the time of aspirin intake are inhibited and, therefore, aspirininduced platelet inhibition may depend on the timing of aspirin intake. The clinical message from the study by Bonten et al. (1) is that taking aspirin at bedtime instead of in the morning may reduce the risk of cardiovascular events in the morning. This message is based on the presumptions that 1) platelet aggregation is higher in the morning and that 2) the platelet inhibitory effect of aspirin is not sustained during the usual 24-hour (h) dosing interval. Evidence supporting a circadian platelet rhythm mainly comes from platelet function studies of healthy, untreated individuals (7–9), whereas evidence of increased platelet aggregation at the end of the 24-h dosing interval with aspirin arises from studies in patients with coronary artery disease (10–12). Interestingly, a circadian variation with higher gastric mucosal resistance in the evening has also been reported (13), which may help to avoid unfavourable discontinuation of low-dose aspirin (14). Several mechanisms likely contribute to platelet hyperreactivity during treatment with antiplatelet drugs (15). With respect to aspirin, insufficient platelet inhibition may in part be explained by its short halflife and the fact that new platelets produced by megakaryocytes are continuously released into the blood from the bone marrow (16). Indeed, as many as 1011 platelets are produced every single day, and in vitro experiments using mixtures of aspirin-free and aspirin-treated platelets have shown that full aggregation is observed with only a few percent of aspirin-free platelets present (17). The low number of uninhibited platelets needed to induce considerable platelet aggregation likely rely on the ability of new platelets to release thromboxane A2,
thus triggering aggregation of the total platelet pool. This hypothesis is in accordance with previous work of FitzGerald et al. who as early as 1983 showed that both thromboxane metabolites and platelet aggregation progressively recovered within 24 h upon administration of a thromboxane synthase inhibitor (18), and similar findings were reported in recent studies after administration of aspirin (10, 19). Bearing these results in mind, the results presented by Bonten et al. may not be overwhelmingly surprising, but still deserve considerable attention owing to the simple but elegantly designed study (1). In a randomised open-label cross-over trial, the authors investigated the hypothesis that intake of low-dose aspirin at bedtime may attenuate the morning peak of platelet aggregation. Using this dosing strategy, cyclooxygenase (COX)-1-dependent platelet reactivity in the morning was reduced by intake of aspirin at bedtime compared with on awakening. Irreversible COX-1 inhibition by aspirin normally compensates for the short halflife, but renewal of the drug target shortens the duration of COX-1 inhibition and may even dictate new dosing strategies particularly in patients with accelerated platelet turnover, such as essential thrombocythaemia (20) or diabetes mellitus (11, 21). Several studies have explored the potential benefit of increased aspirin doses or twicedaily dosing, with the former strategy being suboptimal. Thus, it has previously been shown that even 960 mg of aspirin is not able to fully inhibit platelet aggregation through 24 h (22), whereas twice-daily, low-dose aspirin administration results in greater platelet inhibition than a once-daily regimen (18, 19, 23, 24). Importantly, subtle diurnal differences in COX-1 inhibition may be dwarfed by the fact that thromboxane A2 plays a limited role overall Editorial Focus on ▶Bonten et al. Thromb Haemost 2014; 112: 1209-1218.
© Schattauer 2014
Thrombosis and Haemostasis 112.6/2014 Downloaded from www.thrombosis-online.com on 2015-01-06 | IP: 129.2.19.100 For personal or educational use only. No other uses without permission. All rights reserved.
1078
Invited Editorial Focus
in platelet reactivity and even complete COX-1 inhibition often may be inadequate to prevent atherothrombotic events, as demonstrated by the importance of effective P2Y12 inhibition, in addition to COX-1 inhibition, in preventing cardiovascular events. The study by Bonten et al. was performed on a relatively small number of healthy volunteers, and one may speculate if similar findings would have been obtained in a clinical setting of aspirin-treated patients with coronary artery disease. This should be investigated, but since platelet turnover is slightly higher in patients with coronary artery disease (25), one would expect that a similar – or even higher – benefit of bedtime aspirin dosing would be observed. More evidence lending support to clinical implications of Bonten´s findings comes from the Physicians´ Health Study, a randomised, double-blind, placebo-controlled trial of alternate-day aspirin (325 mg) intake among 22,071 male physicians. During a five-year follow-up period, aspirin reduced the incidence of non-fatal myocardial infarction by 59% during the morning hours, compared with a 34% reduction for the remaining hours of the day (26). Accordingly, aspirin intake abolished the circadian variation and morning peak of infarctions. Daily low-dose aspirin is strongly recommended for all patients with cardiovascular disease, but platelet inhibition with once-daily aspirin declines through 24 h, and the optimal dosing strategy remains unknown. The pharmacodynamic study by Bonten et al. provides a rational basis for clinical trials assessing the efficacy and safety of a novel dosing strategy that may improve the efficacy of low-dose aspirin. Conflicts of interest
Erik L. Grove has received speaker honoraria from AstraZeneca, Baxter, Bayer, Boehringer Ingelheim, Pfizer and Sysmex and has participated in advisory board meetings for AstraZeneca, Bayer and BMS. Robert F. Storey has received research
grants from AstraZeneca, Eli Lilly/Daiichi Sankyo, and Merck; research support from Accumetrics; honoraria from AstraZeneca, Eli Lilly/Daiichi Sankyo, Merck, NOvartis, Sanofi-Aventis, Accumetrics, and Medscape; consultancy fees from AstraZeneca, Daiichi Sankyo, Merck, Novartis, Accumetrics, Regeneron, Roche, Correvio, and The Medicines Company. Steen D. Kristensen has received speaker honoraria from AstraZeneca, Eli Lilly, Sanofi, and The Medicines Company, and research support from AstraZeneca.
References 1. Bonten TN, Oostrom M, Snoep J, et al. Effect of aspirin intake at bedtime versus on awakening on circadian rhythm of platelet reactivity: A randomised crossover trial. Thromb Haemost 2014; 112: 1209-1218. 2. Patrignani P, Filabozzi P, Patrono C. Selective cumulative inhibition of platelet thromboxane production by low-dose aspirin in healthy subjects. J Clin Invest 1982; 69: 1366-1372. 3. Halvorsen S, Andreotti F, ten Berg JM, et al. Aspirin Therapy in Primary Cardiovascular Disease Prevention: A Position Paper of the European Society of Cardiology Working Group on Thrombosis. J Am Coll Cardiol 2014; 64: 319-327. 4. Patrono C, Andreotti F, Arnesen H, et al. Antiplatelet agents for the treatment and prevention of atherothrombosis. Eur Heart J 2011; 32: 2922-2932. 5. Cohen MC, Rohtla KM, Lavery CE, et al. Metaanalysis of the morning excess of acute myocardial infarction and sudden cardiac death. Am J Cardiol 1997; 79: 1512-1516. 6. Mogabgab O, Giugliano RP, Sabatine MS, et al. Circadian variation in patient characteristics and outcomes in ST-segment elevation myocardial infarction. Chronobiol Int 2012; 29: 1390-1396. 7. Tofler GH, Brezinski D, Schafer AI, et al. Concurrent morning increase in platelet aggregability and the risk of myocardial infarction and sudden cardiac death. N Engl J Med 1987; 316: 1514-1518. 8. Scheer FA, Michelson AD, Frelinger AL, III, et al. The Human Endogenous Circadian System Causes Greatest Platelet Activation during the Biological Morning Independent of Behaviors. PLoS One 2011; 6: e24549. 9. Dalby MC, Davidson SJ, Burman JF, et al. Diurnal variation in platelet aggregation iwth the PFA-100 platelet function analyser. Platelets 2000; 11: 320-324. 10. Henry P, Vermillet A, Boval B, et al. 24-hour timedependent aspirin efficacy in patients with stable coronary artery disease. Thromb Haemost 2010; 105: 336-344.
11. Christensen KH, Grove EL, Wurtz M, et al. Reduced antiplatelet effect of aspirin during 24 hours in patients with coronary artery disease and type 2 diabetes. Platelets 2014; Epub ahead of print. 12. Wurtz M, Hvas AM, Jensen LO, et al. 24-hour antiplatelet effect of aspirin in patients with previous definite stent thrombosis. Int J Cardiol 2014; 175: 274-279. 13. Moore JG, Goo RH. Day and night aspirin-induced gastric mucosal damage and protection by ranitidine in man. Chronobiol Int 1987; 4: 111-116. 14. Cea Soriano L, Bueno H, Lanas A, et al. Cardiovascular and upper gastrointestinal bleeding consequences of low-dose acetylsalicylic acid discontinuation. Thromb Haemost 2013; 110: 1298-1304 15. Wurtz M, Grove EL. Interindividual variability in the efficacy of oral antiplatelet drugs: definitions, mechanisms and clinical importance. Curr Pharm Des 2012; 18: 5344-5361. 16. Martin JF, Kristensen SD, Mathur A, et al. The causal role of megakaryocyte-platelet hyperactivity in acute coronary syndromes. Nat Rev Cardiol 2012; 9: 658–670. 17. Di MG, Silver MJ, Murphy S. Monitoring the entry of new platelets into the circulation after ingestion of aspirin. Blood 1983; 61: 1081-1085. 18. FitzGerald GA, Brash AR, Oates JA, et al. Endogenous prostacyclin biosynthesis and platelet function during selective inhibition of thromboxane synthase in man. J Clin Invest 1983; 72: 1336-1343. 19. Rocca B, Santilli F, Pitocco D, et al. The recovery of platelet cyclooxygenase activity explains interindividual variability in responsiveness to low-dose aspirin in patients with and without diabetes. J Thromb Haemost 2012; 10: 1220-1230. 20. Pascale S, Petrucci G, Dragani A, et al. Aspirin-insensitive thromboxane biosynthesis in essential thrombocythemia is explained by accelerated renewal of the drug target. Blood 2012; 119: 3595-3603. 21. Grove EL, Hvas AM, Mortensen SB, et al. Effect of platelet turnover on whole blood platelet aggregation in patients with coronary artery disease. J Thromb Haemost 2011; 9: 185-191. 22. Perneby C, Wallen NH, Rooney C, et al. Dose- and time-dependent antiplatelet effects of aspirin. Thromb Haemost 2006; 95: 652-658. 23. Capodanno D, Patel A, Dharmashankar K, et al. Pharmacodynamic effects of different aspirin dosing regimens in type 2 diabetes mellitus patients with coronary artery disease. Circ Cardiovasc Interv 2011; 4: 180-187. 24. Lordkipanidze M, Harrison P. Aspirin twice a day keeps new COX-1 at bay. J Thromb Haemost 2012; 10: 1217-1219. 25. Grove EL, Hvas AM, Kristensen SD. Immature platelets in patients with acute coronary syndromes. Thromb Haemost 2009; 101: 151-156. 26. Ridker PM, Manson JE, Buring JE, et al. Circadian variation of acute myocardial infarction and the effect of low-dose aspirin in a randomized trial of physicians. Circulation 1990; 82: 897–902.
Thrombosis and Haemostasis 112.6/2014
© Schattauer 2014 Downloaded from www.thrombosis-online.com on 2015-01-06 | IP: 129.2.19.100
For personal or educational use only. No other uses without permission. All rights reserved.
Invited Editorial Focus
Can we improve the efficacy of low-dose aspirin? Erik L. Grove1; Robert F. Storey2; Steen D. Kristensen1 1Department
of Cardiology, Aarhus University Hospital, Aarhus, Denmark; 2Department of Cardiovascular Science, University of Sheffield, Sheffield, UK
Platelets provide primary haemostasis, but also play important roles in the development of atherothrombosis, resulting in stroke and acute coronary syndromes. Cardiovascular events remain the number one cause of death worldwide, and antiplatelet therapy is a cornerstone in the prevention and treatment of cardiovascular disease. At the turn of its 115th anniversary, aspirin remains one of the most widely used antiplatelet drugs. Still, treatment with aspirin continues to spark debate on well-known topics such as optimal dosing to optimise the benefit-risk ratio, the suggested presence of aspirin “low-responders” and its role in combination antithrombotic therapy after coronary stenting. An interesting study presented by Bonten et al. (1) in this issue of Thrombosis and Haemostasis highlights another important, but so far unexplored topic: the optimal timing of oncedaily aspirin intake. Aspirin has a short plasma half-life of only 20 minutes, yet once daily intake of aspirin doses as low as 40 mg prevents atherothrombotic events through cumulative inhibition of platelet aggregation (2). Accordingly, daily low-dose aspirin (75–150 mg) is recommended in patients at risk of first-time or recurrent cardiovascular events (3, 4). Aspirin is usually taken on awakening, although evidence regarding the optimal timing of intake is lacking. Platelet aggregation shows some circadian rhythm with a morning peak that coincides with the well-known morning peak Correspondence to: Erik L. Grove, MD, PhD Department of Cardiology Aarhus University Hospital Brendstrupgaardsvej 100 8200 Aarhus, Denmark Tel.: +45 7845 2029, Fax: +45 7845 2260 E-mail: [email protected] Received: August 5, 2014 Accepted: August 25, 2014 Epub ahead of print: September 11, 2014 http://dx.doi.org/10.1160/TH14-08-0702 Thromb Haemost 2014; 112: 1077–1078
of myocardial infarction (5, 6). Consequently, there is an interest in this biological variation both to explain the phenomenon and to develop new therapeutic strategies. Due to its short half-life, only platelets circulating at the time of aspirin intake are inhibited and, therefore, aspirininduced platelet inhibition may depend on the timing of aspirin intake. The clinical message from the study by Bonten et al. (1) is that taking aspirin at bedtime instead of in the morning may reduce the risk of cardiovascular events in the morning. This message is based on the presumptions that 1) platelet aggregation is higher in the morning and that 2) the platelet inhibitory effect of aspirin is not sustained during the usual 24-hour (h) dosing interval. Evidence supporting a circadian platelet rhythm mainly comes from platelet function studies of healthy, untreated individuals (7–9), whereas evidence of increased platelet aggregation at the end of the 24-h dosing interval with aspirin arises from studies in patients with coronary artery disease (10–12). Interestingly, a circadian variation with higher gastric mucosal resistance in the evening has also been reported (13), which may help to avoid unfavourable discontinuation of low-dose aspirin (14). Several mechanisms likely contribute to platelet hyperreactivity during treatment with antiplatelet drugs (15). With respect to aspirin, insufficient platelet inhibition may in part be explained by its short halflife and the fact that new platelets produced by megakaryocytes are continuously released into the blood from the bone marrow (16). Indeed, as many as 1011 platelets are produced every single day, and in vitro experiments using mixtures of aspirin-free and aspirin-treated platelets have shown that full aggregation is observed with only a few percent of aspirin-free platelets present (17). The low number of uninhibited platelets needed to induce considerable platelet aggregation likely rely on the ability of new platelets to release thromboxane A2,
thus triggering aggregation of the total platelet pool. This hypothesis is in accordance with previous work of FitzGerald et al. who as early as 1983 showed that both thromboxane metabolites and platelet aggregation progressively recovered within 24 h upon administration of a thromboxane synthase inhibitor (18), and similar findings were reported in recent studies after administration of aspirin (10, 19). Bearing these results in mind, the results presented by Bonten et al. may not be overwhelmingly surprising, but still deserve considerable attention owing to the simple but elegantly designed study (1). In a randomised open-label cross-over trial, the authors investigated the hypothesis that intake of low-dose aspirin at bedtime may attenuate the morning peak of platelet aggregation. Using this dosing strategy, cyclooxygenase (COX)-1-dependent platelet reactivity in the morning was reduced by intake of aspirin at bedtime compared with on awakening. Irreversible COX-1 inhibition by aspirin normally compensates for the short halflife, but renewal of the drug target shortens the duration of COX-1 inhibition and may even dictate new dosing strategies particularly in patients with accelerated platelet turnover, such as essential thrombocythaemia (20) or diabetes mellitus (11, 21). Several studies have explored the potential benefit of increased aspirin doses or twicedaily dosing, with the former strategy being suboptimal. Thus, it has previously been shown that even 960 mg of aspirin is not able to fully inhibit platelet aggregation through 24 h (22), whereas twice-daily, low-dose aspirin administration results in greater platelet inhibition than a once-daily regimen (18, 19, 23, 24). Importantly, subtle diurnal differences in COX-1 inhibition may be dwarfed by the fact that thromboxane A2 plays a limited role overall Editorial Focus on ▶Bonten et al. Thromb Haemost 2014; 112: 1209-1218.
© Schattauer 2014
Thrombosis and Haemostasis 112.6/2014 Downloaded from www.thrombosis-online.com on 2015-01-06 | IP: 129.2.19.100 For personal or educational use only. No other uses without permission. All rights reserved.
1078
Invited Editorial Focus
in platelet reactivity and even complete COX-1 inhibition often may be inadequate to prevent atherothrombotic events, as demonstrated by the importance of effective P2Y12 inhibition, in addition to COX-1 inhibition, in preventing cardiovascular events. The study by Bonten et al. was performed on a relatively small number of healthy volunteers, and one may speculate if similar findings would have been obtained in a clinical setting of aspirin-treated patients with coronary artery disease. This should be investigated, but since platelet turnover is slightly higher in patients with coronary artery disease (25), one would expect that a similar – or even higher – benefit of bedtime aspirin dosing would be observed. More evidence lending support to clinical implications of Bonten´s findings comes from the Physicians´ Health Study, a randomised, double-blind, placebo-controlled trial of alternate-day aspirin (325 mg) intake among 22,071 male physicians. During a five-year follow-up period, aspirin reduced the incidence of non-fatal myocardial infarction by 59% during the morning hours, compared with a 34% reduction for the remaining hours of the day (26). Accordingly, aspirin intake abolished the circadian variation and morning peak of infarctions. Daily low-dose aspirin is strongly recommended for all patients with cardiovascular disease, but platelet inhibition with once-daily aspirin declines through 24 h, and the optimal dosing strategy remains unknown. The pharmacodynamic study by Bonten et al. provides a rational basis for clinical trials assessing the efficacy and safety of a novel dosing strategy that may improve the efficacy of low-dose aspirin. Conflicts of interest
Erik L. Grove has received speaker honoraria from AstraZeneca, Baxter, Bayer, Boehringer Ingelheim, Pfizer and Sysmex and has participated in advisory board meetings for AstraZeneca, Bayer and BMS. Robert F. Storey has received research
grants from AstraZeneca, Eli Lilly/Daiichi Sankyo, and Merck; research support from Accumetrics; honoraria from AstraZeneca, Eli Lilly/Daiichi Sankyo, Merck, NOvartis, Sanofi-Aventis, Accumetrics, and Medscape; consultancy fees from AstraZeneca, Daiichi Sankyo, Merck, Novartis, Accumetrics, Regeneron, Roche, Correvio, and The Medicines Company. Steen D. Kristensen has received speaker honoraria from AstraZeneca, Eli Lilly, Sanofi, and The Medicines Company, and research support from AstraZeneca.
References 1. Bonten TN, Oostrom M, Snoep J, et al. Effect of aspirin intake at bedtime versus on awakening on circadian rhythm of platelet reactivity: A randomised crossover trial. Thromb Haemost 2014; 112: 1209-1218. 2. Patrignani P, Filabozzi P, Patrono C. Selective cumulative inhibition of platelet thromboxane production by low-dose aspirin in healthy subjects. J Clin Invest 1982; 69: 1366-1372. 3. Halvorsen S, Andreotti F, ten Berg JM, et al. Aspirin Therapy in Primary Cardiovascular Disease Prevention: A Position Paper of the European Society of Cardiology Working Group on Thrombosis. J Am Coll Cardiol 2014; 64: 319-327. 4. Patrono C, Andreotti F, Arnesen H, et al. Antiplatelet agents for the treatment and prevention of atherothrombosis. Eur Heart J 2011; 32: 2922-2932. 5. Cohen MC, Rohtla KM, Lavery CE, et al. Metaanalysis of the morning excess of acute myocardial infarction and sudden cardiac death. Am J Cardiol 1997; 79: 1512-1516. 6. Mogabgab O, Giugliano RP, Sabatine MS, et al. Circadian variation in patient characteristics and outcomes in ST-segment elevation myocardial infarction. Chronobiol Int 2012; 29: 1390-1396. 7. Tofler GH, Brezinski D, Schafer AI, et al. Concurrent morning increase in platelet aggregability and the risk of myocardial infarction and sudden cardiac death. N Engl J Med 1987; 316: 1514-1518. 8. Scheer FA, Michelson AD, Frelinger AL, III, et al. The Human Endogenous Circadian System Causes Greatest Platelet Activation during the Biological Morning Independent of Behaviors. PLoS One 2011; 6: e24549. 9. Dalby MC, Davidson SJ, Burman JF, et al. Diurnal variation in platelet aggregation iwth the PFA-100 platelet function analyser. Platelets 2000; 11: 320-324. 10. Henry P, Vermillet A, Boval B, et al. 24-hour timedependent aspirin efficacy in patients with stable coronary artery disease. Thromb Haemost 2010; 105: 336-344.
11. Christensen KH, Grove EL, Wurtz M, et al. Reduced antiplatelet effect of aspirin during 24 hours in patients with coronary artery disease and type 2 diabetes. Platelets 2014; Epub ahead of print. 12. Wurtz M, Hvas AM, Jensen LO, et al. 24-hour antiplatelet effect of aspirin in patients with previous definite stent thrombosis. Int J Cardiol 2014; 175: 274-279. 13. Moore JG, Goo RH. Day and night aspirin-induced gastric mucosal damage and protection by ranitidine in man. Chronobiol Int 1987; 4: 111-116. 14. Cea Soriano L, Bueno H, Lanas A, et al. Cardiovascular and upper gastrointestinal bleeding consequences of low-dose acetylsalicylic acid discontinuation. Thromb Haemost 2013; 110: 1298-1304 15. Wurtz M, Grove EL. Interindividual variability in the efficacy of oral antiplatelet drugs: definitions, mechanisms and clinical importance. Curr Pharm Des 2012; 18: 5344-5361. 16. Martin JF, Kristensen SD, Mathur A, et al. The causal role of megakaryocyte-platelet hyperactivity in acute coronary syndromes. Nat Rev Cardiol 2012; 9: 658–670. 17. Di MG, Silver MJ, Murphy S. Monitoring the entry of new platelets into the circulation after ingestion of aspirin. Blood 1983; 61: 1081-1085. 18. FitzGerald GA, Brash AR, Oates JA, et al. Endogenous prostacyclin biosynthesis and platelet function during selective inhibition of thromboxane synthase in man. J Clin Invest 1983; 72: 1336-1343. 19. Rocca B, Santilli F, Pitocco D, et al. The recovery of platelet cyclooxygenase activity explains interindividual variability in responsiveness to low-dose aspirin in patients with and without diabetes. J Thromb Haemost 2012; 10: 1220-1230. 20. Pascale S, Petrucci G, Dragani A, et al. Aspirin-insensitive thromboxane biosynthesis in essential thrombocythemia is explained by accelerated renewal of the drug target. Blood 2012; 119: 3595-3603. 21. Grove EL, Hvas AM, Mortensen SB, et al. Effect of platelet turnover on whole blood platelet aggregation in patients with coronary artery disease. J Thromb Haemost 2011; 9: 185-191. 22. Perneby C, Wallen NH, Rooney C, et al. Dose- and time-dependent antiplatelet effects of aspirin. Thromb Haemost 2006; 95: 652-658. 23. Capodanno D, Patel A, Dharmashankar K, et al. Pharmacodynamic effects of different aspirin dosing regimens in type 2 diabetes mellitus patients with coronary artery disease. Circ Cardiovasc Interv 2011; 4: 180-187. 24. Lordkipanidze M, Harrison P. Aspirin twice a day keeps new COX-1 at bay. J Thromb Haemost 2012; 10: 1217-1219. 25. Grove EL, Hvas AM, Kristensen SD. Immature platelets in patients with acute coronary syndromes. Thromb Haemost 2009; 101: 151-156. 26. Ridker PM, Manson JE, Buring JE, et al. Circadian variation of acute myocardial infarction and the effect of low-dose aspirin in a randomized trial of physicians. Circulation 1990; 82: 897–902.
Thrombosis and Haemostasis 112.6/2014
© Schattauer 2014 Downloaded from www.thrombosis-online.com on 2015-01-06 | IP: 129.2.19.100
For personal or educational use only. No other uses without permission. All rights reserved.
