Eur J Vasc Endovasc Surg (2015) 49, 621e622
EDITORIAL
Dual Antiplatelet Therapy after Carotid Stenting: Lessons from ‘Big Brother’ Although it is accepted that carotid artery stent (CAS) patients should receive dual antiplatelet therapy (currently aspirin and clopidogrel) throughout the perioperative period in order to minimize the risks of acute stent thrombosis/embolization secondary to platelet activation triggered by intimal injury and/or the insertion of a foreign body (stent), there is no evidence-based consensus as to how long dual antiplatelet therapy (DAPT) should continue thereafter. International guidelines provide inconsistent advice regarding the optimal duration of dual antiplatelet therapy after CAS, ranging from “at least 30 days” (American Heart Association [AHA], Society for Vascular Surgery [SVS]1,2 to 3 months [European Society of Vascular Surgery]).3 None of the guidelines recommended long-term or lifelong dual antiplatelet therapy after CAS; all recommended life-long aspirin therapy following discontinuation of clopidogrel, and there were no recommendations regarding the role of the newer generation antiplatelet agents.1,4 It is, however, not unusual for the findings of cardiology based research to be extrapolated into other cardiovascular interventional practices whenever data are “missing”. The decision to recommend that CAS be undertaken using periprocedural dual antiplatelet therapy was, for example, the product of research following coronary stenting, which showed lower rates of in-stent thrombosis and acute coronary events than antiplatelet monotherapy. Thereafter, remaining debate concerned for how long DAPT should continue. For some time now, it has been advised that patients undergoing coronary interventions using drugeluting stents (DESs) should maintain DAPT for 6e12 months. However, the 2014 ESC guidelines on myocardial revascularization recommend that DAPT should stop after 6 months in patients receiving the latest generation DESs (possibly even at 3 months) on the basis that bleeding risks increase if DAPT extends to 12 months and because of a lack of evidence regarding any potential benefit in terms of preventing late ischemic myocardial complications.5 However, notwithstanding the fact that the 2014 ESC guidelines now recommend a shorter duration of DAPT, some of our cardiology colleagues are back to debating about whether DAPT should be extended beyond 12 months.6 The Dual Antiplatelet Therapy (DAPT) study was a large international, multicenter, randomized trial whose goal was 1078-5884/$ e see front matter Ó 2015 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejvs.2015.02.004
to determine the benefits/risks of extending dual antiplatelet therapy beyond 12 months in patients who had received coronary stents.6 In this study, 9961 patients who had completed 12 months of dual antiplatelet therapy after implantation of a DES were randomly assigned to an additional 18 months of thienopyridine therapy (clopidogrel or prasugrel) versus placebo. All patients continued to take aspirin. The main finding was that extending clopidogrel or prasugrel to 30 months significantly reduced the relative risk of suffering a major adverse cardiovascular and/or cerebrovascular event by 29% (absolute risk 4.3% vs. 5.9%, p < .001). The overall reduction in major cardiovascular events at 30 months was more evident in patients taking prasugrel. Of relevance, the reduction in major vascular events was not strictly related to the prevention of coronary DES thrombosis. Continued thienopyridine therapy was associated with both a lower cumulative incidence of stent thrombosis (0.4% vs. 1.4%; hazard ratio 0.29; 95% CI 0.17e 0.48; p < .001) and of myocardial infarction than with placebo (2.1% vs. 4.1%; hazard ratio 0.47; 95% CI 0.37 to 0.61; p < .001). Myocardial infarctions that were not related to stent thrombosis (1.8% vs. 2.9%; hazard ratio 0.59; p < .001) accounted for 55% of the events, suggesting a beneficial effect for prolonged DAPT outside the coronary stented area. In addition, and of greater practical relevance regarding the debate in CAS patients, the DAPT trial included 1687 patients who had a bare-metal stent inserted into their coronary circulation. In these patients, a subgroup analysis showed that continued thienopyridine therapy may confer a relative risk reduction of 51% in late stent thrombosis at 30 months (AHA oral communication). What about adverse events related to prolonged dual antiplatelet therapy? Perhaps not unsurprisingly, the incidence of moderate/severe bleeding was increased in patients randomized to extended thienopyridine treatment (2.5% vs. 1.6%, p ¼ .001).6 However, an unexpected finding (albeit with borderline statistical significance) was an increase in late mortality in patients randomized to extended thienopyridine therapy (2.0% vs. 1.5%, hazard ratio 1.36, p ¼ .05) that may have been due, at least in part, to an imbalance in pre-existing cancer (and subsequently in cancer-related mortality) in patients randomized to extended clopidogrel/prasugrel (0.62% vs. 0.28%, p ¼ .02). This increase in late mortality was not attributable to excess cardiovascular, hemorrhagic or trauma-related events, and when cancer-related deaths were excluded from analysis there was no significant difference in late survival.
622
Subsequent data from post-marketing studies that had contributed to the DAPT trial also showed an alarming rebound in cardiovascular events in the first 3 months after stopping clopidogrel/prasugrel at either 12 or 30 months.6 Previous studies have also shown a possible causal relationship between the recovery of platelet reactivity following cessation of thienopyridine therapy and a susceptibility towards increased cardiovascular events.7 At first sight, therefore, the combination of reduced late cardiovascular events, counterbalanced with an increase in (non-cardiovascular) mortality could be interpreted as a challenge to any benefit from extending dual antiplatelet therapy. It has also been reported that patients with asymptomatic carotid disease who were revascularized and then received long-term dual antiplatelet therapy had reduced survival (47% vs. 40% at 5 years of median followup).8 Accordingly, the risk of increased thrombotic events following discontinuation of DAPT raises the recurring question of whether it is ever safe to discontinue dual antiplatelet therapy in carotid stented patients. It is hard, therefore, to know just how much of the DAPT study data can be extrapolated to help manage CAS patients. However, the observation that patients with baremetal coronary stents who were randomized to extended thienopyridine therapy suffered fewer major cardiovascular events suggests that the mid-term benefit conferred by DAPT may not be exclusive to DESs. It remains to be seen whether a similar phenomenon happens following cessation of dual antiplatelet therapy in CAS patients at 3 months (or whenever it is stopped). Few non-randomized studies have reported outcome data at this time-point and none of the randomized trials has reported whether the time line for recurrent stroke is higher in the first few weeks/months after cessation of dual antiplatelet therapy. This is surely a question that could be answered relatively easily and which could have a major impact in determining whether CAS patients face a similarly high risk of rebound thromboembolic stroke following cessation of DAPT. If they do not, then it would seem reasonable to stop DAPT after 3 months (as is current practice). If there is, however, evidence of an increased risk of stroke following cessation of DAPT, currently accepted guidelines of practice may need to be changed.
Editorial
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American Association of Neuroscience Nurses, American Association of Neurological Surgeons, American College of Radiology, American Society of Neuroradiology, Congress of Neurological Surgeons, Society of Atherosclerosis Imaging and Prevention, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of NeuroInterventional Surgery, Society for Vascular Medicine, and Society for Vascular Surgery. Developed in collaboration with the American Academy of Neurology and Society of Cardiovascular Computed Tomography Catheter Cardiovasc Interv 2013;81:E76e123. Ricotta JJ, Aburahma A, Ascher E, Eskandari M, Faries P, Lal BK. Society for vascular surgery. Updated society for vascular surgery guidelines for management of extracranial carotid disease. J Vasc Surg 2011;54:e1e31. Liapis CD, Bell PR, Mikhailidis D, Sivenius J, Nicolaides A, Fernandes e Fernandes J, et al. ESVS Guidelines Collaborators. ESVS guidelines. Invasive treatment for carotid stenosis: indications, techniques. Eur J Vasc Endovasc Surg 2009;37(Suppl. 4):1e19. European Stroke Organisation, Tendera M, Aboyans V, Bartelink ML, Baumgartner I, Clément D, et al. ESC Committee for Practice Guidelines. ESC guidelines on the diagnosis and treatment of peripheral artery diseases: document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteries: the task force on the diagnosis and treatment of peripheral artery diseases of the European Society of Cardiology (ESC). Eur Heart J 2011;32:2851e906. Windecker S, Alfonso F, Collet J-P, Cremer J, Falk V, Filippatos G, et al. Authors/Task Force Members. 2014 ESC/EACTS guidelines on myocardial revascularization: the task force on myocardial revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J 2014;35:2541e619. Mauri L, Kereiakes DJ, Yeh RW, Driscoll-Shempp P, Cutlip DE, Steg PG, et al. DAPT Study Investigators. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. N Engl J Med 2014;371:2155e66. Ho PM, Peterson ED, Wang L, Magid DJ, Fihn SD, Larsen GC, et al. Incidence of death and acute myocardial infarction associated with stopping clopidogrel after acute coronary syndrome. JAMA 2008;299:532e9. Alcocer F, Novak Z, Combs BR, Lowman B, Passman MA, Mujib M, et al. Dual antiplatelet therapy (clopidogrel and aspirin) is associated with increased all-cause mortality after carotid revascularization for asymptomatic carotid disease. J Vasc Surg 2014;59:950e5.
REFERENCES 1 Brott TG, Halperin JL, Abbara S, Bacharach JM, Barr JD, Bush RL, et al. 2011 ASA/ACCF/AHA/AANN/AANS/ACR/ASNR/CNS/SAIP/ SCAI/SIR/SNIS/SVM/SVS guideline on the management of patients with extracranial carotid and vertebral artery disease: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American Stroke Association,
P. De Rango Vascular and Endovascular Surgery, Hospital S. M., Misericordia, Loc. S. Andrea delle, Fratte, 06134 Perugia, Italy Email-address: [email protected]
EDITORIAL
Dual Antiplatelet Therapy after Carotid Stenting: Lessons from ‘Big Brother’ Although it is accepted that carotid artery stent (CAS) patients should receive dual antiplatelet therapy (currently aspirin and clopidogrel) throughout the perioperative period in order to minimize the risks of acute stent thrombosis/embolization secondary to platelet activation triggered by intimal injury and/or the insertion of a foreign body (stent), there is no evidence-based consensus as to how long dual antiplatelet therapy (DAPT) should continue thereafter. International guidelines provide inconsistent advice regarding the optimal duration of dual antiplatelet therapy after CAS, ranging from “at least 30 days” (American Heart Association [AHA], Society for Vascular Surgery [SVS]1,2 to 3 months [European Society of Vascular Surgery]).3 None of the guidelines recommended long-term or lifelong dual antiplatelet therapy after CAS; all recommended life-long aspirin therapy following discontinuation of clopidogrel, and there were no recommendations regarding the role of the newer generation antiplatelet agents.1,4 It is, however, not unusual for the findings of cardiology based research to be extrapolated into other cardiovascular interventional practices whenever data are “missing”. The decision to recommend that CAS be undertaken using periprocedural dual antiplatelet therapy was, for example, the product of research following coronary stenting, which showed lower rates of in-stent thrombosis and acute coronary events than antiplatelet monotherapy. Thereafter, remaining debate concerned for how long DAPT should continue. For some time now, it has been advised that patients undergoing coronary interventions using drugeluting stents (DESs) should maintain DAPT for 6e12 months. However, the 2014 ESC guidelines on myocardial revascularization recommend that DAPT should stop after 6 months in patients receiving the latest generation DESs (possibly even at 3 months) on the basis that bleeding risks increase if DAPT extends to 12 months and because of a lack of evidence regarding any potential benefit in terms of preventing late ischemic myocardial complications.5 However, notwithstanding the fact that the 2014 ESC guidelines now recommend a shorter duration of DAPT, some of our cardiology colleagues are back to debating about whether DAPT should be extended beyond 12 months.6 The Dual Antiplatelet Therapy (DAPT) study was a large international, multicenter, randomized trial whose goal was 1078-5884/$ e see front matter Ó 2015 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejvs.2015.02.004
to determine the benefits/risks of extending dual antiplatelet therapy beyond 12 months in patients who had received coronary stents.6 In this study, 9961 patients who had completed 12 months of dual antiplatelet therapy after implantation of a DES were randomly assigned to an additional 18 months of thienopyridine therapy (clopidogrel or prasugrel) versus placebo. All patients continued to take aspirin. The main finding was that extending clopidogrel or prasugrel to 30 months significantly reduced the relative risk of suffering a major adverse cardiovascular and/or cerebrovascular event by 29% (absolute risk 4.3% vs. 5.9%, p < .001). The overall reduction in major cardiovascular events at 30 months was more evident in patients taking prasugrel. Of relevance, the reduction in major vascular events was not strictly related to the prevention of coronary DES thrombosis. Continued thienopyridine therapy was associated with both a lower cumulative incidence of stent thrombosis (0.4% vs. 1.4%; hazard ratio 0.29; 95% CI 0.17e 0.48; p < .001) and of myocardial infarction than with placebo (2.1% vs. 4.1%; hazard ratio 0.47; 95% CI 0.37 to 0.61; p < .001). Myocardial infarctions that were not related to stent thrombosis (1.8% vs. 2.9%; hazard ratio 0.59; p < .001) accounted for 55% of the events, suggesting a beneficial effect for prolonged DAPT outside the coronary stented area. In addition, and of greater practical relevance regarding the debate in CAS patients, the DAPT trial included 1687 patients who had a bare-metal stent inserted into their coronary circulation. In these patients, a subgroup analysis showed that continued thienopyridine therapy may confer a relative risk reduction of 51% in late stent thrombosis at 30 months (AHA oral communication). What about adverse events related to prolonged dual antiplatelet therapy? Perhaps not unsurprisingly, the incidence of moderate/severe bleeding was increased in patients randomized to extended thienopyridine treatment (2.5% vs. 1.6%, p ¼ .001).6 However, an unexpected finding (albeit with borderline statistical significance) was an increase in late mortality in patients randomized to extended thienopyridine therapy (2.0% vs. 1.5%, hazard ratio 1.36, p ¼ .05) that may have been due, at least in part, to an imbalance in pre-existing cancer (and subsequently in cancer-related mortality) in patients randomized to extended clopidogrel/prasugrel (0.62% vs. 0.28%, p ¼ .02). This increase in late mortality was not attributable to excess cardiovascular, hemorrhagic or trauma-related events, and when cancer-related deaths were excluded from analysis there was no significant difference in late survival.
622
Subsequent data from post-marketing studies that had contributed to the DAPT trial also showed an alarming rebound in cardiovascular events in the first 3 months after stopping clopidogrel/prasugrel at either 12 or 30 months.6 Previous studies have also shown a possible causal relationship between the recovery of platelet reactivity following cessation of thienopyridine therapy and a susceptibility towards increased cardiovascular events.7 At first sight, therefore, the combination of reduced late cardiovascular events, counterbalanced with an increase in (non-cardiovascular) mortality could be interpreted as a challenge to any benefit from extending dual antiplatelet therapy. It has also been reported that patients with asymptomatic carotid disease who were revascularized and then received long-term dual antiplatelet therapy had reduced survival (47% vs. 40% at 5 years of median followup).8 Accordingly, the risk of increased thrombotic events following discontinuation of DAPT raises the recurring question of whether it is ever safe to discontinue dual antiplatelet therapy in carotid stented patients. It is hard, therefore, to know just how much of the DAPT study data can be extrapolated to help manage CAS patients. However, the observation that patients with baremetal coronary stents who were randomized to extended thienopyridine therapy suffered fewer major cardiovascular events suggests that the mid-term benefit conferred by DAPT may not be exclusive to DESs. It remains to be seen whether a similar phenomenon happens following cessation of dual antiplatelet therapy in CAS patients at 3 months (or whenever it is stopped). Few non-randomized studies have reported outcome data at this time-point and none of the randomized trials has reported whether the time line for recurrent stroke is higher in the first few weeks/months after cessation of dual antiplatelet therapy. This is surely a question that could be answered relatively easily and which could have a major impact in determining whether CAS patients face a similarly high risk of rebound thromboembolic stroke following cessation of DAPT. If they do not, then it would seem reasonable to stop DAPT after 3 months (as is current practice). If there is, however, evidence of an increased risk of stroke following cessation of DAPT, currently accepted guidelines of practice may need to be changed.
Editorial
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American Association of Neuroscience Nurses, American Association of Neurological Surgeons, American College of Radiology, American Society of Neuroradiology, Congress of Neurological Surgeons, Society of Atherosclerosis Imaging and Prevention, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of NeuroInterventional Surgery, Society for Vascular Medicine, and Society for Vascular Surgery. Developed in collaboration with the American Academy of Neurology and Society of Cardiovascular Computed Tomography Catheter Cardiovasc Interv 2013;81:E76e123. Ricotta JJ, Aburahma A, Ascher E, Eskandari M, Faries P, Lal BK. Society for vascular surgery. Updated society for vascular surgery guidelines for management of extracranial carotid disease. J Vasc Surg 2011;54:e1e31. Liapis CD, Bell PR, Mikhailidis D, Sivenius J, Nicolaides A, Fernandes e Fernandes J, et al. ESVS Guidelines Collaborators. ESVS guidelines. Invasive treatment for carotid stenosis: indications, techniques. Eur J Vasc Endovasc Surg 2009;37(Suppl. 4):1e19. European Stroke Organisation, Tendera M, Aboyans V, Bartelink ML, Baumgartner I, Clément D, et al. ESC Committee for Practice Guidelines. ESC guidelines on the diagnosis and treatment of peripheral artery diseases: document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteries: the task force on the diagnosis and treatment of peripheral artery diseases of the European Society of Cardiology (ESC). Eur Heart J 2011;32:2851e906. Windecker S, Alfonso F, Collet J-P, Cremer J, Falk V, Filippatos G, et al. Authors/Task Force Members. 2014 ESC/EACTS guidelines on myocardial revascularization: the task force on myocardial revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J 2014;35:2541e619. Mauri L, Kereiakes DJ, Yeh RW, Driscoll-Shempp P, Cutlip DE, Steg PG, et al. DAPT Study Investigators. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. N Engl J Med 2014;371:2155e66. Ho PM, Peterson ED, Wang L, Magid DJ, Fihn SD, Larsen GC, et al. Incidence of death and acute myocardial infarction associated with stopping clopidogrel after acute coronary syndrome. JAMA 2008;299:532e9. Alcocer F, Novak Z, Combs BR, Lowman B, Passman MA, Mujib M, et al. Dual antiplatelet therapy (clopidogrel and aspirin) is associated with increased all-cause mortality after carotid revascularization for asymptomatic carotid disease. J Vasc Surg 2014;59:950e5.
REFERENCES 1 Brott TG, Halperin JL, Abbara S, Bacharach JM, Barr JD, Bush RL, et al. 2011 ASA/ACCF/AHA/AANN/AANS/ACR/ASNR/CNS/SAIP/ SCAI/SIR/SNIS/SVM/SVS guideline on the management of patients with extracranial carotid and vertebral artery disease: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American Stroke Association,
P. De Rango Vascular and Endovascular Surgery, Hospital S. M., Misericordia, Loc. S. Andrea delle, Fratte, 06134 Perugia, Italy Email-address: [email protected]
