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Strategies to Reduce Bleeding Among Patients with Ischemic Heart Disease Treated with Antiplatelet Therapies
Strategies to Reduce Bleeding Among Patients with Ischemic Heart Disease Treated with Antiplatelet Therapies Sunil V. Rao, MD* Antiplatelet therapy is the cornerstone of management in acute coronary syndromes (ACS) and percutaneous coronary intervention. Combination therapy with aspirin and clopidogrel reduces the risk of death, myocardial infarction, or stroke in ACS but increases the risk of major bleeding, which studies indicate is 1%– 4% higher when clopidogrel is added to aspirin. Given the association between bleeding and adverse outcomes, minimizing bleeding risk is a clinical priority. This review outlines strategies to reduce both acute and chronic bleeding risk with aspirin and clopidogrel and focuses on dosing of concomitant therapies, vascular access techniques, and mitigating the bleeding risk associated with coronary artery bypass grafting surgery. © 2009 Elsevier Inc. All rights reserved. (Am J Cardiol 2009;104[suppl]:60C– 63C)
Antiplatelet therapy is the cornerstone of management in acute coronary syndromes (ACS) and percutaneous coronary intervention (PCI).1,2 Combining aspirin with a thienopyridine (dual antiplatelet therapy) has been shown to reduce the incidence of death, myocardial infarction (MI), or stroke in ACS and protects against recurrent ischemic events, including stent thrombosis in PCI. However, these events are reduced at the cost of an increase in the risk of bleeding, which studies indicate is 1%– 4% higher when clopidogrel is added to aspirin.3,4 Bleeding, in turn, is associated with an increased risk of morbidity and mortality.5 Given this association between hemorrhagic complications and outcomes, reducing the risk for bleeding has taken on clinical significance. The purpose of this review is to outline strategies to reduce the acute- and long-term bleeding risk associated with oral antiplatelet therapies.
Strategies to Reduce Bleeding Risk Associated with Aspirin Aspirin therapy reduces vascular events (death, MI, stroke) across a broad population of patients.6 This effect is balanced by an increase in the risk of extracranial hemorrhage over placebo, primarily manifesting as gastrointestinal bleeding. Studies indicate that gastrointestinal bleeding risk is related to aspirin dose, with higher doses having a greater association with hemorrhage.6,7 In contrast, regardless of whether aspirin is combined with other antiplatelet therapies, such as dipyridamole or clopidogrel, there does not seem to be an association between higher aspirin doses and greater efficacy.8,9 Therefore, Duke Clinical Research Institute, Durham, North Carolina, USA. Statement of author disclosure: Please see the Author Disclosures section at the end of this article. *Address for reprints: Sunil V. Rao, MD, 508 Fulton Street (111A), Durham, North Carolina 27705. E-mail address: [email protected]. 0002-9149/09/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2009.06.024
until randomized data are available,10 the most appropriate dosing strategy for aspirin appears to be ⬍100 mg to maximize efficacy and minimize bleeding risk.
Strategies to Minimize Bleeding Risk with Dual Antiplatelet Therapy The combination of aspirin and the thienopyridine clopidogrel is recommended by the guidelines for both acute and chronic therapy in ACS.1 This is based on the large randomized Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial that randomized 12,562 patients with non–ST-segment elevation ACS to aspirin alone or aspirin plus clopidogrel.3 Clopidogrel was initiated with a 300-mg load followed by 75 mg/day; the aspirin dose was left to the discretion of the investigator. Dual antiplatelet therapy for 3–12 months resulted in a 20% relative risk reduction in the composite end point of death, MI, or stroke. Major bleeding (defined as substantially disabling bleeding), intraocular bleeding leading to the loss of vision, or bleeding necessitating the transfusion of ⱖ2 units of blood was higher among patients assigned to aspirin plus clopidogrel (3.7% vs 2.7%, p ⫽ 0.001). Bleeding risk was also higher among patients treated with dual antiplatelet therapy who underwent coronary artery bypass grafting surgery (CABG) unless the clopidogrel was withheld for ⱖ5 days before CABG.11 The results of the CURE study underscore 2 issues related to bleeding complications with dual antiplatelet therapy: the timing of bleeding risk (acute vs chronic), and the risk of bleeding related to other invasive procedures. Both issues have important implications for managing bleeding risk in patients who are treated with aspirin and another antiplatelet agent. Acute versus chronic bleeding risk: Current treatment guidelines recommend that antiplatelet therapy be given www.AJConline.org
Rao/Strategies to Reduce Bleeding Among Patients with Ischemic Heart Disease
early (ie, before coronary angiography) in ACS because this is the period of highest risk for recurrent MI or death.1,12 Oral antiplatelet therapy with clopidogrel is administered with a loading dose to expedite the therapeutic effect. In contrast to parenteral antithrombotics, chronic treatment with aspirin and clopidogrel is also recommended in patients with ACS to reduce the risk of recurrent ischemic events.1 Therefore, there are 2 periods of risk for bleeding: acute (in-hospital) and chronic (during maintenance). The challenge with assessing the risk of acute bleeding with oral antiplatelet therapy is that there are significant confounders, both pharmacologic and procedural. For example, current guidelines recommend the use of intravenous glycoprotein IIb/IIIa inhibitors along with antithrombin therapy for patients with ACS with high-risk features, such as congestive heart failure or troponin elevation.1,12 This combination of antithrombotic medications coupled with invasive procedures, such as PCI, can account for in-hospital bleeding,5,13 whereas the contribution of any individual medication may be impossible to discern. Given this limitation, data from the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial indicated that the bulk of the bleeding risk is “front loaded” in patients with a history of vascular disease without ACS who are treated with aspirin and clopidogrel, with events becoming manifest in the first 60 –135 days of therapy.14 After this period, the risk of bleeding was similar between patients treated with aspirin alone and those treated with aspirin plus clopidogrel. It is not clear if a similar pattern of risk would be present in ACS, but intuitively, this would seem to be the case because of the natural attrition of patients who develop bleeding and discontinue antiplatelet therapy,15 leaving a balance of patients able to tolerate the drugs. Newer antiplatelet therapies do not seem to follow this pattern of early risk. Prasugrel, a new thienopyridine, provides greater inhibition of platelet activation than clopidogrel, and when combined with aspirin in patients with ACS undergoing PCI, it provides greater protection from death, MI, or stroke compared with the combination of aspirin and clopidogrel.16 It is also associated with a greater risk for non-CABG–related Thrombolysis in Myocardial Infarction (TIMI) major bleeding, including fatal and nonfatal events. In the Trial to Assess Improvement in Therapeutic Outcomes By Optimizing Platelet Inhibition with Prasugrel–TIMI 38 (TRITON-TIMI 38), the bleeding risk with prasugrel appeared after 30 days of therapy; within the first 30 days, there appeared to be no difference in the incidence of TIMI major bleeding between aspirin plus prasugrel or aspirin plus clopidogrel. There may be several reasons for this finding, including different patient populations (all patients underwent PCI in the TRITON-TIMI 38 trial), different bleeding definitions, and different concomitant therapies and management strategies. Because of the issues outlined above, reducing the risk of acute bleeding focuses on managing concomitant antiplate-
61C
let and anticoagulant medications, as well as minimizing the risk of bleeding related to invasive procedures. This includes appropriate dosing of glycoprotein IIb/IIIa inhibitors and antithrombin agents17 or using agents that are associated with a lower bleeding risk, such as fondaparinux18 or bivalirudin.19 Addressing the bleeding risk related to CABG is summarized below. The bleeding risk related to cardiac catheterization and PCI can be accomplished by implementing the pharmacologic strategies outlined, as well as with careful attention to vascular access20 or by using the radial artery approach.21 Reducing the risk of chronic bleeding is related to concomitant antiplatelet and anticoagulant agents. As mentioned above, there are observational data suggesting that doses of aspirin ⬎100 mg are associated with an increased risk of bleeding without any greater benefit as compared with doses ⬍100 mg.7 This is also true when aspirin is combined with clopidogrel. A post hoc analysis of the CURE trial demonstrated that higher doses of aspirin did not accentuate the benefit of dual antiplatelet therapy but did increase the bleeding risk.9 Therefore, it seems prudent to use doses of aspirin ⬍100 mg in patients who require therapy with aspirin and clopidogrel. It is unknown if lowering the aspirin dose would mitigate the bleeding risk to a similar degree when combined with a more powerful platelet inhibitor, such as prasugrel. Patients who require therapy with warfarin pose a particular challenge when dual antiplatelet therapy is indicated. The bleeding risk is significantly higher when warfarin is added to aspirin and clopidogrel.22,23 Although this risk appears to be independent of aspirin dose,23 the most prudent strategy in this setting may be to maintain lower therapeutic levels of the international normalized ratio and use a lower dose of aspirin. Clinical trials addressing this population are necessary to guide clinical practice. Reducing bleeding risk associated with CABG: As mentioned earlier, invasive procedures carry a risk for bleeding that may be exacerbated in the presence of antithrombotic therapy. Data from the CURE trial demonstrate that the risk of major bleeding related to CABG was higher among patients treated with aspirin and clopidogrel compared with those treated with aspirin alone if CABG was performed within 5 days of the last dose of clopidogrel; discontinuing clopidogrel for ⱖ5 days before surgery mitigated this risk.11 The impact of this analysis on clinical practice has been to limit the uniform implementation of early clopidogrel therapy in ACS because of concerns over delaying CABG in the minority of patients who require surgical revascularization.13 Several relevant issues are worthy of note. First, the risk of CABG-related hemorrhage appears variable, with some observational studies demonstrating a risk24 and others showing no risk.13 Second, in the CURE study, there was no significant excess of life-threatening bleeding among patients treated with aspirin and clopidogrel who underwent CABG; the therapeutic benefit of clopidogrel (ie,
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The American Journal of Cardiology (www.AJConline.org) Vol 104 (5A) September 7, 2009
reduction in death, MI, or stroke) was manifest early— before CABG— even among patients in whom clopidogrel was discontinued to prepare for CABG. Third, patients assigned to the aspirin plus clopidogrel strategy who underwent CABG in the CURE trial had a 19% relative risk reduction in the incidence of death, MI, or stroke at 1 year.11 Taken together, these data indicate that (1) early therapy with clopidogrel is beneficial in ACS, regardless of the revascularization strategy; (2) the benefit of clopidogrel in patients who require CABG is manifest before surgery is performed; and (3) the CABG-related bleeding risk is likely higher compared with aspirin alone if the surgery is performed within 5 days of withholding clopidogrel. Therefore, to minimize bleeding risk and to maximize benefit in ACS, implementation of guidelines-recommended therapy1 is important: clopidogrel should be administered early, and if CABG is necessary, clopidogrel should be withheld for 5–7 days. Most importantly, clopidogrel should be restarted after CABG, and therapy should be maintained for ⱖ1 year. The risk of CABG-related bleeding may be much higher with prasugrel because of its greater antiplatelet effect. Very few patients underwent CABG in the TRITON-TIMI 38 trial because it was specifically focused on patients undergoing PCI. However, among the 30 patients who did undergo CABG, the rate of CABG-related TIMI major bleeding was significantly higher among patients treated with aspirin and prasugrel compared with those treated with aspirin alone.16 It is not known whether withholding prasugrel before CABG would reduce the risk of bleeding. Moreover, it is unknown how long before surgery prasugrel would need to be discontinued to minimize surgery-related hemorrhagic complications.
Conclusion Antiplatelet therapy is a fundamental part of the treatment of acute ischemic heart disease but carries a risk for bleeding. This risk is compounded because antithrombotic medications are used in combination. Recent studies indicate that bleeding is associated with adverse short- and longterm outcomes; therefore, reducing bleeding risk is a clinical priority. With respect to oral antiplatelet therapy, bleeding risk is manifested both acutely and chronically. Strategies to maximize efficacy and minimize the bleeding risk associated with clopidogrel include (1) lowering the dose of aspirin, regardless of thienopyridine use; (2) appropriately dosing concomitant antithrombin and parenteral antiplatelet agents; (3) using vascular access strategies that minimize access site bleeding; and (4) discontinuing clopidogrel therapy for several days before CABG. Whether these strategies will minimize the bleeding risk associated with new antiplatelet agents is unknown but should be the focus of future investigations.
Author Disclosures The author who contributed to this article has disclosed the following industry relationships. Sunil V. Rao, MD, receives research funding from Momenta Pharmaceuticals, Portola Pharmaceuticals, Cordis Corporation; and receives honoraria for consulting or speaking for sanofi-aventis, Bristol Myers Squibb, and The Medicines Company. 1. Anderson JL, Adams CD, Antman EM, Bridges CR, Califf RM, Casey DE Jr, Chavey WE II, Fesmire FM, Hochman JS, Levin TN, et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non ST-Elevation Myocardial Infarction): developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons: endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. Circulation 2007;116:e148 –304. 2. Grines CL, Bonow RO, Casey DE Jr, Gardner TJ, Lockhart PB, Moliterno DJ, O’Gara P, Whitlow P. Prevention of premature discontinuation of dual antiplatelet therapy in patients with coronary artery stents: a science advisory from the American Heart Association, American College of Cardiology, Society for Cardiovascular Angiography and Interventions, American College of Surgeons, and American Dental Association, with representation from the American College of Physicians. Circulation 2007;115:813– 818. 3. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345:494 –502. 4. Leon MB, Baim DS, Popma JJ, Gordon PC, Cutlip DE, Ho KK, Giambartolomei A, Diver DJ, Lasorda DM, Williams DO, Pocock SJ, Kuntz RE, for the Stent Anticoagulation Restenosis Study Investigators. A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting. N Engl J Med 1998;339:1665–1671. 5. Rao SV, Eikelboom JA, Granger CB, Harrington RA, Califf RM, Bassand JP. Bleeding and blood transfusion issues in patients with non-ST-segment elevation acute coronary syndromes. Eur Heart J 2007;28:1193–1204. 6. Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002;324: 71– 86. 7. Campbell CL, Smyth S, Montalescot G, Steinhubl SR. Aspirin dose for the prevention of cardiovascular disease: a systematic review. JAMA 2007;297:2018 –2024. 8. Steinhubl SR, Bhatt DL, Brennan DM, Montalescot G, Hankey GJ, Eikelboom JW, Berger PB, Topol EJ. Aspirin to prevent cardiovascular disease: the association of aspirin dose and clopidogrel with thrombosis and bleeding. Ann Intern Med 2009;150:379 –386. 9. Peters RJ, Mehta SR, Fox KA, Zhao F, Lewis BS, Kopecky SL, Diaz R, Commerford PJ, Valentin V, Yusuf S. Effects of aspirin dose when used alone or in combination with clopidogrel in patients with acute coronary syndromes: observations from the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) study. Circulation 2003; 108:1682–1687. 10. Mehta SR, Bassand JP, Chrolavicius S, Diaz R, Fox KA, Granger CB, Jolly S, Rupprecht HJ, Widimsky P, Yusuf S. Design and rationale of CURRENT-OASIS 7: a randomized, 2 x 2 factorial trial evaluating optimal dosing strategies for clopidogrel and aspirin in patients with
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ST and non-ST-elevation acute coronary syndromes managed with an early invasive strategy. Am Heart J 2008;156:1080 –1088.e1. Fox KA, Mehta SR, Peters R, Zhao F, Lakkis N, Gersh BJ, Yusuf S. Benefits and risks of the combination of clopidogrel and aspirin in patients undergoing surgical revascularization for non-ST-elevation acute coronary syndrome: the Clopidogrel in Unstable angina to prevent Recurrent ischemic Events (CURE) Trial. Circulation 2004;110: 1202–1208. Bassand JP, Hamm CW, Ardissino D, Boersma E, Budaj A, Fernandez-Aviles F, Fox KA, Hasdai D, Ohman EM, Wallentin L, Wijns W. Guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes. Eur Heart J 2007;28:1598 –1660. Kim JH, Newby LK, Clare RM, Shaw LK, Lodge AJ, Smith PK, Jolicoeur EM, Rao SV, Becker RC, Mark DB, Granger CB. Clopidogrel use and bleeding after coronary artery bypass graft surgery. Am Heart J 2008;156:886 – 892. Bhatt DL, Flather MD, Hacke W, Berger PB, Black HR, Boden WE, Cacoub P, Cohen EA, Creager MA, Easton JD, et al. Patients with prior myocardial infarction, stroke, or symptomatic peripheral arterial disease in the CHARISMA trial. J Am Coll Cardiol 2007;49:1982– 1988. Wang TY, Xiao L, Alexander KP, Rao SV, Kosiborod MN, Rumsfeld JS, Spertus JA, Peterson ED. Antiplatelet therapy use after discharge among acute myocardial infarction patients with in-hospital bleeding. Circulation 2008;118:2139 –2145. Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, Neumann FJ, Ardissino D, De Servi S, Murphy SA, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007;357:2001–2015. Alexander KP, Chen AY, Roe MT, Newby LK, Gibson CM, AllenLaPointe NM, Pollack C, Gibler WB, Ohman EM, Peterson ED.
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Excess dosing of antiplatelet and antithrombin agents in the treatment of non-ST-segment elevation acute coronary syndromes. JAMA 2005;294:3108 –3116. The OASIS-5 Investigators. Comparison of fondaparinux and enoxaparin in acute coronary syndromes. N Engl J Med 2006;354:1464 – 1476. Stone GW, McLaurin BT, Cox DA, Bertrand ME, Lincoff AM, Moses JW, White HD, Pocock SJ, Ware JH, Feit F, et al. Bivalirudin for patients with acute coronary syndromes. N Engl J Med 2006;355: 2203–2216. Sherev DA, Shaw RE, Brent BN. Angiographic predictors of femoral access site complications: implication for planned percutaneous coronary intervention. Catheter Cardiovasc Interv 2005;65:196 –202. Rao SV, Ou FS, Wang TY, Roe MT, Brindis R, Rumsfeld JS, Peterson ED. Trends in the prevalence and outcomes of radial and femoral approaches to percutaneous coronary intervention: a report from the National Cardiovascular Data Registry. JACC Cardiovasc Interv 2008; 1:379 –386. Orford JL, Fasseas P, Melby S, Burger K, Steinhubl SR, Holmes DR, Berger PB. Safety and efficacy of aspirin, clopidogrel, and warfarin after coronary stent placement in patients with an indication for anticoagulation. Am Heart J 2004;147:463– 467. Khurram Z, Chou E, Minutello R, Bergman G, Parikh M, Naidu S, Wong SC, Hong MK. Combination therapy with aspirin, clopidogrel and warfarin following coronary stenting is associated with a significant risk of bleeding. J Invasive Cardiol 2006;18:162–164. Berger JS, Frye CB, Harshaw Q, Edwards FH, Steinhubl SR, Becker RC. Impact of clopidogrel in patients with acute coronary syndromes requiring coronary artery bypass surgery: a multicenter analysis. J Am Coll Cardiol 2008;52:1693–1701.
Antiplatelet therapy is the cornerstone of management in acute coronary syndromes (ACS) and percutaneous coronary intervention (PCI).1,2 Combining aspirin with a thienopyridine (dual antiplatelet therapy) has been shown to reduce the incidence of death, myocardial infarction (MI), or stroke in ACS and protects against recurrent ischemic events, including stent thrombosis in PCI. However, these events are reduced at the cost of an increase in the risk of bleeding, which studies indicate is 1%– 4% higher when clopidogrel is added to aspirin.3,4 Bleeding, in turn, is associated with an increased risk of morbidity and mortality.5 Given this association between hemorrhagic complications and outcomes, reducing the risk for bleeding has taken on clinical significance. The purpose of this review is to outline strategies to reduce the acute- and long-term bleeding risk associated with oral antiplatelet therapies.
Strategies to Reduce Bleeding Risk Associated with Aspirin Aspirin therapy reduces vascular events (death, MI, stroke) across a broad population of patients.6 This effect is balanced by an increase in the risk of extracranial hemorrhage over placebo, primarily manifesting as gastrointestinal bleeding. Studies indicate that gastrointestinal bleeding risk is related to aspirin dose, with higher doses having a greater association with hemorrhage.6,7 In contrast, regardless of whether aspirin is combined with other antiplatelet therapies, such as dipyridamole or clopidogrel, there does not seem to be an association between higher aspirin doses and greater efficacy.8,9 Therefore, Duke Clinical Research Institute, Durham, North Carolina, USA. Statement of author disclosure: Please see the Author Disclosures section at the end of this article. *Address for reprints: Sunil V. Rao, MD, 508 Fulton Street (111A), Durham, North Carolina 27705. E-mail address: [email protected]. 0002-9149/09/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2009.06.024
until randomized data are available,10 the most appropriate dosing strategy for aspirin appears to be ⬍100 mg to maximize efficacy and minimize bleeding risk.
Strategies to Minimize Bleeding Risk with Dual Antiplatelet Therapy The combination of aspirin and the thienopyridine clopidogrel is recommended by the guidelines for both acute and chronic therapy in ACS.1 This is based on the large randomized Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial that randomized 12,562 patients with non–ST-segment elevation ACS to aspirin alone or aspirin plus clopidogrel.3 Clopidogrel was initiated with a 300-mg load followed by 75 mg/day; the aspirin dose was left to the discretion of the investigator. Dual antiplatelet therapy for 3–12 months resulted in a 20% relative risk reduction in the composite end point of death, MI, or stroke. Major bleeding (defined as substantially disabling bleeding), intraocular bleeding leading to the loss of vision, or bleeding necessitating the transfusion of ⱖ2 units of blood was higher among patients assigned to aspirin plus clopidogrel (3.7% vs 2.7%, p ⫽ 0.001). Bleeding risk was also higher among patients treated with dual antiplatelet therapy who underwent coronary artery bypass grafting surgery (CABG) unless the clopidogrel was withheld for ⱖ5 days before CABG.11 The results of the CURE study underscore 2 issues related to bleeding complications with dual antiplatelet therapy: the timing of bleeding risk (acute vs chronic), and the risk of bleeding related to other invasive procedures. Both issues have important implications for managing bleeding risk in patients who are treated with aspirin and another antiplatelet agent. Acute versus chronic bleeding risk: Current treatment guidelines recommend that antiplatelet therapy be given www.AJConline.org
Rao/Strategies to Reduce Bleeding Among Patients with Ischemic Heart Disease
early (ie, before coronary angiography) in ACS because this is the period of highest risk for recurrent MI or death.1,12 Oral antiplatelet therapy with clopidogrel is administered with a loading dose to expedite the therapeutic effect. In contrast to parenteral antithrombotics, chronic treatment with aspirin and clopidogrel is also recommended in patients with ACS to reduce the risk of recurrent ischemic events.1 Therefore, there are 2 periods of risk for bleeding: acute (in-hospital) and chronic (during maintenance). The challenge with assessing the risk of acute bleeding with oral antiplatelet therapy is that there are significant confounders, both pharmacologic and procedural. For example, current guidelines recommend the use of intravenous glycoprotein IIb/IIIa inhibitors along with antithrombin therapy for patients with ACS with high-risk features, such as congestive heart failure or troponin elevation.1,12 This combination of antithrombotic medications coupled with invasive procedures, such as PCI, can account for in-hospital bleeding,5,13 whereas the contribution of any individual medication may be impossible to discern. Given this limitation, data from the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial indicated that the bulk of the bleeding risk is “front loaded” in patients with a history of vascular disease without ACS who are treated with aspirin and clopidogrel, with events becoming manifest in the first 60 –135 days of therapy.14 After this period, the risk of bleeding was similar between patients treated with aspirin alone and those treated with aspirin plus clopidogrel. It is not clear if a similar pattern of risk would be present in ACS, but intuitively, this would seem to be the case because of the natural attrition of patients who develop bleeding and discontinue antiplatelet therapy,15 leaving a balance of patients able to tolerate the drugs. Newer antiplatelet therapies do not seem to follow this pattern of early risk. Prasugrel, a new thienopyridine, provides greater inhibition of platelet activation than clopidogrel, and when combined with aspirin in patients with ACS undergoing PCI, it provides greater protection from death, MI, or stroke compared with the combination of aspirin and clopidogrel.16 It is also associated with a greater risk for non-CABG–related Thrombolysis in Myocardial Infarction (TIMI) major bleeding, including fatal and nonfatal events. In the Trial to Assess Improvement in Therapeutic Outcomes By Optimizing Platelet Inhibition with Prasugrel–TIMI 38 (TRITON-TIMI 38), the bleeding risk with prasugrel appeared after 30 days of therapy; within the first 30 days, there appeared to be no difference in the incidence of TIMI major bleeding between aspirin plus prasugrel or aspirin plus clopidogrel. There may be several reasons for this finding, including different patient populations (all patients underwent PCI in the TRITON-TIMI 38 trial), different bleeding definitions, and different concomitant therapies and management strategies. Because of the issues outlined above, reducing the risk of acute bleeding focuses on managing concomitant antiplate-
61C
let and anticoagulant medications, as well as minimizing the risk of bleeding related to invasive procedures. This includes appropriate dosing of glycoprotein IIb/IIIa inhibitors and antithrombin agents17 or using agents that are associated with a lower bleeding risk, such as fondaparinux18 or bivalirudin.19 Addressing the bleeding risk related to CABG is summarized below. The bleeding risk related to cardiac catheterization and PCI can be accomplished by implementing the pharmacologic strategies outlined, as well as with careful attention to vascular access20 or by using the radial artery approach.21 Reducing the risk of chronic bleeding is related to concomitant antiplatelet and anticoagulant agents. As mentioned above, there are observational data suggesting that doses of aspirin ⬎100 mg are associated with an increased risk of bleeding without any greater benefit as compared with doses ⬍100 mg.7 This is also true when aspirin is combined with clopidogrel. A post hoc analysis of the CURE trial demonstrated that higher doses of aspirin did not accentuate the benefit of dual antiplatelet therapy but did increase the bleeding risk.9 Therefore, it seems prudent to use doses of aspirin ⬍100 mg in patients who require therapy with aspirin and clopidogrel. It is unknown if lowering the aspirin dose would mitigate the bleeding risk to a similar degree when combined with a more powerful platelet inhibitor, such as prasugrel. Patients who require therapy with warfarin pose a particular challenge when dual antiplatelet therapy is indicated. The bleeding risk is significantly higher when warfarin is added to aspirin and clopidogrel.22,23 Although this risk appears to be independent of aspirin dose,23 the most prudent strategy in this setting may be to maintain lower therapeutic levels of the international normalized ratio and use a lower dose of aspirin. Clinical trials addressing this population are necessary to guide clinical practice. Reducing bleeding risk associated with CABG: As mentioned earlier, invasive procedures carry a risk for bleeding that may be exacerbated in the presence of antithrombotic therapy. Data from the CURE trial demonstrate that the risk of major bleeding related to CABG was higher among patients treated with aspirin and clopidogrel compared with those treated with aspirin alone if CABG was performed within 5 days of the last dose of clopidogrel; discontinuing clopidogrel for ⱖ5 days before surgery mitigated this risk.11 The impact of this analysis on clinical practice has been to limit the uniform implementation of early clopidogrel therapy in ACS because of concerns over delaying CABG in the minority of patients who require surgical revascularization.13 Several relevant issues are worthy of note. First, the risk of CABG-related hemorrhage appears variable, with some observational studies demonstrating a risk24 and others showing no risk.13 Second, in the CURE study, there was no significant excess of life-threatening bleeding among patients treated with aspirin and clopidogrel who underwent CABG; the therapeutic benefit of clopidogrel (ie,
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The American Journal of Cardiology (www.AJConline.org) Vol 104 (5A) September 7, 2009
reduction in death, MI, or stroke) was manifest early— before CABG— even among patients in whom clopidogrel was discontinued to prepare for CABG. Third, patients assigned to the aspirin plus clopidogrel strategy who underwent CABG in the CURE trial had a 19% relative risk reduction in the incidence of death, MI, or stroke at 1 year.11 Taken together, these data indicate that (1) early therapy with clopidogrel is beneficial in ACS, regardless of the revascularization strategy; (2) the benefit of clopidogrel in patients who require CABG is manifest before surgery is performed; and (3) the CABG-related bleeding risk is likely higher compared with aspirin alone if the surgery is performed within 5 days of withholding clopidogrel. Therefore, to minimize bleeding risk and to maximize benefit in ACS, implementation of guidelines-recommended therapy1 is important: clopidogrel should be administered early, and if CABG is necessary, clopidogrel should be withheld for 5–7 days. Most importantly, clopidogrel should be restarted after CABG, and therapy should be maintained for ⱖ1 year. The risk of CABG-related bleeding may be much higher with prasugrel because of its greater antiplatelet effect. Very few patients underwent CABG in the TRITON-TIMI 38 trial because it was specifically focused on patients undergoing PCI. However, among the 30 patients who did undergo CABG, the rate of CABG-related TIMI major bleeding was significantly higher among patients treated with aspirin and prasugrel compared with those treated with aspirin alone.16 It is not known whether withholding prasugrel before CABG would reduce the risk of bleeding. Moreover, it is unknown how long before surgery prasugrel would need to be discontinued to minimize surgery-related hemorrhagic complications.
Conclusion Antiplatelet therapy is a fundamental part of the treatment of acute ischemic heart disease but carries a risk for bleeding. This risk is compounded because antithrombotic medications are used in combination. Recent studies indicate that bleeding is associated with adverse short- and longterm outcomes; therefore, reducing bleeding risk is a clinical priority. With respect to oral antiplatelet therapy, bleeding risk is manifested both acutely and chronically. Strategies to maximize efficacy and minimize the bleeding risk associated with clopidogrel include (1) lowering the dose of aspirin, regardless of thienopyridine use; (2) appropriately dosing concomitant antithrombin and parenteral antiplatelet agents; (3) using vascular access strategies that minimize access site bleeding; and (4) discontinuing clopidogrel therapy for several days before CABG. Whether these strategies will minimize the bleeding risk associated with new antiplatelet agents is unknown but should be the focus of future investigations.
Author Disclosures The author who contributed to this article has disclosed the following industry relationships. Sunil V. Rao, MD, receives research funding from Momenta Pharmaceuticals, Portola Pharmaceuticals, Cordis Corporation; and receives honoraria for consulting or speaking for sanofi-aventis, Bristol Myers Squibb, and The Medicines Company. 1. Anderson JL, Adams CD, Antman EM, Bridges CR, Califf RM, Casey DE Jr, Chavey WE II, Fesmire FM, Hochman JS, Levin TN, et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non ST-Elevation Myocardial Infarction): developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons: endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. Circulation 2007;116:e148 –304. 2. Grines CL, Bonow RO, Casey DE Jr, Gardner TJ, Lockhart PB, Moliterno DJ, O’Gara P, Whitlow P. Prevention of premature discontinuation of dual antiplatelet therapy in patients with coronary artery stents: a science advisory from the American Heart Association, American College of Cardiology, Society for Cardiovascular Angiography and Interventions, American College of Surgeons, and American Dental Association, with representation from the American College of Physicians. Circulation 2007;115:813– 818. 3. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345:494 –502. 4. Leon MB, Baim DS, Popma JJ, Gordon PC, Cutlip DE, Ho KK, Giambartolomei A, Diver DJ, Lasorda DM, Williams DO, Pocock SJ, Kuntz RE, for the Stent Anticoagulation Restenosis Study Investigators. A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting. N Engl J Med 1998;339:1665–1671. 5. Rao SV, Eikelboom JA, Granger CB, Harrington RA, Califf RM, Bassand JP. Bleeding and blood transfusion issues in patients with non-ST-segment elevation acute coronary syndromes. Eur Heart J 2007;28:1193–1204. 6. Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002;324: 71– 86. 7. Campbell CL, Smyth S, Montalescot G, Steinhubl SR. Aspirin dose for the prevention of cardiovascular disease: a systematic review. JAMA 2007;297:2018 –2024. 8. Steinhubl SR, Bhatt DL, Brennan DM, Montalescot G, Hankey GJ, Eikelboom JW, Berger PB, Topol EJ. Aspirin to prevent cardiovascular disease: the association of aspirin dose and clopidogrel with thrombosis and bleeding. Ann Intern Med 2009;150:379 –386. 9. Peters RJ, Mehta SR, Fox KA, Zhao F, Lewis BS, Kopecky SL, Diaz R, Commerford PJ, Valentin V, Yusuf S. Effects of aspirin dose when used alone or in combination with clopidogrel in patients with acute coronary syndromes: observations from the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) study. Circulation 2003; 108:1682–1687. 10. Mehta SR, Bassand JP, Chrolavicius S, Diaz R, Fox KA, Granger CB, Jolly S, Rupprecht HJ, Widimsky P, Yusuf S. Design and rationale of CURRENT-OASIS 7: a randomized, 2 x 2 factorial trial evaluating optimal dosing strategies for clopidogrel and aspirin in patients with
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