- Email: [email protected]
Clopidogrel for Cardiac Surgery
Con: Continuation of Aspirin/Clopidogrel for Cardiac Surgery Bruce D. Spiess, MD, FAHA
T
HE PRECEDING PRO ARTICLE by van der Linden contains a wonderful review of the action of aspirin and clopidogrel. Platelets are all important for normal hemostasis as well as the formation of an intraluminal thrombosis from acute coronary syndrome (ACS). Indeed, platelets are to a great degree responsible for the inflammatory and long-term growth of atherosclerotic plaque.1,2 These cells (platelets) are complex and very active. They interact with the microenvironment of the blood vessel, shear forces, endothelium, and the surrounding tissues (tissue factor, collagen, and thrombin).2,3 Metabolic activity is maintained within them, through adenosine triphosphate consumption.2 Platelets exhibit graded and appropriate responsiveness to a wide range of stimuli, leading to expression of more glycoproteins, cytoskeletal contraction, shape change, and discharge of stored messengers. They do not overreact or always fully activate when stimulated. Clinicians ( in cardiac anesthesia/surgery) tend to lump all of platelets’ many reactions into a poorly understood and widely unmonitored mystery state known as “platelet function.” It is often said in cardiac surgery/anesthesia that the biggest cause of bleeding in cardiac surgery is “platelet dysfunction.”4,5 By day 3 to 5 after surgery, the platelets are actually more hyperactive than before cardiac surgery.5 Aspirin irreversibly blocks the formation of thromboxane A2 in the platelet during its formation within the megakarocyte. Clopidogrel permanently blocks the adenosine diphosphate (ADP)-P2-Y12 receptor on the surface of a platelet. To reestablish “normal” platelets, these drugs must be eliminated and new platelets need to be released from the patient’s own bone marrow (5-7 days). Transfusion of platelet concentrates from the blood bank introduces a whole new set of problems and should not be considered a viable or acceptable option. The thromboxane and ADP stimuli of platelet activation are weak messengers. They are chemoattractant messages from platelets to other platelets leading to a “cross talk” within a platelet neotissue (platelet clump). These activators may be important for chemoattraction of white cells and for the platelet neotissue to develop enough self-activation to proceed to a thrombin burst.2,3 Thrombin is the most potent activator of clot formation and platelet stimulation.6 The thrombin burst is the single key event in the stabilization of a platelet nidus. The release of platelet thrombin through ADP and thromboxane stimulation is only 1 method of creating the necessary threshold for reaction. External thrombin can easily overcome, perhaps by a factor of 1,000 or more, the blockade of ADP or thromboxane. External thrombin comes from tissue factor activa-
From the VCURES Shock Center, Virginia Commonwealth University Medical Center, Richmond, VA. Address reprint requests to Bruce D. Spiess, MD, FAHA, VCURES Shock Center, Virginia Commonwealth University Medical Center, Box 980695, 1200 East Broad St, Richmond, VA 23298-0695. E-mail: [email protected] © 2007 Elsevier Inc. All rights reserved. 1053-0770/07/2104-0029$32.00/0 doi:10.1053/j.jvca.2007.04.018 Key words: clopidogrel, aspirin, bleeding, transfusion, coronary artery bypass graft surgery, outcomes 606
tion as well as surgical trauma.7 It may well be that the preservation of the PAR-1 thrombin receptor by aprotinin on the surface of platelets is why that drug is effective in partially reversing the bleeding tendency from clopidogrel and/or aspirin.8 Thrombin is what causes microvascular bleeding to cease during surgery, and, although ADP and thromboxane are important as modulators, they are not the lead actors in the play of clot formation. Both aspirin and clopidogrel exhibit a wide patient variability in response, and aspirin tolerance has been linked to early thrombosis.9-11 The variability in platelet function and the variability in drug response need to be understood. Today, clinicians still have little insight into what is the definition of “platelet dysfunction.” Cardiopulmonary bypass (CPB), including the use of high-dose unfractionated heparin, causes a complex coagulopathy characterized by near-universal stimulation of the fibrinolytic system, “platelet dysfunction,” and protein consumption.4 The fibrinolytic activation, although written as universal, is far from that. There exists large variability within the population.12 Some patients release large amounts of tissue plasminogen activator (TPA) from their endothelium, whereas others respond with barely a bump from baseline levels. Most research is done looking at mean values for a population or average amounts of TPA produced. Plasminogen activator inhibitor (PAI-1) is the controlling protein for TPA. Its levels after CPB are also highly variable and not linked to the magnitude of intravascular response of TPA.12 PAI-1 response is variable because of several polymorphisms (5G insertion/deletion and 4G polymorphism), and is enhanced by cytokine production or exogenous cytokine administration (blood transfusion).13,14 The fibrinolytic response of humans to CPB leads to platelet inhibition through downregulation of some of the surface glycoproteins (GP-1B and possibly GPIIB/IIIA). The overall activity of platelets to stimuli, fibrinogen concentration, prothrombin, PAI-1, TPA, and a number of the cytokines are all determined through genetics and polymorphisms. The “wild type” (average for the population) might well be a midrange of platelet activity or responsiveness, whereas those individuals who display very large outpourings of either TPA or PAI-1 may possess at least one and possibly many polymorphisms. When considering that there are probably genetic variants for each of the proteins that the platelet uses to sense its environment as well as each of the coagulation proteins, cytokines, and complement the complexity is enormous. There must certainly be genetic variability in both clopidogrel metabolism from the prodrug to active compound, and aspirin responsiveness. Genetic variability is the stuff of life. Clinicians are just now beginning to explore the molecular causes of many disease states and responses. There is no doubt that patients with coronary artery disease (CAD) and therefore ACS are as a population hypercoagulable.15 A number of genetic studies in large medical populations have noted associations among certain known single-nucleotide polymorphisms and myocardial infarction.16-20 TPA and PAI-1 and GP IIB/IIIA have been implicated. Related to CAD are a number of the cytokine polymorphisms.16-20 The point here is that when a population of
Journal of Cardiothoracic and Vascular Anesthesia, Vol 21, No 4 (August), 2007: pp 606-609
PRO AND CON
patients for coronary artery bypass graft (CABG) surgery is studied that population will contain any number of polymorphisms leading to hypercoagulability and proinflammation. The platelets of patients from this population may well be relatively hyperactive compared with a population without CAD. Monitoring for platelet ADP and aspirin effects is available with the Accumetrics (San Diego, CA) test (automated bedside aggregometry) and the Thromboelastogram (TEG, Haemoscope, Niles, IL; platelet mapping). Few institutions use these technologies for their diagnosis of bleeding risk after surgery, but those that do use them have (at least with TEG) shown a difference in transfusions.10,21 The forthcoming new guidelines for transfusion and blood conservation will recommend the widespread adoption of such technologies in efforts to decrease platelet and coagulation precursor transfusions. If such technologies were routinely used, it might be possible to understand more of the individual risk for either hypercoagulability and/or bleeding. Research into categorizing the risk analysis of platelet hyperactivity needs to be done for CABG patients using these or other future technologies. As a population, CABG patients tend to be more hypercoagulable than non-CAD populations. Should individuals not be treated? Does the population predominance of hypercoagulability therefore mean that all patients should be kept on aspirin/ clopidogrel through CABG surgery? The universality of the application of any single therapy alone distresses this author as a physician and a scientist. Is there any one drug or combination of drugs that should be given to everybody? Or is there such a combination of drugs that should be given to everyone with a single disease state? The subject is the source of headlines, at least for cardiology.22-26 The CURES study should be reviewed. On the surface, this was a large study, with 12,000 patients randomized to aspirin or aspirin and clopidogrel.22 The data are not so fantastic. A 20% drop in a combined endpoint was noted and heralded as the reason why everyone with ACS should get this regimen. The invocation of combined endpoints means that single endpoints alone (myocardial infarction, stroke, or others) were not significant alone. The 20% relative drop, although statistically significant, represented only a 2.1% real drop in overall combined event rate. Other factors in the CURE trial such as numbers of patients needing to be revascularized and those having a stroke or myocardial infarction before percutaneous coronary intervention (PCI) were again in favor (statistically) of the combination therapy. The absolute differences were all less than 5% (a very small absolute effect but one of which great things are made in the cardiology literature). These are real findings (despite small absolute gains) and perhaps important ones, but the effect of adding the 2 drugs is far from curative or profound. When patients from the CURE study went to CABG surgery, there were differences in transfusion and a trend toward worse life-threatening bleeding was present. The study was neither designed nor powered to answer any question regarding bleeding or outcome after cardiac surgery. Obviously, those patients going into CABG surgery in the CURE study were a population different from the rest of the CURE population. The author would suspect if genetic testing was done on the entire CURE population, those patients proceeding to CABG surgery would have been the patients with the many prothrombotic polymorphisms. These patients failed all medical therapy and cardiol-
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ogy interventions; therefore, there was a selection bias for severe hypercoagulability. These patients by preselection would have the least tendency to bleed. Nevertheless, there was a trend toward life-threatening bleeding in the patients who had combination therapy. There was no exploration of the link between transfusion and worse outcomes in cardiac surgery. In PCI, bleeding and transfusion are now thought to be perhaps the biggest risks of adverse outcome and death. How much contribution the combination therapy of clopidogrel and aspirin together has on this relationship is at present not completely known. Surgical studies have shown that patients who have the combination of clopidogrel and aspirin continued until CABG have a dramatic increased risk of bleeding, transfusion, prolonged hospital stay, and adverse outcomes.27-32 Some of these studies have shown a profound and convincing association; they are retrospective, but with interesting associations. From such retrospective studies, hypotheses are generated, not causeand-effect relationships. The evidence is substantial and gathering that transfusion of allogeneic blood products is associated with adverse events, prolonged hospitalization, increased perioperative infection, and death.33-40 In the only prospective trial of transfusion in seriously ill medicine patients, Hébert et al41 found those patients allowed to bleed to a lower transfusion trigger did at least as well and had a 25% lower hospital mortality rate than those patients more liberally transfused. This finding of worse outcome with transfusion was cause and effect. Investigations from CABG surgery have shown that those patients transfused perioperatively had twice the long-term mortality than those not transfused at all.33 Koch et al from the Cleveland Clinic have confirmed this earlier finding and shown that an increase in mortality over 10 months has a dose-dependent association to the number of units of red cells transfused.35 Those patients who received more blood transfusions had a progressively worse outcome, and, when confounders were taken into account by multivariate analysis, the associations continued. In similar work from the same institution, patients who received more blood had a worse ability to perform their activities of daily living.36 There is a dose-dependent relationship between transfusion and perioperative infection as well. The relationship between infection and transfusion appears to be independent of other confounding events. That relationship is not just in cardiac surgery but also is seen in orthopedics, neurosurgery, and trauma surgery as well. In 2001, a landmark study was published from the Northern New England consortium studying low hematocrit (Hct) on bypass and the inability to wean from CPB, need for inotropes, and balloon pump usage.42 They concluded that patients in whom Hct levels were encountered below 21% to 24% on CPB, adverse event rates at least doubled. In the last year, this same group has gone further and examined not only Hct on CPB as a relationship but the physician response to low Hct (ie, transfusion).40 They have shown that the association persists today between low Hct and adverse events, but that transfusion may have more of an association than low Hct alone. Therefore, if clopidogrel and aspirin in combination increase the need for transfusions, must these drugs be stopped before elective CABG surgery? The crux of the question is a tradeoff between the relative risk reductions for myocardial infarction
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and stroke because of continuance of the drug therapy versus the increased risk associated with bleeding and transfusion. What is being argued about here is speculation, and there are no prospective randomized data. What is the risk of thrombosis in a 2- to 3-day window of withdrawal from clopidogrel/aspirin? This small number of days is really all that is being talked about. The data from the cardiology studies showing increased risk of thrombosis are over months (not days), and, although withdrawal from these medications can cause rebound hypercoagulability, it is unknown when that becomes important. Can or should such a relative risk study be conducted ethically? In this author’s opinion, the evidence put forth in CURE is soft and cannot be directly transcribed to a CABG population. It appears unethical at this time to undertake such a study considering what is known about the 2 therapies’ relative risks. The differences in outcome associations in the CURE study are small (relative change 20% and real effect 2.1-4.4% improvement). The effects of transfusion on outcome are huge (50100% increased relative risk of mortality long-term, infection 150-550% increased). The decision to favor a 1% to 5% reduction in combined endpoints from a nonsurgical study in favor of ignoring the massive risks associated with transfusion seems irresponsible. If a patient bleeds after cardiac surgery and needs reoperation, the risks of morbidity and mortality skyrocket. The use of platelet transfusions also has risk. This single point alone has produced disagreement. Two studies showed that platelet transfusions were associated with an increased use of inotropes and pulmonary medications, a 500% increase in stroke rate, and a 700% increase in mortality.43,44 Contradicting evidence has been published from a single center in which there appeared by univariate analysis to be a larger association between platelet transfusions and adverse outcomes, but in multivariate analysis the independence of platelet transfusions was
not upheld.45 The platelet storage defect that occurs in the blood bank creates hypercoagulable platelets. If the use of clopidogrel and aspirin together means that more patients will be receiving platelet transfusions (a physician behavior response to the drug regimen), then are clinicians not just defeating the effects of the drug therapies? The studies examining platelet transfusions and associations with adverse outcomes differ. The earlier work had nonleukoreduced blood, and the later studies had only leukoreduced blood administered. If a patient bleeds after CABG surgery in which clopidogrel was used, the propensity for that patient to receive a platelet transfusion would be high. It seems to be counterproductive. No one knows what risk exists for ACS in the 5-day window of stopping clopidogrel. That should be prospectively studied. Those patients with truly unstable hypercoagulable states should be placed on intravenous heparin therapy in the intensive care unit. Almost all patients immediately after surgery, once the acute bleeding is stopped, resume antiplatelet therapy. What is truly needed is more research so that genetic risk profiling (yet a ways in the future) and platelet activity profiling can be done for each patient. Therapy should be targeted to the individual patient. Clinicians have the right tools available today in the Accumetrics and TEG devices. What clinicians lack seem to be the willingness to embrace these technologies, truly understand platelet physiology, and do the correct research. Universal prescribing, maintenance, or removal of this drug combination seem to be incorrect. Today, it appears clinicians should do all they can to avoid the use of allogeneic transfusion. Clopdiogrel/aspirin combination therapy probably contributes substantially to the risk of bleeding. There are no data to suggest that the risk of a potential myocardial infarction/ stroke or other thrombotic event in a 5-day window outweighs the quantified risks associated with transfusion and bleeding.
REFERENCES 1. Cicala C, Cirino G: Linkage between inflammation and coagulation: An update on the molecular basis of crosstalk. Life Sci 62:1817-1824, 1998 2. Rinder C: Platelet physiology: Cellular and protein interactions, in Spiess BD, Spence RK, Shander A, et al (eds): Baltimore, MD, Lippincott, Williams and Wilkins, 2006, pp 93-102 3. Kulkarni S, Dopheide SM, Yap SL, et al: A revised model of platelet aggregation. J Clin Invest 105:783-791, 2000 4. Body SC, Morse DS: Coagulation, transfusion and cardiac surgery, in Spiess BD, Spence RK, Shander A, (eds): Perioperative Transfusion Medicine. Baltimore, MD, Lippincott, Williams and Wilkins, 2006, pp 513-556 5. Kobzar G, Mardla V, Ratsep I, et al: Platelet activity before and after coronary artery bypass grafting. Platelets 17:289-291, 2006 6. Levy JH: The relationship between coagulation, inflammation and endothelium: Inflammation responds, in Spiess BD (ed): The Relationship Between Coagulation, Inflammation and Endothelium, SCA Monograph. Baltimore, MD, Lippincott, Williams and Wilkins, 2000, pp 91-104 7. Edmunds LH Jr, Colman RW: Thrombin during cardiopulmonary bypass. Ann Thorac Surg 82:2315-2322, 2006 8. van der Linden J, Lindvall G, Sartipy U: Aprotinin decreases postoperative bleeding and number of transfusions in patients on clopidogrel undergoing coronary artery bypass graft surgery: A doubleblind, placebo-controlled, randomized clinical trial. Circulation 112: I276-I280, 2005
9. Zimmermann N, Wenk A, Kim U, et al: Functional and biochemical evaluation of platelet aspirin resistance after coronary artery bypass surgery. Circulation 108:542-547, 2003 10. Poston R, Gu J, Manchio J, et al: Platelet function tests predict bleeding and thrombotic events after off-pump coronary artery bypass grafting. Eur J Cardiothorac Surg 27:584-591, 2005 11. Poston RS, Go J, Brown JM, et al: Endothelial injury and acquired aspirin resistance as promoters of regional thrombin formation and early vein graft failure after coronary artery bypass grafting. J Thorac Cardiovasc Surg 131:122-130, 2006 12. Chandler WL, Fitch JCK, Wall MH, et al: Individual variations in the fibrinolytic response during and after cardiopulmonary bypass. Thromb Haemost 74:1293-1297, 1995 13. Spiess BD, Chandler WL: Genetic basis of procoagulant and fibrinolytic perioperative adverse events. Best Pract Res Clin Anesthesiol 15:195-211, 2001 14. Fay WP, Parker AC, Condrey LR, et al: Human plasminogen activator inhibitor-I (PAI-I) deficiency: Characterization of a large kindred with a null mutation in the PAI-I gene. Blood 90:204-208, 1997 15. Zotz RB, Winkelman BR, Nauk M, et al: Polymorphism of platelet membrane IIIa: Human platelet antigen Ib (HPA-Ib/PIA2) is an inherited risk factor for premature myocardial infarction in coronary artery disease. Thromb Haemost 79:731-735, 1998
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16. Eriksson P, Kallin B, van’tHooft FM, et al: Allele-specific increase in basal transcription of the plasminogen activator inhibitor-I gene is associated with myocardial infarction. Proc Natl Acad Sci U S A 92:1851-1855, 1995 17. Williams MS, Ng’alla LS, Vaida D: Platelet function implications of glycoprotein Ib alpha polymorphisms in African Americans. Am J Hematol 82:15-22, 2007 18. Oda K, Tamaka N, Arait T, et al: Polymorphisms in pro- and anti-inflammatory cytokine genes and susceptibility to atherosclerosis: A pathological study of 1503 consecutive autopsy cases. Hum Mol Genet 16:592-599, 2007 19. Yamsaki Y, Katakani N, Sakamoto K, et al: Combination of multiple genetic risk factors is synergistically associated with carotid atherosclerosis in Japanese subjects with type 2 diabetes. Diabetes Care 29:2445-2451, 2006 20. Markus HS, Labrum R, Bevan S, et al: Genetic and acquired inflammatory conditions are synergistically associated with early carotid atherosclerosis. Stroke 37:2253-2259, 2006 21. Shore-Lesserson L, Manspeizer HE, DePero M, et al: Thromboelastography-guided transfusion algorithm reduces transfusion in complex cardiac surgery. Anesth Analg 88:312-319, 1999 22. Mehta SR, Yusuf S, Peters RJ, et al: Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: The PCI-CURE study. Lancet 358:527-533, 2001 23. Steinhubl SR, Berger PB, Mann JTR, et al: Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: A randomized controlled trial. JAMA 288:2411-2420, 2002 24. Yusuf S, Zhao F, Mehta SR, et al: Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 345:494-502, 2001 25. Chen ZM, Jiang LX, Chen YP, et al: Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: Randomised placebo-controlled trial. Lancet 366:1607-1621, 2005 26. Sabatine MS, Cannon CP, Gibson CM, et al: Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med 352:1179-1189, 2005 27. Ascione R, Ghosh A, Rogers CA, et al: In-hospital patients exposed to clopidogrel before coronary artery bypass graft surgery: A word of caution. Ann Thorac Surg 79:1210-1216, 2005 28. Chen L, Bracey AW, Radovancevic R, et al: Clopidogrel and bleeding in patients undergoing elective coronary artery bypass grafting. J Thorac Cardiovasc Surg 128:425-431, 2004 29. Kapetanakis EI, Medlam DA, Boyce SW, et al: Clopidogrel administration prior to coronary artery bypass grafting surgery: The cardiologist’s panacea or the surgeon’s headache? Eur Heart J 26: 576-583, 2005 30. Leong JY, Baker RA, Shah PJ, et al: Clopidogrel and bleeding after coronary artery bypass graft surgery. Ann Thorac Surg 80:928933, 2005
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31. Ray JG, Deniz S, Olivieri A, et al: Increased blood product use among coronary artery bypass patients prescribed preoperative aspirin and clopidogrel. BMC Cardiovasc Disord 3:3, 2003 32. Spiess BD: Choose one: Damned if you do/Damned if you don’t! Crit Care Med 33:1871-1874, 2005 33. Engoren MC, Habib RH, Zacharaias A, et al: Effect of blood transfusion on long-term survival after cardiac operation. Ann Thorac Surg 74:1180-1186, 2002 34. Habib RH, Zacharias A, Schwann TA, et al: Role of hemodilutional anemia and transfusion during cardiopulmonary bypass in renal injury after coronary revascularization: Implications on operative outcome. Crit Care Med 33:1749-1756, 2005 35. Koch CG, Khandwala F, Li L, et al: Persistent effect of red cell transfusion on health-related quality of life after cardiac surgery. Ann Thorac Surg 82:13-20, 2006 36. Banbury MK, Brizzio ME, Rajeswaran J, et al: Transfusion increases the risk of postoperative infection after cardiac surgery. J Am Coll Surg 202:131-138, 2006 37. Leal-Noval SR, Rincón-Ferrari MD, García-Curiel A, et al: Transfusion of blood components and postoperative infection in patients undergoing cardiac surgery. Chest 119:1461-1468, 2001 38. Basran S, Frumento RJ, Cohen A, et al: The association between duration of storage of transfused red blood cells and morbidity and mortality after reoperative cardiac surgery. Anesth Analg 103:15-20, 2006 39. Rawat S, et al: Impact of blood transfusion during cardiopulmonary bypass on operative outcomes in women undergoing coronary revascularization surgery. 10th International Congress of CV and Thoracic Anesthesia. Prague, Czech Republic, August 28, 2006 40. Surgenor SD, et al: Intraoperative red blood cell transfusion during coronary artery bypass graft surgery increases the risk of postoperative low-output heart failure. Circulation 114:43-48, 2006 (suppl) 41. Hébert PC, Wells G, Blajchman MA, et al: A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. N Engl J Med 340:409-417, 1999 42. DeFoe GR, Ross CS, Olmsted EM, et al: Lowest hematocrit on bypass and adverse outcomes associated with coronary artery bypass grafting: Northern New England Cardiovascular Disease Study group. Ann Thorac Surg 71:769-776, 2001 43. Spiess BD, Royston D, Levy JH, et al: Platelet transfusions during coronary artery bypass grafting surgery are associated with serious adverse outcomes. Transfusion 44:1143-1148, 2004 44. Mangano DT: Multicenter study of Perioperative Ischemia Research Group. Aspirin and mortality from coronary bypass surgery. N Engl J Med 34:1309-1317, 2002 45. Karkouti K, Wijeysundera DN, Yau TM, et al: Platelet transfusions are not associated with increased morbidity and mortality in cardiac surgery. Can J Anaesth 53:279-287, 2006
T
HE PRECEDING PRO ARTICLE by van der Linden contains a wonderful review of the action of aspirin and clopidogrel. Platelets are all important for normal hemostasis as well as the formation of an intraluminal thrombosis from acute coronary syndrome (ACS). Indeed, platelets are to a great degree responsible for the inflammatory and long-term growth of atherosclerotic plaque.1,2 These cells (platelets) are complex and very active. They interact with the microenvironment of the blood vessel, shear forces, endothelium, and the surrounding tissues (tissue factor, collagen, and thrombin).2,3 Metabolic activity is maintained within them, through adenosine triphosphate consumption.2 Platelets exhibit graded and appropriate responsiveness to a wide range of stimuli, leading to expression of more glycoproteins, cytoskeletal contraction, shape change, and discharge of stored messengers. They do not overreact or always fully activate when stimulated. Clinicians ( in cardiac anesthesia/surgery) tend to lump all of platelets’ many reactions into a poorly understood and widely unmonitored mystery state known as “platelet function.” It is often said in cardiac surgery/anesthesia that the biggest cause of bleeding in cardiac surgery is “platelet dysfunction.”4,5 By day 3 to 5 after surgery, the platelets are actually more hyperactive than before cardiac surgery.5 Aspirin irreversibly blocks the formation of thromboxane A2 in the platelet during its formation within the megakarocyte. Clopidogrel permanently blocks the adenosine diphosphate (ADP)-P2-Y12 receptor on the surface of a platelet. To reestablish “normal” platelets, these drugs must be eliminated and new platelets need to be released from the patient’s own bone marrow (5-7 days). Transfusion of platelet concentrates from the blood bank introduces a whole new set of problems and should not be considered a viable or acceptable option. The thromboxane and ADP stimuli of platelet activation are weak messengers. They are chemoattractant messages from platelets to other platelets leading to a “cross talk” within a platelet neotissue (platelet clump). These activators may be important for chemoattraction of white cells and for the platelet neotissue to develop enough self-activation to proceed to a thrombin burst.2,3 Thrombin is the most potent activator of clot formation and platelet stimulation.6 The thrombin burst is the single key event in the stabilization of a platelet nidus. The release of platelet thrombin through ADP and thromboxane stimulation is only 1 method of creating the necessary threshold for reaction. External thrombin can easily overcome, perhaps by a factor of 1,000 or more, the blockade of ADP or thromboxane. External thrombin comes from tissue factor activa-
From the VCURES Shock Center, Virginia Commonwealth University Medical Center, Richmond, VA. Address reprint requests to Bruce D. Spiess, MD, FAHA, VCURES Shock Center, Virginia Commonwealth University Medical Center, Box 980695, 1200 East Broad St, Richmond, VA 23298-0695. E-mail: [email protected] © 2007 Elsevier Inc. All rights reserved. 1053-0770/07/2104-0029$32.00/0 doi:10.1053/j.jvca.2007.04.018 Key words: clopidogrel, aspirin, bleeding, transfusion, coronary artery bypass graft surgery, outcomes 606
tion as well as surgical trauma.7 It may well be that the preservation of the PAR-1 thrombin receptor by aprotinin on the surface of platelets is why that drug is effective in partially reversing the bleeding tendency from clopidogrel and/or aspirin.8 Thrombin is what causes microvascular bleeding to cease during surgery, and, although ADP and thromboxane are important as modulators, they are not the lead actors in the play of clot formation. Both aspirin and clopidogrel exhibit a wide patient variability in response, and aspirin tolerance has been linked to early thrombosis.9-11 The variability in platelet function and the variability in drug response need to be understood. Today, clinicians still have little insight into what is the definition of “platelet dysfunction.” Cardiopulmonary bypass (CPB), including the use of high-dose unfractionated heparin, causes a complex coagulopathy characterized by near-universal stimulation of the fibrinolytic system, “platelet dysfunction,” and protein consumption.4 The fibrinolytic activation, although written as universal, is far from that. There exists large variability within the population.12 Some patients release large amounts of tissue plasminogen activator (TPA) from their endothelium, whereas others respond with barely a bump from baseline levels. Most research is done looking at mean values for a population or average amounts of TPA produced. Plasminogen activator inhibitor (PAI-1) is the controlling protein for TPA. Its levels after CPB are also highly variable and not linked to the magnitude of intravascular response of TPA.12 PAI-1 response is variable because of several polymorphisms (5G insertion/deletion and 4G polymorphism), and is enhanced by cytokine production or exogenous cytokine administration (blood transfusion).13,14 The fibrinolytic response of humans to CPB leads to platelet inhibition through downregulation of some of the surface glycoproteins (GP-1B and possibly GPIIB/IIIA). The overall activity of platelets to stimuli, fibrinogen concentration, prothrombin, PAI-1, TPA, and a number of the cytokines are all determined through genetics and polymorphisms. The “wild type” (average for the population) might well be a midrange of platelet activity or responsiveness, whereas those individuals who display very large outpourings of either TPA or PAI-1 may possess at least one and possibly many polymorphisms. When considering that there are probably genetic variants for each of the proteins that the platelet uses to sense its environment as well as each of the coagulation proteins, cytokines, and complement the complexity is enormous. There must certainly be genetic variability in both clopidogrel metabolism from the prodrug to active compound, and aspirin responsiveness. Genetic variability is the stuff of life. Clinicians are just now beginning to explore the molecular causes of many disease states and responses. There is no doubt that patients with coronary artery disease (CAD) and therefore ACS are as a population hypercoagulable.15 A number of genetic studies in large medical populations have noted associations among certain known single-nucleotide polymorphisms and myocardial infarction.16-20 TPA and PAI-1 and GP IIB/IIIA have been implicated. Related to CAD are a number of the cytokine polymorphisms.16-20 The point here is that when a population of
Journal of Cardiothoracic and Vascular Anesthesia, Vol 21, No 4 (August), 2007: pp 606-609
PRO AND CON
patients for coronary artery bypass graft (CABG) surgery is studied that population will contain any number of polymorphisms leading to hypercoagulability and proinflammation. The platelets of patients from this population may well be relatively hyperactive compared with a population without CAD. Monitoring for platelet ADP and aspirin effects is available with the Accumetrics (San Diego, CA) test (automated bedside aggregometry) and the Thromboelastogram (TEG, Haemoscope, Niles, IL; platelet mapping). Few institutions use these technologies for their diagnosis of bleeding risk after surgery, but those that do use them have (at least with TEG) shown a difference in transfusions.10,21 The forthcoming new guidelines for transfusion and blood conservation will recommend the widespread adoption of such technologies in efforts to decrease platelet and coagulation precursor transfusions. If such technologies were routinely used, it might be possible to understand more of the individual risk for either hypercoagulability and/or bleeding. Research into categorizing the risk analysis of platelet hyperactivity needs to be done for CABG patients using these or other future technologies. As a population, CABG patients tend to be more hypercoagulable than non-CAD populations. Should individuals not be treated? Does the population predominance of hypercoagulability therefore mean that all patients should be kept on aspirin/ clopidogrel through CABG surgery? The universality of the application of any single therapy alone distresses this author as a physician and a scientist. Is there any one drug or combination of drugs that should be given to everybody? Or is there such a combination of drugs that should be given to everyone with a single disease state? The subject is the source of headlines, at least for cardiology.22-26 The CURES study should be reviewed. On the surface, this was a large study, with 12,000 patients randomized to aspirin or aspirin and clopidogrel.22 The data are not so fantastic. A 20% drop in a combined endpoint was noted and heralded as the reason why everyone with ACS should get this regimen. The invocation of combined endpoints means that single endpoints alone (myocardial infarction, stroke, or others) were not significant alone. The 20% relative drop, although statistically significant, represented only a 2.1% real drop in overall combined event rate. Other factors in the CURE trial such as numbers of patients needing to be revascularized and those having a stroke or myocardial infarction before percutaneous coronary intervention (PCI) were again in favor (statistically) of the combination therapy. The absolute differences were all less than 5% (a very small absolute effect but one of which great things are made in the cardiology literature). These are real findings (despite small absolute gains) and perhaps important ones, but the effect of adding the 2 drugs is far from curative or profound. When patients from the CURE study went to CABG surgery, there were differences in transfusion and a trend toward worse life-threatening bleeding was present. The study was neither designed nor powered to answer any question regarding bleeding or outcome after cardiac surgery. Obviously, those patients going into CABG surgery in the CURE study were a population different from the rest of the CURE population. The author would suspect if genetic testing was done on the entire CURE population, those patients proceeding to CABG surgery would have been the patients with the many prothrombotic polymorphisms. These patients failed all medical therapy and cardiol-
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ogy interventions; therefore, there was a selection bias for severe hypercoagulability. These patients by preselection would have the least tendency to bleed. Nevertheless, there was a trend toward life-threatening bleeding in the patients who had combination therapy. There was no exploration of the link between transfusion and worse outcomes in cardiac surgery. In PCI, bleeding and transfusion are now thought to be perhaps the biggest risks of adverse outcome and death. How much contribution the combination therapy of clopidogrel and aspirin together has on this relationship is at present not completely known. Surgical studies have shown that patients who have the combination of clopidogrel and aspirin continued until CABG have a dramatic increased risk of bleeding, transfusion, prolonged hospital stay, and adverse outcomes.27-32 Some of these studies have shown a profound and convincing association; they are retrospective, but with interesting associations. From such retrospective studies, hypotheses are generated, not causeand-effect relationships. The evidence is substantial and gathering that transfusion of allogeneic blood products is associated with adverse events, prolonged hospitalization, increased perioperative infection, and death.33-40 In the only prospective trial of transfusion in seriously ill medicine patients, Hébert et al41 found those patients allowed to bleed to a lower transfusion trigger did at least as well and had a 25% lower hospital mortality rate than those patients more liberally transfused. This finding of worse outcome with transfusion was cause and effect. Investigations from CABG surgery have shown that those patients transfused perioperatively had twice the long-term mortality than those not transfused at all.33 Koch et al from the Cleveland Clinic have confirmed this earlier finding and shown that an increase in mortality over 10 months has a dose-dependent association to the number of units of red cells transfused.35 Those patients who received more blood transfusions had a progressively worse outcome, and, when confounders were taken into account by multivariate analysis, the associations continued. In similar work from the same institution, patients who received more blood had a worse ability to perform their activities of daily living.36 There is a dose-dependent relationship between transfusion and perioperative infection as well. The relationship between infection and transfusion appears to be independent of other confounding events. That relationship is not just in cardiac surgery but also is seen in orthopedics, neurosurgery, and trauma surgery as well. In 2001, a landmark study was published from the Northern New England consortium studying low hematocrit (Hct) on bypass and the inability to wean from CPB, need for inotropes, and balloon pump usage.42 They concluded that patients in whom Hct levels were encountered below 21% to 24% on CPB, adverse event rates at least doubled. In the last year, this same group has gone further and examined not only Hct on CPB as a relationship but the physician response to low Hct (ie, transfusion).40 They have shown that the association persists today between low Hct and adverse events, but that transfusion may have more of an association than low Hct alone. Therefore, if clopidogrel and aspirin in combination increase the need for transfusions, must these drugs be stopped before elective CABG surgery? The crux of the question is a tradeoff between the relative risk reductions for myocardial infarction
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and stroke because of continuance of the drug therapy versus the increased risk associated with bleeding and transfusion. What is being argued about here is speculation, and there are no prospective randomized data. What is the risk of thrombosis in a 2- to 3-day window of withdrawal from clopidogrel/aspirin? This small number of days is really all that is being talked about. The data from the cardiology studies showing increased risk of thrombosis are over months (not days), and, although withdrawal from these medications can cause rebound hypercoagulability, it is unknown when that becomes important. Can or should such a relative risk study be conducted ethically? In this author’s opinion, the evidence put forth in CURE is soft and cannot be directly transcribed to a CABG population. It appears unethical at this time to undertake such a study considering what is known about the 2 therapies’ relative risks. The differences in outcome associations in the CURE study are small (relative change 20% and real effect 2.1-4.4% improvement). The effects of transfusion on outcome are huge (50100% increased relative risk of mortality long-term, infection 150-550% increased). The decision to favor a 1% to 5% reduction in combined endpoints from a nonsurgical study in favor of ignoring the massive risks associated with transfusion seems irresponsible. If a patient bleeds after cardiac surgery and needs reoperation, the risks of morbidity and mortality skyrocket. The use of platelet transfusions also has risk. This single point alone has produced disagreement. Two studies showed that platelet transfusions were associated with an increased use of inotropes and pulmonary medications, a 500% increase in stroke rate, and a 700% increase in mortality.43,44 Contradicting evidence has been published from a single center in which there appeared by univariate analysis to be a larger association between platelet transfusions and adverse outcomes, but in multivariate analysis the independence of platelet transfusions was
not upheld.45 The platelet storage defect that occurs in the blood bank creates hypercoagulable platelets. If the use of clopidogrel and aspirin together means that more patients will be receiving platelet transfusions (a physician behavior response to the drug regimen), then are clinicians not just defeating the effects of the drug therapies? The studies examining platelet transfusions and associations with adverse outcomes differ. The earlier work had nonleukoreduced blood, and the later studies had only leukoreduced blood administered. If a patient bleeds after CABG surgery in which clopidogrel was used, the propensity for that patient to receive a platelet transfusion would be high. It seems to be counterproductive. No one knows what risk exists for ACS in the 5-day window of stopping clopidogrel. That should be prospectively studied. Those patients with truly unstable hypercoagulable states should be placed on intravenous heparin therapy in the intensive care unit. Almost all patients immediately after surgery, once the acute bleeding is stopped, resume antiplatelet therapy. What is truly needed is more research so that genetic risk profiling (yet a ways in the future) and platelet activity profiling can be done for each patient. Therapy should be targeted to the individual patient. Clinicians have the right tools available today in the Accumetrics and TEG devices. What clinicians lack seem to be the willingness to embrace these technologies, truly understand platelet physiology, and do the correct research. Universal prescribing, maintenance, or removal of this drug combination seem to be incorrect. Today, it appears clinicians should do all they can to avoid the use of allogeneic transfusion. Clopdiogrel/aspirin combination therapy probably contributes substantially to the risk of bleeding. There are no data to suggest that the risk of a potential myocardial infarction/ stroke or other thrombotic event in a 5-day window outweighs the quantified risks associated with transfusion and bleeding.
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