- Email: [email protected]
Update in Hematology: Heparin-Induced Thrombocytopenia and Bivalirudin
EXPERT REVIEW John G.T. Augoustides, MD, FASE, FAHA Section Editor
Update in Hematology: Heparin-Induced Thrombocytopenia and Bivalirudin John G.T. Augoustides, MD, FASE, FAHA Heparin-induced thrombocytopenia (HIT) is important because it is common, and it significantly increases mortality after cardiac surgery. Although thrombocytopenia after cardiac surgery is common, it predicts serious adverse outcome when it is severe. Despite the high prevalence of heparin/ platelet factor 4 antibodies in cardiac surgical patients, they typically do not indicate a higher perioperative risk. Recent evidence suggests, however, that when these antibodies are in the immunoglobulin M class, there is an increased risk of nonthrombotic adverse outcomes after cardiac surgery. According to the guidelines from the American College of Chest Physicians, patients with HIT require parenteral anticoagulation with a direct thrombin inhibitor such as lepirudin, argatroban, or bivalirudin. The transition to oral anticoagulation must be undertaken cautiously and only after the platelet count has recovered. Patients with a remote history
of HIT can have cardiac surgery safely with unfractionated heparin. Patients with clinically active HIT who require cardiac surgery before the resolution of the HIT preferably should be anticoagulated with bivalirudin, dosed according to body weight and the goal-activated coagulation time. Given that bivalirudin is an established alternative to heparin as a thrombin inhibitor for cardiac surgery, it is likely that future trials will investigate which anticoagulant confers better outcomes after cardiac surgery, as is the case in percutaneous coronary intervention. © 2011 Elsevier Inc. All rights reserved.
H
EPARIN-INDUCED THROMBOCYTOPENIA (HIT) is a disease that remains the focus of ongoing clinical investigation because it is relatively common and clinically serious but eminently treatable. There has been a steady effort toward a higher index of suspicion, earlier diagnosis, and prompt anticoagulation with a heparin alternative. This disease remains relevant for the cardiovascular anesthesiologist and intensivist because patients with HIT may require specialized perioperative management, including anticoagulation. Beyond the specialized management of patients with HIT, this disease also highlights the utility of the direct thrombin inhibitors, especially bivalirudin. Bivalirudin has emerged as the heparin alternative of choice for patients with clinically active HIT who require cardiac surgery. It is likely that the role of this direct thrombin inhibitor will expand in cardiac surgery based on the results of adequately powered clinical trials with heparin as the comparator. This review details the recent advances in the clinical management of HIT with an emphasis on the clinical utility of bivalirudin both in HIT and cardiac surgery.
registry has enrolled 3,536 patients from 48 hospitals across the United States.4 Thrombocytopenia had an incidence of 36.4% and was significantly associated with clinical thrombosis or death (odds ratio, 1.5; 95% confidence interval, 1.2-1.9). Clinical suspicion of HIT frequently was delayed despite suggestive clinical presentations; and even after HIT diagnosis, patients frequently continued to receive heparin.4 Furthermore, the clinical application of a direct thrombin inhibitor was infrequent. The authors concluded that thrombocytopenia is common and serious, with significant opportunities available for clinical improvement in the diagnosis and management of HIT.4 In a large single-center observational series (N ⬎ 30,000), the risk of HIT was related significantly to the type of heparin exposure; it was 0.48% in patients receiving unfractionated heparin, but only 0.08% in patients receiving low–molecular-weight heparin (p ⫽ 0.02).5 Consequently, these investigators suggested that the incidence of HIT could be minimized by reducing exposure to unfractionated heparin.
WHAT IS THE CONTEMPORARY INCIDENCE OF HEPARIN-INDUCED THROMBOCYTOPENIA?
From the Department of Anesthesiology and Critical Care, University of Pennsylvania School of Medicine, Philadelphia, PA. Address reprint requests to John G.T. Augoustides, MD, FASE, FAHA, Cardiothoracic Section, Anesthesiology and Critical Care, Dulles 680, HUP, 3400 Spruce Street, Philadelphia, PA 19104-4283. E-mail: [email protected] © 2011 Elsevier Inc. All rights reserved. 1053-0770/2502-0030$36.00/0 doi:10.1053/j.jvca.2010.12.015
The incidence of HIT is approximately 1% to 5% of all patients receiving heparin.1 Furthermore, about 25% to 50% of the patients subsequently develop HIT with clinical thrombosis.2 The Complication after Thrombocytopenia Caused by Heparin (CATCH) Registry was developed to track the incidence of HIT in contemporary clinical practice.3 The CATCH
KEY WORDS: heparin, thrombocytopenia, heparin-induced thrombocytopenia, thrombosis, direct thrombin inhibitor, low–molecular-weight heparin, lepirudin, bivalirudin, warfarin, platelet blockade, antibodies, cardiac surgery, percutaneous coronary intervention
Journal of Cardiothoracic and Vascular Anesthesia, Vol 25, No 2 (April), 2011: pp 371-375
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IS THROMBOCYTOPENIA AFTER CARDIAC SURGERY IMPORTANT?
A recent observational single-center study (N ⬎ 10,000 adult cardiac surgical patients: 1999-2007) investigated the outcome relevance of perioperative thrombocytopenia, which was defined as a platelet count below 50% of baseline or an absolute platelet count of less than 50,000 per microliter.6 Thrombocytopenia had an incidence of 1.5% and was associated with a perioperative mortality of 59%. The incidence of HIT in the thrombocytopenic cohort was 13.7% and was associated significantly with central venous and pulmonary thromboembolism as compared with the thrombocytopenic non-HIT cohort (10% v 2%, p ⫽ 0.04).6 The multivariate predictors of mortality in this series were patient age (p ⫽ 0.04; 95% confidence interval, 1.00-1.08), female sex (p ⫽ 0.03; 95% confidence interval, 1.51-7.86), and sepsis (p ⬍ 0.001; 95% confidence interval, 2.96-16.02). It is clear, then, that advanced thrombocytopenia after cardiac surgery significantly increases the risk of perioperative mortality. A recent study investigated whether HIT has a typical onset in the adult cardiac surgical period (N ⫽ 581).7 In this series, 3 patients who developed thrombocytopenia between postoperative days 5 and 10 tested positive for HIT. In contrast, all 25 patients who developed thrombocytopenia before postoperative day 5 tested negative for HIT. Thus, the incidence of HIT in this trial was 0.5% (3/581). The investigators concluded that the onset of thrombocytopenia 5 to 10 days after cardiac surgery is strongly predictive for HIT.7 The impact of HIT on outcome after cardiac surgery was measured in a single-center observational study (N ⫽ 3,465: 2002-2004).8 The onset of HIT was typically within 7 days of surgery and had an incidence in this large study of 0.5%.8 HIT was associated significantly with thromboembolic complications (p ⫽ 0.001) and prolonged stay in the intensive care unit (p ⬍ 0.001). The mortality rate in the HIT cohort was 45% and was caused by thrombotic complications in 35% of cases.8 These devastating perioperative outcomes have been consistent across multiple studies.8-11 This explains the imperative for prompt diagnosis and management of HIT. Overall, the development of significant thrombocytopenia, whether associated with HIT or not, is an independent predictor for adverse perioperative outcome. Furthermore, HIT is associated with devastating outcomes after cardiac surgery. Consequently, HIT remains an important clinical consideration in the perioperative care of cardiac surgical patient. DO HEPARIN/PLATELET FACTOR 4 ANTIBODIES AFFECT OUTCOME AFTER CARDIAC SURGERY?
Although heparin/platelet factor 4 antibodies play a role in the pathogenesis of HIT, their presence alone does not diagnose this important disease.11 In an adult cardiac surgical series (N ⫽ 299: 2003-2005), the preoperative prevalence of these antibodies was 4.3%, and this prevalence increased 5 times to 22.4% postoperatively.12 Postoperative, thrombocytopenia predicted for adverse outcome, regardless of antibody status.12 In a pediatric cardiac surgical series (N ⫽ 135), the incidence of heparin/platelet factor 4 antibody seroconversion was 50% in children undergoing reoperative cardiac surgery.13 The risk
of seroconversion was dependent on age and previous heparin exposure.13,14 Consequently, the rate of seroconversion in neonates undergoing first-time cardiac surgery was only 1.7%. The incidence of HIT in this trial was 1.3%; this single case did not develop thrombosis or skin lesions. Again, as in the adult series, heparin/platelet factor 4 antibodies may be very common and not related to adverse perioperative outcome.11-14 The heparin/platelet factor 4 antibodies typically belong to 1 of the following 3 antibody classes: immunoglobulin G, immunoglobulin A, or immunoglobulin M.15 A recent trial (N ⫽ 591) investigated whether antibody class affects outcome after adult cardiac surgery.15 The preoperative prevalence of antibodies was 21.7%. Immunoglobulins G and A did not correlate with adverse perioperative outcomes. Although immunoglobulin M was a significant risk factor for nonthromboembolic complications (hazard ratio, 1.73; 95% confidence interval, 1.15-2.61) and longer hospital stay (p ⫽ 0.02), it was not associated with HIT or thrombotic complications.15 The investigators concluded that heparin/platelet factor 4 antibodies of the immunoglobulin M class might represent a surrogate marker for outcome risk factors that are unrelated to heparin. In summary, heparin/platelet factor 4 antibodies commonly are present perioperatively in cardiac surgical patients and mostly are unrelated to the development and presentation of HIT. WHAT ARE THE CURRENT GUIDELINES FOR THE MANAGEMENT OF HIT?
The American College of Chest Physicians (ACCP) published guidelines in 2008 for the diagnosis and management of HIT, including in cardiac surgical patients.16 The recommendations from this important article that pertain to the cardiovascular anesthesiologist and intensivist are now reviewed in depth. The first recommendation states that after cardiac surgery, HIT should be suspected if the platelet count falls below 50% of baseline and/or a clinical thrombosis occurs, especially between 5 and 15 days after cardiac surgery.7,16 The cardiac surgical patient is at risk for HIT because of perioperative heparin exposure. Because the risk of HIT is relatively high in this surgical cohort, the ACCP has recommended perioperative platelet count monitoring for this population. Furthermore, in the setting of suspected or definite HIT, platelet transfusion is only recommended in the presence of active significant bleeding.16 When the diagnosis of HIT is strongly suspected, the ACCP recommends anticoagulation with a direct thrombin inhibitor such as argatroban, lepirudin, or bivalirudin.16,17 In the case of lepirudin, initial dosing should be conservative and carefully tailored to creatinine clearance, given that lepirudin is dependent on renal elimination.17,18 Furthermore, the bolus dose should either be omitted or given at a significantly reduced dose. The goal of partial thromboplastin time with this conservative regimen is 1.5 to 2.0 times the patient’s baseline with the partial thromboplastin time monitored every 4 hours until a steady state is attained.16 In the case of argatroban, initial dosing also is recommended in the conservative range, with careful titration in the setting of liver dysfunction, given that argatroban relies on hepatic elimination.17,18 The ongoing therapy of HIT with oral anticoagulation with vitamin K antagonists such as coumadin can contribute to
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venous limb gangrene.19-21 This has been attributed to the deficiency of protein C, a naturally circulating anticoagulant.16,19 To prevent this devastating complication, the ACCP Expert Panel has recommended that coumadin therapy only be initiated in HIT when the platelet count has significantly recovered to levels exceeding 150,000 per microliter.16 Furthermore, it is recommended that the therapy be initiated conservatively with low maintenance doses and that the parenteral anticoagulation be continued until the platelet count has stabilized, the international normalized ratio goal has been attained, and there has been a minimum of 5 days overlap between these 2 anticoagulation strategies.16 If coumadin therapy has been started before the diagnosis of HIT was made, the ACCP Panel recommends that it be reversed with vitamin K to prevent gangrene and allow accurate dosing of the parenteral anticoagulant.16-22 In summary, these recommendations pertain to the diagnosis and management of HIT that typically would develop after heparin exposure during cardiac surgery. It is important to remember that currently there is no agent for rapid reversal of parenteral anticoagulation with direct thrombin inhibitors such as protamine in the case of heparin-based anticoagulation. This consideration becomes even more important when considering the anticoagulation for cardiac surgery in the patient with HIT, as discussed in the next section. WHAT IS THE MANAGEMENT OF PATIENTS WITH HIT WHO REQUIRE CARDIAC SURGERY?
Although this topic has been covered in a review article in the Journal, this article was published in 2007, a year before the release of the ACCP guidelines.16,23 This update highlights the ACCP guidelines. There are 2 possible clinical scenarios: the patient with recent HIT and the patient with acute/subacute HIT. The patient with recent HIT is defined as one who has completed HIT therapy, whose platelet count has recovered, and who is antibody negative. The patient with acute HIT is defined as one who currently is undergoing anticoagulation for HIT, who is still thrombocytopenic, and who is still antibody positive. The patient with subacute HIT is defined as one who currently is undergoing anticoagulation for HIT, who is no longer thrombocytopenic, and who is still antibody positive. Although the ACCP panel has distinguished between acute and subacute HIT, from a practical point of view, they have been considered together in this review as the recommendations for management of anticoagulation for cardiac surgery are essentially the same. WHAT IS THE APPROACH IN PATIENTS WITH RECENT HIT WHO REQUIRE CARDIAC SURGERY?
The ACCP recommendation in this clinical setting is to proceed with standard heparin-based anticoagulation because the HIT episode is over. The immune response in HIT does not follow typical immune anamnesis in which re-exposure to the drug triggers a dramatic and rapid immune-based response such as anaphylaxis.24-26 In patients with recent HIT, the antibodies that first disappear are those that are detected by the platelet activation assay. The cumulative evidence suggests that when platelet activation by HIT antibodies is no longer apparent,
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heparin exposure is safe and does not carry risk for clinical HIT. Consequently, patients with recent HIT who are positive for nonplatelet-activating HIT antibodies still may undergo cardiac surgery with heparin-based anticoagulation.16 It is not clinically necessary to wait for the complete disappearance of all HIT antibodies from the plasma in this scenario.11,16,17,23 WHAT IS THE APPROACH IN ACUTE/SUBACUTE HIT PATIENTS WHO REQUIRE CARDIAC SURGERY?
The ideal anticoagulant for cardiac surgery is still heparin despite its limitations. Heparin remains the gold standard. Consequently, the ACCP has recommended that in this clinical scenario, the cardiac surgical procedure be delayed if possible until the HIT episode has resolved and the platelet-activating HIT antibodies are no longer measurable. If the cardiac surgery cannot be delayed until resolution of the HIT, then the AACP recommends anticoagulation with the direct thrombin inhibitor bivalirudin as the next best option, with the caveat that perioperative techniques be suitably adapted.16,27-31 Although the ACCP panel also has recommended anticoagulation with lepirudin, danaparoid, and heparin with platelet blockers such as epoprostenol or tirofiban, these options are less strongly recommended.16 The ACCP has strongly endorsed bivalirudin because it is the best-studied alternative to heparin for anticoagulation in cardiac surgery, both for onpump and off-pump procedures. Consequently, in this review, bivalirudin is considered in detail because it represents the best alternative to heparin in the scenario of urgent cardiac surgery in a patient with clinically active HIT. The focus on bivalirudin is the subject of the next section. It is possible that bivalirudin may challenge heparin as the gold standard in the future conduct of anticoagulation for cardiac surgery. WHY IS BIVALIRUDIN THE HEPARIN ALTERNATIVE OF CHOICE IN CARDIAC SURGERY?
Bivalirudin (Angiomax; The Medicines Company, Parsippany, NJ) is a direct thrombin inhibitor with a short half-life of about 25 minutes.16,17 Its elimination is both enzymatic (80%) and renal (20%). Its anticoagulation effects can be monitored with the activated coagulation time. The short half-life, relative freedom from organ-based elimination, and easy intraoperative monitoring explain its emergence as the heparin alternative of choice.32,33 Unfortunately, there is currently no drug that rapidly reverses bivalirudin. This drug has a high clinical priority and could even have the name of bivalirudinase, analogous to the development of heparinase as part of the search for a protamine alternative.34 When this drug enters clinical practice, it is even more likely that heparin as the gold standard anticoagulant for cardiac surgery will have a serious rival. It is essential with bivalirudin to avoid intraoperative stasis of blood because bivalirudin is then metabolized by thrombin with a consequent loss of anticoagulation and the risk of thrombosis.16,17 Therefore, in the conduct of cardiopulmonary bypass, it is important to minimize hemostasis in the venous reservoir. Furthermore, shed pericardial and mediastinal blood should be processed in cell-salvage systems before retransfusion to minimize the risk of thromboemboli that result from metabolism of bivalirudin by thrombin in stagnant pericardial and mediastinal blood.17
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Bivalirudin was shown in 2 clinical trials (cumulative N ⫽ 100) to be a safe and effective heparin alternative for cardiac surgery in patients with HIT, both for on-pump and off-pump procedures.30,31 Bivalirudin was also safe and effective in these 2 trials in patients with impaired renal function.30,31 Furthermore, in a second set of trials (cumulative N ⫽ 251), bivalirudin, as compared with heparin, proved to be a safe, reliable, and effective anticoagulant both for on-pump and off-pump cardiac surgery.28,29 The details of the dosing regimens are outlined in those publications. In summary, bivalirudin when used correctly, is the heparin alternative of choice for patients with active HIT who require urgent cardiac surgery. It is possible that the application of bivalirudin in cardiac surgery will expand, as has been the case in percutaneous coronary intervention (PCI), an evolution that is the subject of the following section. COULD BIVALIRUDIN REPLACE HEPARIN AS THE GOLD STANDARD IN CARDIAC SURGERY?
This question develops from the efficacy of bivalirudin as an alternative to heparin for cardiac surgery in patients with clinically active HIT. Because heparin has been the unchallenged gold standard anticoagulant for cardiac surgery since the beginning of cardiopulmonary bypass, it is difficult to imagine a serious alternative. Yet, the evolution of bivalirudin in anticoagulation for PCI since the 1990s sheds light on what could happen in the world of cardiac surgical intervention in the decade to come. Bivalirudin emerged in the 1990s when landmark clinical trials showed its safety and efficacy as an alternative anticoagulant to heparin for PCI.35 In the contemporary era, the anticoagulation options for PCI have expanded far beyond unfractionated heparin; they include enoxaparin, fondaparinux, bivalirudin, as well the family of oral and parenteral platelet blockers.36 All the anticoagulants act directly or indirectly on thrombin, with each thrombin inhibitor having relative advantages and disadvantages in PCI.36 The advantages of bivalirudin in PCI include its lack of platelet activation, its tendency to cause less bleeding, and its association with a lower mortality in primary PCI.36,37 The future in anticoagulation for PCI likely will focus on the selection of the best antithrombin therapy for a particular patient, taking into account the patient, the coronary anatomy, and the entire clinical setting. The challenge in antithrombin therapy for PCI is to individualize this therapy so that a particular patient will have the greatest freedom possible from both coronary ischemia and significant bleeding.
This advanced menu of antithrombin therapy in PCI is in contrast to the more limited menu in cardiac surgery. Despite the longstanding experience with heparin, there is still significant variability in the conduct of anticoagulation for cardiac surgery.38 Advances in anticoagulation for cardiac surgery are required because the limitations of heparin and protamine are well established. The major challenges in this field of endeavor should be addressed by multidisciplinary teams conducting adequately powered perioperative trials linked to meaningful clinical outcomes.39 There is a powerful lesson from the aprotinin saga that is relevant here. Aprotinin was introduced into clinical practice more than 20 years ago.40 It was only recently that an adequately powered, randomized controlled trial finally evaluated the safety and efficacy of the 3 antifibrinolytics commonly used in cardiac surgery.41,42 Because bivalirudin now appears to be clinically equivalent to heparin, is it not time to perform an adequately powered trial to test which thrombin inhibitor leads to superior outcomes after cardiac surgery? These meaningful outcomes should be studied not only in the short term but also in the long term, as in the example of the PCI trials.36 CONCLUSIONS
HIT is important because it is common, and it significantly increases mortality after cardiac surgery. Although thrombocytopenia after cardiac surgery is common, it predicts serious adverse outcome when it is severe. Despite the high prevalence of heparin/platelet factor 4 antibodies in cardiac surgical patients, they typically do not indicate a higher perioperative risk. Recent evidence suggests, however, that when these antibodies are in the immunoglobulin M class, there is an increased risk of nonthrombotic adverse outcomes after cardiac surgery. According to the guidelines from the ACCP, patients with HIT require parenteral anticoagulation with a thrombin inhibitor such as lepirudin, argatroban, or bivalirudin. Transition to oral anticoagulation with coumadin must be undertaken cautiously and only after the platelet count has recovered to prevent the onset of devastating clinical thrombosis. Patients with a remote history of HIT safely can have cardiac surgery with unfractionated heparin. Patients with clinically active HIT who require cardiac surgery before the resolution of the HIT preferably should be anticoagulated with bivalirudin, dosed according to body weight and goal-activated clotting time. Given that bivalirudin is an established alternative to heparin as a thrombin inhibitor for cardiac surgery, it is likely that future trials will investigate which anticoagulant confers better outcomes after cardiac surgery, as is the case in PCI.
REFERENCES 1. Spencer FA: Heparin-induced thrombocytopenia: patient profiles and clinical manifestations. J Thromb Thrombolysis 10:S21-S26, 2000 2. Wallenga JM, Jeske WP, Messmore HL: Mechanisms of venous and arterial thrombosis in heparin induced thrombocytopenia. J Thromb Thrombolysis 10:S13-S20, 2000 3. Ohman EM, Granger CB, Rice L, et al: Identification, diagnosis and treatment of heparin-induced thrombocytopenia and thrombosis: A registry of prolonged heparin use and thrombocytopenia among hospitalized patients with and without cardiovascular disease. J Thromb Thrombolysis 10:11-19, 2005
4. Crespo EM, Oliveira GBF, Honeycut EF, et al: Evaluation and management of thrombocytopenia and suspected heparin-induced thrombocytopenia in hospitalized patients: The Complications after Thrombocytopenia Caused by heparin (CATCH) registry. Am Heart J 157:651-657, 2009 5. Ban-Hoefen M, Francis C: Heparin-induced thrombocytopenia and thrombosis in a tertiary care hospital. Thromb Res 124:189-192, 2009 6. Thielmann M, Bunschkowski M, Tossios P, et al: Perioperative thrombocytopenia in cardiac surgical patients—Incidence of hepa-
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rin-induced thrombocytopenia, morbidities and mortality. Eur J Cardiothorac Surg 37:1391-1395, 2010 7. Selleng S, Malowsky, Strobel U, et al: Early-onset and persisting thrombocytopenia in post-cardiac surgery patients is rarely due to heparin-induced thrombocytopenia, even when antibody tests are positive. J Thromb Haemaost 8:30-36, 2010 8. Kuitunen A, Suojaranta-Ylinen R, Raivio P, et al: Heparin-induced thrombocytopenia following cardiac surgery is associated with poor outcome. J Cardiothorac Vasc Anesth 21:18-22, 2007 9. Kerendi F, Thourani VH, Puskas JD, et al: Impact of heparininduced thrombocytopenia on postoperative outcomes after cardiac surgery? Ann Thorac Surg 84:1548-1553, 2007 10. Assman A, Boeken IJ, Feindl P, et al: Heparin-induced thrombocytopenia type II after cardiac surgery: predictors and outcome. Thorac Cardiovasc Surg 58:463-467, 2010 11. Levy JH, Tanaka KA, Hursting MJ, et al: Reducing thrombotic complications in the perioperative setting: an update on heparin-induced thrombocytopenia. Anesth Analg 105:570-582, 2007 12. Everett BM, Yeh R, Foo SY, et al: Prevalence of heparin/platelet factor 4 antibodies before and after cardiac surgery. Ann Thorac Surg 83:592-597, 2007 13. Mullen MP, Wessel DL, Thomas KC, et al: The incidence and implications of anti-heparin-platelet factor 4 antibody formation in a pediatric cardiac surgical population. Anesth Analg 107:371-378, 2008 14. Greinacher A, Levy JH: HIT happens: Diagnosing and evaluating the patient with heparin-induced thrombocytopenia. Anesth Analg 107:356-358, 2008 15. Selleng S, Malowsky B, Itterman T, et al: Incidence and clinical relevance of anti-platelet factor 4/heparin antibodies before cardiac surgery. Am Heart J 160:362-369, 2010 16. Warkentin TE, Greinacher A, Koster A, et al: Treatment and prevention of heparin-induced thrombocytopenia. Chest 133:340S380S, 2008 17. Levy JH, Winkler AM: Heparin-induced thrombocytopenia and cardiac surgery. Curr Opin Anaesthesiol 23:74-79, 2010 18. Greinacher A: Heparin-induced thrombocytopenia. J Thromb Haemost 7:9-12, 2009 19. Warkentin TE, Elavathil LJ, Hayward CPM, et al: The pathogenesis of venous limb gangrene associated with heparin-induced thrombocytoipenia. Ann Intern Med 127:804-812, 1997 20. Srinivasan AF, Rice L. Bartholomew JR, et al: Warfarin-induced skin necrosis and venous limb gangrene in the setting of heparininduced thrombocytopenia. Arch Intern Med 164:66-70, 2004 21. Warkentin TE, Roberts RS, Hirsh J, et al: Heparin-induced skin lesions and other unusual sequelae of the heparin-induced thrombocytopenia syndrome: A nested cohort study. Chest 127:1857-1861, 2005 22. Warkentin TE: Should vitamin K be administered when HIT is diagnosed after administration of coumarin? J Thromb Haemost 4:894896, 2006 23. Murphy GS, Marymont JH: Alternative anticoagulation management strategies for the patient with heparin-induced thrombocytopenia undergoing cardiac surgery. J Cardiothorac Vasc Anesth 21: 113-126, 2007 24. Warkentin TE, Kelton JG: Temporal aspects of heparin-induced thrombocytopenia. N Engl J Med 344:1286-1292, 2001
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25. Lubenow N, Kempf R, Eichner A, et al: Heparin-induced thrombocytopenia: Temporal pattern of thrombocytopenia in relation to initial use or reexposure to heparin. Chest 122:37-42, 2002 26. Otis SA, Zehnder JL: Heparin-induced thrombocytopenia: Current status and diagnostic challenges. Am J Hematol 85:700-706, 2010 27. Smedira NG, Dyke CM, Koster A, et al: Anticoagulation with bivalirudin for off-pump coronary artery bypass grafting: The results of the EVOLUTION-OFF study. J Thorac Cardiovasc Surg 131:686-692, 2006 28. Koster A, Spiess B, Jurmann M, et al: Bivalirudin provides rapid, effective, and reliable anticoagulation during off-pump coronary revascularization: Results of the “EVOLUTION OFF” trial. Anesth Analg 103:540-544, 2006 29. Dyke CM, Smedira NG, Koster A, et al: A comparison of bivalirudin to heparin with protamine reversal in patients undergoing cardiac surgery with cardiopulmonary bypass: The EVOLUTION-ON study. J Thorac Cardiovasc Surg 131:533-539, 2006 30. Koster A, Dyke CM, Aldea G, et al: Bivalirudin during cardiopulmonary bypass in patients with heparin-induced thrombocytopenia and heparin antibodies: The CHOOSE-ON trial. Ann Thorac Surg 83:572-577, 2007 31. Dyke CM, Aldea G, Koster A, et al: Off-pump coronary artery bypass with bivalirudin for patients with heparin-induced thrombocytopenia or antiplatelet factor 4/heparin antibodies. Ann Thorac Surg 84:836-839, 2007 32. Van De Car DA, Rao SV, Ohman EM: Bivalirudin: A review of the pharmacology and clinical application. Expert Rev Cardiovasc Ther 8:1673-1681, 2010 33. Anand SX, Villes-Gonzalez JF, Mahboobi SK, et al: Bivalirudin utilization in cardiac surgery: Shifting anticoagulation from indirect to direct thrombin inhibition. Can J Anaesth 2010 [Epub ahead of print] 34. Stafford-Smith M, Lefrak EA, Qazi AG, et al: Efficacy and safety of heparinase-1 versus protamine in patients undergoing coronary artery bypass grafting with and without cardiopulmonary bypass. Anesthesiology 103:229-240, 2005 35. Bittl JA, Strony J, Brinker JA, et al: Treatment with bivalirudin (hirulog) as compared with heparin during coronary angioplasty for unstable or postinfarction angina. N Engl J Med 333:764-769, 1995 36. Rao SV, Ohman EM: Anticoagulant therapy for percutaneous coronary intervention. Circ Cardiovasc Interv 3:80-88, 2010 37. Lindsey JB, Cohen DJ, Stolker JM, et al: The impact of bivalirudin on percutaneous coronary intervention-related bleeding. Eurointervention 6:206-213, 2010 38. Lobato RL, Despotis GJ, Levy JH, et al: Anticoagulation management during cardiopulmonary bypass: A survey of 54 North American institutions. J Thorac Cardiovasc Surg 139:1665-1666, 2010 39. Levy JH, Dutton RP, Hemphill JC, et al: Multidisciplinary approach to the challenge of hemostasis. Anesth Analg 110:354-354, 2010 40. Augoustides JG: Aprotinin and renal dysfunction: What does history teach us? Expert Opin Drug Saf 8:5-7, 2009 41. Augoustides JG: Perioperative safety of aprotinin in coronary artery bypass graft surgery: Is there life after BART? Drug Saf 31:557560, 2008 42. Fergusson DA, Hebert PC, Mazer CD, et al: A comparison of aprotinin and lysine analogues in high-risk cardiac surgery. N Engl J Med 358:2319-2331, 2008
Update in Hematology: Heparin-Induced Thrombocytopenia and Bivalirudin John G.T. Augoustides, MD, FASE, FAHA Heparin-induced thrombocytopenia (HIT) is important because it is common, and it significantly increases mortality after cardiac surgery. Although thrombocytopenia after cardiac surgery is common, it predicts serious adverse outcome when it is severe. Despite the high prevalence of heparin/ platelet factor 4 antibodies in cardiac surgical patients, they typically do not indicate a higher perioperative risk. Recent evidence suggests, however, that when these antibodies are in the immunoglobulin M class, there is an increased risk of nonthrombotic adverse outcomes after cardiac surgery. According to the guidelines from the American College of Chest Physicians, patients with HIT require parenteral anticoagulation with a direct thrombin inhibitor such as lepirudin, argatroban, or bivalirudin. The transition to oral anticoagulation must be undertaken cautiously and only after the platelet count has recovered. Patients with a remote history
of HIT can have cardiac surgery safely with unfractionated heparin. Patients with clinically active HIT who require cardiac surgery before the resolution of the HIT preferably should be anticoagulated with bivalirudin, dosed according to body weight and the goal-activated coagulation time. Given that bivalirudin is an established alternative to heparin as a thrombin inhibitor for cardiac surgery, it is likely that future trials will investigate which anticoagulant confers better outcomes after cardiac surgery, as is the case in percutaneous coronary intervention. © 2011 Elsevier Inc. All rights reserved.
H
EPARIN-INDUCED THROMBOCYTOPENIA (HIT) is a disease that remains the focus of ongoing clinical investigation because it is relatively common and clinically serious but eminently treatable. There has been a steady effort toward a higher index of suspicion, earlier diagnosis, and prompt anticoagulation with a heparin alternative. This disease remains relevant for the cardiovascular anesthesiologist and intensivist because patients with HIT may require specialized perioperative management, including anticoagulation. Beyond the specialized management of patients with HIT, this disease also highlights the utility of the direct thrombin inhibitors, especially bivalirudin. Bivalirudin has emerged as the heparin alternative of choice for patients with clinically active HIT who require cardiac surgery. It is likely that the role of this direct thrombin inhibitor will expand in cardiac surgery based on the results of adequately powered clinical trials with heparin as the comparator. This review details the recent advances in the clinical management of HIT with an emphasis on the clinical utility of bivalirudin both in HIT and cardiac surgery.
registry has enrolled 3,536 patients from 48 hospitals across the United States.4 Thrombocytopenia had an incidence of 36.4% and was significantly associated with clinical thrombosis or death (odds ratio, 1.5; 95% confidence interval, 1.2-1.9). Clinical suspicion of HIT frequently was delayed despite suggestive clinical presentations; and even after HIT diagnosis, patients frequently continued to receive heparin.4 Furthermore, the clinical application of a direct thrombin inhibitor was infrequent. The authors concluded that thrombocytopenia is common and serious, with significant opportunities available for clinical improvement in the diagnosis and management of HIT.4 In a large single-center observational series (N ⬎ 30,000), the risk of HIT was related significantly to the type of heparin exposure; it was 0.48% in patients receiving unfractionated heparin, but only 0.08% in patients receiving low–molecular-weight heparin (p ⫽ 0.02).5 Consequently, these investigators suggested that the incidence of HIT could be minimized by reducing exposure to unfractionated heparin.
WHAT IS THE CONTEMPORARY INCIDENCE OF HEPARIN-INDUCED THROMBOCYTOPENIA?
From the Department of Anesthesiology and Critical Care, University of Pennsylvania School of Medicine, Philadelphia, PA. Address reprint requests to John G.T. Augoustides, MD, FASE, FAHA, Cardiothoracic Section, Anesthesiology and Critical Care, Dulles 680, HUP, 3400 Spruce Street, Philadelphia, PA 19104-4283. E-mail: [email protected] © 2011 Elsevier Inc. All rights reserved. 1053-0770/2502-0030$36.00/0 doi:10.1053/j.jvca.2010.12.015
The incidence of HIT is approximately 1% to 5% of all patients receiving heparin.1 Furthermore, about 25% to 50% of the patients subsequently develop HIT with clinical thrombosis.2 The Complication after Thrombocytopenia Caused by Heparin (CATCH) Registry was developed to track the incidence of HIT in contemporary clinical practice.3 The CATCH
KEY WORDS: heparin, thrombocytopenia, heparin-induced thrombocytopenia, thrombosis, direct thrombin inhibitor, low–molecular-weight heparin, lepirudin, bivalirudin, warfarin, platelet blockade, antibodies, cardiac surgery, percutaneous coronary intervention
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IS THROMBOCYTOPENIA AFTER CARDIAC SURGERY IMPORTANT?
A recent observational single-center study (N ⬎ 10,000 adult cardiac surgical patients: 1999-2007) investigated the outcome relevance of perioperative thrombocytopenia, which was defined as a platelet count below 50% of baseline or an absolute platelet count of less than 50,000 per microliter.6 Thrombocytopenia had an incidence of 1.5% and was associated with a perioperative mortality of 59%. The incidence of HIT in the thrombocytopenic cohort was 13.7% and was associated significantly with central venous and pulmonary thromboembolism as compared with the thrombocytopenic non-HIT cohort (10% v 2%, p ⫽ 0.04).6 The multivariate predictors of mortality in this series were patient age (p ⫽ 0.04; 95% confidence interval, 1.00-1.08), female sex (p ⫽ 0.03; 95% confidence interval, 1.51-7.86), and sepsis (p ⬍ 0.001; 95% confidence interval, 2.96-16.02). It is clear, then, that advanced thrombocytopenia after cardiac surgery significantly increases the risk of perioperative mortality. A recent study investigated whether HIT has a typical onset in the adult cardiac surgical period (N ⫽ 581).7 In this series, 3 patients who developed thrombocytopenia between postoperative days 5 and 10 tested positive for HIT. In contrast, all 25 patients who developed thrombocytopenia before postoperative day 5 tested negative for HIT. Thus, the incidence of HIT in this trial was 0.5% (3/581). The investigators concluded that the onset of thrombocytopenia 5 to 10 days after cardiac surgery is strongly predictive for HIT.7 The impact of HIT on outcome after cardiac surgery was measured in a single-center observational study (N ⫽ 3,465: 2002-2004).8 The onset of HIT was typically within 7 days of surgery and had an incidence in this large study of 0.5%.8 HIT was associated significantly with thromboembolic complications (p ⫽ 0.001) and prolonged stay in the intensive care unit (p ⬍ 0.001). The mortality rate in the HIT cohort was 45% and was caused by thrombotic complications in 35% of cases.8 These devastating perioperative outcomes have been consistent across multiple studies.8-11 This explains the imperative for prompt diagnosis and management of HIT. Overall, the development of significant thrombocytopenia, whether associated with HIT or not, is an independent predictor for adverse perioperative outcome. Furthermore, HIT is associated with devastating outcomes after cardiac surgery. Consequently, HIT remains an important clinical consideration in the perioperative care of cardiac surgical patient. DO HEPARIN/PLATELET FACTOR 4 ANTIBODIES AFFECT OUTCOME AFTER CARDIAC SURGERY?
Although heparin/platelet factor 4 antibodies play a role in the pathogenesis of HIT, their presence alone does not diagnose this important disease.11 In an adult cardiac surgical series (N ⫽ 299: 2003-2005), the preoperative prevalence of these antibodies was 4.3%, and this prevalence increased 5 times to 22.4% postoperatively.12 Postoperative, thrombocytopenia predicted for adverse outcome, regardless of antibody status.12 In a pediatric cardiac surgical series (N ⫽ 135), the incidence of heparin/platelet factor 4 antibody seroconversion was 50% in children undergoing reoperative cardiac surgery.13 The risk
of seroconversion was dependent on age and previous heparin exposure.13,14 Consequently, the rate of seroconversion in neonates undergoing first-time cardiac surgery was only 1.7%. The incidence of HIT in this trial was 1.3%; this single case did not develop thrombosis or skin lesions. Again, as in the adult series, heparin/platelet factor 4 antibodies may be very common and not related to adverse perioperative outcome.11-14 The heparin/platelet factor 4 antibodies typically belong to 1 of the following 3 antibody classes: immunoglobulin G, immunoglobulin A, or immunoglobulin M.15 A recent trial (N ⫽ 591) investigated whether antibody class affects outcome after adult cardiac surgery.15 The preoperative prevalence of antibodies was 21.7%. Immunoglobulins G and A did not correlate with adverse perioperative outcomes. Although immunoglobulin M was a significant risk factor for nonthromboembolic complications (hazard ratio, 1.73; 95% confidence interval, 1.15-2.61) and longer hospital stay (p ⫽ 0.02), it was not associated with HIT or thrombotic complications.15 The investigators concluded that heparin/platelet factor 4 antibodies of the immunoglobulin M class might represent a surrogate marker for outcome risk factors that are unrelated to heparin. In summary, heparin/platelet factor 4 antibodies commonly are present perioperatively in cardiac surgical patients and mostly are unrelated to the development and presentation of HIT. WHAT ARE THE CURRENT GUIDELINES FOR THE MANAGEMENT OF HIT?
The American College of Chest Physicians (ACCP) published guidelines in 2008 for the diagnosis and management of HIT, including in cardiac surgical patients.16 The recommendations from this important article that pertain to the cardiovascular anesthesiologist and intensivist are now reviewed in depth. The first recommendation states that after cardiac surgery, HIT should be suspected if the platelet count falls below 50% of baseline and/or a clinical thrombosis occurs, especially between 5 and 15 days after cardiac surgery.7,16 The cardiac surgical patient is at risk for HIT because of perioperative heparin exposure. Because the risk of HIT is relatively high in this surgical cohort, the ACCP has recommended perioperative platelet count monitoring for this population. Furthermore, in the setting of suspected or definite HIT, platelet transfusion is only recommended in the presence of active significant bleeding.16 When the diagnosis of HIT is strongly suspected, the ACCP recommends anticoagulation with a direct thrombin inhibitor such as argatroban, lepirudin, or bivalirudin.16,17 In the case of lepirudin, initial dosing should be conservative and carefully tailored to creatinine clearance, given that lepirudin is dependent on renal elimination.17,18 Furthermore, the bolus dose should either be omitted or given at a significantly reduced dose. The goal of partial thromboplastin time with this conservative regimen is 1.5 to 2.0 times the patient’s baseline with the partial thromboplastin time monitored every 4 hours until a steady state is attained.16 In the case of argatroban, initial dosing also is recommended in the conservative range, with careful titration in the setting of liver dysfunction, given that argatroban relies on hepatic elimination.17,18 The ongoing therapy of HIT with oral anticoagulation with vitamin K antagonists such as coumadin can contribute to
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venous limb gangrene.19-21 This has been attributed to the deficiency of protein C, a naturally circulating anticoagulant.16,19 To prevent this devastating complication, the ACCP Expert Panel has recommended that coumadin therapy only be initiated in HIT when the platelet count has significantly recovered to levels exceeding 150,000 per microliter.16 Furthermore, it is recommended that the therapy be initiated conservatively with low maintenance doses and that the parenteral anticoagulation be continued until the platelet count has stabilized, the international normalized ratio goal has been attained, and there has been a minimum of 5 days overlap between these 2 anticoagulation strategies.16 If coumadin therapy has been started before the diagnosis of HIT was made, the ACCP Panel recommends that it be reversed with vitamin K to prevent gangrene and allow accurate dosing of the parenteral anticoagulant.16-22 In summary, these recommendations pertain to the diagnosis and management of HIT that typically would develop after heparin exposure during cardiac surgery. It is important to remember that currently there is no agent for rapid reversal of parenteral anticoagulation with direct thrombin inhibitors such as protamine in the case of heparin-based anticoagulation. This consideration becomes even more important when considering the anticoagulation for cardiac surgery in the patient with HIT, as discussed in the next section. WHAT IS THE MANAGEMENT OF PATIENTS WITH HIT WHO REQUIRE CARDIAC SURGERY?
Although this topic has been covered in a review article in the Journal, this article was published in 2007, a year before the release of the ACCP guidelines.16,23 This update highlights the ACCP guidelines. There are 2 possible clinical scenarios: the patient with recent HIT and the patient with acute/subacute HIT. The patient with recent HIT is defined as one who has completed HIT therapy, whose platelet count has recovered, and who is antibody negative. The patient with acute HIT is defined as one who currently is undergoing anticoagulation for HIT, who is still thrombocytopenic, and who is still antibody positive. The patient with subacute HIT is defined as one who currently is undergoing anticoagulation for HIT, who is no longer thrombocytopenic, and who is still antibody positive. Although the ACCP panel has distinguished between acute and subacute HIT, from a practical point of view, they have been considered together in this review as the recommendations for management of anticoagulation for cardiac surgery are essentially the same. WHAT IS THE APPROACH IN PATIENTS WITH RECENT HIT WHO REQUIRE CARDIAC SURGERY?
The ACCP recommendation in this clinical setting is to proceed with standard heparin-based anticoagulation because the HIT episode is over. The immune response in HIT does not follow typical immune anamnesis in which re-exposure to the drug triggers a dramatic and rapid immune-based response such as anaphylaxis.24-26 In patients with recent HIT, the antibodies that first disappear are those that are detected by the platelet activation assay. The cumulative evidence suggests that when platelet activation by HIT antibodies is no longer apparent,
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heparin exposure is safe and does not carry risk for clinical HIT. Consequently, patients with recent HIT who are positive for nonplatelet-activating HIT antibodies still may undergo cardiac surgery with heparin-based anticoagulation.16 It is not clinically necessary to wait for the complete disappearance of all HIT antibodies from the plasma in this scenario.11,16,17,23 WHAT IS THE APPROACH IN ACUTE/SUBACUTE HIT PATIENTS WHO REQUIRE CARDIAC SURGERY?
The ideal anticoagulant for cardiac surgery is still heparin despite its limitations. Heparin remains the gold standard. Consequently, the ACCP has recommended that in this clinical scenario, the cardiac surgical procedure be delayed if possible until the HIT episode has resolved and the platelet-activating HIT antibodies are no longer measurable. If the cardiac surgery cannot be delayed until resolution of the HIT, then the AACP recommends anticoagulation with the direct thrombin inhibitor bivalirudin as the next best option, with the caveat that perioperative techniques be suitably adapted.16,27-31 Although the ACCP panel also has recommended anticoagulation with lepirudin, danaparoid, and heparin with platelet blockers such as epoprostenol or tirofiban, these options are less strongly recommended.16 The ACCP has strongly endorsed bivalirudin because it is the best-studied alternative to heparin for anticoagulation in cardiac surgery, both for onpump and off-pump procedures. Consequently, in this review, bivalirudin is considered in detail because it represents the best alternative to heparin in the scenario of urgent cardiac surgery in a patient with clinically active HIT. The focus on bivalirudin is the subject of the next section. It is possible that bivalirudin may challenge heparin as the gold standard in the future conduct of anticoagulation for cardiac surgery. WHY IS BIVALIRUDIN THE HEPARIN ALTERNATIVE OF CHOICE IN CARDIAC SURGERY?
Bivalirudin (Angiomax; The Medicines Company, Parsippany, NJ) is a direct thrombin inhibitor with a short half-life of about 25 minutes.16,17 Its elimination is both enzymatic (80%) and renal (20%). Its anticoagulation effects can be monitored with the activated coagulation time. The short half-life, relative freedom from organ-based elimination, and easy intraoperative monitoring explain its emergence as the heparin alternative of choice.32,33 Unfortunately, there is currently no drug that rapidly reverses bivalirudin. This drug has a high clinical priority and could even have the name of bivalirudinase, analogous to the development of heparinase as part of the search for a protamine alternative.34 When this drug enters clinical practice, it is even more likely that heparin as the gold standard anticoagulant for cardiac surgery will have a serious rival. It is essential with bivalirudin to avoid intraoperative stasis of blood because bivalirudin is then metabolized by thrombin with a consequent loss of anticoagulation and the risk of thrombosis.16,17 Therefore, in the conduct of cardiopulmonary bypass, it is important to minimize hemostasis in the venous reservoir. Furthermore, shed pericardial and mediastinal blood should be processed in cell-salvage systems before retransfusion to minimize the risk of thromboemboli that result from metabolism of bivalirudin by thrombin in stagnant pericardial and mediastinal blood.17
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Bivalirudin was shown in 2 clinical trials (cumulative N ⫽ 100) to be a safe and effective heparin alternative for cardiac surgery in patients with HIT, both for on-pump and off-pump procedures.30,31 Bivalirudin was also safe and effective in these 2 trials in patients with impaired renal function.30,31 Furthermore, in a second set of trials (cumulative N ⫽ 251), bivalirudin, as compared with heparin, proved to be a safe, reliable, and effective anticoagulant both for on-pump and off-pump cardiac surgery.28,29 The details of the dosing regimens are outlined in those publications. In summary, bivalirudin when used correctly, is the heparin alternative of choice for patients with active HIT who require urgent cardiac surgery. It is possible that the application of bivalirudin in cardiac surgery will expand, as has been the case in percutaneous coronary intervention (PCI), an evolution that is the subject of the following section. COULD BIVALIRUDIN REPLACE HEPARIN AS THE GOLD STANDARD IN CARDIAC SURGERY?
This question develops from the efficacy of bivalirudin as an alternative to heparin for cardiac surgery in patients with clinically active HIT. Because heparin has been the unchallenged gold standard anticoagulant for cardiac surgery since the beginning of cardiopulmonary bypass, it is difficult to imagine a serious alternative. Yet, the evolution of bivalirudin in anticoagulation for PCI since the 1990s sheds light on what could happen in the world of cardiac surgical intervention in the decade to come. Bivalirudin emerged in the 1990s when landmark clinical trials showed its safety and efficacy as an alternative anticoagulant to heparin for PCI.35 In the contemporary era, the anticoagulation options for PCI have expanded far beyond unfractionated heparin; they include enoxaparin, fondaparinux, bivalirudin, as well the family of oral and parenteral platelet blockers.36 All the anticoagulants act directly or indirectly on thrombin, with each thrombin inhibitor having relative advantages and disadvantages in PCI.36 The advantages of bivalirudin in PCI include its lack of platelet activation, its tendency to cause less bleeding, and its association with a lower mortality in primary PCI.36,37 The future in anticoagulation for PCI likely will focus on the selection of the best antithrombin therapy for a particular patient, taking into account the patient, the coronary anatomy, and the entire clinical setting. The challenge in antithrombin therapy for PCI is to individualize this therapy so that a particular patient will have the greatest freedom possible from both coronary ischemia and significant bleeding.
This advanced menu of antithrombin therapy in PCI is in contrast to the more limited menu in cardiac surgery. Despite the longstanding experience with heparin, there is still significant variability in the conduct of anticoagulation for cardiac surgery.38 Advances in anticoagulation for cardiac surgery are required because the limitations of heparin and protamine are well established. The major challenges in this field of endeavor should be addressed by multidisciplinary teams conducting adequately powered perioperative trials linked to meaningful clinical outcomes.39 There is a powerful lesson from the aprotinin saga that is relevant here. Aprotinin was introduced into clinical practice more than 20 years ago.40 It was only recently that an adequately powered, randomized controlled trial finally evaluated the safety and efficacy of the 3 antifibrinolytics commonly used in cardiac surgery.41,42 Because bivalirudin now appears to be clinically equivalent to heparin, is it not time to perform an adequately powered trial to test which thrombin inhibitor leads to superior outcomes after cardiac surgery? These meaningful outcomes should be studied not only in the short term but also in the long term, as in the example of the PCI trials.36 CONCLUSIONS
HIT is important because it is common, and it significantly increases mortality after cardiac surgery. Although thrombocytopenia after cardiac surgery is common, it predicts serious adverse outcome when it is severe. Despite the high prevalence of heparin/platelet factor 4 antibodies in cardiac surgical patients, they typically do not indicate a higher perioperative risk. Recent evidence suggests, however, that when these antibodies are in the immunoglobulin M class, there is an increased risk of nonthrombotic adverse outcomes after cardiac surgery. According to the guidelines from the ACCP, patients with HIT require parenteral anticoagulation with a thrombin inhibitor such as lepirudin, argatroban, or bivalirudin. Transition to oral anticoagulation with coumadin must be undertaken cautiously and only after the platelet count has recovered to prevent the onset of devastating clinical thrombosis. Patients with a remote history of HIT safely can have cardiac surgery with unfractionated heparin. Patients with clinically active HIT who require cardiac surgery before the resolution of the HIT preferably should be anticoagulated with bivalirudin, dosed according to body weight and goal-activated clotting time. Given that bivalirudin is an established alternative to heparin as a thrombin inhibitor for cardiac surgery, it is likely that future trials will investigate which anticoagulant confers better outcomes after cardiac surgery, as is the case in PCI.
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25. Lubenow N, Kempf R, Eichner A, et al: Heparin-induced thrombocytopenia: Temporal pattern of thrombocytopenia in relation to initial use or reexposure to heparin. Chest 122:37-42, 2002 26. Otis SA, Zehnder JL: Heparin-induced thrombocytopenia: Current status and diagnostic challenges. Am J Hematol 85:700-706, 2010 27. Smedira NG, Dyke CM, Koster A, et al: Anticoagulation with bivalirudin for off-pump coronary artery bypass grafting: The results of the EVOLUTION-OFF study. J Thorac Cardiovasc Surg 131:686-692, 2006 28. Koster A, Spiess B, Jurmann M, et al: Bivalirudin provides rapid, effective, and reliable anticoagulation during off-pump coronary revascularization: Results of the “EVOLUTION OFF” trial. Anesth Analg 103:540-544, 2006 29. Dyke CM, Smedira NG, Koster A, et al: A comparison of bivalirudin to heparin with protamine reversal in patients undergoing cardiac surgery with cardiopulmonary bypass: The EVOLUTION-ON study. J Thorac Cardiovasc Surg 131:533-539, 2006 30. Koster A, Dyke CM, Aldea G, et al: Bivalirudin during cardiopulmonary bypass in patients with heparin-induced thrombocytopenia and heparin antibodies: The CHOOSE-ON trial. Ann Thorac Surg 83:572-577, 2007 31. Dyke CM, Aldea G, Koster A, et al: Off-pump coronary artery bypass with bivalirudin for patients with heparin-induced thrombocytopenia or antiplatelet factor 4/heparin antibodies. Ann Thorac Surg 84:836-839, 2007 32. Van De Car DA, Rao SV, Ohman EM: Bivalirudin: A review of the pharmacology and clinical application. Expert Rev Cardiovasc Ther 8:1673-1681, 2010 33. Anand SX, Villes-Gonzalez JF, Mahboobi SK, et al: Bivalirudin utilization in cardiac surgery: Shifting anticoagulation from indirect to direct thrombin inhibition. Can J Anaesth 2010 [Epub ahead of print] 34. Stafford-Smith M, Lefrak EA, Qazi AG, et al: Efficacy and safety of heparinase-1 versus protamine in patients undergoing coronary artery bypass grafting with and without cardiopulmonary bypass. Anesthesiology 103:229-240, 2005 35. Bittl JA, Strony J, Brinker JA, et al: Treatment with bivalirudin (hirulog) as compared with heparin during coronary angioplasty for unstable or postinfarction angina. N Engl J Med 333:764-769, 1995 36. Rao SV, Ohman EM: Anticoagulant therapy for percutaneous coronary intervention. Circ Cardiovasc Interv 3:80-88, 2010 37. Lindsey JB, Cohen DJ, Stolker JM, et al: The impact of bivalirudin on percutaneous coronary intervention-related bleeding. Eurointervention 6:206-213, 2010 38. Lobato RL, Despotis GJ, Levy JH, et al: Anticoagulation management during cardiopulmonary bypass: A survey of 54 North American institutions. J Thorac Cardiovasc Surg 139:1665-1666, 2010 39. Levy JH, Dutton RP, Hemphill JC, et al: Multidisciplinary approach to the challenge of hemostasis. Anesth Analg 110:354-354, 2010 40. Augoustides JG: Aprotinin and renal dysfunction: What does history teach us? Expert Opin Drug Saf 8:5-7, 2009 41. Augoustides JG: Perioperative safety of aprotinin in coronary artery bypass graft surgery: Is there life after BART? Drug Saf 31:557560, 2008 42. Fergusson DA, Hebert PC, Mazer CD, et al: A comparison of aprotinin and lysine analogues in high-risk cardiac surgery. N Engl J Med 358:2319-2331, 2008