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IIIa Inhibitor Tirofiban
Successful Treatment of Rotary Pump Thrombus With the Glycoprotein IIb/IIIa Inhibitor Tirofiban Martin D. Thomas, BM,a Clare Wood, MN,a Mike Lovett, BSc,a Lawrence Dembo, MB BS,a and Gerry O’Driscoll, MB BCh, PhDa,b Despite advances in blood pump technology, thrombus formation within left ventricular assist devices (LVADs) is a life-threatening complication with few therapeutic options. A 38-year-old woman who underwent rotary LVAD implantation as a bridge to cardiac transplant developed labile flows (4 to ⬎10 liters), associated with power spikes (4 to 12 watts) and an increase in plasma free hemoglobin (0.86 g/liter), consistent with pump thrombus at Day 140 post-LVAD implantation, despite thromboprophylaxis with aspirin and warfarin. Within 12 hours of commencing an intravenous infusion of tirofiban at a rate of 0.1 g/kg/min, there were signs of improvement of pump dysfunction, and complete resolution was evident at Day 4 with, stable flows, power consumption and normalization of plasma free hemoglobin. Tirofiban may be considered as an alternative thrombolytic treatment strategy in rotary pump thrombus to avoid the need for LVAD replacement. J Heart Lung Transplant 2008;27: 925–7. Copyright © 2008 by the International Society for Heart and Lung Transplantation.
Cardiac transplantation provides the optimum treatment for end-stage heart failure in a select group of patients. However, the recent decline in organ donations contrasts starkly with the increasing number of suitable recipients and ⬎15% of patients die while waiting for a cardiac transplant.1 Left ventricular assist devices (LVADs) are now an established form of treatment for patients with end-stage heart failure as a bridge to cardiac transplantation. Despite advances in blood pump technology, pump thrombus is a life-threatening complication with few therapeutic options, although surgical device change, thrombolysis with tissue plasminogen activator (t-PA) and clopidogrel therapy have been utilized.2– 4 We report the successful use of tirofiban (Aggrastat; Merck & Co.), a platelet glycoprotein IIb/IIIa receptor inhibitor, as a thrombolytic agent in the presence of a pump thrombus in a patient with a rotary LVAD. CASE REPORT A 38-year-old woman with severe idiopathic dilated cardiomyopathy who was inotrope-dependent, with an ejection fraction of 20% and a cardiac index of 2.1
From the aAdvanced Heart Failure and Cardiac Transplant Service, Royal Perth Hospital, Perth; and bSchool of Medicine, University of Notre Dame, Fremantle, Western Australia, Australia. Submitted February 11, 2008; revised May 13, 2008; accepted May 19, 2008. Reprint requests: Martin D. Thomas, MD, Advanced Heart Failure and Cardiac Transplant Service, Royal Perth Hospital, GPO Box X2213, Perth WA 6847, Australia. Telephone: 00-61-8-9224-1387. Fax: 00-61-8-9224-1464. E-mail: [email protected] Copyright © 2008 by the International Society for Heart and Lung Transplantation. 1053-2498/08/$–see front matter. doi:10.1016/ j.healun.2008.05.015
liters/min, underwent implantation of a HeartWare HVAD system. There were no peri- or post-operative complications and she was extubated and discharged from the ICU after 48 hours. The thromboembolic prophylaxis regimen consisted of warfarin, to maintain an international normalized ratio (INR) of 2.5 to 3.5, and aspirin 150 mg/day. She was discharged from the hospital on Day 19 but re-presented at Day 132 with a percutaneous drive-line infection. On Day 140 she had evidence of LVAD dysfunction consistent with pump thrombus. At a constant pump speed of 2,400 revolutions per minute (rpm) and an INR of 3.2, flows increased to ⬎10 liters/min and were associated with an increase in power to 12 watts (Figure 1). The pump was “noisy” and the plasma free hemoglobin level was elevated at 0.86 g/liter, an increase from 0.08 g/liter 24 hours earlier. Thromboembolic prophylaxis was then changed. Warfarin was discontinued, and an intravenous infusion of heparin was commenced and titrated to maintain an activated partial prothrombin time (aPTT) of 60 to 80 seconds. Clopidogrel (Plavix; Sanofi-Aventis, Paris, France) was commenced with an oral loading dose of 600 mg and then 75 mg/day. Transthoracic echocardiography, recorded at 2,600 rpm with flows ⬎10 liters/m, indicated a left ventricular end-diastolic diameter of 5.2 cm, peak cannular velocities of 2.2 meters/second, and opening of the aortic valve with every cardiac cycle. Flows remained labile with associated power spikes and it was therefore decided to administer an intravenous infusion of tirofiban at a rate of 0.1 g/kg/min. Within 12 hours there were signs of improvement and complete resolution was evident at Event Day 4 with loss of LVAD noise, stable flows and power 925
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The Journal of Heart and Lung Transplantation August 2008
Figure 1. Initial power demand surges and labile flows in the patient’s Heartware HVAD pump indicating device thrombus and subsequent time course to normalization following administration of tirofiban.
consumption (Figure 1). On Event Day 5, technical analysis confirmed optimal pump function. Tirofiban was continued for 6 days in total, and during this time the pump speed was increased to 2,800 rpm and the Lavare cycle suspended to halt the cyclical slowing of the device and maintain an optimal blood flow across the LVAD and optimize drug delivery while the tirofiban infusion was in progress. Warfarin was recommenced (INR 2.5 to 3) on Event Day 4 and both aspirin and clopidogrel were continued. Plasma hemoglobin levels were monitored daily and peaked at 2.7 g/liter on Event Day 2, but normalized at 0.10 g/liter by Event Day 6. There was no reported hemodynamic instability. The patient was menstruating heavily during tirofiban infusion and required a 2-unit blood transfusion. Repeat transthoracic echocardiogram recorded on Event Day 6 at 2,800 rpm reported a left ventricular end-diastolic diameter of 3.7 cm with a flow of 6 liters/min and a markedly reduced opening of the aortic valve when compared with the previous study. The patient was discharged with no recurrence of thrombosis and was successfully transplanted on Day 156. At explantation of the device there was no evidence of intracardiac thrombi or abnormality of inflow cannula position. DISCUSSION Pump thrombus has previously been described after implantation of rotary LVADs.5,6 The mechanism for device thrombus formation is multifactorial. Platelet activation markers are elevated in end-stage heart fail-
ure and remain high after LVAD implantation.7 The surface roughness of the LVAD and shear forces within the device contribute to platelet activation in rotary blood pumps.8 This, together with the persistent inflammatory state and endothelial activation observed after ventricular support,9 results in platelet aggregation mediated primarily by the interaction of activated platelet glycoprotein IIb/IIIa receptors with fibrinogen and von Willebrand factor to form an organized platelet-rich thrombus.10 These so-called “white thrombi” differ from “red thrombi” that are rich in fibrin and trapped red blood cells, which are generally treated with anticoagulants. Heparin and warfarin are routinely used to reduce the risk of thrombosis by inhibiting the coagulation cascade and reducing fibrin formation, but they have no effect on platelet function, which may be equally important in initiating and sustaining device thrombosis.11 Anti-coagulation protocols after LVAD implantation usually combine anti-coagulation with heparin or warfarin together with one or more anti-platelet agent. Aspirin is the most frequently used anti-platelet agent but aspirin resistance occurs in 5% to 60% of aspirin-treated patients12 and is exacerbated by consumption of platelets during cardiopulmonary bypass and mechanical assistance, in part due to the formation of platelet microaggregates in the blood pump.13 The thienopyridine derivative, clopidogrel, is an alternative anti-platelet agent, which inhibits adenosine diphosphate receptor–induced platelet aggregation,14
The Journal of Heart and Lung Transplantation Volume 27, Number 8
but resistance to clopidogrel has also been reported.15 In view of aspirin and clopidogrel resistance, dual anti-platelet therapy may be more effective in preventing pump thrombus. This approach has proven to be highly effective at reducing the risk of thrombosis after percutaneous coronary intervention,16 but there is no consensus on the most effective anti-coagulation and anti-platelet regime after LVAD implantation. The diagnosis of pump thrombus formation is indirectly made from rising flows and power demands with evidence of intravascular hemolysis. Although t-PA has been used successfully to treat pump thrombus,3 we were reluctant to use it in our patient as she was menstruating heavily. Clopidogrel has been reported as an alternative thrombolytic agent in the presence of pump thrombus,17 but its administration had little immediate effect in our patient. Tirofiban is a platelet glycoprotein IIb/IIIa receptor inhibitor that has been described as an effective thrombolytic agent in the management of acute coronary syndromes.18 We postulated that tirofiban would produce effective thrombolysis in the presence of pump thrombus. Meola et al demonstrated that heparin alone does not provide adequate protection against thrombosis, but the addition of tirofiban results in a reduction of device-induced thrombus formation and number of thromboemboli.19 After tirofiban administration in our patient there was a gradual improvement in flow and power surges, which returned to baseline within 96 hours, indicating resolution of pump thrombus. The slow onset of resolution may be due to the fact that a loading dose of tirofiban was not administered, resulting in a slower onset of platelet aggregation inhibition. In conclusion, tirofiban may be considered as an alternative thrombolytic treatment strategy in pump thrombus in rotary LVADs. The optimal anti-coagulation regime for these patients is a continuing conundrum, but aggressive dual anti-platelet therapy may be more appropriate.
Thomas et al.
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REFERENCES 1. Orens JB, Shearon TH, Freudenberger RS, et al. Thoracic organ transplantation in the United States, 1995–2004. Am J Transplant 2006;6:1188 –97. 2. Birks EJ, Tansley PD, Yacoub MH, et al. Incidence and clinical management of life-threatening left ventricular assist device failure. J Heart Lung Transplant 2004;23:964 –9. 3. Rothenburger M, Wilhelm MJ, Hammel D, et al. Treatment of thrombus formation associated with the MicroMed DeBakey VAD
18.
19.
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using recombinant tissue plasminogen activator. Circulation 2002;106(suppl I):I-189 –92. Studer MA, Kennedy CE, Dreyer WJ, et al. An alternative treatment strategy for pump thrombus in the DeBakey VAD Child: use of clopidogrel as a thrombolytic agent. J Heart Lung Transplant 2006;25:857– 61. Delgado R, Frazier OH, Myers TJ, et al. Direct thrombolytic therapy for intraventricular thrombosis in patients with the Jarvik 2000 left ventricular assist device. J Heart Lung Transplant 2005;24:231–3. Hayes H, Dembo L, Larbalestier R, O’Driscoll G. Successful treatment of ventricular assist device associated ventricular thrombus with systemic tenecteplase. Heart Lung Circ 2008;17: 235–55. Dewald O, Schmitz C, Diem H, et al. Platelet activation markers in patients with heart assist device. Artif Organs 2005;29:292–9. Linneweber J, Dohmen PM, Kertzscher U, et al. The effect of surface roughness on activation of the coagulation system and platelet adhesion in rotary blood pumps. Artif Organs 2007;31: 345–51. Houel R, Mazoyer E, Boval B, et al. Platelet activation and aggregation profile in prolonged external ventricular support. J Thorac Cardiovasc Surg 2004;128:197–202. Steinhubl SR, Moliterno DJ. The role of platelets in the pathogenesis of atherothrombosis. Am J Cardiovasc Drugs 2005;5:399 – 408. Gorbet MB, Sefton MV. Biomaterial-associated thrombosis: roles of coagulation factors, complement, platelets and leukocytes. Biomaterials 2004;25:5681–703. Michelson AD, Cattaneo M, Eikelboom JW, et al. Aspirin resistance: position paper of the Working Group on Aspirin Resistance. J Thromb Haemost 2005;3:1309 –11. Linneweber J, Chow TW, Kawamura M, Moake JL, Nose Y. In vitro comparison of blood pump induced platelet microaggregates between a centrifugal and roller pump during cardiopulmonary bypass. Int J Artif Organs 2002;25:549 –55. Savi P, Pereillo JM, Uzabiaga MF, et al. Identification and biological activity of the active metabolite of clopidogrel. Thromb Haemost 2000;84:891– 6. Matetzky S, Shenkman B, Guetta V, et al. Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction. Circulation 2004;109:3171–5. Steinhubl SR, Berger PB, Mann JT III, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA 2002;288: 2411–20. Studer MA, Kennedy CE, Dreyer WJ, et al. An alternative treatment strategy for pump thrombus in the DeBakey VAD Child: use of clopidogrel as a thrombolytic agent. J Heart Lung Transplant 2006;25:857– 61. Theroux P, Alexander J, Dupuis J, et al. Upstream use of tirofiban in patients admitted for an acute coronary syndrome in hospitals with or without facilities for invasive management. Am J Cardiol 2001;87:375– 80. Meola S, Burns G, Sukavaneshvar S, Solen K, Mohammad S. Mitigation of device-associated thrombosis and thromboembolism using combinations of heparin and tirofiban. J Extra Corpor Technol 2006;38:230 – 4.
Cardiac transplantation provides the optimum treatment for end-stage heart failure in a select group of patients. However, the recent decline in organ donations contrasts starkly with the increasing number of suitable recipients and ⬎15% of patients die while waiting for a cardiac transplant.1 Left ventricular assist devices (LVADs) are now an established form of treatment for patients with end-stage heart failure as a bridge to cardiac transplantation. Despite advances in blood pump technology, pump thrombus is a life-threatening complication with few therapeutic options, although surgical device change, thrombolysis with tissue plasminogen activator (t-PA) and clopidogrel therapy have been utilized.2– 4 We report the successful use of tirofiban (Aggrastat; Merck & Co.), a platelet glycoprotein IIb/IIIa receptor inhibitor, as a thrombolytic agent in the presence of a pump thrombus in a patient with a rotary LVAD. CASE REPORT A 38-year-old woman with severe idiopathic dilated cardiomyopathy who was inotrope-dependent, with an ejection fraction of 20% and a cardiac index of 2.1
From the aAdvanced Heart Failure and Cardiac Transplant Service, Royal Perth Hospital, Perth; and bSchool of Medicine, University of Notre Dame, Fremantle, Western Australia, Australia. Submitted February 11, 2008; revised May 13, 2008; accepted May 19, 2008. Reprint requests: Martin D. Thomas, MD, Advanced Heart Failure and Cardiac Transplant Service, Royal Perth Hospital, GPO Box X2213, Perth WA 6847, Australia. Telephone: 00-61-8-9224-1387. Fax: 00-61-8-9224-1464. E-mail: [email protected] Copyright © 2008 by the International Society for Heart and Lung Transplantation. 1053-2498/08/$–see front matter. doi:10.1016/ j.healun.2008.05.015
liters/min, underwent implantation of a HeartWare HVAD system. There were no peri- or post-operative complications and she was extubated and discharged from the ICU after 48 hours. The thromboembolic prophylaxis regimen consisted of warfarin, to maintain an international normalized ratio (INR) of 2.5 to 3.5, and aspirin 150 mg/day. She was discharged from the hospital on Day 19 but re-presented at Day 132 with a percutaneous drive-line infection. On Day 140 she had evidence of LVAD dysfunction consistent with pump thrombus. At a constant pump speed of 2,400 revolutions per minute (rpm) and an INR of 3.2, flows increased to ⬎10 liters/min and were associated with an increase in power to 12 watts (Figure 1). The pump was “noisy” and the plasma free hemoglobin level was elevated at 0.86 g/liter, an increase from 0.08 g/liter 24 hours earlier. Thromboembolic prophylaxis was then changed. Warfarin was discontinued, and an intravenous infusion of heparin was commenced and titrated to maintain an activated partial prothrombin time (aPTT) of 60 to 80 seconds. Clopidogrel (Plavix; Sanofi-Aventis, Paris, France) was commenced with an oral loading dose of 600 mg and then 75 mg/day. Transthoracic echocardiography, recorded at 2,600 rpm with flows ⬎10 liters/m, indicated a left ventricular end-diastolic diameter of 5.2 cm, peak cannular velocities of 2.2 meters/second, and opening of the aortic valve with every cardiac cycle. Flows remained labile with associated power spikes and it was therefore decided to administer an intravenous infusion of tirofiban at a rate of 0.1 g/kg/min. Within 12 hours there were signs of improvement and complete resolution was evident at Event Day 4 with loss of LVAD noise, stable flows and power 925
926
Thomas et al.
The Journal of Heart and Lung Transplantation August 2008
Figure 1. Initial power demand surges and labile flows in the patient’s Heartware HVAD pump indicating device thrombus and subsequent time course to normalization following administration of tirofiban.
consumption (Figure 1). On Event Day 5, technical analysis confirmed optimal pump function. Tirofiban was continued for 6 days in total, and during this time the pump speed was increased to 2,800 rpm and the Lavare cycle suspended to halt the cyclical slowing of the device and maintain an optimal blood flow across the LVAD and optimize drug delivery while the tirofiban infusion was in progress. Warfarin was recommenced (INR 2.5 to 3) on Event Day 4 and both aspirin and clopidogrel were continued. Plasma hemoglobin levels were monitored daily and peaked at 2.7 g/liter on Event Day 2, but normalized at 0.10 g/liter by Event Day 6. There was no reported hemodynamic instability. The patient was menstruating heavily during tirofiban infusion and required a 2-unit blood transfusion. Repeat transthoracic echocardiogram recorded on Event Day 6 at 2,800 rpm reported a left ventricular end-diastolic diameter of 3.7 cm with a flow of 6 liters/min and a markedly reduced opening of the aortic valve when compared with the previous study. The patient was discharged with no recurrence of thrombosis and was successfully transplanted on Day 156. At explantation of the device there was no evidence of intracardiac thrombi or abnormality of inflow cannula position. DISCUSSION Pump thrombus has previously been described after implantation of rotary LVADs.5,6 The mechanism for device thrombus formation is multifactorial. Platelet activation markers are elevated in end-stage heart fail-
ure and remain high after LVAD implantation.7 The surface roughness of the LVAD and shear forces within the device contribute to platelet activation in rotary blood pumps.8 This, together with the persistent inflammatory state and endothelial activation observed after ventricular support,9 results in platelet aggregation mediated primarily by the interaction of activated platelet glycoprotein IIb/IIIa receptors with fibrinogen and von Willebrand factor to form an organized platelet-rich thrombus.10 These so-called “white thrombi” differ from “red thrombi” that are rich in fibrin and trapped red blood cells, which are generally treated with anticoagulants. Heparin and warfarin are routinely used to reduce the risk of thrombosis by inhibiting the coagulation cascade and reducing fibrin formation, but they have no effect on platelet function, which may be equally important in initiating and sustaining device thrombosis.11 Anti-coagulation protocols after LVAD implantation usually combine anti-coagulation with heparin or warfarin together with one or more anti-platelet agent. Aspirin is the most frequently used anti-platelet agent but aspirin resistance occurs in 5% to 60% of aspirin-treated patients12 and is exacerbated by consumption of platelets during cardiopulmonary bypass and mechanical assistance, in part due to the formation of platelet microaggregates in the blood pump.13 The thienopyridine derivative, clopidogrel, is an alternative anti-platelet agent, which inhibits adenosine diphosphate receptor–induced platelet aggregation,14
The Journal of Heart and Lung Transplantation Volume 27, Number 8
but resistance to clopidogrel has also been reported.15 In view of aspirin and clopidogrel resistance, dual anti-platelet therapy may be more effective in preventing pump thrombus. This approach has proven to be highly effective at reducing the risk of thrombosis after percutaneous coronary intervention,16 but there is no consensus on the most effective anti-coagulation and anti-platelet regime after LVAD implantation. The diagnosis of pump thrombus formation is indirectly made from rising flows and power demands with evidence of intravascular hemolysis. Although t-PA has been used successfully to treat pump thrombus,3 we were reluctant to use it in our patient as she was menstruating heavily. Clopidogrel has been reported as an alternative thrombolytic agent in the presence of pump thrombus,17 but its administration had little immediate effect in our patient. Tirofiban is a platelet glycoprotein IIb/IIIa receptor inhibitor that has been described as an effective thrombolytic agent in the management of acute coronary syndromes.18 We postulated that tirofiban would produce effective thrombolysis in the presence of pump thrombus. Meola et al demonstrated that heparin alone does not provide adequate protection against thrombosis, but the addition of tirofiban results in a reduction of device-induced thrombus formation and number of thromboemboli.19 After tirofiban administration in our patient there was a gradual improvement in flow and power surges, which returned to baseline within 96 hours, indicating resolution of pump thrombus. The slow onset of resolution may be due to the fact that a loading dose of tirofiban was not administered, resulting in a slower onset of platelet aggregation inhibition. In conclusion, tirofiban may be considered as an alternative thrombolytic treatment strategy in pump thrombus in rotary LVADs. The optimal anti-coagulation regime for these patients is a continuing conundrum, but aggressive dual anti-platelet therapy may be more appropriate.
Thomas et al.
4.
5.
6.
7. 8.
9.
10.
11.
12.
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15.
16.
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REFERENCES 1. Orens JB, Shearon TH, Freudenberger RS, et al. Thoracic organ transplantation in the United States, 1995–2004. Am J Transplant 2006;6:1188 –97. 2. Birks EJ, Tansley PD, Yacoub MH, et al. Incidence and clinical management of life-threatening left ventricular assist device failure. J Heart Lung Transplant 2004;23:964 –9. 3. Rothenburger M, Wilhelm MJ, Hammel D, et al. Treatment of thrombus formation associated with the MicroMed DeBakey VAD
18.
19.
927
using recombinant tissue plasminogen activator. Circulation 2002;106(suppl I):I-189 –92. Studer MA, Kennedy CE, Dreyer WJ, et al. An alternative treatment strategy for pump thrombus in the DeBakey VAD Child: use of clopidogrel as a thrombolytic agent. J Heart Lung Transplant 2006;25:857– 61. Delgado R, Frazier OH, Myers TJ, et al. Direct thrombolytic therapy for intraventricular thrombosis in patients with the Jarvik 2000 left ventricular assist device. J Heart Lung Transplant 2005;24:231–3. Hayes H, Dembo L, Larbalestier R, O’Driscoll G. Successful treatment of ventricular assist device associated ventricular thrombus with systemic tenecteplase. Heart Lung Circ 2008;17: 235–55. Dewald O, Schmitz C, Diem H, et al. Platelet activation markers in patients with heart assist device. Artif Organs 2005;29:292–9. Linneweber J, Dohmen PM, Kertzscher U, et al. The effect of surface roughness on activation of the coagulation system and platelet adhesion in rotary blood pumps. Artif Organs 2007;31: 345–51. Houel R, Mazoyer E, Boval B, et al. Platelet activation and aggregation profile in prolonged external ventricular support. J Thorac Cardiovasc Surg 2004;128:197–202. Steinhubl SR, Moliterno DJ. The role of platelets in the pathogenesis of atherothrombosis. Am J Cardiovasc Drugs 2005;5:399 – 408. Gorbet MB, Sefton MV. Biomaterial-associated thrombosis: roles of coagulation factors, complement, platelets and leukocytes. Biomaterials 2004;25:5681–703. Michelson AD, Cattaneo M, Eikelboom JW, et al. Aspirin resistance: position paper of the Working Group on Aspirin Resistance. J Thromb Haemost 2005;3:1309 –11. Linneweber J, Chow TW, Kawamura M, Moake JL, Nose Y. In vitro comparison of blood pump induced platelet microaggregates between a centrifugal and roller pump during cardiopulmonary bypass. Int J Artif Organs 2002;25:549 –55. Savi P, Pereillo JM, Uzabiaga MF, et al. Identification and biological activity of the active metabolite of clopidogrel. Thromb Haemost 2000;84:891– 6. Matetzky S, Shenkman B, Guetta V, et al. Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction. Circulation 2004;109:3171–5. Steinhubl SR, Berger PB, Mann JT III, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA 2002;288: 2411–20. Studer MA, Kennedy CE, Dreyer WJ, et al. An alternative treatment strategy for pump thrombus in the DeBakey VAD Child: use of clopidogrel as a thrombolytic agent. J Heart Lung Transplant 2006;25:857– 61. Theroux P, Alexander J, Dupuis J, et al. Upstream use of tirofiban in patients admitted for an acute coronary syndrome in hospitals with or without facilities for invasive management. Am J Cardiol 2001;87:375– 80. Meola S, Burns G, Sukavaneshvar S, Solen K, Mohammad S. Mitigation of device-associated thrombosis and thromboembolism using combinations of heparin and tirofiban. J Extra Corpor Technol 2006;38:230 – 4.