J Thromb Thrombolysis (2014) 38:73–77 DOI 10.1007/s11239-014-1055-8
Treatment of mechanical aortic valve thrombosis with heparin and eptifibatide Amit N. Vora • Thomas Gehrig • Thomas M. Bashore Todd L. Kiefer
•
Published online: 28 January 2014 Ó Springer Science+Business Media New York 2014
Abstract A 75-year old woman with a history of coronary disease status post 3-vessel coronary artery bypass grafting (CABG) 8 years ago and a repeat one-vessel CABG 2 years ago in the setting of aortic valve replacement with a #19 mm St. Jude bileaflet mechanical valve for severe aortic stenosis presented with two to three weeks of progressive dyspnea and increasing substernal chest discomfort. Echocardiography revealed a gradient to 31 mmHg across her aortic valve, increased from a baseline of 13 mmHg five months previously. Fluoroscopy revealed thrombosis of her mechanical aortic valve. She was not a candidate for surgery given her multiple comorbidities, and fibrinolysis was contraindicated given a recent subdural hematoma 1 year prior to presentation. She was treated with heparin and eptifibatide and subsequently demonstrated resolution of her aortic valve thrombosis. We report the first described successful use of eptifibatide in addition to unfractionated heparin for the management of subacute valve thrombosis in a patient at high risk for repeat surgery or fibrinolysis. Keywords Mechanical valve thrombosis Platelets Anticoagulants Eptifibatide
Electronic supplementary material The online version of this article (doi:10.1007/s11239-014-1055-8) contains supplementary material, which is available to authorized users. A. N. Vora (&) T. Gehrig T. M. Bashore T. L. Kiefer Duke University Medical Center, 2301 Erwin Road Room 7411A, Durham, NC 27710, USA e-mail: [email protected]
Case presentation A 75-year old woman presented to the emergency department with two to three weeks of progressive dyspnea and increasing substernal chest discomfort, noting that recently she had been using her sublingual nitroglycerin multiple times daily. She had a history of coronary disease status post 3-vessel coronary artery bypass grafting (CABG) in 2005 and a repeat one vessel CABG in 2011 in the setting of aortic valve replacement (AVR) with a #19 mm St. Jude bileaflet mechanical valve for severe aortic stenosis. She also had a history of sick sinus syndrome and atrial fibrillation with permanent pacemaker placement. Given the mechanical aortic valve and atrial fibrillation, she was anticoagulated with warfarin. In addition, she suffered a fall 1 year ago with a subdual hematoma that was medically managed; her warfarin was temporarily stopped at that time, but subsequently reinitiated. On physical examination, her systemic blood pressure was 131/61 mmHg with a heart rate of 95 beats per minute. She was frail but well-appearing and in no acute distress. Her jugular venous pressure was normal. Cardiac auscultation revealed a regular rate and rhythm, a soft S1 and a mechanical S2, with a II/VI harsh ejection murmur at the left sternal border. Her lungs were clear to auscultation and she had trace bilateral pedal edema. Laboratory testing revealed a creatinine of 1.2 mg/dL, normocytic anemia with a hemoglobin of 10.8 g/dL, and three sets of negative cardiac biomarkers. Her international normalized ration (INR) was 1.1 despite taking warfarin daily. Her INR had been difficult to control in the two months prior to admission, with values ranging from 1.2 to 4.7. Her electrocardiogram revealed an atrial-paced rhythm at 80 beats per minute and right axis deviation (Fig. 1). Transthoracic echocardiography revealed a left ventricular ejection fraction of 45 % with global hypokinesis. A peak velocity of 3.5 m/s and a mean gradient
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of 31 mmHg were measured across the prosthetic aortic valve (Fig. 2a); previous transthoracic echocardiogram performed five months earlier revealed a peak velocity of 2.4 m/s and a mean gradient of 13 mmHg (Fig. 2b). Chest radiograph revealed mild bilateral pleural effusions that were unchanged from a previous radiograph. Given that the patient’s clinical presentation was concerning for unstable angina with a mild congestive heart failure exacerbation, she was started on unfractionated heparin and taken to the cardiac catheterization laboratory for coronary angiography, a right heart catheterization, and fluoroscopy of her mechanical AVR. Coronary angiography revealed severe native three-vessel disease with patent grafts that was grossly unchanged from her most recent cardiac catheterization 1 year ago. Right heart catheterization revealed mild pulmonary hypertension (pulmonary artery mean 33 mmHg), a mildly elevated pulmonary capillary wedge pressure (PCWP) to 18 mmHg, and a preserved cardiac index of 2.6 L/min-m2. Fluoroscopy demonstrated that one of the mechanical aortic valve leaflets was fixed in the closed position (Fig. 1, Movie 1). This was consistent with the abrupt increase in her aortic valve gradient since her last echocardiogram several months earlier. It was felt this represented thrombus on the mechanical leaflet, and not pannus, given the subtherapeutic INR on admission and the time frame of change in the valve gradient. The patient was considered for redo aortic valve replacement, but was felt to be very high risk given her multiple comorbidities and two prior median sternotomies. Fibrinolysis was also considered but contraindicated given her history
A. N. Vora et al. Fig. 2 a A peak velocity of 3.5 m/s and a mean gradient of c 31 mmHg were measured across the prosthetic aortic valve. Fluoroscopy demonstrated that one of the mechanical aortic valve leaflets was fixed in the closed position (arrow). b The most recent echocardiogram performed five months prior to admission revealed a peak velocity of 2.4 m/s and a mean gradient of 13 mmHg
of subdural hematoma. After extensive discussion and determination that she was not a candidate for redo-valve surgery or fibrinolysis, she was started on eptifibatide 1 mcg/kg/min (renally dosed for her creatinine clearance) without bolus. The UFH dose was titrated to a goal activated partial thromboplastin time (aPTT) of 60–90 s. She underwent repeat transthoracic echocardiogram three days later that revealed a peak velocity of 3.2 m/s with a mean gradient of 23 mmHg across the mechanical aortic valve (Fig. 3, Movie 2). Repeat fluoroscopy after five days of treatment with UFH and eptifibatide revealed markedly improved motion of the previously fixed leaflet, now opening out to 65°–70°. She was continued on heparin and eptifibatide for a total of seven days and then was transitioned to warfarin with an UFH bridge with a goal INR of 2.5–3.5. Subsequent echocardiogram performed two days prior to discharge revealed a peak velocity of 2.8 m/s and a mean gradient of 19 mmHg across the aortic valve.
Discussion Thrombosis of a prosthetic heart valve is a rare but potentially serious and fatal complication in patients with
Fig. 1 Baseline electrocardiogram on admission revealed atrial paced rhythm and right axis deviation
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Treatment of mechanical aortic valve thrombosis
75
123
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A. N. Vora et al.
Fig. 3 Repeat fluoroscopy after treatment showed improved motion of the previously fixed leaflet. Transthoracic echocardiography prior to discharge revealed a peak velocity of 2.8 m/s with a mean gradient of 19 mmHg across the mechanical aortic valve
valve replacement. Thrombotic risk is related not only to the type and position of the prosthetic valve but also to the patient’s other comorbidities. Caged-ball valves have the highest risk of thrombosis [1], followed by tilting disc valves. Bileaflet valves are thought to have the lowest thrombotic risk owing to the fact that they generate central, nonturbulent flow [2]. Mechanical valves have higher thrombotic risk than bioprosthetic valves. Additionally, prosthetic valves in the mitral position have higher thrombotic risk than valves in the aortic position due to the lower transvalvular pressure across the mitral valve. Comorbidities such as low ejection fraction, atrial fibrillation, hypercoaguable states, and prior thromboembolism also have been associated with increased rates of thrombosis. Antithrombotic therapy with an oral vitamin K antagonist (VKA) and aspirin (75–100 mg) is recommended for all patients with mechanical valves, regardless of the type and position of the valve. The American College of
123
Cardiology/American Heart Association (ACC/AHA) guidelines recommend [3], along with concomitant lowdose aspirin therapy, a target INR of 2.0–3.0 in low-risk patients with aortic valve replacement (AVR) and a goal of INR 2.5–3.5 for mitral valve replacement (MVR) or highrisk patients with AVR or MVR (i.e. previous thromboembolism, atrial fibrillation, low ejection fraction, or hypercoaguable state). Importantly, the novel oral anticoagulants are not U.S. Food and Drug Administration (FDA) approved or society guideline recommended for patients with mechanical prosthetic valves. Treatment of valvular thrombosis has centered on fibrinolytic therapy or surgical replacement of the valve [3]. Fibrinolytic therapy has been showed to be of limited benefit owing to low rates of success and high rates of embolic and hemorrhagic complications and is generally reserved for patients in whom surgery would be considered extreme risk. Current ACC/AHA guidelines state that emergency surgery is considered reasonable for patients
Treatment of mechanical aortic valve thrombosis
with a thrombosed left-sided valve and New York Heart Association (NYHA) Class III/IV symptoms (Class IIa, LOE C) or in patients who have a large clot burden. Fibrinolytic therapy for right-sided valve thrombosis with NYHA III/IV symptoms should also be considered (Class IIa). Treatment of patients with left-sided valve thrombosis, a small thrombus, and NYHA Class I/II symptoms with UFH therapy is an alternative to fibrinolytic therapy (Class IIb). Eptifibatide is an intravenous glycoprotein IIb/IIIa (GP IIb/IIIa) inhibitor that has been extensively studied as an antiplatelet agent in the management of acute coronary syndromes [4, 5]. It is well known that high levels of shear stress, typically seen in atherosclerotic vessels but also in the setting of turbulent flow from a stenotic valve, activate and aggregate platelets. These processes are thought to be mediated by the interaction of von Willebrand factor (vWF) with glycoprotein Ib/IX complex for platelet activation and vWF with GP IIb/IIIa for platelet aggregation [6, 7]. Generally speaking, antiplatelet therapy alone is not considered appropriate for the management of patients with mechanical prosthetic valves. However, a recent metaanalysis noted that the addition of an antiplatelet agent (aspirin or dipyridamole) to standard therapy reduced the risk of thromboembolism and mortality in patients with mechanical valves, albeit at increased hazard for bleeding [8]. In this clinical situation, the patient’s previous history of a subdural hematoma was a contraindication for fibrinolytic therapy and her two prior median sternotomies would place her at high risk for repeat surgery. Given that she presented with substernal chest discomfort and NYHA Class II symptoms, we felt that eptifibatide in addition to UFH would be a reasonable option in balancing her bleeding risk with procedural and hemorrhagic risks of more traditional therapies.
77
To our knowledge, this is the first published report of the successful use of eptifibatide in addition to UFH in the management of subacute valve thrombosis in a patient at high risk for repeat surgery or fibrinolysis. While this strategy should not replace the use of fibrinolytic therapy or repeat surgery in most patients with mechanical valve thrombosis, it may be a reasonable conservative strategy in patients who are not eligible for traditional therapies.
References 1. Yoganathan AP, He Z, Casey S (2004) Jones, fluid mechanics of heart valves. Annu Rev Biomed Eng 6:331–362 2. Butany J et al (2003) Mechanical heart valve prostheses: identification and evaluation. Cardiovasc Pathol 12(1):1–22 3. Bonow RO et al (2008) 2008 focused update incorporated into the ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to revise the 1998 guidelines for the management of patients with valvular heart disease). Endorsed by the Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol 52(13):e1–e142 4. (1998) Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes. N Engl J Med 339(7):436–443 5. Giugliano RP et al (2009) Early versus delayed, provisional eptifibatide in acute coronary syndromes. N Engl J Med 360(21):2176–2190 6. Ikeda Y et al (1991) The role of von Willebrand factor and fibrinogen in platelet aggregation under varying shear stress. J Clin Invest 87(4):1234–1240 7. Moake JL et al (1986) Involvement of large plasma von Willebrand factor (vWF) multimers and unusually large vWF forms derived from endothelial cells in shear stress-induced platelet aggregation. J Clin Invest 78(6):1456–1461 8. Massel DR, Little SH (2013) Antiplatelet and anticoagulation for patients with prosthetic heart valves. Cochrane Database Syst Rev 7:CD003464
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Treatment of mechanical aortic valve thrombosis with heparin and eptifibatide Amit N. Vora • Thomas Gehrig • Thomas M. Bashore Todd L. Kiefer
•
Published online: 28 January 2014 Ó Springer Science+Business Media New York 2014
Abstract A 75-year old woman with a history of coronary disease status post 3-vessel coronary artery bypass grafting (CABG) 8 years ago and a repeat one-vessel CABG 2 years ago in the setting of aortic valve replacement with a #19 mm St. Jude bileaflet mechanical valve for severe aortic stenosis presented with two to three weeks of progressive dyspnea and increasing substernal chest discomfort. Echocardiography revealed a gradient to 31 mmHg across her aortic valve, increased from a baseline of 13 mmHg five months previously. Fluoroscopy revealed thrombosis of her mechanical aortic valve. She was not a candidate for surgery given her multiple comorbidities, and fibrinolysis was contraindicated given a recent subdural hematoma 1 year prior to presentation. She was treated with heparin and eptifibatide and subsequently demonstrated resolution of her aortic valve thrombosis. We report the first described successful use of eptifibatide in addition to unfractionated heparin for the management of subacute valve thrombosis in a patient at high risk for repeat surgery or fibrinolysis. Keywords Mechanical valve thrombosis Platelets Anticoagulants Eptifibatide
Electronic supplementary material The online version of this article (doi:10.1007/s11239-014-1055-8) contains supplementary material, which is available to authorized users. A. N. Vora (&) T. Gehrig T. M. Bashore T. L. Kiefer Duke University Medical Center, 2301 Erwin Road Room 7411A, Durham, NC 27710, USA e-mail: [email protected]
Case presentation A 75-year old woman presented to the emergency department with two to three weeks of progressive dyspnea and increasing substernal chest discomfort, noting that recently she had been using her sublingual nitroglycerin multiple times daily. She had a history of coronary disease status post 3-vessel coronary artery bypass grafting (CABG) in 2005 and a repeat one vessel CABG in 2011 in the setting of aortic valve replacement (AVR) with a #19 mm St. Jude bileaflet mechanical valve for severe aortic stenosis. She also had a history of sick sinus syndrome and atrial fibrillation with permanent pacemaker placement. Given the mechanical aortic valve and atrial fibrillation, she was anticoagulated with warfarin. In addition, she suffered a fall 1 year ago with a subdual hematoma that was medically managed; her warfarin was temporarily stopped at that time, but subsequently reinitiated. On physical examination, her systemic blood pressure was 131/61 mmHg with a heart rate of 95 beats per minute. She was frail but well-appearing and in no acute distress. Her jugular venous pressure was normal. Cardiac auscultation revealed a regular rate and rhythm, a soft S1 and a mechanical S2, with a II/VI harsh ejection murmur at the left sternal border. Her lungs were clear to auscultation and she had trace bilateral pedal edema. Laboratory testing revealed a creatinine of 1.2 mg/dL, normocytic anemia with a hemoglobin of 10.8 g/dL, and three sets of negative cardiac biomarkers. Her international normalized ration (INR) was 1.1 despite taking warfarin daily. Her INR had been difficult to control in the two months prior to admission, with values ranging from 1.2 to 4.7. Her electrocardiogram revealed an atrial-paced rhythm at 80 beats per minute and right axis deviation (Fig. 1). Transthoracic echocardiography revealed a left ventricular ejection fraction of 45 % with global hypokinesis. A peak velocity of 3.5 m/s and a mean gradient
123
74
of 31 mmHg were measured across the prosthetic aortic valve (Fig. 2a); previous transthoracic echocardiogram performed five months earlier revealed a peak velocity of 2.4 m/s and a mean gradient of 13 mmHg (Fig. 2b). Chest radiograph revealed mild bilateral pleural effusions that were unchanged from a previous radiograph. Given that the patient’s clinical presentation was concerning for unstable angina with a mild congestive heart failure exacerbation, she was started on unfractionated heparin and taken to the cardiac catheterization laboratory for coronary angiography, a right heart catheterization, and fluoroscopy of her mechanical AVR. Coronary angiography revealed severe native three-vessel disease with patent grafts that was grossly unchanged from her most recent cardiac catheterization 1 year ago. Right heart catheterization revealed mild pulmonary hypertension (pulmonary artery mean 33 mmHg), a mildly elevated pulmonary capillary wedge pressure (PCWP) to 18 mmHg, and a preserved cardiac index of 2.6 L/min-m2. Fluoroscopy demonstrated that one of the mechanical aortic valve leaflets was fixed in the closed position (Fig. 1, Movie 1). This was consistent with the abrupt increase in her aortic valve gradient since her last echocardiogram several months earlier. It was felt this represented thrombus on the mechanical leaflet, and not pannus, given the subtherapeutic INR on admission and the time frame of change in the valve gradient. The patient was considered for redo aortic valve replacement, but was felt to be very high risk given her multiple comorbidities and two prior median sternotomies. Fibrinolysis was also considered but contraindicated given her history
A. N. Vora et al. Fig. 2 a A peak velocity of 3.5 m/s and a mean gradient of c 31 mmHg were measured across the prosthetic aortic valve. Fluoroscopy demonstrated that one of the mechanical aortic valve leaflets was fixed in the closed position (arrow). b The most recent echocardiogram performed five months prior to admission revealed a peak velocity of 2.4 m/s and a mean gradient of 13 mmHg
of subdural hematoma. After extensive discussion and determination that she was not a candidate for redo-valve surgery or fibrinolysis, she was started on eptifibatide 1 mcg/kg/min (renally dosed for her creatinine clearance) without bolus. The UFH dose was titrated to a goal activated partial thromboplastin time (aPTT) of 60–90 s. She underwent repeat transthoracic echocardiogram three days later that revealed a peak velocity of 3.2 m/s with a mean gradient of 23 mmHg across the mechanical aortic valve (Fig. 3, Movie 2). Repeat fluoroscopy after five days of treatment with UFH and eptifibatide revealed markedly improved motion of the previously fixed leaflet, now opening out to 65°–70°. She was continued on heparin and eptifibatide for a total of seven days and then was transitioned to warfarin with an UFH bridge with a goal INR of 2.5–3.5. Subsequent echocardiogram performed two days prior to discharge revealed a peak velocity of 2.8 m/s and a mean gradient of 19 mmHg across the aortic valve.
Discussion Thrombosis of a prosthetic heart valve is a rare but potentially serious and fatal complication in patients with
Fig. 1 Baseline electrocardiogram on admission revealed atrial paced rhythm and right axis deviation
123
Treatment of mechanical aortic valve thrombosis
75
123
76
A. N. Vora et al.
Fig. 3 Repeat fluoroscopy after treatment showed improved motion of the previously fixed leaflet. Transthoracic echocardiography prior to discharge revealed a peak velocity of 2.8 m/s with a mean gradient of 19 mmHg across the mechanical aortic valve
valve replacement. Thrombotic risk is related not only to the type and position of the prosthetic valve but also to the patient’s other comorbidities. Caged-ball valves have the highest risk of thrombosis [1], followed by tilting disc valves. Bileaflet valves are thought to have the lowest thrombotic risk owing to the fact that they generate central, nonturbulent flow [2]. Mechanical valves have higher thrombotic risk than bioprosthetic valves. Additionally, prosthetic valves in the mitral position have higher thrombotic risk than valves in the aortic position due to the lower transvalvular pressure across the mitral valve. Comorbidities such as low ejection fraction, atrial fibrillation, hypercoaguable states, and prior thromboembolism also have been associated with increased rates of thrombosis. Antithrombotic therapy with an oral vitamin K antagonist (VKA) and aspirin (75–100 mg) is recommended for all patients with mechanical valves, regardless of the type and position of the valve. The American College of
123
Cardiology/American Heart Association (ACC/AHA) guidelines recommend [3], along with concomitant lowdose aspirin therapy, a target INR of 2.0–3.0 in low-risk patients with aortic valve replacement (AVR) and a goal of INR 2.5–3.5 for mitral valve replacement (MVR) or highrisk patients with AVR or MVR (i.e. previous thromboembolism, atrial fibrillation, low ejection fraction, or hypercoaguable state). Importantly, the novel oral anticoagulants are not U.S. Food and Drug Administration (FDA) approved or society guideline recommended for patients with mechanical prosthetic valves. Treatment of valvular thrombosis has centered on fibrinolytic therapy or surgical replacement of the valve [3]. Fibrinolytic therapy has been showed to be of limited benefit owing to low rates of success and high rates of embolic and hemorrhagic complications and is generally reserved for patients in whom surgery would be considered extreme risk. Current ACC/AHA guidelines state that emergency surgery is considered reasonable for patients
Treatment of mechanical aortic valve thrombosis
with a thrombosed left-sided valve and New York Heart Association (NYHA) Class III/IV symptoms (Class IIa, LOE C) or in patients who have a large clot burden. Fibrinolytic therapy for right-sided valve thrombosis with NYHA III/IV symptoms should also be considered (Class IIa). Treatment of patients with left-sided valve thrombosis, a small thrombus, and NYHA Class I/II symptoms with UFH therapy is an alternative to fibrinolytic therapy (Class IIb). Eptifibatide is an intravenous glycoprotein IIb/IIIa (GP IIb/IIIa) inhibitor that has been extensively studied as an antiplatelet agent in the management of acute coronary syndromes [4, 5]. It is well known that high levels of shear stress, typically seen in atherosclerotic vessels but also in the setting of turbulent flow from a stenotic valve, activate and aggregate platelets. These processes are thought to be mediated by the interaction of von Willebrand factor (vWF) with glycoprotein Ib/IX complex for platelet activation and vWF with GP IIb/IIIa for platelet aggregation [6, 7]. Generally speaking, antiplatelet therapy alone is not considered appropriate for the management of patients with mechanical prosthetic valves. However, a recent metaanalysis noted that the addition of an antiplatelet agent (aspirin or dipyridamole) to standard therapy reduced the risk of thromboembolism and mortality in patients with mechanical valves, albeit at increased hazard for bleeding [8]. In this clinical situation, the patient’s previous history of a subdural hematoma was a contraindication for fibrinolytic therapy and her two prior median sternotomies would place her at high risk for repeat surgery. Given that she presented with substernal chest discomfort and NYHA Class II symptoms, we felt that eptifibatide in addition to UFH would be a reasonable option in balancing her bleeding risk with procedural and hemorrhagic risks of more traditional therapies.
77
To our knowledge, this is the first published report of the successful use of eptifibatide in addition to UFH in the management of subacute valve thrombosis in a patient at high risk for repeat surgery or fibrinolysis. While this strategy should not replace the use of fibrinolytic therapy or repeat surgery in most patients with mechanical valve thrombosis, it may be a reasonable conservative strategy in patients who are not eligible for traditional therapies.
References 1. Yoganathan AP, He Z, Casey S (2004) Jones, fluid mechanics of heart valves. Annu Rev Biomed Eng 6:331–362 2. Butany J et al (2003) Mechanical heart valve prostheses: identification and evaluation. Cardiovasc Pathol 12(1):1–22 3. Bonow RO et al (2008) 2008 focused update incorporated into the ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to revise the 1998 guidelines for the management of patients with valvular heart disease). Endorsed by the Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol 52(13):e1–e142 4. (1998) Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes. N Engl J Med 339(7):436–443 5. Giugliano RP et al (2009) Early versus delayed, provisional eptifibatide in acute coronary syndromes. N Engl J Med 360(21):2176–2190 6. Ikeda Y et al (1991) The role of von Willebrand factor and fibrinogen in platelet aggregation under varying shear stress. J Clin Invest 87(4):1234–1240 7. Moake JL et al (1986) Involvement of large plasma von Willebrand factor (vWF) multimers and unusually large vWF forms derived from endothelial cells in shear stress-induced platelet aggregation. J Clin Invest 78(6):1456–1461 8. Massel DR, Little SH (2013) Antiplatelet and anticoagulation for patients with prosthetic heart valves. Cochrane Database Syst Rev 7:CD003464
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