Journal of Thrombosis and Haemostasis, 12: 1216–1217
DOI: 10.1111/jth.12640
COMMENTARY
Clots and cardiac valve prostheses R. R. JEFFREY Department of Cardiothoracic Surgery, Aberdeen Royal Infirmary, Aberdeen, UK
To cite this article: Jeffrey RR. Clots and cardiac valve prostheses. J Thromb Haemost 2014; 12:1216–7. See also Castilho FM, Sousa MR, Mendonc¸a ALP, Ribeiro ALP, Ca´ceres-Lo´riga FM. Thrombolytic therapy or surgery for valve prosthesis thrombosis: systematic review and meta-analysis. This issue, pp 1218–28.
Thrombosis of a cardiac valve prosthesis is a potentially life threatening but thankfully relatively rare complication following heart valve replacement. Management of this difficult situation is either by repeat surgery or thrombolytic therapy. Not surprisingly, there is no randomized controlled trial evaluating these two treatments and the published guidelines offer no definitive solution, with some indicating thrombolysis and others repeat surgery as the primary optimum treatment. In an attempt to clarify these mixed messages, Castilho et al. [1] in this issue of the journal publish a systematic review and meta-analysis comparing thrombolytic therapy or surgery for valve prosthesis thrombosis. The clinical presentation of these patients ranges from asymptomatic, to those with dyspnoea and those with acute life threatening cardiogenic shock and this spectrum of symptom severity compounds the difficulties in the comparison of treatment modalities. The authors have used a recognized methodology for collecting and analysing non-randomized studies and only included those studies where 10 or more patients were evaluated. Outcome measures recorded included death, bleeding, treatment success, embolic events and stroke. Partial success in thrombolysed patients was defined as incomplete recovery of leaflet motion and in this analysis was considered as treatment failure if patients required further surgical intervention for prosthetic dysfunction. Treatment outcomes were assigned according to the first therapy offered to the patient. The authors recognize the heterogeneity of the published studies and make efforts to minimize compounding Correspondence: Robert R. Jeffrey, Department of Cardiothoracic Surgery, Aberdeen Royal Infirmary Foresterhill, Aberdeen AB25 2ZN, UK. Tel.: +44 1224 552298; fax: +44 1224 553506. E-mail: [email protected] Received 9 June 2014 Manuscript handled by: F. R. Rosendaal Final decision: F. R. Rosendaal, 13 June 2014
factors, including publication bias and where the treatment chosen was the preferred option of the service. Forty-eight studies were identified and included 2239 patients. There was only one prospective surgical study and eight prospective thrombolytic studies. 27 studies or study arms were evaluated with 1132 patients in the surgery cohort and 26 studies with 1107 patients were included in the thrombolysis cohort. There was a highly significant difference in mortality between the two groups: surgery, 18.1% (CI, 14.6–22.1%); thrombolysis, 6.6% (CI, 4.8–9.9%) (P < 0.001). There was no difference if mitral valve prostheses were evaluated independently, which gave similar treatment results. Further subgroup analysis essentially confirmed the superiority of primary thrombolytic therapy. An attempt was made to evaluate the results depending on the type of prosthesis – mono leaflet or bileaflet – but no influence on mortality was demonstrable in either treatment arm, with the thrombolytic group again showing a lower mortality. The incidence of stroke was similar in both treatment groups: surgery, 5.6%; thrombolysis, 4.3% (P = 0.29). Not surprisingly, embolic events were more common in the thrombolysis group (4.6 vs. 12.8%, P < 0.01) but there was no statistical difference in the bleeding rate (4.6% and 6.8%). It would appear from this meta-analysis that the primary treatment for a clotted prosthesis should be thrombolysis. So why do we have differing published guidelines? [2–4]. The AHA guideline (2008) gives a Class 2a recommendation based on level C evidence for thrombolysis in right-sided prosthetic valve thrombosis but suggests early operation for left-sided lesions, noting that the high risk of cerebral emboli with fibrinolysis contradicts its use, particularly with a large clot burden. In the presented paper, a higher embolic rate with thrombolysis was confirmed but the stroke rate was similar in both cohorts. For smaller clots in patients in NYHA functional class I or II, fibrinolysis may be considered but the guidelines note that there is an absence of large cohort studies to help in decision making. The EACTS guideline (2012) also suggests surgery as a primary treatment because of the high incidence of bleed© 2014 International Society on Thrombosis and Haemostasis
Clots and cardiac valve prostheses 1217
ing, systemic embolism and recurrent thrombosis in those treated by thrombolysis. This guideline also suggests thrombolytic therapy in patients with hemodynamic instability, acknowledging the high surgical mortality in those patients with prior severely impaired left ventricular function. However, these authors also indicate that the risks and benefits of thrombolysis should be considered as patient characteristics and local resources permit. Both guidelines emphasize the higher embolism and bleeding rate with thrombolysis, but this has to be considered against the significantly lower mortality demonstrated in this systematic review. All published guidelines stress the importance of transthoracic (TOE) and transoesophageal (TEE) echocardiography in the assessment of patients with obstructed prostheses and note the difficulty of differentiating pannus from thrombus. The size of the thrombus may be determined by TOE or TEE and may be a useful guide in determining what should be the most appropriate primary intervention if one considers that the clot burden determines the risk of systemic embolism. In hemodynamically stable patients with small thrombi, oral anticoagulation may be supplemented with subcutaneous heparin to allow endogenous fibrinolysis but there is little published evidence on this treatment. Although systematic reviews and meta-analysis are appropriate when considering multiple randomized control trials, in attempting to write a guideline, the situation in the real world is probably different. Patients may have multiple co-morbidities that preclude their entry into a trial. The authors are fully aware of the shortcomings of their review but the implications are probably valid. In the absence of large prospective randomized trials, which are unlikely in this typically acute situation, Castilho et al. suggest that a prospective multicenter registry
© 2014 International Society on Thrombosis and Haemostasis
of all patients who sustain a thrombosed valve and are treated by either surgery or thrombolysis would be the most likely way to provide a clear answer to what is the best treatment for this relatively rare condition. However, this systematic review and meta-analysis provides evidence to support a primary role for thrombolysis in patients with thrombotic occlusion of a cardiac valve prosthesis. Disclosure of Conflict of Interests The author states that he has no conflict of interests. References 1 Castilho FM, Sousa MR, Mendonc¸a ALP, Ribeiro ALP, Ca´ceresLo´riga FM. Thrombolytic therapy or surgery for valve prosthesis thrombosis: systematic review and meta-analysis. J Thromb Haemost 2014; 12: 1218–28. 2 Bonow RO, Carabello BA, Chatterjee K, de Leon AC Jr, Faxon DP, Freed MD, Gaasch WH, Lytle BW, Nishimura RA, O’Gara PT, O’Rourke RA, Otto CM, Shah PM, Shanewise JS; 2006 Writing Committee Members; American College of Cardiology/American Heart Association Task Force. 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. Circulation 2008; 118: e523–661. 3 Lengyel M, Horstkotte D, Voller H, Mistiaen WP. Recommendations for the management of prosthetic valve thrombosis. J Heart Valve Dis 2005; 14: 567–75. 4 Taylor J. ESC/EACTS guidelines on the management of valvular heart disease. Eur Heart J 2012; 33: 2371–2.
DOI: 10.1111/jth.12640
COMMENTARY
Clots and cardiac valve prostheses R. R. JEFFREY Department of Cardiothoracic Surgery, Aberdeen Royal Infirmary, Aberdeen, UK
To cite this article: Jeffrey RR. Clots and cardiac valve prostheses. J Thromb Haemost 2014; 12:1216–7. See also Castilho FM, Sousa MR, Mendonc¸a ALP, Ribeiro ALP, Ca´ceres-Lo´riga FM. Thrombolytic therapy or surgery for valve prosthesis thrombosis: systematic review and meta-analysis. This issue, pp 1218–28.
Thrombosis of a cardiac valve prosthesis is a potentially life threatening but thankfully relatively rare complication following heart valve replacement. Management of this difficult situation is either by repeat surgery or thrombolytic therapy. Not surprisingly, there is no randomized controlled trial evaluating these two treatments and the published guidelines offer no definitive solution, with some indicating thrombolysis and others repeat surgery as the primary optimum treatment. In an attempt to clarify these mixed messages, Castilho et al. [1] in this issue of the journal publish a systematic review and meta-analysis comparing thrombolytic therapy or surgery for valve prosthesis thrombosis. The clinical presentation of these patients ranges from asymptomatic, to those with dyspnoea and those with acute life threatening cardiogenic shock and this spectrum of symptom severity compounds the difficulties in the comparison of treatment modalities. The authors have used a recognized methodology for collecting and analysing non-randomized studies and only included those studies where 10 or more patients were evaluated. Outcome measures recorded included death, bleeding, treatment success, embolic events and stroke. Partial success in thrombolysed patients was defined as incomplete recovery of leaflet motion and in this analysis was considered as treatment failure if patients required further surgical intervention for prosthetic dysfunction. Treatment outcomes were assigned according to the first therapy offered to the patient. The authors recognize the heterogeneity of the published studies and make efforts to minimize compounding Correspondence: Robert R. Jeffrey, Department of Cardiothoracic Surgery, Aberdeen Royal Infirmary Foresterhill, Aberdeen AB25 2ZN, UK. Tel.: +44 1224 552298; fax: +44 1224 553506. E-mail: [email protected] Received 9 June 2014 Manuscript handled by: F. R. Rosendaal Final decision: F. R. Rosendaal, 13 June 2014
factors, including publication bias and where the treatment chosen was the preferred option of the service. Forty-eight studies were identified and included 2239 patients. There was only one prospective surgical study and eight prospective thrombolytic studies. 27 studies or study arms were evaluated with 1132 patients in the surgery cohort and 26 studies with 1107 patients were included in the thrombolysis cohort. There was a highly significant difference in mortality between the two groups: surgery, 18.1% (CI, 14.6–22.1%); thrombolysis, 6.6% (CI, 4.8–9.9%) (P < 0.001). There was no difference if mitral valve prostheses were evaluated independently, which gave similar treatment results. Further subgroup analysis essentially confirmed the superiority of primary thrombolytic therapy. An attempt was made to evaluate the results depending on the type of prosthesis – mono leaflet or bileaflet – but no influence on mortality was demonstrable in either treatment arm, with the thrombolytic group again showing a lower mortality. The incidence of stroke was similar in both treatment groups: surgery, 5.6%; thrombolysis, 4.3% (P = 0.29). Not surprisingly, embolic events were more common in the thrombolysis group (4.6 vs. 12.8%, P < 0.01) but there was no statistical difference in the bleeding rate (4.6% and 6.8%). It would appear from this meta-analysis that the primary treatment for a clotted prosthesis should be thrombolysis. So why do we have differing published guidelines? [2–4]. The AHA guideline (2008) gives a Class 2a recommendation based on level C evidence for thrombolysis in right-sided prosthetic valve thrombosis but suggests early operation for left-sided lesions, noting that the high risk of cerebral emboli with fibrinolysis contradicts its use, particularly with a large clot burden. In the presented paper, a higher embolic rate with thrombolysis was confirmed but the stroke rate was similar in both cohorts. For smaller clots in patients in NYHA functional class I or II, fibrinolysis may be considered but the guidelines note that there is an absence of large cohort studies to help in decision making. The EACTS guideline (2012) also suggests surgery as a primary treatment because of the high incidence of bleed© 2014 International Society on Thrombosis and Haemostasis
Clots and cardiac valve prostheses 1217
ing, systemic embolism and recurrent thrombosis in those treated by thrombolysis. This guideline also suggests thrombolytic therapy in patients with hemodynamic instability, acknowledging the high surgical mortality in those patients with prior severely impaired left ventricular function. However, these authors also indicate that the risks and benefits of thrombolysis should be considered as patient characteristics and local resources permit. Both guidelines emphasize the higher embolism and bleeding rate with thrombolysis, but this has to be considered against the significantly lower mortality demonstrated in this systematic review. All published guidelines stress the importance of transthoracic (TOE) and transoesophageal (TEE) echocardiography in the assessment of patients with obstructed prostheses and note the difficulty of differentiating pannus from thrombus. The size of the thrombus may be determined by TOE or TEE and may be a useful guide in determining what should be the most appropriate primary intervention if one considers that the clot burden determines the risk of systemic embolism. In hemodynamically stable patients with small thrombi, oral anticoagulation may be supplemented with subcutaneous heparin to allow endogenous fibrinolysis but there is little published evidence on this treatment. Although systematic reviews and meta-analysis are appropriate when considering multiple randomized control trials, in attempting to write a guideline, the situation in the real world is probably different. Patients may have multiple co-morbidities that preclude their entry into a trial. The authors are fully aware of the shortcomings of their review but the implications are probably valid. In the absence of large prospective randomized trials, which are unlikely in this typically acute situation, Castilho et al. suggest that a prospective multicenter registry
© 2014 International Society on Thrombosis and Haemostasis
of all patients who sustain a thrombosed valve and are treated by either surgery or thrombolysis would be the most likely way to provide a clear answer to what is the best treatment for this relatively rare condition. However, this systematic review and meta-analysis provides evidence to support a primary role for thrombolysis in patients with thrombotic occlusion of a cardiac valve prosthesis. Disclosure of Conflict of Interests The author states that he has no conflict of interests. References 1 Castilho FM, Sousa MR, Mendonc¸a ALP, Ribeiro ALP, Ca´ceresLo´riga FM. Thrombolytic therapy or surgery for valve prosthesis thrombosis: systematic review and meta-analysis. J Thromb Haemost 2014; 12: 1218–28. 2 Bonow RO, Carabello BA, Chatterjee K, de Leon AC Jr, Faxon DP, Freed MD, Gaasch WH, Lytle BW, Nishimura RA, O’Gara PT, O’Rourke RA, Otto CM, Shah PM, Shanewise JS; 2006 Writing Committee Members; American College of Cardiology/American Heart Association Task Force. 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. Circulation 2008; 118: e523–661. 3 Lengyel M, Horstkotte D, Voller H, Mistiaen WP. Recommendations for the management of prosthetic valve thrombosis. J Heart Valve Dis 2005; 14: 567–75. 4 Taylor J. ESC/EACTS guidelines on the management of valvular heart disease. Eur Heart J 2012; 33: 2371–2.
