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Three Part Question

In [patients with obstructive prosthetic valve thrombosis] is [thrombolytic therapy or surgery] the best treatment in terms of [survival]?

Clinical Scenario

You are seeing a 72-year-old with a 12-year old mechanical mitral valve replacement, presenting 'in-extremis' with breathlessness, dizziness and hypotension. Her family report that she has been confused recently and might not have taken her warfarin. An echocardiogram shows severely restricted movement of the prosthetic mitral valve leaflets with the appearance of thrombus in-situ. You wonder whether first-line treatment should be emergency surgery or thrombolytic therapy.

Search Strategy

MEDLINE 1950-August 2007 using the OVID interface.
Fibrinolytic Agents/OR Thrombolytic Therapy/OR thrombolysis.mp.]AND[prosthetic valve thrombosis.mp.OR prosthetic heart valve thrombosis.mp.]LIMIT to Human

Search Outcome

Ninety-six papers were found in MEDLINE. Twelve papers were deemed to be relevant. Only case series of a reasonable size (at and above 30) were included. Two of these papers were systematic reviews with recommendations. Guidelines by the American Heart Association/American College of Cardiology (AHA/ACC) were also included. Two large case series of surgical management of PVT were additionally included for comparison. These papers are documented in the table

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
ACC/AHA 2006 Guidelines for the Management of Patients with Valvular Heart Disease, 2006, USA	A review and guidelines from the ACC/AHA	Systematic Review (level 2a)	Recommendations	Emergency operation is reasonable for patients with a thrombosed left-sided prosthetic valve and NYHA functional class III-IV symptoms (Class IIa, Level of Evidence: C) Emergency operation is reasonable for patients with a thrombosed left-sided prosthetic valve and a large clot burden (Class IIa, Level of Evidence: C) Fibrinolytic therapy may be considered as a first-line therapy for patients with a thrombosed left-sided prosthetic valve, NYHA functional class I-II symptoms, and a small clot burden (Class IIb, Level of Evidence: B) Fibrinolytic therapy may be considered as a first-line therapy for patients with a thrombosed left-sided prosthetic valve, NYHA functional class III-IV symptoms, and a small clot burden if surgery is high risk or not available (Class IIb, Level of Evidence: B) Fibrinolytic therapy may be considered for patients with an obstructed, thrombosed left-sided prosthetic valve who have NYHA functional class II-IV symptoms and a large clot burden if emergency surgery is high risk or not available (Class IIb, Level of Evidence: C)
Lengyel et al, 2005 (1),	A review and guidelines from the Society for Heart Valve Disease	Systematic Review (level 2a)	Recommendations	Thrombolytic therapy is the first-line treatment in all patients with obstructive PVT independently of NYHA class if there are no contraindications (Class I, Level of Evidence B) Surgery should be reserved for patients with in whom thrombolysis is contraindicated, or has failed (Class I, Level of Evidence B) Patients who are critically ill (cardiogenic shock or pulmonary oedema) should be treated intravenously with rTPA immediately according to the accelerated thrombolytic protocol (Class IIa, Level of Evidence C) Patients at lower risk should be given either low-dose streptokinase (for no longer than 72 hours, until the disappearance of PVT as demonstrated by TOE or fibrinogen drops to zero) or high-dose streptokinase. Serial thrombolytic protocols may be given to low-risk patients if the first or second agents fail to dissolve the thrombus (Class IIa, Level of Evidence C) Surgery should be urgently undertaken after administration of fresh-frozen plasma in high-risk patients if the accelerated It is not recommended to perform thrombolysis in the presence of ischaemic stroke as documented by cerebral CT performed after 4 hours from the beginning of symptoms, in patients with vegetation, early post-operatively (within 4 days following surgery), and in those having large atrial thrombi (Class III)
Cáceres-Lóriga et al, 2006 Cuba	Review paper	Systematic review (level 2a)	Recommendations	Patients who are critically ill when presenting with PVT (pulmonary oedema, hypotension, NYHA class III/IV symptoms) should receive immediate intravenous thrombolytic therapy following confirmation of PVT by echocardiography Serial echocardiographic studies should be performed in these patients, and repeated infusions of thrombolytic agents should be administered if complete resolution of prosthetic valve thrombus is not achieved At the end of thrombolytic therapy a continuous infusion of unfractionated heparin should be initiated when fibrinogen level is higher than 0.5 g/l Cardiac surgical consultation should be sought urgently Re-do valve replacement should be seriously considered if repeated infusions of thrombolytic agents fail to adequately dissolve the thrombus on the prosthetic valve Patients with PVT who are clinically stable, i.e. in NYHA clinical class I or II, may be managed medically with thrombolytic and antithrombotic therapy or surgically with re-do valve replacement depending on the physician's and patient's preference.
Lengyel 2005 (2), Hungary	Meta-analysis of 53 studies of thrombolysis for PVT, divided into periods from 1974 to 1995 and 1996 to 2003	Meta-analysis ( level 2a)	Recommendations	1974–1995 1996–2003 No. episodes: 235 234 Success rate: 77% 90% Embolism rate: 13% 4% Mortality rate: 7.5% 2.5% Suggests consideration of thrombolysis in all patients irrespective of functional class and thrombus size unless C/I exist	Meta-analysis published as a letter in JACC, therefore not fully referenced
Tong et al, 2004, Multi-centre	A registry of 107 patients from 14 centres with PVT between 1985 and 2001 undergoing 2D/Doppler and TOE before thrombolysis	Registry with retrospective analysis ( Level 2b)	Success and complication rates of thrombolysis, predictors of adverse outcomes and recommendations	Success rate: 85%, Haemorrhagic events: 5.6%, Embolic events: 12.1%, Mortality rate: 5.6%, Predictor of success: soft mass Predictors of complications: NYHA class, shock, sinus tachycardia, hypotension, previous stroke, thrombus extension beyond the valve ring, and larger thrombus area Independent predictors: thrombus area > 0.8cm squared and prior history of stroke, Thrombus area:<0.8 0.8-1.59 >0.8, Complications: 6% 29% 47%, Mortality rate: 3% 4% 20% Recommend TOE imaging in all cases of suspected PVT and thrombolysis in patients with small (0.8cm2) thrombus, especially those in NYHA Class III-IV, whose surgical mortality would be high	Possible selection bias as variable indications for thrombolysis in different centres – could influence success/ complication rates. Different thrombolytic regimens used between centres.
Cáceres-Lóriga et al, 2006, Cuba	Case series of 68 patients over 6 years treated with recombinant streptokinase with subsequent evaluation based on clinical and echocardiographic findings	Case series ( Level 4)	Success and complication rates of thrombolysis	Presentation: 94% in NYHA class III–IV heart failure Complete response: 85.3%, Partial response: 5.9%, Failure rate: 8.8%, Haemorrhagic events: 2.9%, Embolic events: 7.4%, Mortality rate: 5.9% Rethrombosis rate: 17.7% (90.9% of these successfully re-treated with thrombolysis)
Roudaut et al, 2003, France	Retrospective case series of 136 patients over 23 years with PVT treated with surgery	Case series (level 4)	Success and mortality rates of surgery for PVT	Presentation: 63% in NYHA class III–IV heart failure Success rate: 89%, Embolic events: 0.7% Mortality rate: 10.3% (24% if NYHA IV; 4% if NYHA I–III) Rethrombosis rate: 8.1%	Retrospective analysis In 37 patients, surgery was a secondary treatment after failed medical therapy
Kumar et al, 2001, India	Case series of 48 episodes of PVT in 41 patients treated with thrombolysis (streptokinase in 44 and urokinase in 4)	Case series (level 4)	Success and complication rates of thrombolysis	Presentation: NYHA class II in 43.9%, NYHA class III in 47.9%, Success rate: 87.5%, Failure rate: 6.2%, Haemorrhagic events: 4.2%, Embolic events: 10.4%, Mortality rate: 7.3% Rethrombosis rate: 14.6% (76.9% of these successfully re-treated with thrombolysis
Lengyel et al, 2001, Hungary	Case series of 59 patients (of whom 54 had obstructive PVT) over 7 years treated with thrombolysis (32 patients), IV heparin (4 patients) or surgery (18 patients)	Case series (level 4)	Comparison of success and mortality rates for thrombolysis, surgery and IV heparin	Success Mortality Thrombolysis: 84.4% 6.2%, IV heparin: 0% 25%, Surgery: 66.7% 33.3% Complications in thrombolysed pts: Embolic=9.3%; Haemorrhagic=2.3% Rethrombosis rate in thrombolysed patients = 21.6% (80% successfully re-treated with thrombolysis)	Non-randomised study with small numbers - therefore comparative success and mortality rates should be interpreted with caution
Gupta et al, 2000, India	Case series of 110 patients over 10 years treated with thrombolysis (108 with streptokinase; 2 with urokinase)	Case series (level 4)	Success and complication rates of thrombolysis	Complete response: 81.8% (80% for NYHA I-II; 86.3% for NYHA III; 81.5% for NYHA IV) Partial response: 10% Failure rate: 8.2% Embolic events: 19.1% (commoner in patients in AF – odds ratio 2.3) 71.4% mortality if presentation in cardiogenic shock Rethrombosis rate: 27.8% (70% success rate for re-thrombolysis)
Ozcan et al, 2000, Turkey	Case series of 32 patients (of whom 25 had obstructive PVT) over 4 years treated with repeated doses of thrombolysis guided by TOE/TTE	Case series (level4)	Success and complication rates of thrombolysis	Success after 1st dose: 40% Success after repeated doses: 88% Haemorrhagic events: 8.3% Embolic events: 5.6% Mortality rate: 2.8% Rethrombosis rate: 11.1%	Initial two thrombolysis treatments with streptokinase; TPA or urokinase used subsequently
Agrawal et al, 1997, India	Case series of 42 patients over 10 years with mitral tilting-disc PVT treated with streptokinase	Case series (level 4)	Success and mortality rates of thrombolysis	Success rate: 88% Mortality rate: 9.5%
Reddy et al, 1994, India	Case series of 44 episodes of PVT in 38 patients treated with thrombolysis	Case series (level 4)	Success and complication rates of thrombolysis	Presentation: 75% in NYHA IV Overall success rate: 88.6% (Complete response: 40.9% Partial response:47.7%) Rethrombosis rate: 23.7% (83.3% success rate for re-thrombolysis)
Roudaut et al, 2003, France	Retrospective case series of 127 episodes of PVT in 110 patients over 23 years treated with thrombolysis (streptokinase in 49, urokinase in 41, rTPA in 37)	Case series (level 4)	Success and complication rates of thrombolysis	Presentation: 70.9% in NYHA class III–IV heart failure Complete response: 70.9%, Partial response: 17.3%, Failure rate: 11.8%, Haemorrhagic events: 4.7%, Embolic events: 15.0% (Complication rate 28% for NYHA III-IV pts; 16% for NYHA I-II pts) Mortality rate: 11.8% (15.6% for NYHA III-IV; 2.7% for NYHA I-II) Rethrombosis rate: 18.9% (75% success rate for re-thrombolysis)	Varying thrombolytic regimens used may have affected outcomes (streptokinase appeared more effective than rTPA, which appeared effective than urokinase)
Deviri et al, 1991, South Africa	Case series of 112 episodes of PVT in 100 patients over 10 years treated with surgery	Case series (level 4)	Mortality rates of surgery for PVT	Presentation: 63% in NYHA class IV heart failure Mortality rate: 12.3% (17.5% if NYHA IV; 4.7% if NYHA I–III)

Comment(s)

The AHA/ACC published recommendations in this area in 2006. All recommendations were class IIa or IIb, based on B or C level evidence. They suggest that surgery is a reasonable first-line strategy for most patients, with consideration of thrombolysis reserved for specific situations: where the patient is in a lower NYHA class with a small clot burden, or where the patient is in a higher NYHA class (with a large or small) clot burden and high operative risk. Recommendations have also been produced by a Working Group of the Society for Heart Valve Disease in 2005 [Lengyel 2005 1]. These took a differing line in that they gave class I guidance strongly in favour of thrombolysis for almost all patients with PVT, with surgery reserved for those in whom there is a contra-indication to thrombolysis, or in whom thrombolysis has failed. Further recommendations regarding types of thrombolytic therapy are also given, along with potential contraindications. A further review paper by Cáceres-Lóriga [Int J Cardiol 2006] also recommends thrombolysis as first line treatment for patients with PVT presenting with NYHA class III–IV symptoms or cardiogenic shock. Repeated infusions of thrombolytic agents with serial echocardiographic assessments until thrombus resolution are also advocated, with surgery to be considered in the event of failure of thrombus dissolution despite repeated infusions. They feel that patients with NYHA class I–II symptoms may be appropriately managed with either thrombolysis or surgery depending on patient and physician preference. A meta-analysis of outcomes from thrombolysis for PVT has also been performed by Lengyel [J Am Coll Cardiol 2005]. This was published as a letter and therefore is not fully detailed or referenced. The meta-analysis incorporates 53 studies, and results are divided into the periods 1974–1995 and 1996–2003. This shows an improvement in outcomes from thrombolysis in recent years, with a success rate of 90%, embolic event rate of 4% and mortality rate of 2.5%. The author suggests consideration of thrombolysis in all patients irrespective of functional class and thrombus size unless a contra-indication exists. Lengyel's comments regarding thrombus size are interesting in the context of a paper published the same year by Tong. This multicentre registry was designed to evaluate the role of transoesophageal echocardiography(TOE) in risk-stratifying patients undergoing thrombolysis of PVT. It demonstrated that TOE has a potentially important role by establishing lower thrombus density as a predictor of success with thrombolysis, and larger thrombus size (along with previous history of stroke) as an independent predictor of complications. A cut-off of 0.8cm2 was derived from ROC curve analysis. The authors therefore recommend TOE imaging in all cases of suspected PVT and thrombolysis in patients with small (0.8cm2) thrombus, especially those in NYHA Class III–IV, whose surgical mortality would be high. A number of reasonably-sized case series of patients treated with thrombolysis have been published in recent years[Caceres J Thromb Thrombolysis 2006, Roudaut, Kumar, Lengyel 2001, Gupta]. These demonstrate that the majority of patients present in higher NYHA classes. Success rates were consistently reported in the region of 85–90%, with mortality rates of around 5–10%. In terms of complications, embolic events were reported at rates of 6–19%, haemorrhagic events were seen in 2–8% of patients, and re-thrombosis occurred in 11–28% (many of these patients were subsequently successfully re-thrombolysed). These figures are rather less favourable than those published in the meta-analysis by Lengyel, but as discussed, it is unclear which case series were included in that paper as it was not fully referenced. Comparatively, two large case series of patients undergoing surgery for acute PVT have also been published. These were published by Deviri in 1991 and Roudaut in 2003. Overall mortality rates were found to be 12.3% in the 1991 paper and 10.3% in 2003. However, break-downs by presenting NYHA class in both papers show a marked rise in mortality from patients in NYHA class I–III (4.7% in 1991; 4% in 2003) to patients in NYHA class IV (17.5% in 1991; 24% in 2003).

Clinical Bottom Line

Surgery has been the traditional management of choice for obstructive PVT, but thrombolysis has recently been proposed as a first-line therapy. There are no randomised controlled trials comparing these two management strategies. Therefore recommendations are based on case series reporting success, mortality and complication rates for each. Thrombolytic therapy in recent years appears to have high success rates, with relatively low complication and mortality rates. However, complication rates are higher in patients with larger size thrombus (as measured by TOE) and in those with a previous history of stroke. Surgical management again has a high rate of success overall, but the mortality rate for patients presenting in NYHA class IV heart failure is considerably higher than that for patients in the lower NYHA classes. Essentially, therefore, either strategy may reasonably be considered for a patient with obstructive PVT, but NYHA class, thrombus size and previous history of stroke should be taken into account when making this decision. Small thrombus size (<0.8cm2), particularly in the absence of previous stroke disease, may favour thrombolysis in view of the high success rates and low complication rates demonstrated in this situation. Additionally, treatment with a thrombolytic does not preclude subsequently reverting to surgical management in the event of failure. Higher NYHA class, with its associated higher surgical mortality risk, may also favour thrombolysis; this is especially so if the thrombus size is small.

References

1. American College of Cardiology/American Heart Association Task Force on Practice Guidelines ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: Circulation 2006;114(5):e84-231.
2. Lengyel M, Horstkotte D, Völler H et al. Recommendations for the management of prosthetic valve thrombosis. J Heart Valve Dis 2005;14(5):567-75.
3. Cáceres-Lóriga FM, Pérez-López H, Santos-Gracia J et al. Prosthetic heart valve thrombosis: pathogenesis, diagnosis and management. Int J Cardiol 2006;110(1):1-6.
4. Lengyel M. Thrombolysis should be regarded as first-line therapy for prosthetic valve thrombosis in the absence of contraindications. J Am Coll Cardiol 2005;45(2):325.
5. Tong AT, Roudaut R, Ozkan M et al. Transesophageal echocardiography improves risk assessment of thrombolysis of prosthetic valve thrombosis: results of the international PRO-TEE registry. J Am Coll Cardiol 2004;43(1):77-84.
6. Cáceres-Lóriga FM, Pérez-López H, Morlans-Hernández K et al. Thrombolysis as first choice therapy in prosthetic heart valve thrombosis. A study of 68 patients. J Thromb Thrombolysis 2006;21(2):185-90.
7. Roudaut R, Lafitte S, Roudaut MF et al. Fibrinolysis of mechanical prosthetic valve thrombosis: a single-center study of 127 cases. J Am Coll Cardiol 2003;41(4):653-8.
8. Kumar S, Garg N, Tewari S et al. Role of thrombolytic therapy for stuck prosthetic valves: a serial echocardiographic study. Indian Heart J 2001;53(4):451-7.
9. Lengyel M, Vandor L. The role of thrombolysis in the management of left-sided prosthetic valve thrombosis: a study of 85 cases diagnosed by transesophageal echocardiography. J Heart Valve Dis 2001;10(5):636-49.
10. Gupta D, Kothari SS, Bahl VK et al. Thrombolytic therapy for prosthetic valve thrombosis: short- and long-term results. Am Heart J 2000;140(6):906-16.
11. Ozkan M, Kaymaz C, Kirma C et al. Intravenous thrombolytic treatment of mechanical prosthetic valve thrombosis: a study using serial transesophageal echocardiography. J Am Coll Cardiol 2000;35(7):1881-9.
12. Agrawal D, Dubey S, Saket B et al. Thrombolytic therapy for prosthetic valve thrombosis in Third World countries. Indian Heart J 1997;49(4):383-6.
13. Reddy NK, Padmanabhan TN, Singh S et al. Thrombolysis in left-sided prosthetic valve occlusion: immediate and follow-up results. Ann Thorac Surg 1994;58(2):462-70.
14. Roudaut R, Roques X, Lafitte S et al. Surgery for prosthetic valve obstruction. A single center study of 136 patients. Eur J Cardiothorac Surg 2003;24(6):868-72.
15. Deviri E, Sareli P, Wisenbaugh T et al. Obstruction of mechanical heart valve prostheses: clinical aspects and surgical management. J Am Coll Cardiol 1991;17(3):646-50.