Journal of the Practice of Cardiovascular Sciences

ORIGINAL ARTICLE
Year
: 2022  |  Volume : 8  |  Issue : 1  |  Page : 30--34

The efficacy and safety of thrombolytic agents for patients with prosthetic valve thrombosis


Vinod Sharma1, Brig Y K. Arora1, Lokesh Chandra Gupta1, Amitabh Poonia1, Sukriti Raina1, Uday Singh Yadav1, Ruchi Sharma2, S Dwivedi1,  
1 Department of Cardiology, National Heart Institute, New Delhi, India
2 Department of Cardiology, Hamdard Institute of Medical Sciences and Research, New Delhi, India

Correspondence Address:
Vinod Sharma
National Heart Institute, New Delhi
India

Abstract

Introduction: Prosthetic valve thrombosis (PVT) is a serious complication seen with mechanical prosthetic cardiac valves and is associated with high mortality. Emergency surgery (thrombectomy or valve replacement) had been the traditional treatment, but now with intravenous thrombolytic therapy as an alternative to emergency surgery in patients with PVT has shown excellent success rate and acceptable risk. This study is aimed to determine efficacy and safety of use of thrombolytic agents (tPA or STK) in patients with PVT. Materials and Methods: This was a retrospective, single-center study of patients with PVT admitted between 2004 and 2020 at a tertiary care center in North India. The diagnosis of PVT was based on a history of prosthetic heart valve replacement, clinical presentation, and by diagnostic methods. All patients received either tenecteplase or streptokinase given as a bolus dose of 2.5 lac units over ½ h, followed by 1 lac units/h for 24–48 h depending on clinical response and complication, whereas tenecteplase (1 mg/kg of body weight) was given as bolus. Results: Of 72 patients, 45 patients received t-PA as a thrombolytic drug. Complete success was obtained in 39 patients (86.66%), whereas partial success in 3 (17.77%) and failure in 3 (6.66%). Among the patients who received streptokinase (n = 27), complete success was found in 23 patients (85.19%), whereas partial success was seen in 3 (11.11%) and failure was seen in 1 patient (3.7%). Conclusion: Thrombolysis is a reasonable option in patients with PVT. Our study has reiterated that major factors for PVT are warfarin poor compliance and subtherapeutic international normalized ratio. Postclosure clinical follow-up along with patient education should be followed in patients with mechanical prosthetic valve.



How to cite this article:
Sharma V, K. Arora BY, Gupta LC, Poonia A, Raina S, Yadav US, Sharma R, Dwivedi S. The efficacy and safety of thrombolytic agents for patients with prosthetic valve thrombosis.J Pract Cardiovasc Sci 2022;8:30-34


How to cite this URL:
Sharma V, K. Arora BY, Gupta LC, Poonia A, Raina S, Yadav US, Sharma R, Dwivedi S. The efficacy and safety of thrombolytic agents for patients with prosthetic valve thrombosis. J Pract Cardiovasc Sci [serial online] 2022 [cited 2022 Jul 4 ];8:30-34
Available from: https://www.j-pcs.org/text.asp?2022/8/1/30/344132


Full Text



 Introduction



Prosthetic valve thrombosis (PVT) is a serious complication seen with mechanical prosthetic cardiac valves and is associated with high mortality. PVT incidence was reported to be 0.03% in bioprosthetic valve and 0.5%–8% in mechanical valves in mitral and aortic positions.[1] Emergency surgery (thrombectomy or valve replacement) had been traditional treatment, but now with intravenous thrombolytic therapy as an alternative to emergency surgery in patients with PVT has shown excellent success rate and acceptable risk.[2] Ours is a single-center retrospective study aimed to determine the efficacy and safety of use of thrombolytic agents (tPA or STK) in patients with PVT.

 Materials and Methods



Patients selection

This was a retrospective, single-center study of patients with PVT admitted between 2004 and 2020 at a tertiary care center in North India. The study was approved by the Institutional Ethics Committee, All India Heart Foundation, New Delhi, on September 8, 2021 (Ref. No. F.No. 3/9/2021). Informed consent was waived due to the study being retrospective in nature. The clinical profiles, including their demographic characteristics, clinical symptoms on presentations, time of presentation to hospital after onset of symptom, and the interval between valve replacement and onset of symptoms suggestive of PVT, were analyzed. The diagnosis of PVT was based on the history of prosthetic heart valve replacement, clinical presentation, and by diagnostic methods including transthoracic echocardiography (TTE), transesophageal echocardiography (TEE), and fluoroscopy. PVT was considered obstructive if TTE showed a high pressure gradient across prosthetic valve along with reduced or fixed leaflet mobility on fluoroscopy. Patients with infective endocarditis or those with patient's prosthesis mismatch (characterized by high gradient on TTE but normal leaflet motion on fluoroscopy) were excluded from the study. All patients received either tenecteplase or streptokinase given as a bolus dose of 2.5 lac units over ½ h, followed by 1 lac units/h for 24–48 h depending on clinical response and complication, whereas tenecteplase (1 mg/kg of body weight) was given as a bolus. TTE and fluoroscopy were repeated after completion of thrombolysis in all patients [Table 1].{Table 1}

Analyzing outcomes

Postthrombolysis valve function was considered to be normally restored if the TTE revealed 50% or equal or more than 50% reduction in transvalvular gradient as compared to baseline with restoration of normal leaflet motion on fluoroscopy. “Complete success” of fibrinolytic therapy was considered if there was restoration of normal valve function along with clinical improvement in the absence of death, need for surgical intervention, or any major complication including stroke or major bleeding (intracranial bleed or bleeding requiring transfusion or surgical treatment) during the hospital stay. “Partial success” was defined if the restoration of normal valve function was associated with any major complication or incomplete restoration of valve function (characterized by restricted movement of valve leaflets on fluoroscopy despite normalize transvalvular gradient) requires surgical referral. Death or absence of hemodynamic response (after 24 h of fibrinolysis) was considered as “failure of fibrinolysis,” whereas near normalization of transvalvular gradient irrespective of leaflet mobility was considered as “hemodynamic success.”

Statistical analysis

Statistical analysis was done using SPSS version 16.0 software (SPSS Inc., Chicago, USA), and the data were presented as mean, standard deviation, and percentages.

 Results



During the study, 72 patients were diagnosed with PVT and received thrombolytic treatment with either tenecteplase or streptokinase as first-line treatment. Out of these patients, 29 were male (40.27%) and 43 were female (59.73%) with age group between 19 and 53 years with a mean age of 39 years.

Majority of the patients presented with symptoms of breathlessness and palpitation. While 13 patients (18%) were in NYHA class II, 41 patients (56.94%) were in NYHA class III and 11 patients (15.27%) were in NYHA Class IV. Out of these 11 patients in class IV, 7 patients (9.72%) had hemodynamic instability in the form of blood pressure less than 90 mm of Hg. Majority of the patients (n = 59; 55%) had an international normalized ratio (INR) in nontherapeutic range (<2). Acenocoumarol was the most commonly prescribed anticoagulant (58%), followed by warfarin (42%). Twenty-eight patients (38.80%) received aspirin + coumarin. 79% of patients were poorly complaint with the use of oral anticoagulant drug and monitoring of prothrombin time [Table 2].{Table 2}

Of all the valves implanted, almost all were bileaflet tilting disk type (St Jude, Medtronic Hall valve). The average interval following their prosthetic heart valve thrombosis varied from 2 to 5 years with an average of 3.1 years. Seventy-one (98.3%) patients presented with first-time thrombosis after prosthetic valve replacement, whereas 1 had prior history of PVT [Table 3].{Table 3}

The valves affected were mitral valve in 56 patients (77.77%) and aortic valve in 7 patients (9.72%) and mitral and aortic in 9 patients (12.5%) each [Table 4]. Of 72 patients, 56 patients (77.78%) were in atrial fibrillation and 16 were in sinus rhythm (22.22%). The left ventricular ejection fraction was normal (more than 50%) in 53 patients (73.60%) and impaired (<35%) in 19 patients (26.4%). Fluoroscopic findings showed that 58 patients presented with hypomobile leaflets, 12 presented with one completely struck leaflet, and one patient presented with both completely struck leaflet [Table 5]. The mean transvalvular gradient across the thrombosed mitral valve varied from 18 to 28 mm with an average of 24 mm, whereas in aortic prosthesis, the gradient varied from 32 to 58 with an average of 46 mm. Floating thrombus in atria was found in 3 patients on TEE.{Table 4}{Table 5}

The thrombolytic drug was streptokinase in 27 patients and t-PA in 45 patients as per the dose. All patients received either tenecteplase or streptokinase given as a bolus dose of 2.5 lac units over ½ h, followed by 1 lac units/h for 24–48 h depending on clinical response and complication, whereas tenecteplase (1 mg/kg of body weight) was given as a bolus [Table 6]. The complete success was seen in 39 out of 45 patients (86.66%) in t-PA group, whereas 3 patients out of 45 (6.8%) had partial success. Three patients out of 45 (6.88%) did not have significant fall in gradient nor improvement in the mobility of prosthetic heart valve disk. Of the 27 patients who received streptokinase, 27 (85.18%) had complete success while 3 (11.11%) had partial success. Two patients from t-PA group and one patient in STK group did not have response to the thrombolysis, who were subjected to semiurgent valve replacement. Only one patient in tPA group suffered major bleed (intracranial hemorrhage), whereas minor bleed in the form of gum bleed was seen in 5 patients in tPA group and 3 patients in STK group. Patient in tPA group who suffered intracranial bleed subsequently expired. One patient from tPA group had thromboembolism to the left dorsalis pedis artery which was managed conservatively, whereas 2 patients in STK group had thromboembolism to femoral artery, both required embolectomy.{Table 6}

All patients underwent fluoroscopy to ascertain the degree of opening of the valve. Of those who had successful thrombolysis, follow-up echocardiogram after 3 months revealed the adequate opening of prosthetic valve in all patients. They were put on oral anticoagulant with antiplatelet drugs with the strict monitoring of anticoagulation profile and keeping the INR in range of 2.5–3 [Table 7] and [Table 8].{Table 7}{Table 8}

 Discussion



Mechanical valve thrombosis is a serious complication of valve replacement. It is typically a subacute to acute event, resulting in rapid valve dysfunction and needing urgent diagnostic evaluation and appropriate treatment.

The annual rate of PVT with mechanical valve varies from 0.1% to 5.7%. Mechanical valves in mitral or tricuspid position are more prone to thrombosis compared with aortic position.[3]

In India, the prevalence of prosthetic heart thrombosis within 6 months of valve replacement is 6.1%.[4]

Inadequate anticoagulation, atrial fibrillation, left ventricular dysfunction-associated hypercoagulable state such as pregnancy, and early postoperative period are common risk factors for PHT. A higher rate of mechanical valve thrombosis is seen in old design and secondary to pannus or vegetation.

It has been observed that even with proper anticoagulation, the incidence rate of valve thrombosis is 0.12%–5.7% per patient per year. Even with use of warfarin, the risk of thromboembolism is 1%–2% per year, the risk is considerably high without treatment with warfarin.[5],[6]

A variable time between valve replacement and PHT has been reported from as early as 10 days after replacement to more than 10 years. The mean time interval between valve replacement and thrombosis of 4.3 years (range, 14 days–18 years) was reported in a series of 127 cases by Roudaut et al.[7] In the present study, we found that 37 (51.38%) patients had valve replacement within 3 years, while 28 (38.88%) patients had valve replacement within 3–5 years and 7 (9.72%) had valve replacement above 5 years. Majority of valve thrombosis in our series falls into the category of very late thrombosis.[8] Subtherapeutic anticoagulation was the major (79.17%) risk factor associated with PVT, which was mainly due to a lack of regular follow-up and poor treatment compliance. Similar observations were also found in the study conducted from India, which shows variable rate of inadequate anticoagulation ranging from 41.5% to 90.3%.[9] Mitral valve prosthesis is 2–3 times more frequent than thrombosis in aortic position, which was also found in previous Indian studies.[2],[10] In our study also, 77.7% of PVT episode occurred in mitral position alone, while 12.5% occurred in both mitral and aortic position. The diagnosis of PVT requires clinical suspicion along with investigations such as TTE, TEE showing elevated transvalvular gradient along with reduced or fixed leaflets mobility on echocardiography and/or fluoroscopy. Besides the TTE, TEE is helpful in evaluating thrombus burden and differentiating thrombus from the pannus.

In majority of the patients (49/72), transthoracic echocardiography was reasonably informative in our study to suggest for PVT. However, in 23 patients with a diagnostic doubt, TEE was performed. Whenever there is diagnostic doubt about PVT on TTE and color flow mapping, TEE can be used to confirm the diagnosis and decide the treatment strategies. TEE, besides diagnosing PVT causing obstruction, also helps in assessing the thrombus size, its location, and mobility. Large thrombi can lead to thromboembolic events, heart failure, and even cardiac arrest. Thrombus size measured by transesophageal echocardiogram is crucial in determining the best treatment strategies. Higher success rate with thrombolysis has been reported in cases with prosthetic valve thrombus size <1.0 cm2.[11]

Treatment of prosthetic valve thrombosis

Currently, there is no evidence in the form of results of randomized controlled trials favoring surgery over thrombolysis for the treatment of prosthetic heart valve thrombus. The superiority of surgery or thrombolytic therapy is related to the patients' hemodynamic condition. Thrombolytic therapy for left-sided PVT is associated with bleeding, thromboembolism, and recurrent thrombosis of prosthetic valve, while surgery is associated with high mortality. The mortality of surgery in some of the series is as high as 61% according to the functional class and to the emergency of intervention in these patients.[8]

Thrombolysis has been treatment of choice for prosthetic heart valve thrombosis due to its ease of availability and comparatively low cost. The success rate of thrombolysis for prosthetic heart valve thrombosis has been from 67% to 93.3% in various series.[8] Lim et al.[10] in a systematic review of trials of thrombolytic therapy in PHT reported success rate of 58%–90%, with 30-day mortality rate ranging from 0.8% to 16.7%, thromboembolism from 1.7%–17.6%, and major bleeding ranged from 1.7% to 12%. Similarly, Lengyel and Venderin, a recollection of 10 studies (515 cases), showed a success rate of 84%, mortality of 5%, major bleed in 3%, systemic embolism in 9%, brain embolism in 1.5%, and a recurrence rate of 16%.[12] Gupta et al.[13] in a series of 110 patients reported complete hemodynamic response in 81.1% of patients, partial response in 10%, and failure in 8.2%. Embolic events were seen in 21 (19.1%) cases, out of which 6 (5.5%) had cerebral embolism. In our study, out of 72 patients, 45 patients received t-PA as a thrombolytic drug and complete success was obtained in 39 patients (86.66%), while partial success in 3 (17.77%) and failure in 3 patients (6.66%). Among the patients who received streptokinase (n = 27), complete success was found in 23 patients (85.19%), while partial success was seen in 3 (11.11%) and failure was seen in 1 patient (3.7%). Only one patient in t-PA group had major bleed and of minor bleed was seen in 3 patients of STK and 5 patients of t-PA group. Thromboembolism was seen in 1 patient in t-PA group, while among the group which received streptokinase, 2 patients had peripheral thromboembolism, which requires embolectomy. One patient in t-PA group developed intracranial hemorrhage who subsequently died. The complication rate in our series was comparable with previous studies.

Our study has re-emphasized the fact that poor compliance with warfarin and subtherapeutic INR are still a major factor in the occurrence of PVT and therefore re-emphasizes the fact that patients with mechanical prosthetic valve need a closure clinical follow-up along with patient education.

The limitation of our study is that it is a single-centered retrospective study. It has a reasonable sample size for this specific study population. However, all the patients included in this study were of mechanical valve thrombosis. The applicability of this finding to the bio-PVT may be questionable. Another limitation is being retrospective in nature, and all the patients did not have fluoroscopic and transesophageal imaging, which could help in better definition of PVT and thrombus size.

This study was done in a single center restricting to patients of North India, which was the limitation of the study.

 Conclusion



Prosthetic heart valve thrombosis is a common occurrence, especially the left-sided prosthetic heart valve. Subtherapeutic anticoagulation and atrial fibrillation are major risk factors for developing prosthetic heart valve thrombosis, which can be prevented by a close follow-up to ensure the patient's treatment compliance. Thrombolysis is a reasonable option in patients with left-sided PVT with an excellent success rate and acceptable complication.

Ethics clearance

The study was approved by Institutional Ethics Committee, All India Heart Foundation, New Delhi.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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