Successful fibrinolytic treatment of prosthetic heart valve thrombosis using streptokinase Sherif A. Sakr, Hani Abdel-Shakour, Mahmoud M. Ramadan Department of Cardiology, Faculty of Medicine, Mansoura University, Egypt Objectives: This study aims to evaluate the clinical outcome of fibrinolytic treatment of prosthetic valve thrombosis (PVT) with ‘streptokinase’ as a first line treatment for these cases. Methods: The study group was 20 consecutive patients (10 females) diagnosed with PVT. The protocol for streptokinase administration was either accelerated (intravenous infusion of 0.5 million IU over 30 minutes followed by 0.15 million IU/h) or conventional (intravenous infusion of 0.25 million IU over 30 minutes followed by 0.15 million IU/h). Success of fibrinolytic therapy was defined as complete restoration of valve function in the presence or absence of complications. Results: Eighteen patients (90%) had mitral PVT and two (10%) had aortic PVT. Thrombolytic therapy with streptokinase was successful in all but one case, with a total mortality of four cases (20%). In PVT episodes, before streptokinase therapy, the prosthetic valve areas (in all cases, mitral and aortic positions) were 0.8260.21, 0.8360.21, and 0.7360.18 cm2; and the peak and mean transvalvular gradients were 38.7616.7 and 25.468.7, 34.168.8 and 23.265.4, and 80.0614.1 and 45.067.1 mmHg, respectively. After streptokinase therapy, the prosthetic valve area and peak and mean transvalvular gradients improved significantly (for all cases, mitral and aortic positions: valve area 2.1760.58, 2.2160.61, and 1.8560.07 cm2, peak gradient 18.7611.0, 16.467.7, and 39.0618.4, and mean gradient 9.667.1, 8.265.3, and 22.0611.3 mmHg, respectively; paired t-test, P,0.001 for pre- versus post-streptokinase infusion for all variables). Conclusion: Fibrinolytic therapy using streptokinase was an effective therapeutic strategy for the management of PVT and is a reasonable alternative to surgery. Keywords: Thrombolytic, Fibrinloytic, Streptokinase, Valve, Thrombosis
Introduction Prosthetic valve thrombosis (PVT) is a serious and potentially lethal complication of heart valve replacement. The reported incidence of PVT varies from 0.5 to 6 per hundred patient-years, and is higher for the mitral than for the aortic valve.1 The reported incidence of PVT in the first year after replacement of either the mitral or the aortic valve is as high as 13%.2 Inadequate anticoagulant therapy remains the main cause of PVT, but pitfalls in the surgical technique and pannus formation can also act as contributing factors.3 The Society for Heart Valve Disease recommends fibrinolytic therapy (FT) for all patients with PVT, and surgery is recommended only if FT is contraindicated.4 However, the European Society of Cardiology recommends FT only if the risk of surgery is prohibitive or if surgery is not available and the patient cannot be transferred, and advocates
Correspondence to: M. M. Ramadan, Department of Cardiology, Specialized Medicine Hospital, Mansoura University, Mansoura City, Egypt. E-mail: [email protected]
ß Acta Clinica Belgica 2014 DOI 10.1179/2295333714Y.0000000107
surgery in all critically ill patients.5 In the most recent American College of Cardiology/American Heart Association guidelines, surgery is recommended for patients in New York Heart Association (NYHA) functional class III or IV unless they are deemed high risk (class IIA).6 FT is given a class IIA indication in patients with right-side valve thrombosis and a class IIB indication in patients with a small, left-side thrombus. Surgical management of PVT has been associated with a significant death risk for over 40 years.23 Despite an improvement in mortality in the past decade,23 surgery is still associated with a high risk of death. Therefore, establishment of a more effective strategy to treat PVT is crucial, especially in developing countries where this condition is prevalent.23 FT has become the first-line treatment for PVT in much of the developing world,8–11 presumably because of the limited availability and high cost of surgery. Currently, there is no agreement on the optimal type, dose, or route of administration of thrombolytic agents,7 and practice is therefore dictated by local availability of
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resources and physician preferences rather than by considerations of benefit and harm. The purpose of this study was to evaluate the efficacy and clinical outcome of FT of PVT using the economic and widely available drug ‘streptokinase’ as a first-line treatment for these cases, particularly in developing countries where surgery is not always feasible, costly, and carries a high mortality risk.
Patients and Methods Study design and participants This consecutive case series study included 20 PVT patients (10 females) who were admitted to the Cardiology Department of Mansoura Medicine Specialized Hospital between January 2010 and August 2014 and underwent intravenous FT using ‘streptokinase’ for PVT. The included patients were given streptokinase as the primary therapeutic option for PVT so long as no contraindication for thrombolytic therapy exists (such as bleeding tendency, ongoing bleeding, or expanding or haemorrhagic cerebral infarcts). The risks and benefits of streptokinase in comparison to surgery were explained for all patients before obtaining their consent to participate in this study. The Institutional Review Board approved the study protocol and written informed consent was obtained from each patient before entry into the study.
Echocardiography Transthoracic echocardiography (TTE) was performed with a 3.25-MHz transducer. All TTE examinations were performed at baseline (index admission) and 60– 90 minutes after completion of the initial infusion of the loading dose of streptokinase. TTE examinations were then repeated every 2–3 hours during the maintenance infusion of streptokinase till success occur. Thus, a total number of eight TTE examinations were performed in the first 24 hours of admission. Initially, two echocardiographers independently evaluated the TTE recordings done at the index admission and 24 hours after the start of streptokinase therapy before reaching a consensus regarding treatment success or the need to transfer to surgery.
For aortic prostheses, maximum and mean transvalvular gradients, effective aortic valve area, and Doppler velocity index were calculated. Doppler velocity index was calculated as the ratio of velocity of the left ventricular outflow to velocity of the aortic jet.12 For mitral prostheses, mean transvalvular gradient, pressure half-time, and effective mitral valve area were calculated.13,14 Effective mitral valve area was calculated from pressure half-time. Ejection fraction was measured using the multiple-diameters method15 for both aortic and mitral prosthetic valves. A significant narrowing of the valve was diagnosed when the Doppler mitral valve area was ,1.5 cm2 and the mitral valve mean transvalvular gradient was .10 mmHg, or when the aortic valve mean transvalvular gradient was .40 mmHg. The presence and severity of concomitant prosthetic valve regurgitation were evaluated by TTE and trans-esophageal echocardiography (TEE) using conventional criteria for aortic and mitral prostheses.14,16 For all cases except one (no. 15), TEE was performed twice (on admission and before discharge) by a 5MHz multiplane transducer connected to a Vingmed system (Vingmed CFM 800) after oropharyngeal anaesthesia (10% lidocaine) and conscious sedation (intravenous midazolam, 1–3 mg). Regarding case no. 15, TEE was not performed as the patient was severely distressed and resuscitated from aborted sudden death. The length and area of any mass seen on a prosthetic valve were measured from the view that showed the largest extent of mass. PVT was classified as mobile or fixed echo densities located at the valve occluder and/or valve struts. The largest diameter of the thrombus and the length of the mobile portion (if present) were measured by TEE. Large thrombus was defined as §10 mm base diameter and/or §5 mm mobile segment length.
Thrombolytic protocol For all cases, streptokinase administration was carried out using one of two protocols irrespective of patient’s body weight (Table 1). The ‘Accelerated’ protocol involved intravenous infusion of 0.5 million
Table 1 Streptokinase administration protocols stratified by gender and prosthetic valve position Streptokinase infusion protocol Accelerated Mechanical valve position
Gender
Standard
Extended
Standard
Extended
Total
Mitral
Male Female Male Female
2 2 2 … 6
6 5 … … 11
… 2 … … 2
… 1 … … 1
8 10 2 … 20
Aortic Total
2
Conventional
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IU over 30 minutes, followed by 0.15 million IU/h. The ‘Conventional’ protocol involved intravenous infusion of 0.25 million IU over 30 minutes followed by 0.15 IU/h. The accelerated protocol was used for patients with big thrombus burden (defined as §10 mm base diameter and/or §5 mm mobile segment length) or international normalized ratio (INR) ,1.5 upon admission, and the conventional protocol was used for patients with small thrombus burden or INR.1.5 upon admission. The duration of the maintenance (0.15 million IU/ h) streptokinase administration was either standard (,24 hours) or extended (.24 hours), and was determined according to the results of repeated echocardiographic examinations performed during streptokinase infusion. Streptokinase infusion was continued until the mechanical valve area was satisfactorily increased with consequent reduction of peak and mean gradients across the mechanical valve. Satisfactory increase of mechanical valve area was objectively determined by TEE carried out (in almost all cases) on admission and again before discharge (on average after 1 week of admission), and was defined as §75% increase of mechanical valve area compared to the original valve area measured on index admission. If there was no initial haemodynamic improvement after the first 24 hours (neither increase in valve area nor reduction in peak or mean transvalvular gradients), or the mechanical valve area was never satisfactorily increased after completing the maximum streptokinase infusion dose (3 ampoules54.5 million IU), streptokinase was discontinued and surgical management was considered.17 Streptokinase was contraindicated in patients with a bleeding tendency and in those with expanding or haemorrhagic cerebral infarcts.
Definition of FT success The response of obstructive thrombi to streptokinase was defined as a complete success if there was objectively documented complete restoration of valve function in the presence or absence of complications, with no narrowing of the valve according to haemodynamic measurements and .75% reduction in the largest diameter of the thrombus. The response of non-obstructive thrombi to streptokinase was defined as a complete success if there was .75% reduction in thrombus diameter or complete lysis of the mobile portion of the thrombus. Un-fractionated heparin (UFH) and warfarin treatment was started in patients with complete success (except for pregnant patients who were not given warfarin), and UFH therapy was continued until an INR.2.5 was achieved. In only one case (no. 9), a shift from UFH to low-molecular-weight
Streptokinase treatment for prosthetic heart valve thrombosis
heparin (LMWH) was carried out in a trial to seek a more effective anticoagulation. Response to streptokinase was screened by TTE every 2–3 hours.
Outcomes In addition to FT success, the following outcomes were recorded: in-hospital death, stroke or transient ischaemic attack, non-central nervous system systemic embolism, major bleeding, and recurrence of PVT. Major fatal complication was defined as allcause in-hospital mortality, and major non-fatal complications included ischaemic stroke, intracranial haemorrhage, systemic thromboembolism, bleeding requiring transfusion, or surgery. Minor complications were bleeding without the need for transfusion and transient ischaemic attack.
Statistical analyses Continuous data are expressed as mean6one standard deviation, while non-continuous data were expressed as proportions. Comparisons of means of continuous data across a factor with two levels were carried out using Student’s t-test. Proportions were compared using the Chi-square test (or Fisher’s exact test when at least one cell in the n6m table has expected count ,5). A two-sided significance level of 0.05 was used for all analyses, which were conducted using SPSS 21 for Windows (SPSS Inc., Chicago, IL, USA). During the study period, a total of nine patients were excluded from analyses. Two patients preferred surgical management and refused streptokinaserelated risk. Patients with valve dysfunction due to pannus formation (defined as the presence of fixed, bright echodense structures, sometimes containing focal calcific deposits, along the valve ring with extension into the valve orifice) were also excluded from the analyses (n54 patients, all referred to surgery). We excluded three more patients with thrombosis of tissue valves (two patients) or rightsided prosthetic valves (one patient).
Results Patient characteristics The study group included 20 patients (10 females) diagnosed with PVT. Their mean age was 37.0613.8 years (range: 16–63 years). Males were older than females (41.8612.5 versus 32.2613.9 years), but this difference was not statistically significant (P50.122). The demographic and clinical characteristics of all patients are shown in Table 2. Eighteen cases (90%; 8 males, 10 females) had mitral PVT and two cases (10%; both males) had aortic PVT. Two patients were pregnant (one 5-month pregnant and the other 6-week pregnant), both of which had mitral PVT and died from cardiogenic shock. The most common symptom on admission was dyspnea (19 cases, 95%). This was the sole presentation in 16 cases (80%) and was combined with other
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40 19 25 41 22
63 42 28
28 35
10*
11 12 13 14 15*
16 17 18
19 20
III III III III IV
Female IV Male III
Male IV Female IV Female III
Female Female Female Male Male
Female III
Female III
Female III
IV IV III I
Mitral Mitral Mitral Mitral Mitral
Mitral
Mitral
Mitral
Dyspnea Dyspnea
Mitral Mitral
Dyspnea Mitral Dyspnea, fever Mitral Dyspnea Mitral
Dyspnea Dyspnea Dyspnea Dyspnea Dyspnea
Dyspnea
Dyspnea, haemoptysis Dyspnea
Small, fixed Small, mobile Small, fixed Large, fixed Large, fixed
Accel. Conv. Accel. Accel. Accel.
Accel.
… …
Small, mobile Accel. Large, fixed Accel.
Yes Small, fixed Accel. … Large, mobile Accel. … Large, fixed Accel.
… … Yes … …
Conv.
Accel. Accel. Accel. Accel.
Small, mobile Conv.
Large, fixed Large, mobile Small, mobile No thrombus seen Small, mobile
Yes Small, fixed
…
…
Yes … … …
44 26 90 70
33 42 26 39 28
Extended 28 Extended 33
Extended 33 Extended 37 Extended 35
Standard Standard Standard Extended Extended
Extended 23
Standard 35
Extended 25
Extended Extended Standard Standard
17 17
18 19 36
8 25 9 22 11
10
17
8
26 12 52 26
10 7 23
23 22
22 28 22
22 30 20 23 22
15
21
18
28 22 50 40
18 22 40
7 9
5 6 24
4 14 6 13 9
4.5
6
4
6 8 30 14
4.5 3 15
1.4 0.9
0.7 1.0 0.8
1.0 0.9 0.9 0.6 0.5
0.9
0.9
0.6
0.8 0.8 0.6 0.85
0.8 0.9 0.5
2.0 2.1
3.0 3.0 0.7
2.1 2.4 2.3 1.2 2.0
2.0
2.4
1.8
3.2 2.6 1.8 1.9
2.1 2.2 2.6
Cardiac shock and death (pregnant) Fever, brain infarction, and death … … … … Massive brain infarction and death … Brain infarction Cardiac shock and death (pregnant) … …
…
… … … …
Censored censored
Censored Censored Died
Censored Censored Censored Censored Died
Died
Died
Censored
Censored Censored Censored Censored
Transient MVO Censored … Censored … Censored
Valve Valve Peak PG Peak PG Mean PG Mean area area after before SK after SK before SK PG after before 2 (mmHg) (mmHg) (mmHg) SK (mmHg) SK (cm ) SK (cm2) Complications Survival
Extended 27 Standard 40 Standard 59
SK SK infusion infusion protocol duration
Large, mobile Accel. Small, fixed Accel. Small, fixed Accel.
Thrombus size and type
Notes: *Case no. 1: Female patient with successful fibrinolysis who suffered acute abdominal pain a few hours after streptokinase infusion. The patient was diagnosed with mesenteric vascular occlusion, and this resolved with conservative treatment (no surgical interference). Case no. 9: Pregnant female patient who died 5 days after successful fibrinolysis (one day after the shift from un-fractionated to lowmolecular-weight heparin). Case no. 10: Female patient with successful fibrinolysis who experienced a cerebral infarction and died. Case no. 15: Male patient who presented with cardiogenic shock, aborted sudden death, and was resuscitated. Fibrinolysis was successful, but was complicated with massive cerebral infarction and anti-coagulation was therefore withheld. The patient then developed valve rethrombosis, cardiogenic shock, and died after 5 days. Case no. 17: Female patient with a huge, friable, mobile thrombus that covered most of the atrial surface of the mitral prosthesis and protruded on the ventricular surface of the prosthetic valve. Approximately 2 hours after streptokinase infusion, the patient developed severe pulmonary oedema and transient cardiac arrest and was resuscitated and mechanically ventilated. On follow-up, the valve was open and its area had increased to 3 cm2, but the case was complicated with cerebral infarction. Case no. 18: Pregnant female patient (6 weeks) with a large thrombus over the mitral valve prosthesis who partially responded to streptokinase infusion (valve area increased from 0.6 to 1.1 cm2). However, 24 hours after streptokinase infusion, the patient deteriorated due to prosthetic valve re-thrombosis with marked valve area reduction. At 48 hours after streptokinase infusion, the patient developed cardiac arrest and died. This was the only case of failed fibrinolysis. Accel.: accelerated; AF: atrial fibrillation; Conv.: conventional; MVO: mesenteric vascular occlusion; NYHA: New York Heart Association; PG; pressure gradient; SK: streptokinase.
19
9*
16
8
Male Male Male Male
Mitral Mitral Aortic Aortic
45 26 57 46
4 5 6 7
… … …
Mitral Mitral Mitral
58 43 40
1* 2 3
Dyspnea Dyspnea Dyspnea, fever, haemoptysis Dyspnea Dyspnea Dyspnea Asymptomatic
Case Age NYHA Clinical no. (years) Gender class presentation
Female IV Male IV Male IV
Prosthetic valve position AF
Table 2 The demographic and clinical characteristics of all patients
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symptoms in three cases (haemoptysis, n51; fever, n51; haemoptysis and fever, n51). Only one case (no. 7; a male with aortic PVT) was asymptomatic. Four cases (20%) had chronic atrial fibrillation, and one of them (no. 10) died. No cases had hypertension or diabetes mellitus. Three cases (15%) were using lowdose aspirin (100 mg) in addition to warfarin upon admission. Poor compliance to warfarin with subtherapeutic INR level was detected in 15 patients (75%) upon admission.
Echocardiographic results Large prosthetic valve thrombus (defined as §10 mm base diameter and/or §5 mm mobile segment length) was found in eight cases (40%; all with mitral prostheses), while small thrombus was found in 11 cases (55%; 10 mitral and one aortic prosthesis) and one case (no. 7, with aortic prosthesis) had no thrombus. The majority (five out of eight) of large thrombi were fixed, while three only were mobile (P50.377). One of the four cases with AF had a large fixed mitral PV thrombus. Out of the eight cases with large thrombi, two only passed away (in which the thrombi were fixed). In PVT episodes, before streptokinase therapy, the prosthetic valve area (in all cases, mitral and aortic
Streptokinase treatment for prosthetic heart valve thrombosis
positions) were 0.8260.21, 0.8360.21, and 0.7360.18 cm2; and the peak and mean transvalvular gradients were 38.7616.7 and 25.468.7, 34.168.8 and 23.265.4, and 80.0614.1 and 45.067.1 mmHg, respectively. After streptokinase therapy, the prosthetic valve area and peak and mean transvalvular gradients improved significantly (in all cases, mitral and aortic positions: valve area 2.1760.58, 2.2160.61, and 1.8560.07 cm2, peak gradient 18.7611.0, 16.467.7, and 39.0618.4, and mean gradient 9.667.1, 8.265.3, and 22.0611.3 mmHg, respectively; P,0.001 for all comparisons using paired t-test).
Complications Streptokinase was fully successful in all but one case (case no. 18; pregnant and died) with a total mortality of four cases (20%, all with mitral PVT). Death occurred 6 days after the start of streptokinase in two cases (nos. 9 and 10) and 2 days after the start of streptokinase in two cases (nos. 15 and 18). Transient mesenteric vascular occlusion occurred in one case (no. 1), and non-fatal cerebral stroke occurred in one case (no. 17), both with mitral PVT. Table 3 compares the characteristics of censored and mortality cases. Owing to the small sample size, all comparisons were statistically non-significant.
Table 3 Characteristics of censored and mortality cases
Demographic data Age (years) Gender Male Female Clinical data NYHA class I III IV Atrial fibrillation Prosthetic valve position Mitral Aortic Echocardiographic data Thrombus type Mobile obstructive Fixed obstructive None Prosthetic valve area (cm2) Pre-SK Post-SK Transvalvular pressure gradient (mmHg) Pre-SK Peak pressure gradient Mean pressure gradient Post-SK Peak pressure gradient Mean pressure gradient SK infusion protocol Accelerated Conventional SK infusion duration Standard Extended
Censored (n516)
Died (n54)
p value
39.0613.7
29.0612.6
0.202 0.582
9 (45.0%) 7 (35.0%)
1 (5.0%) 3 (15.0%)
1 7 8 3
0 3 1 1
0.517 (5.0%) (35.0%) (40.0%) (15.0%)
(0.0%) (15.0%) (5.0%) (5.0%)
14 (70.0%) 2 (10.0%)
4 (20.0%) 0 (0.0%)
7 (35.0%) 8 (40.0%) 1 (5.0%)
1 (5.0%) 3 (15.0%) 0 (0.0%)
0.780 0.998
0.639
0.8360.22 2.3060.52
0.7760.19 1.7760.74
0.657 0.134
40.8617.9 26.869.1
30.365.8 20.063.4
0.159 0.169
18.7611.2 9.366.8
18.5612.1 10.968.9
0.951 0.697 0.509
14 (70.0%) 2 (10.0%)
3 (15.0%) 1 (5.0%)
7 (35.0%) 9 (45.0%)
1 (5.0%) 3 (15.0%)
0.619
Note: NYHA: New York Heart Association; SK: streptokinase.
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Our study included two pregnant cases, both of which died after streptokinase therapy. The first case (no. 9) died 6 days after successful thrombolysis with streptokinase, and 2 days after the shift from UFH to LMWH. The second case (no. 18; 6-week pregnant) had a large thrombus over the mitral valve prosthesis. Streptokinase infusion was not completely successful, with an increase of the prosthetic valve area from 0.6 to just 1.1 cm2. After 24 hours, the patient deteriorated due to prosthetic valve re-thrombosis with marked valve area reduction; and at 48 hours after the start of streptokinase infusion, the patient developed cardiac arrest and died.
Discussion PVT is a serious complication of heart valve replacement. There are no generally accepted criteria for the management of PVT patients, and there are two lines of treatment available: thrombolytic therapy and surgical replacement of the obstructed prosthetic valve. The goal of this study was to evaluate the efficacy and clinical outcome of FT of PVT using the economic and widely available drug ‘streptokinase’ as a first-line treatment for these cases, particularly in developing countries where surgery is not always feasible, costly, and carries a high mortality risk. We performed a single-centre consecutive case series study of 20 patients with PVT and found that FT with streptokinase using two different administration regimens was associated with successful thrombus lysis in almost all cases. The incidence of complications was lower than that reported with surgery or non-FTbased medical treatment.23 Lengyel and co-workers consider FT as the firstline treatment for PVT if there is no contraindication, independent of NYHA class and thrombus size.4 However, in a recent series of 210 patients reported by Roudaut et al., surgical treatment was associated with significantly better long-term results regarding recurrence and mortality and a lower incidence of embolic complications than FT.18 A recent metaanalysis evaluated seven eligible studies with 690 episodes of PVT, 446 treated with surgery and 244 treated with FT, and found that urgent surgery was not superior to FT at restoring valve function, but substantially reduced the occurrence of thromboembolic events, major bleeding, and recurrent PVT.19 In the current study, FT using streptokinase was successful in treating PVT in 19 out of 20 patients (95%) with this condition, still favouring FT to urgent surgery. The use of FT for left-sided PVT has shown promising results.7–11,19–21 The reported rate of clinical resolution with streptokinase is 64–92%.7,20,21 A large meta-analysis of 515 cases reported an initial success rate of 84%, mortality of 5%, and bleeding complications
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in 3% of patients and systemic embolism in 9% of patients receiving FT for PVT.21 Similarly, in the current study, streptokinase was successful in treating left-sided PVT in 19 out of 20 patients (95%), but the mortality rate reached to 20% and systemic embolism occurred in four patients (20%): three with cerebral embolism (two had fatal outcome) and one case with transient mesenteric vascular occlusion which resolved spontaneously. Surgery for PVT is associated with high mortality, with 30-day operative mortality and total in-hospital mortality reported at 25% and 41%, respectively.22 In fact, FT and surgery were not considered as alternative treatment options in past clinical practice, but rather as complementary ones. Hence, FT using streptokinase was the first treatment option for almost all patients with PVT in our institution; and during the study period, surgery was only performed for patients with a major contraindication for FT or for patients in whom FT failed.23 The Society for Heart Valve Disease recommends FT for all patients, and recommends surgery only if FT is contraindicated,4 whereas the European Society of Cardiology recommends FT only if the risk of surgery is prohibitive or when surgery is unavailable and the patient cannot be transferred.5 FT is the firstline treatment for PVT in much of the developing world,8–11 presumably because of the limited availability and high initial cost of surgery. Although it is acknowledged that surgery may be more successful than FT and may cause fewer strokes and bleeding, the risk of death is higher and the magnitude of these risk/benefit trade-offs is not clear. Our study supports the use of FT. FT with streptokinase was effective and relatively safe, and we suggest it as a first-line therapy for PVT, particularly when surgery is not immediately available or is deemed high risk. In 2009, a randomized trial found no difference in outcomes between an accelerated (1.5 million units of streptokinase over 1 hour followed by 0.1 million units/h infusion) and a conventional dose (0.25 million units of streptokinase over 30 minutes followed by a 0.1 million units/h infusion) of streptokinase for the treatment of PVT.20 In our study, streptokinase treatment was successful in 19 of 20 cases (95%), which is a higher percentage when compared to the abovementioned trial, with a total mortality of four cases (20%) all occurring within a few days of the start of streptokinase therapy. Besides, we used lower loading streptokinase dose for the accelerated protocol than that used in the aforementioned randomized trial (0.5 compared to 1.5 million IU), which was given over a shorter duration (30 minutes compared to 1 hour), while using a slightly higher streptokinase maintenance dose for both accelerated and conventional protocols
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(0.15 compared to 0.1 million IU/h) and using the same initial streptokinase loading dose for conventional protocol (0.25 million IU over 30 minutes). Our study included two pregnant patients, both of which died after streptokinase therapy. They were maintained on subcutaneous LMWH (enoxaparin: 1 mg/kg) twice daily throughout pregnancy. After admission to our hospital, subcutaneous UFH was given instead of LMWH every 12 hours to keep the mid-interval activated partial thromboplastin time at least twice in control. UFH was continued in one patient (no. 18), while shift to LMWH was carried out in the other patient (no. 9) who died just 24 hours after this therapeutic shift. The other patient (no. 18) deteriorated 24 hours after streptokinase infusion due to prosthetic valve re-thrombosis with marked valve area reduction; and at 48 hours after streptokinase infusion, the patient developed cardiac arrest and died (the only case of failed fibrinolysis). The safety and efficacy of LMWH in PVT during pregnancy is questionable,24 and treatment failures with LMWH have been described.25 Such treatment failures may be minimized if trough and peak anti-Xa levels are used to guide dose adjustments.24 The American College of Chest Physicians recommend an adjusted dose of LMWH twice daily throughout pregnancy, with the dose adjusted to achieve manufacturer’s peak anti-Xa at 4 hours post-dose.26 Women who were compliant with a twice-daily therapeutic dose of LMWH adjusted via using antiXa levels had good outcomes.27 The trough anti-Xa level is likely to be more informative and important than the peak anti-Xa level for indicating an adequate baseline anticoagulant effect; however, measurement of both peak and trough anti-Xa levels is only advocated by two researcher groups.28,29 Despite the high NYHA functional class of most of our patients (19 of 20 patients in NYHA class III or IV), the success rate of FT using streptokinase was 95%. Studies from the American College of Cardiology Foundation indicate that a small amount of thrombus at the hinges of a mechanical valve can result in obstructive PVT and be associated with severe symptoms.30 We propose that this accounts for the rapid and complete success of FT in at least some of the patients who were in NYHA functional class III or IV.30 In a previous report, 39% of PVT patients had subtherapeutic anticoagulation at the time of clinical presentation.30 In our study, 75% of patients had poor compliance with warfarin with sub-therapeutic INR at admission. The possible reasons for this high percentage in our study could be the patient’s lower socioeconomic standards, lower level of education, and carelessness regarding regular follow-up (including INR check). Poor anticoagulation status leads to
Streptokinase treatment for prosthetic heart valve thrombosis
thrombus formation.31,32 Thus, the anticoagulation status at clinical presentation may not be representative of anticoagulation status at the time of start of thrombus formation, which occurs weeks or months before the diagnosis of PVT.30 The success rate of FT in patients in NYHA class II or below was similar to that in patients in NYHA class III or above.7 Hurrell et al. recommended direct surgical treatment rather than FT for patients in NYHA class IV,33 because of a high medical mortality reported in some series.7 The American College of Cardiology/American Heart Association valve disease guidelines also recommend surgical treatment for class IV patients except those who are not candidates for surgery.34 However, surgical mortality is highest in this group of patients.35,36 Recently published guidelines proposed thrombolytic therapy as the treatment of choice for critically ill patients in NYHA class III or IV, although the definition of ‘critically ill’ was subjective.37 In conclusion, FT with streptokinase was an effective therapeutic strategy for the management PVT and is a reasonable alternative to surgery irrespective of NYHA class.
Disclaimer Statements Contributors None. Funding None. Conflicts of interest None. Ethics approval The Institutional Review Board approved the study protocol and written informed consent was obtained from each patient before entry into the study.
References 1 Vongpatanasin W, Hillis LD, Lange RA. Prosthetic heart valves. N Engl J Med. 1996;335:407–16. 2 Roudaut R, Labbe T, Lorient-Roudaut MF, Gosse P, Baudet E, Fontan F, et al. Mechanical cardiac valve thrombosis. Is fibrinolysis justified? Circulation. 1992;86(5 Suppl):II 8–15. 3 Barbetseas J, Nagueh SF, Pitsavos C, Toutouzas PK, Quin˜ones MA, Zoghbi WA. Differentiating thrombus from pannus formation in obstructed mechanical prosthetic valves: an evaluation of clinical, transthoracic and transesophageal echocardiographic parameters. J Am Coll Cardiol. 1998;32: 1410–7. 4 Lengyel M, Horstkotte D, Vo¨ller H, Mistiaen WP; Working Group Infection, Thrombosis, Embolism and Bleeding of the Society for Heart Valve Disease. Recommendations for the management of prosthetic valve thrombosis. J Heart Valve Dis. 2005;14:567–75. 5 Joint Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology (ESC); European Association for Cardio-Thoracic Surgery (EACTS), Vahanian A, Alfieri O, Andreotti F, Antunes MJ, Baro´n-Esquivias G, Baumgartner H, et al. Guidelines on the management of valvular heart disease (version 2012). Eur Heart J. 2012;33:2451–96. 6 Bonow RO, Carabello BA, Chatterjee K, de Leon AC, Jr, Faxon DP, Freed MD, et al. American College of Cardiology/ American Heart Association Task Force on Practice Guidelines. 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
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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. 2008;52:e1–142. Ozkan M, Kaymaz C, Kirma C, So¨nmez K, Ozdemir N, Balkanay M, et al. Intravenous thrombolytic treatment of mechanical prosthetic valve thrombosis: a study using serial transesophageal echocardiography. J Am Coll Cardiol. 2000;35:1881–9. Balasundaram RP, Karthikeyan G, Kothari SS, Talwar KK, Venugopal P. Fibrinolytic treatment for recurrent left sided prosthetic valve thrombosis. Heart. 2005;91:821–2. Gupta D, Kothari SS, Bahl VK, Goswami KC, Talwar KK, Manchanda SC, et al. Thrombolytic therapy for prosthetic valve thrombosis: short- and long-term results. Am Heart J. 2000;140:906–16. Ca´ceres-Lo´riga FM, Pe´rez-Lo´pez H, Morlans-Herna´ndez K, Facundo-Sa´nchez H, Santos-Gracia J, Valiente-Mustelier J, et al. Thrombolysis as first choice therapy in prosthetic heart valve thrombosis. A study of 68 patients. J Thromb Thromb. 2006;21:185–90. Reddy NK, Padmanabhan TN, Singh S, Kumar DN, Raju PR, Satyanarayana PV, et al. Thrombolysis in left-sided prosthetic valve occlusion: immediate and follow-up results. Ann Thorac Surg. 1994;58:462–70; discussion 470–1. Chafizadeh ER, Zoghbi WA. Doppler echocardiographic assessment of the St. Jude Medical prosthetic valve in the aortic position using the continuity equation. Circulation. 1991;83:213–23. Wilkins GT, Gillam LD, Kritzer GL, Levine RA, Palacios IF, Weyman AE. Validation of continuous-wave Doppler echocardiographic measurements of mitral and tricuspid prosthetic valve gradients: a simultaneous Doppler-catheter study. Circulation. 1986;74:786–95. Kapur KK, Fan P, Nanda NC, Yoganathan AP, Goyal RG. Doppler color flow mapping in the evaluation of prosthetic mitral and aortic valve function. J Am Coll Cardiol. 1989;13: 1561–71. Quinones MA, Waggoner AD, Reduto LA, Nelson JG, Young JB, Winters WL, Jr, et al. A new, simplified and accurate method for determining ejection fraction with two-dimensional echocardiography. Circulation. 1981;64:744–53. Nellessen U, Schnittger I, Appleton CP, Masuyama T, Bolger A, Fischell TA, et al. Transesophageal two-dimensional echocardiography and color Doppler flow velocity mapping in the evaluation of cardiac valve prostheses. Circulation. 1988;78:848–55. Nanda NC, Cooper JW, Mahan EF 3rd, Fan P. Echocardiographic assessment of prosthetic valves. Circulation. 1991;84 (3 Suppl):I228–39. Roudaut R, Lafitte S, Roudaut MF, Reant P, Pillois X, Durrieu-Jaı¨s C, et al. Management of prosthetic heart valve obstruction: fibrinolysis versus surgery. Early results and longterm follow-up in a single-centre study of 263 cases. Arch Cardiovasc Dis. 2009;102:269–77. Karthikeyan G, Senguttuvan NB, Joseph J, Devasenapathy N, Bahl VK, Airan B. Urgent surgery compared with fibrinolytic therapy for the treatment of left-sided prosthetic heart valve thrombosis: a systematic review and meta-analysis of observational studies. Eur Heart J. 2013;34:1557–66. Karthikeyan G, Math RS, Mathew N, Shankar B, Kalaivani M, Singh S, et al. Accelerated infusion of streptokinase for the treatment of left-sided prosthetic valve thrombosis: a randomized controlled trial. Circulation. 2009;120:1108–14. Lo´pez HP, Ca´ceres Lo´riga FM, Herna`ndez KM, Sa´nchez HF, Gonza´lez Jimenez N, Marrero Mirayaga MA, et al.
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Thrombolytic therapy with recombinant streptokinase for prosthetic valve thrombosis. J Card Surg. 2002;17:387–93. Du¨rrleman N, Pellerin M, Bouchard D, He´bert Y, Cartier R, Perrault LP, et al. Prosthetic valve thrombosis: twenty-year experience at the Montreal Heart Institute. J Thorac Cardiovasc Surg. 2004;127:1388–92. ¨ zkan M, Gu¨ndu¨z S, Biteker M, Astarcioglu MA, C O ¸ evik C, Kaynak E, et al. Comparison of different TEE-guided thrombolytic regimens for prosthetic valve thrombosis: the TROIA trial. JACC Cardiovasc Imaging. 2013;6:206–16. McLintock C. Anticoagulant choices in pregnant women with mechanical heart valves: balancing maternal and fetal risks — the difference the dose makes. Thromb Res. 2013;131(Suppl 1):S8–10. Yinon Y, Siu SC, Warshafsky C, Maxwell C, McLeod A, Colman JM, et al. Use of low molecular weight heparin in pregnant women with mechanical heart valves. Am J Cardiol. 2009;104:1259–63. Bates SM, Greer IA, Middeldorp S, Veenstra DL, Prabulos AM, Vandvik PO; American College of Chest Physicians. VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e691S– 736S. McLintock C. Anticoagulant therapy in pregnant women with mechanical prosthetic heart valves: no easy option. Thromb Res. 2011;127(Suppl 3):S56–60. McLintock C, McCowan LM, North RA. Maternal complications and pregnancy outcome in women with mechanical prosthetic heart valves treated with enoxaparin. BJOG. 2009;116:1585–92. Elkayam U, Goland S. The search for a safe and effective anticoagulation regimen in pregnant women with mechanical prosthetic heart valves. J Am Coll Cardiol. 2012;59:1116–8. Huang G, Schaff HV, Sundt TM, Rahimtoola SH. Treatment of obstructive thrombosed prosthetic heart valve. J Am Coll Cardiol. 2013;62:1731–6. Gitter MJ, Jaeger TM, Petterson TM, Gersh BJ, Silverstein MD. Bleeding and thromboembolism during anticoagulant therapy: a population-based study in Rochester, Minnesota. Mayo Clin Proc. 1995;70:725–33. Huber KC, Gersh BJ, Bailey KR, Schaff HV, Hodge DO, Cha RH, et al. Variability in anticoagulation control predicts thromboembolism after mechanical cardiac valve replacement: a 23-year population-based study. Mayo Clin Proc. 1997;72: 1103–10. Hurrell DG, Schaff HV, Tajik Aj. Thrombolytic therapy for obstruction of mechanical prosthetic valves. Mayo Clin Proc. 1996;71:605–13. ACC/AHA 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 (Committee on Management of Patients with Valvular Heart Disease). J Am Coll Cardiol. 1998;32: 1486–588. Husebye DG, Pluth JR, Piehler JM, Schaff HV, Orszulak TA, Puga FJ, et al. Reoperation on prosthetic heart valves. An analysis of risk factors in 552 patients. J Thorac Cardiovasc Surg. 1983;86:543–52. Deviri E, Sareli P, Wisenbaugh T, Cronje SL. Obstruction of mechanical heart valve prostheses: clinical aspects and surgical management. J Am Coll Cardiol. 1991;17:646–50. Lengyel M, Fuster V, Keltai M, Roudaut R, Schulte HD, Seward JB, et al. Guidelines for management of left-sided prosthetic valve thrombosis: a role for thrombolytic therapy. Consensus Conference on Prosthetic Valve Thrombosis. J Am Coll Cardiol. 1997;30:1521–6.
Introduction Prosthetic valve thrombosis (PVT) is a serious and potentially lethal complication of heart valve replacement. The reported incidence of PVT varies from 0.5 to 6 per hundred patient-years, and is higher for the mitral than for the aortic valve.1 The reported incidence of PVT in the first year after replacement of either the mitral or the aortic valve is as high as 13%.2 Inadequate anticoagulant therapy remains the main cause of PVT, but pitfalls in the surgical technique and pannus formation can also act as contributing factors.3 The Society for Heart Valve Disease recommends fibrinolytic therapy (FT) for all patients with PVT, and surgery is recommended only if FT is contraindicated.4 However, the European Society of Cardiology recommends FT only if the risk of surgery is prohibitive or if surgery is not available and the patient cannot be transferred, and advocates
Correspondence to: M. M. Ramadan, Department of Cardiology, Specialized Medicine Hospital, Mansoura University, Mansoura City, Egypt. E-mail: [email protected]
ß Acta Clinica Belgica 2014 DOI 10.1179/2295333714Y.0000000107
surgery in all critically ill patients.5 In the most recent American College of Cardiology/American Heart Association guidelines, surgery is recommended for patients in New York Heart Association (NYHA) functional class III or IV unless they are deemed high risk (class IIA).6 FT is given a class IIA indication in patients with right-side valve thrombosis and a class IIB indication in patients with a small, left-side thrombus. Surgical management of PVT has been associated with a significant death risk for over 40 years.23 Despite an improvement in mortality in the past decade,23 surgery is still associated with a high risk of death. Therefore, establishment of a more effective strategy to treat PVT is crucial, especially in developing countries where this condition is prevalent.23 FT has become the first-line treatment for PVT in much of the developing world,8–11 presumably because of the limited availability and high cost of surgery. Currently, there is no agreement on the optimal type, dose, or route of administration of thrombolytic agents,7 and practice is therefore dictated by local availability of
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resources and physician preferences rather than by considerations of benefit and harm. The purpose of this study was to evaluate the efficacy and clinical outcome of FT of PVT using the economic and widely available drug ‘streptokinase’ as a first-line treatment for these cases, particularly in developing countries where surgery is not always feasible, costly, and carries a high mortality risk.
Patients and Methods Study design and participants This consecutive case series study included 20 PVT patients (10 females) who were admitted to the Cardiology Department of Mansoura Medicine Specialized Hospital between January 2010 and August 2014 and underwent intravenous FT using ‘streptokinase’ for PVT. The included patients were given streptokinase as the primary therapeutic option for PVT so long as no contraindication for thrombolytic therapy exists (such as bleeding tendency, ongoing bleeding, or expanding or haemorrhagic cerebral infarcts). The risks and benefits of streptokinase in comparison to surgery were explained for all patients before obtaining their consent to participate in this study. The Institutional Review Board approved the study protocol and written informed consent was obtained from each patient before entry into the study.
Echocardiography Transthoracic echocardiography (TTE) was performed with a 3.25-MHz transducer. All TTE examinations were performed at baseline (index admission) and 60– 90 minutes after completion of the initial infusion of the loading dose of streptokinase. TTE examinations were then repeated every 2–3 hours during the maintenance infusion of streptokinase till success occur. Thus, a total number of eight TTE examinations were performed in the first 24 hours of admission. Initially, two echocardiographers independently evaluated the TTE recordings done at the index admission and 24 hours after the start of streptokinase therapy before reaching a consensus regarding treatment success or the need to transfer to surgery.
For aortic prostheses, maximum and mean transvalvular gradients, effective aortic valve area, and Doppler velocity index were calculated. Doppler velocity index was calculated as the ratio of velocity of the left ventricular outflow to velocity of the aortic jet.12 For mitral prostheses, mean transvalvular gradient, pressure half-time, and effective mitral valve area were calculated.13,14 Effective mitral valve area was calculated from pressure half-time. Ejection fraction was measured using the multiple-diameters method15 for both aortic and mitral prosthetic valves. A significant narrowing of the valve was diagnosed when the Doppler mitral valve area was ,1.5 cm2 and the mitral valve mean transvalvular gradient was .10 mmHg, or when the aortic valve mean transvalvular gradient was .40 mmHg. The presence and severity of concomitant prosthetic valve regurgitation were evaluated by TTE and trans-esophageal echocardiography (TEE) using conventional criteria for aortic and mitral prostheses.14,16 For all cases except one (no. 15), TEE was performed twice (on admission and before discharge) by a 5MHz multiplane transducer connected to a Vingmed system (Vingmed CFM 800) after oropharyngeal anaesthesia (10% lidocaine) and conscious sedation (intravenous midazolam, 1–3 mg). Regarding case no. 15, TEE was not performed as the patient was severely distressed and resuscitated from aborted sudden death. The length and area of any mass seen on a prosthetic valve were measured from the view that showed the largest extent of mass. PVT was classified as mobile or fixed echo densities located at the valve occluder and/or valve struts. The largest diameter of the thrombus and the length of the mobile portion (if present) were measured by TEE. Large thrombus was defined as §10 mm base diameter and/or §5 mm mobile segment length.
Thrombolytic protocol For all cases, streptokinase administration was carried out using one of two protocols irrespective of patient’s body weight (Table 1). The ‘Accelerated’ protocol involved intravenous infusion of 0.5 million
Table 1 Streptokinase administration protocols stratified by gender and prosthetic valve position Streptokinase infusion protocol Accelerated Mechanical valve position
Gender
Standard
Extended
Standard
Extended
Total
Mitral
Male Female Male Female
2 2 2 … 6
6 5 … … 11
… 2 … … 2
… 1 … … 1
8 10 2 … 20
Aortic Total
2
Conventional
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IU over 30 minutes, followed by 0.15 million IU/h. The ‘Conventional’ protocol involved intravenous infusion of 0.25 million IU over 30 minutes followed by 0.15 IU/h. The accelerated protocol was used for patients with big thrombus burden (defined as §10 mm base diameter and/or §5 mm mobile segment length) or international normalized ratio (INR) ,1.5 upon admission, and the conventional protocol was used for patients with small thrombus burden or INR.1.5 upon admission. The duration of the maintenance (0.15 million IU/ h) streptokinase administration was either standard (,24 hours) or extended (.24 hours), and was determined according to the results of repeated echocardiographic examinations performed during streptokinase infusion. Streptokinase infusion was continued until the mechanical valve area was satisfactorily increased with consequent reduction of peak and mean gradients across the mechanical valve. Satisfactory increase of mechanical valve area was objectively determined by TEE carried out (in almost all cases) on admission and again before discharge (on average after 1 week of admission), and was defined as §75% increase of mechanical valve area compared to the original valve area measured on index admission. If there was no initial haemodynamic improvement after the first 24 hours (neither increase in valve area nor reduction in peak or mean transvalvular gradients), or the mechanical valve area was never satisfactorily increased after completing the maximum streptokinase infusion dose (3 ampoules54.5 million IU), streptokinase was discontinued and surgical management was considered.17 Streptokinase was contraindicated in patients with a bleeding tendency and in those with expanding or haemorrhagic cerebral infarcts.
Definition of FT success The response of obstructive thrombi to streptokinase was defined as a complete success if there was objectively documented complete restoration of valve function in the presence or absence of complications, with no narrowing of the valve according to haemodynamic measurements and .75% reduction in the largest diameter of the thrombus. The response of non-obstructive thrombi to streptokinase was defined as a complete success if there was .75% reduction in thrombus diameter or complete lysis of the mobile portion of the thrombus. Un-fractionated heparin (UFH) and warfarin treatment was started in patients with complete success (except for pregnant patients who were not given warfarin), and UFH therapy was continued until an INR.2.5 was achieved. In only one case (no. 9), a shift from UFH to low-molecular-weight
Streptokinase treatment for prosthetic heart valve thrombosis
heparin (LMWH) was carried out in a trial to seek a more effective anticoagulation. Response to streptokinase was screened by TTE every 2–3 hours.
Outcomes In addition to FT success, the following outcomes were recorded: in-hospital death, stroke or transient ischaemic attack, non-central nervous system systemic embolism, major bleeding, and recurrence of PVT. Major fatal complication was defined as allcause in-hospital mortality, and major non-fatal complications included ischaemic stroke, intracranial haemorrhage, systemic thromboembolism, bleeding requiring transfusion, or surgery. Minor complications were bleeding without the need for transfusion and transient ischaemic attack.
Statistical analyses Continuous data are expressed as mean6one standard deviation, while non-continuous data were expressed as proportions. Comparisons of means of continuous data across a factor with two levels were carried out using Student’s t-test. Proportions were compared using the Chi-square test (or Fisher’s exact test when at least one cell in the n6m table has expected count ,5). A two-sided significance level of 0.05 was used for all analyses, which were conducted using SPSS 21 for Windows (SPSS Inc., Chicago, IL, USA). During the study period, a total of nine patients were excluded from analyses. Two patients preferred surgical management and refused streptokinaserelated risk. Patients with valve dysfunction due to pannus formation (defined as the presence of fixed, bright echodense structures, sometimes containing focal calcific deposits, along the valve ring with extension into the valve orifice) were also excluded from the analyses (n54 patients, all referred to surgery). We excluded three more patients with thrombosis of tissue valves (two patients) or rightsided prosthetic valves (one patient).
Results Patient characteristics The study group included 20 patients (10 females) diagnosed with PVT. Their mean age was 37.0613.8 years (range: 16–63 years). Males were older than females (41.8612.5 versus 32.2613.9 years), but this difference was not statistically significant (P50.122). The demographic and clinical characteristics of all patients are shown in Table 2. Eighteen cases (90%; 8 males, 10 females) had mitral PVT and two cases (10%; both males) had aortic PVT. Two patients were pregnant (one 5-month pregnant and the other 6-week pregnant), both of which had mitral PVT and died from cardiogenic shock. The most common symptom on admission was dyspnea (19 cases, 95%). This was the sole presentation in 16 cases (80%) and was combined with other
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40 19 25 41 22
63 42 28
28 35
10*
11 12 13 14 15*
16 17 18
19 20
III III III III IV
Female IV Male III
Male IV Female IV Female III
Female Female Female Male Male
Female III
Female III
Female III
IV IV III I
Mitral Mitral Mitral Mitral Mitral
Mitral
Mitral
Mitral
Dyspnea Dyspnea
Mitral Mitral
Dyspnea Mitral Dyspnea, fever Mitral Dyspnea Mitral
Dyspnea Dyspnea Dyspnea Dyspnea Dyspnea
Dyspnea
Dyspnea, haemoptysis Dyspnea
Small, fixed Small, mobile Small, fixed Large, fixed Large, fixed
Accel. Conv. Accel. Accel. Accel.
Accel.
… …
Small, mobile Accel. Large, fixed Accel.
Yes Small, fixed Accel. … Large, mobile Accel. … Large, fixed Accel.
… … Yes … …
Conv.
Accel. Accel. Accel. Accel.
Small, mobile Conv.
Large, fixed Large, mobile Small, mobile No thrombus seen Small, mobile
Yes Small, fixed
…
…
Yes … … …
44 26 90 70
33 42 26 39 28
Extended 28 Extended 33
Extended 33 Extended 37 Extended 35
Standard Standard Standard Extended Extended
Extended 23
Standard 35
Extended 25
Extended Extended Standard Standard
17 17
18 19 36
8 25 9 22 11
10
17
8
26 12 52 26
10 7 23
23 22
22 28 22
22 30 20 23 22
15
21
18
28 22 50 40
18 22 40
7 9
5 6 24
4 14 6 13 9
4.5
6
4
6 8 30 14
4.5 3 15
1.4 0.9
0.7 1.0 0.8
1.0 0.9 0.9 0.6 0.5
0.9
0.9
0.6
0.8 0.8 0.6 0.85
0.8 0.9 0.5
2.0 2.1
3.0 3.0 0.7
2.1 2.4 2.3 1.2 2.0
2.0
2.4
1.8
3.2 2.6 1.8 1.9
2.1 2.2 2.6
Cardiac shock and death (pregnant) Fever, brain infarction, and death … … … … Massive brain infarction and death … Brain infarction Cardiac shock and death (pregnant) … …
…
… … … …
Censored censored
Censored Censored Died
Censored Censored Censored Censored Died
Died
Died
Censored
Censored Censored Censored Censored
Transient MVO Censored … Censored … Censored
Valve Valve Peak PG Peak PG Mean PG Mean area area after before SK after SK before SK PG after before 2 (mmHg) (mmHg) (mmHg) SK (mmHg) SK (cm ) SK (cm2) Complications Survival
Extended 27 Standard 40 Standard 59
SK SK infusion infusion protocol duration
Large, mobile Accel. Small, fixed Accel. Small, fixed Accel.
Thrombus size and type
Notes: *Case no. 1: Female patient with successful fibrinolysis who suffered acute abdominal pain a few hours after streptokinase infusion. The patient was diagnosed with mesenteric vascular occlusion, and this resolved with conservative treatment (no surgical interference). Case no. 9: Pregnant female patient who died 5 days after successful fibrinolysis (one day after the shift from un-fractionated to lowmolecular-weight heparin). Case no. 10: Female patient with successful fibrinolysis who experienced a cerebral infarction and died. Case no. 15: Male patient who presented with cardiogenic shock, aborted sudden death, and was resuscitated. Fibrinolysis was successful, but was complicated with massive cerebral infarction and anti-coagulation was therefore withheld. The patient then developed valve rethrombosis, cardiogenic shock, and died after 5 days. Case no. 17: Female patient with a huge, friable, mobile thrombus that covered most of the atrial surface of the mitral prosthesis and protruded on the ventricular surface of the prosthetic valve. Approximately 2 hours after streptokinase infusion, the patient developed severe pulmonary oedema and transient cardiac arrest and was resuscitated and mechanically ventilated. On follow-up, the valve was open and its area had increased to 3 cm2, but the case was complicated with cerebral infarction. Case no. 18: Pregnant female patient (6 weeks) with a large thrombus over the mitral valve prosthesis who partially responded to streptokinase infusion (valve area increased from 0.6 to 1.1 cm2). However, 24 hours after streptokinase infusion, the patient deteriorated due to prosthetic valve re-thrombosis with marked valve area reduction. At 48 hours after streptokinase infusion, the patient developed cardiac arrest and died. This was the only case of failed fibrinolysis. Accel.: accelerated; AF: atrial fibrillation; Conv.: conventional; MVO: mesenteric vascular occlusion; NYHA: New York Heart Association; PG; pressure gradient; SK: streptokinase.
19
9*
16
8
Male Male Male Male
Mitral Mitral Aortic Aortic
45 26 57 46
4 5 6 7
… … …
Mitral Mitral Mitral
58 43 40
1* 2 3
Dyspnea Dyspnea Dyspnea, fever, haemoptysis Dyspnea Dyspnea Dyspnea Asymptomatic
Case Age NYHA Clinical no. (years) Gender class presentation
Female IV Male IV Male IV
Prosthetic valve position AF
Table 2 The demographic and clinical characteristics of all patients
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symptoms in three cases (haemoptysis, n51; fever, n51; haemoptysis and fever, n51). Only one case (no. 7; a male with aortic PVT) was asymptomatic. Four cases (20%) had chronic atrial fibrillation, and one of them (no. 10) died. No cases had hypertension or diabetes mellitus. Three cases (15%) were using lowdose aspirin (100 mg) in addition to warfarin upon admission. Poor compliance to warfarin with subtherapeutic INR level was detected in 15 patients (75%) upon admission.
Echocardiographic results Large prosthetic valve thrombus (defined as §10 mm base diameter and/or §5 mm mobile segment length) was found in eight cases (40%; all with mitral prostheses), while small thrombus was found in 11 cases (55%; 10 mitral and one aortic prosthesis) and one case (no. 7, with aortic prosthesis) had no thrombus. The majority (five out of eight) of large thrombi were fixed, while three only were mobile (P50.377). One of the four cases with AF had a large fixed mitral PV thrombus. Out of the eight cases with large thrombi, two only passed away (in which the thrombi were fixed). In PVT episodes, before streptokinase therapy, the prosthetic valve area (in all cases, mitral and aortic
Streptokinase treatment for prosthetic heart valve thrombosis
positions) were 0.8260.21, 0.8360.21, and 0.7360.18 cm2; and the peak and mean transvalvular gradients were 38.7616.7 and 25.468.7, 34.168.8 and 23.265.4, and 80.0614.1 and 45.067.1 mmHg, respectively. After streptokinase therapy, the prosthetic valve area and peak and mean transvalvular gradients improved significantly (in all cases, mitral and aortic positions: valve area 2.1760.58, 2.2160.61, and 1.8560.07 cm2, peak gradient 18.7611.0, 16.467.7, and 39.0618.4, and mean gradient 9.667.1, 8.265.3, and 22.0611.3 mmHg, respectively; P,0.001 for all comparisons using paired t-test).
Complications Streptokinase was fully successful in all but one case (case no. 18; pregnant and died) with a total mortality of four cases (20%, all with mitral PVT). Death occurred 6 days after the start of streptokinase in two cases (nos. 9 and 10) and 2 days after the start of streptokinase in two cases (nos. 15 and 18). Transient mesenteric vascular occlusion occurred in one case (no. 1), and non-fatal cerebral stroke occurred in one case (no. 17), both with mitral PVT. Table 3 compares the characteristics of censored and mortality cases. Owing to the small sample size, all comparisons were statistically non-significant.
Table 3 Characteristics of censored and mortality cases
Demographic data Age (years) Gender Male Female Clinical data NYHA class I III IV Atrial fibrillation Prosthetic valve position Mitral Aortic Echocardiographic data Thrombus type Mobile obstructive Fixed obstructive None Prosthetic valve area (cm2) Pre-SK Post-SK Transvalvular pressure gradient (mmHg) Pre-SK Peak pressure gradient Mean pressure gradient Post-SK Peak pressure gradient Mean pressure gradient SK infusion protocol Accelerated Conventional SK infusion duration Standard Extended
Censored (n516)
Died (n54)
p value
39.0613.7
29.0612.6
0.202 0.582
9 (45.0%) 7 (35.0%)
1 (5.0%) 3 (15.0%)
1 7 8 3
0 3 1 1
0.517 (5.0%) (35.0%) (40.0%) (15.0%)
(0.0%) (15.0%) (5.0%) (5.0%)
14 (70.0%) 2 (10.0%)
4 (20.0%) 0 (0.0%)
7 (35.0%) 8 (40.0%) 1 (5.0%)
1 (5.0%) 3 (15.0%) 0 (0.0%)
0.780 0.998
0.639
0.8360.22 2.3060.52
0.7760.19 1.7760.74
0.657 0.134
40.8617.9 26.869.1
30.365.8 20.063.4
0.159 0.169
18.7611.2 9.366.8
18.5612.1 10.968.9
0.951 0.697 0.509
14 (70.0%) 2 (10.0%)
3 (15.0%) 1 (5.0%)
7 (35.0%) 9 (45.0%)
1 (5.0%) 3 (15.0%)
0.619
Note: NYHA: New York Heart Association; SK: streptokinase.
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Our study included two pregnant cases, both of which died after streptokinase therapy. The first case (no. 9) died 6 days after successful thrombolysis with streptokinase, and 2 days after the shift from UFH to LMWH. The second case (no. 18; 6-week pregnant) had a large thrombus over the mitral valve prosthesis. Streptokinase infusion was not completely successful, with an increase of the prosthetic valve area from 0.6 to just 1.1 cm2. After 24 hours, the patient deteriorated due to prosthetic valve re-thrombosis with marked valve area reduction; and at 48 hours after the start of streptokinase infusion, the patient developed cardiac arrest and died.
Discussion PVT is a serious complication of heart valve replacement. There are no generally accepted criteria for the management of PVT patients, and there are two lines of treatment available: thrombolytic therapy and surgical replacement of the obstructed prosthetic valve. The goal of this study was to evaluate the efficacy and clinical outcome of FT of PVT using the economic and widely available drug ‘streptokinase’ as a first-line treatment for these cases, particularly in developing countries where surgery is not always feasible, costly, and carries a high mortality risk. We performed a single-centre consecutive case series study of 20 patients with PVT and found that FT with streptokinase using two different administration regimens was associated with successful thrombus lysis in almost all cases. The incidence of complications was lower than that reported with surgery or non-FTbased medical treatment.23 Lengyel and co-workers consider FT as the firstline treatment for PVT if there is no contraindication, independent of NYHA class and thrombus size.4 However, in a recent series of 210 patients reported by Roudaut et al., surgical treatment was associated with significantly better long-term results regarding recurrence and mortality and a lower incidence of embolic complications than FT.18 A recent metaanalysis evaluated seven eligible studies with 690 episodes of PVT, 446 treated with surgery and 244 treated with FT, and found that urgent surgery was not superior to FT at restoring valve function, but substantially reduced the occurrence of thromboembolic events, major bleeding, and recurrent PVT.19 In the current study, FT using streptokinase was successful in treating PVT in 19 out of 20 patients (95%) with this condition, still favouring FT to urgent surgery. The use of FT for left-sided PVT has shown promising results.7–11,19–21 The reported rate of clinical resolution with streptokinase is 64–92%.7,20,21 A large meta-analysis of 515 cases reported an initial success rate of 84%, mortality of 5%, and bleeding complications
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in 3% of patients and systemic embolism in 9% of patients receiving FT for PVT.21 Similarly, in the current study, streptokinase was successful in treating left-sided PVT in 19 out of 20 patients (95%), but the mortality rate reached to 20% and systemic embolism occurred in four patients (20%): three with cerebral embolism (two had fatal outcome) and one case with transient mesenteric vascular occlusion which resolved spontaneously. Surgery for PVT is associated with high mortality, with 30-day operative mortality and total in-hospital mortality reported at 25% and 41%, respectively.22 In fact, FT and surgery were not considered as alternative treatment options in past clinical practice, but rather as complementary ones. Hence, FT using streptokinase was the first treatment option for almost all patients with PVT in our institution; and during the study period, surgery was only performed for patients with a major contraindication for FT or for patients in whom FT failed.23 The Society for Heart Valve Disease recommends FT for all patients, and recommends surgery only if FT is contraindicated,4 whereas the European Society of Cardiology recommends FT only if the risk of surgery is prohibitive or when surgery is unavailable and the patient cannot be transferred.5 FT is the firstline treatment for PVT in much of the developing world,8–11 presumably because of the limited availability and high initial cost of surgery. Although it is acknowledged that surgery may be more successful than FT and may cause fewer strokes and bleeding, the risk of death is higher and the magnitude of these risk/benefit trade-offs is not clear. Our study supports the use of FT. FT with streptokinase was effective and relatively safe, and we suggest it as a first-line therapy for PVT, particularly when surgery is not immediately available or is deemed high risk. In 2009, a randomized trial found no difference in outcomes between an accelerated (1.5 million units of streptokinase over 1 hour followed by 0.1 million units/h infusion) and a conventional dose (0.25 million units of streptokinase over 30 minutes followed by a 0.1 million units/h infusion) of streptokinase for the treatment of PVT.20 In our study, streptokinase treatment was successful in 19 of 20 cases (95%), which is a higher percentage when compared to the abovementioned trial, with a total mortality of four cases (20%) all occurring within a few days of the start of streptokinase therapy. Besides, we used lower loading streptokinase dose for the accelerated protocol than that used in the aforementioned randomized trial (0.5 compared to 1.5 million IU), which was given over a shorter duration (30 minutes compared to 1 hour), while using a slightly higher streptokinase maintenance dose for both accelerated and conventional protocols
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(0.15 compared to 0.1 million IU/h) and using the same initial streptokinase loading dose for conventional protocol (0.25 million IU over 30 minutes). Our study included two pregnant patients, both of which died after streptokinase therapy. They were maintained on subcutaneous LMWH (enoxaparin: 1 mg/kg) twice daily throughout pregnancy. After admission to our hospital, subcutaneous UFH was given instead of LMWH every 12 hours to keep the mid-interval activated partial thromboplastin time at least twice in control. UFH was continued in one patient (no. 18), while shift to LMWH was carried out in the other patient (no. 9) who died just 24 hours after this therapeutic shift. The other patient (no. 18) deteriorated 24 hours after streptokinase infusion due to prosthetic valve re-thrombosis with marked valve area reduction; and at 48 hours after streptokinase infusion, the patient developed cardiac arrest and died (the only case of failed fibrinolysis). The safety and efficacy of LMWH in PVT during pregnancy is questionable,24 and treatment failures with LMWH have been described.25 Such treatment failures may be minimized if trough and peak anti-Xa levels are used to guide dose adjustments.24 The American College of Chest Physicians recommend an adjusted dose of LMWH twice daily throughout pregnancy, with the dose adjusted to achieve manufacturer’s peak anti-Xa at 4 hours post-dose.26 Women who were compliant with a twice-daily therapeutic dose of LMWH adjusted via using antiXa levels had good outcomes.27 The trough anti-Xa level is likely to be more informative and important than the peak anti-Xa level for indicating an adequate baseline anticoagulant effect; however, measurement of both peak and trough anti-Xa levels is only advocated by two researcher groups.28,29 Despite the high NYHA functional class of most of our patients (19 of 20 patients in NYHA class III or IV), the success rate of FT using streptokinase was 95%. Studies from the American College of Cardiology Foundation indicate that a small amount of thrombus at the hinges of a mechanical valve can result in obstructive PVT and be associated with severe symptoms.30 We propose that this accounts for the rapid and complete success of FT in at least some of the patients who were in NYHA functional class III or IV.30 In a previous report, 39% of PVT patients had subtherapeutic anticoagulation at the time of clinical presentation.30 In our study, 75% of patients had poor compliance with warfarin with sub-therapeutic INR at admission. The possible reasons for this high percentage in our study could be the patient’s lower socioeconomic standards, lower level of education, and carelessness regarding regular follow-up (including INR check). Poor anticoagulation status leads to
Streptokinase treatment for prosthetic heart valve thrombosis
thrombus formation.31,32 Thus, the anticoagulation status at clinical presentation may not be representative of anticoagulation status at the time of start of thrombus formation, which occurs weeks or months before the diagnosis of PVT.30 The success rate of FT in patients in NYHA class II or below was similar to that in patients in NYHA class III or above.7 Hurrell et al. recommended direct surgical treatment rather than FT for patients in NYHA class IV,33 because of a high medical mortality reported in some series.7 The American College of Cardiology/American Heart Association valve disease guidelines also recommend surgical treatment for class IV patients except those who are not candidates for surgery.34 However, surgical mortality is highest in this group of patients.35,36 Recently published guidelines proposed thrombolytic therapy as the treatment of choice for critically ill patients in NYHA class III or IV, although the definition of ‘critically ill’ was subjective.37 In conclusion, FT with streptokinase was an effective therapeutic strategy for the management PVT and is a reasonable alternative to surgery irrespective of NYHA class.
Disclaimer Statements Contributors None. Funding None. Conflicts of interest None. Ethics approval The Institutional Review Board approved the study protocol and written informed consent was obtained from each patient before entry into the study.
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