Download Ozkan et al, European Heart Journal (under review) The ultra

Left sided prosthetic thrombosis
Epidemiology
• Obstruction of prosthetic heart valves may be
caused by thrombus formation, pannus
ingrowth, or a combination of both.
• Mechanical prosthetic heart valve thrombosis
has a prevalence of only 0.3% to 1.3% per
patient-year in developed countries but is as
high as 6.1% per patient-year in developing
countries.
Epidemiology
• Thromboembolic complications, including
systemic emboli, are more frequent and occur
at a rate of 0.7–6% patient years.
• Non-obstructive PVT is a relatively frequent
finding in the postoperative period, with a
reported incidence as high as 10% in recent
transoesophageal echocardiography (TOE)
Studies.
Epidemiology
• Obstruction of a tricuspid mechanical
prosthesis is 20 times more frequent than leftsided PVT.
• Similarly for haemodynamic reasons, mitral
PVT is 2–3 times more frequent than
thrombosis of an aortic prosthesis.
Risk factors
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1- Atrial fibrillation.
2- Previous thromboembolism.
3- Left ventricular dysfunction (LVEF < 30%).
4- Mechanical mitral or tricuspid prosthesis.
5- Older-generation thrombogenic valves (e.g.
Starr-Edwards, and mechanical disc valves).
• 6-Those with demonstrated thrombotic problems
when previously off Warfarin therapy.
• 7- More than one mechanical valves.
• 8- Hypercoagulable state.
Diagnosis
• The clinical presentation of PVT is highly variable,
often depending on the presence or absence of
obstruction.
• Severe obstructive PVT is typically associated
with overt heart failure, whereas non-obstructive
PVT is often an incidental finding or can present
as an embolic episode.
• Partial obstruction (for example, obstruction of
one leaflet) can manifest itself with abnormal
dyspnoea, or systemic embolism.
• muffling or disappearance of prosthetic
sounds.
• appearance of a new regurgitant or
obstructive murmur.
Diagnosis
• The initial diagnostic work-up includes a
transthoracic echocardiogram (TTE) and
cinefluoroscopy of mechanical valves.
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• TOE will often be performed to complete the
investigation.
Echocardiography
• Abnormal transprosthetic flow (aliasing or
central regurgitation flow).
• Transprosthetic gradients and effective orifice
area are determined using continuous Doppler.
• Pulmonary artery pressures should also be
measured.
• Abnormal movement of the prosthesis (immobile
hemi-disc, incomplete or delayed opening)
• visualisation of a paraprosthetic thrombus.
Echocardiography
• For mitral prostheses:
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Mean gradient 8 mm Hg
Effective area less than 1.3 cm2
Peak E velocity >1.9 m/s,
VTImitral/VTIaortic >2.2,
Pressure half-time >130 ms
Echocardiography
• For aortic prostheses
• Mean gradient >45 mm Hg
• Obstructive index <0.25
PPM or malfunction
• In the case of small size aortic prostheses (for
example, mechanical valve sizes 19 or 21),
• Against a diagnosis of PVT:
• An already elevated gradient on previous
echocardiographic examinations,
• Obstructive index >0.25,
• Effective orifice area >0.7 cm2,
• Valvular resistance ,280 dynes.s.cm25,
• Normal leaflet mobility on cinefluoroscopy
Thrombus or pannus
• Pannus:
• Usually annular in location.
• More frequent on aortic than on mitral
prostheses.
• Typically presenting as a very dense immobile
echo,
• Typically encountered in patients with a normal
anticoagulation profile and with subacute or
chronic symptoms.
Thrombus or pannus
• PVT:
• Immobility or reduced leaflet mobility,
• Presence of thrombus on either side of the
prosthesis, with or without obstruction
• Disappearance of the normal physiological
• prosthesis regurgitant flow
• Presence of central prosthesis regurgitation
• Pronounced spontaneous echo contrasts in
• the left atrium
Management of left sided
prosthetic thrombosis
Optimal treatment of left-sided PVT is
unclear
-Anticoagulation
-Fibrinolysis
-Surgery
• Absence of randomized controlled trials
• Guidelines differ in their recommendations
regarding the choice of treatment for PVT
Surgery
• Urgent or emergency valve replacement is
recommended for obstructive thrombosis in
critically ill patients without serious
comorbidity.
(recommendation class I, level of evidence C)
Fibrinolysis
• Critically ill patients unlikely to survive surgery because of
comorbidities or severely impaired cardiac function before
developing valve thrombosis.
• Situations in which surgery is not immediately available and
the patient cannot be transferred.
• Thrombosis of tricuspid or pulmonary valve replacements,
because of the higher success rate and low risk of systemic
embolism.
Thrombolysis protocole
• Short protocol :
Intravenous recombinant tissue plasminogen
activator 10 mg bolus + 90 mg in 90 minutes
with UFH, or
• Streptokinase 1 500 000 U in 60 minutes
without UFH.
• Surgery should be considered for large (≥10
mm) non-obstructive prosthetic thrombus
complicated by embolism (recommendation
class IIa, level of evidence C) or which persists
despite optimal anticoagulation.
• Fibrinolysis may be considered if surgery is at
high risk.
• Although fibrinolytic therapy of a left-sided
obstructed prosthetic heart valve is associated
with an overall rate of thromboembolism and
bleeding of 17.8%, the degree of risk is
directly related to thrombus size.
• Patients with a small thrombus (<1.0 cm in
diameter or 0.8 cm2 in area) have fewer
thrombolysis-related complications, whereas
those with a large thrombus (>1.0 cm
diameter or 0.8 cm2 in area) have a 2.4–fold
higher rate of complications per 1.0 cm2
increase in size.
Risk factor for fibrinolytic therapy
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Active internal bleeding,
History of hemorrhagic stroke,
Recent cranial trauma or neoplasm
Diabetic hemorrhagic retinopathy,
Large thrombi, mobile thrombi,
systemic hypertension(>200 mm Hg/120 mm Hg),
Hypotension or shock,
NYHA class III to IV symptoms
Fibrinolysis
• With mild symptoms due to aortic or mitral
valve thrombosis with a small thrombus
burden, it is prudent to reassess after several
days of intravenous UFH.
• If valve thrombosis persists, fibrinolysis with a
recombinant tissue plasminogen activator
dose of a 10 mg IV bolus followed by 90 mg
infused IV over 2 hours is reasonable.
Fibrinolysis
• Heparin and glycoprotein IIb/IIIa inhibitors are
held, but aspirin can be continued.
• A lower tissue plasminogen activator dose of
a 20 mg IV bolus followed by 10 mg per hour
for 3 hours may be appropriate in some
situations.
• Alternatively, streptokinase may be used with
a loading dose of 500,000 IU in 20 minutes
followed by 1,500,000 IU over 10 hours.
• If fibrinolytic therapy is successful, it is
followed by intravenous UFH until VKA
achieves an INR of 3.0 to 4.0 for aortic
prosthetic valves and 3.5 to 4.5 for mitral
prosthetic valves.
Surgery vs fibrinolysis
• Surgical treatment of a thrombosed prosthetic
Heart : success rate close to 90%
• Fibrinolytic therapy: 70% success rate
Surgery vs fibrinolysis
• There was no difference in mortality between
surgical and fibrinolytic therapy for left-sided
prosthetic valve thrombosis,
• Surgery was associated with lower rates of
thromboembolism (1.6% versus 16%), major
• bleeding (1.4% versus 5%), and recurrent
prosthetic valve thrombosis (7.1% versus
25.4%)
systematic review and meta-analysis of the
available literature comparing emergency
surgery with FT for left-sided PVT
Characteristics of recently published Review and
Metaanalyses
1: Bonou et al, EHJ Acute cardiovascular Care ,2012,
2: Karthikeyan et al , EHJ,2013
3: Huang et al, JACC,2013
4: Castilho et al, J Thromb. Haemost. 2014
-Systematic review (2013)
-Forty-eight studies were included (2302 patients)
.-No randomized studies was identified, and all were
observational in design
mortality
Embolic
event
Stroke
Success
bleeding
Death or
stroke
surgery
18.1%
4.6%
4.3%
81.9%
4.6%
19%
FT
6.6%
12.8%
5.6%
80.7%
6.8%
11.4%
Conclusion
-Mortality in patients treated by thrombolytic therapy for
valve prosthesis thrombosis is significantly lower than in
patients treated surgically.
-In addition, in our meta-regression, NYHA class IV was
associated with mortality in the surgical group, but not in
the thrombolytic group
-As we cannot yet ascertain whether this difference is due
to the treatment alone, more studies are now necessary
to further clarify these findings
Metaanalytic reviews dictate to establish a new
treatment strategies
• Surgery has been the traditional management
of PVT , but thrombolysis has been proposed
as first line of therapy
• Thrombolytic therapy in recent years apears
to have high success rate with relatively with
low complication and mortality
New thrombolytic therapy protocols?
(Why low-dose, slow infusion of tPA?)
Comparison of different TRansesophageal echOcardiographic guided
thrombolytIc regimens for prosthetic vAlve thrombosis:
(The TROIA Trial)
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A 16-year study in a single center, prospective
220 episodes,
5 different thrombolytic regimens,
Group 1- Rapid SKZ (1.5 mU,3 hours): 1993-1997
Group 2- Slow SKZ (1.5 mU, 24 hours):1997-2001
Group 3- 100 mg tPA ( 5 hours):2001-2002
Group 4- 50 mg tPA ( 6 hours ):2002-2005
Group 5- 25 mg tPA ( 6 hours, without bolus, without concomitant
UFH, repetitive up to 150 mg ):2005-2009
Overall success rate % 82, (for Group 5: 85%)
Özkan et al, J Am Coll Cardiol CV imaging, 2013
• The overall success did not differ significantly
among Groups I through V.
• Although the overall complication rate was
similar among Groups I through IV , it was
significantly lower in Group V.
• The combined rates of mortality and nonfatal
major complications were also lower in Group
V than in the other groups.
• There was no mortality in Group V
CONCLUSIONS
• Low-dose slow infusion of t-PA repeated as
needed without a bolus provides effective
and safe thrombolysis in patients with
prosthetic valve thrombosis.
Ultra-slow thrombolytic therapy: A
novel strategy in the management of
PROsthetic MEchanical valve
Thrombosis and the prEdictors of
outcomE: The ultra-slow PROMETEE
trial
Mehmet Özkan , Sabahattin Gündüz , Ozan Mustafa Gürsoy, Süleyman Karakoyun ,
Mehmet Ali Astarcıoğlu , Macit Kalçık, Ahmet Çağrı Aykan, Beytullah Çakal , Zübeyde
Bayram , Ali Emrah Oğuz Emre Ertürk , Mahmut Yesin , Tayyar Gökdeniz , Nilüfer Ekşi
Duran , Mustafa Yıldız , Ali Metin Esen
European Heart Journal (under review)
The ultra-slow PROMETEE trial
• The safety and efficacy of 25 mg tPA/6 hours infusion
has been established in TROIA trial.
• Further prolongation of the TT regimen may be
associated with lower complication rates without
compromising efficacy
• Between 2009-2013, 114 patients, 120 episodes
• 25 mg tPA/ 25 h infusion (without bolus, without
concominant UFH)
• 6 h of UFH infusions between tPA sessions
• Maximum 8 episodes (200 mg)
Ozkan et al, European Heart Journal (under review)
The ultra-slow PROMETEE trial
• Total success : 90 %
• Total complications: 6,7 % (in the TROIA Trial : 10.5%)
(Non-fatal major complications: 3,3 %)
- Cerebral embolism (n:1, 0,8 %)
-İntraabdominal bleeding (n:1, 0,8 %)
-GIS bleeding (n:1, 0,8 %)
-Periferal embolism (n:1, 0,8 %)
- No intracranial bleeding
(Minor complications: 2,5 %)
- Intraabdominal bleeding without need for Tx (n:2, 1,6 %)
- Vaginal bleeding (n:1, 0,8 %)
• Mortality : %0,8
Ozkan et al, European Heart Journal (under review)
Univariate predictors of thrombolytic failure
(for the ultra-slow PROMETEE Trial)
YES
NO
Atrial fibrillation
Pregnancy
NYHA class IV status
*
Higher baseline thrombus area
Smaller valve area
Greater duration of suboptimal INR
Stroke or transient ischemic attack
Nonobstructive/obstructive thrombus
Age (years)
Elapsed time since valve surgery (months)
Gender
Hypertension
Diabetes mellitus
Aspirin use
Thrombus site
Clinical presentation
Make of valve
*:independent predictor
Ozkan et al, European Heart Journal (under review)
‘‘Thrombolytic therapy with low-dose
(25 mg) and slow infusion (6 to 25 hours)
of tPA is a miracle’’
CASE :
OBSTRUCTIVE THROMBOSIS
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29 year-old, 30 weeks of pregnancy
Mechanical MVR 11 year ago
Dyspnea (NYHA Class IV)
No sound of closing of mechanical valve
INR: 1.2 on admission,
MVA: 0.6 cm2 ; Grad: 29mmHg(mean)
Low dose slow tPA infusion (75mg)
NON-OBSTRUCTIVE THROMBUS
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41 year-old, female
2006- MVR
Presentation: TIA
Admission INR: 1,2
Cranial CT: Normal
MVA:2,9 cm2 ,Mean Grad:7mmHg
After 25 mg tPA infusion for 25 hours