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Current Status of Thrombolysis
for Venous Thromboembolism
Anthony J. Comerota, MD, FACS, FACCMedical Director, Eastern Region
Inova Heart and Vascular Institute
Alexandria Hospital, Alexandria, VA
Disclosures
BMS/Pfizer: Consultant
Speakers Bureau
Tactile, Inc Consultant
Current status of Thrombolysis for VTE
Venous Thromboembolism
• Acute DVT
• Acute Pulmonary Embolism
Systemic and Catheter Directed Thrombolysis
Current status of Thrombolysis for VTE
Acute DVT
Systemic Thrombolysis: No longer used to lyse
DVT due to inefficient clot resolution and increased
bleeding complications.
Catheter Directed Thrombolysis: Preferred treatment
for mod-severe symptomatic IFDVT. Supported by the
ATTRACT Trial results
The ATTRACT Trial: Iliofemoral DVT
Summary: Iliofemoral DVT
1. PCDT reduced all PTS (VCSS)
2. PCDT reduced: overall severity of PTS
mod-severe PTS
severe PTS …..and
reduced pain
reduced edema
4. Improved disease - specific QOL
5. PCDT did not increase risk of major bleeding
Current status of Thrombolysis for VTE
Pulmonary Embolism
Systemic Thrombolysis: Has fallen into disfavor
due to results of PEITHO Trial.
Catheter Directed Thrombolysis: Increasing in
popularity; however, proper patient selection,
objective benefit, defined risks and randomized trial
results are lacking.
Pulmonary Embolism
All should undergo
risk stratification!
Grade 1C
2008
• Biomarkers
• Cardiac echo
• RV/LV ratio
Group Characteristic
Low Risk
Hemodynamically Stable
Normal Echocardiogram
Normal Biomarkers
Submassive
A. Low Risk
B. High Risk
Abnormal Echocardiogram
Abnormal Biomarkers
MassiveHemodynamically Unstable
Abnormal Biomarkers
Current Status of Thrombolysis for PE
Risk Stratification
Kucher N, Goldhaber S Z
Circulation 2003;108:2191-2194
Pulmonary Embolism: Mortality
Patients with massive and submassive pulmonary
embolism face significant morbidity and mortality
Short-Term Death
Massive >50%
Submassive 15%
CTPH Death at 5 Years
PA Pressure > 40 mmHg 70%
PA Pressure > 50 mmHg 90%
Kucher N et al
Circulation 2006; 113:577
Meta-Analysis
Ten Wolde M et al
Arch Int Med 2004; 164:1685
Pulmonary Embolism: Mortality
Right Ventricular Dysfunction
Author/Year RVD (+) RVD (-)
Goldhaber et al 1993 4% 0%
Ribeiro et al 1997 13% 0%
Kasper et al 1997 13% 1%
Grifoni et al 2000 12% 0%
Jerjes - Sanchez et al 2001 14% 0%
- Short-Term Mortality to PE -
Klok F A et al
Am J Resp Crit Care Med 2008; 178:425
Pulmonary Embolism: Mortality
Outcome
Elevated BNP
(Odds Ratio) p-value
Death 6.52 0.002
Adverse Clinical
Outcome6.77 0.00001
R-Ventricular
Dysfunction38.61 0.00001
B Naturetic Polypeptide
- Myocardial stretch -
Troponin
< 0.07mg/ml
0.7 – 1.5mg/ml
>1.5mg/ml
Konstantinides S et al
Circulation 2002; 106:1263
Troponin-I and Risk from PE
- Troponins-
- Myocardial damage-
“Dose related” adverse outcomes
Massive Pulmonary Embolism
• Systemic Thrombolysis
• Catheter-Based Thrombolysis/Thrombectomy
• Operative Thromboembolectomy
Strategies of Thrombus Removal
Protection from Additional Emboli
• IVC Filter
Pulmonary Embolism
Systemic Thrombolysis
Evidence for safety
& effectiveness
Pulmonary Embolism
NIH Randomized Trials
• Streptokinase PE Trial
• Urokinase-Streptokinase PE Trial
• Urokinase PE Trial
Increased risk of bleed with no mortality benefit
Randomized all patients with PE…not just high risk patients!
Massive Pulmonary Embolism
Lytic Rx vs. Anticoagulation
• Prospective
• Controlled
• Massive PE
– > 9 segments on V/Q scan; or
– < 9 segments w/ R. ventricle dysfunction
• Randomized– 1.5 million units SK
– 10,000u heparin bolus + infusionor
Jerjes-Sanchez C et al
J Thromb Thrombolyis 1995; 2:227
Mortality Benefit with Massive PE
100% (4/4)0% (0/4)Mortality*
Heparin AloneSK + Heparin
*Ethics committee terminated trial!
Massive Pulmonary Embolism
Lytic Rx vs. Anticoagulation
Trial criticized because
of small sample size!
Jerjes-Sanchez C et al
J Thromb Thrombolyis 1995; 2:227
• 72,230 patients with massive PE
• National inpatient sample 1999 – 2008
• All cause mortality
• Lytic Rx vs. no lytic Rx
• IVC filters vs. no IVC filters
Am J Med 2012; 125:465
Stein P D, Matta F
Am J Med 2012; 125:465
– Lytic Rx and IVC Filters –
0%
10%
20%
30%
40%
50%
60%
• No Lytic• No Filter
• No Lytic• Filter
• Lytic• No Filter
• Lytic• Filter
51%
33%
15%
7.6%
All Cause Case Fatality(In Hospital)
N=38,000
N=12,850
N=21,390
N=6,630
Lowest mortality in patients with
massive PE reported to date!
NEJM 2014; 370: 1402
Meyer G, et al
NEJM 2014; 370: 1402
Methods
• 1005 patients evaluated
• Randomized double-blind
• Tenecteplase 30-50mgvs.
Unfractionated heparin
• All lytic Pts. received therapeutic heparin
• Efficacy: death/hemodyn collapse
• Safety: major bleed; ischemic/hemorrhagic stroke by day 7
Outcome Tenecteplase(N=506)
Placebo(N=499)
P-value
Primary
outcome2.6% 5.6% 0.02%
All cause
mortality 1.2% 1.8% 0.42%
Hemodyn
Collapse1.6% 5.0% 0.002%
Recurr. PE
(By day 5)0.2% 1.0 0.12
Results
- Efficacy -
Meyer G, et al
NEJM 2014; 370: 1402
Meyer G, et al
NEJM 2014; 370: 1402
Results
- Safety -
Outcome Tenecteplase(N=506)
Placebo(N=499)
P-value
Stroke 2.4% 0.2% 0.003%
Hemorrhagic 2.0% 0.2%
Ischemic 0.4% 0.0%
Major extrcran.
bleed6.3% 1.2% <0.001%
Patients received therapeutic heparin during lysis!
Conclusions
In patients with submassive PE, tenecteplase:
- Reduced hemodynamic decompensation
- Increased major bleeding and stroke
Meyer G, et al
NEJM 2014; 370: 1402
Lead to aversion of systemic lysis for submassive PE!
Current status of Thrombolysis for PE
Important Questions
1. Can patients at risk for ICB be identified
before Rx?
2. Will an alternative PA reduce risk?
3. Will reduced dose of PA be as effective….
but safer?
Current Status of Thrombolysis for Acute VTE
Pulmonary Embolism
- Massive
- High Risk Submassive
My Recommendation…..
Obtain CT of Head during CTA of chest, after Dx of PE
Changing Management of Acute VTE
CT Scan of Head @ time of CTA
1. Adds another 60 sec. to diagnostic
study
2. Identifies leukoariosis
3. Identifies prior infarcts
4. Identifies AVMs
….. patients at risk of ICB
Thrombolytic Rx for PE: rtPA
• 100mg dose of rtPA was arbitrary!
• Infusion time was arbitrary!
• 100mg dose of rtPA is effective
…but associated with 1 – 4% IC bleed
…other major bleeding
• Randomized trial:1.
50mg rtPA vs. 100mg rtPA over 2 hours
Is dose reduction beneficial?
1. Wang C et al
CHEST 2010; 137(2):254
CHEST 2010; 137(2):254
• 118 patients
• Acute PE– Hemodynamic instability
– Massive PA obstruction
• Randomized: 50mg rtPA x 2 hrs (N=65)
vs.
100mg rtPA x 2 hrs (N=53)
• Efficacy: R. vent dysfunction on echo
Lung perfusion defects
PA obstruction
• Adverse Events: Death, bleeding, recurrence
Wang C et al
CHEST 2010; 137(2):254
Wang C et al
CHEST 2010; 137(2):254
Efficacy
RV/LV Ratio SPAP (mmHg)
Efficacy
Perfusion Defect Score PA Obstruction Score
Wang C et al
CHEST 2010; 137(2):254
Adverse Event100mg(N=48)
50mg(N=55) p-value
Death 6% 2% 0.47
Bleeding 32% 17% 0.05
Recurrent VTE 4% 2% 0.85
Complications
Wang C et al
CHEST 2010; 137(2):254
1. 50mg rtPA IV x 2hrs as efficacious as 100mg
2. 50mg dose associated with less bleeding
3. Reduced bleeding risk especially
in low wt. patients
Conclusions
Wang C et al
CHEST 2010; 137(2):254
ACCP 2016
CHEST 2016; 15: 1469
Massive PE
Treatment of Acute VTE
2016
Antithrombotic and Thrombolytic
Therapy: American College of Chest
Physicians Evidenced-Based Clinical
Practice Guidelines (10th edition)
Kearon C et alCHEST 2016; epub
Systemic lytic Rx over
anticoagulation
Grade 2C
Grade 2B
Systemic lytic Rx over CDT
No mention of IVC filters!
Submassive PE
Treatment of Acute VTE
2016
Antithrombotic and Thrombolytic
Therapy: American College of Chest
Physicians Evidenced-Based Clinical
Practice Guidelines (10th edition)
Kearon C et alCHEST 2016; epub
In most patients we
recommend against systemic
lytic Rx
Grade 2B
In selected patients who
deteriorate after starting
anticoagulation, we suggest
systemic lytic therapy.
Submassive PE
Treatment of Acute VTE
2016
Antithrombotic and Thrombolytic
Therapy: American College of Chest
Physicians Evidenced-Based Clinical
Practice Guidelines (10th edition)
Kearon C et alCHEST 2016; epub
Grade 2C
Initial Therapy
Massive PE and Submassive PE
Goal: Eliminate thrombus without
increasing risk of bleeding….
– Adopting a strategy of thrombus removal –
Pulmonary Embolism
…led to catheter based approaches…
Bilateral PE
Massive PE with GI Bleed
Catheter based lytic fragmentation/lysisTreatment?
Catheter Directed Rx: Left
Massive PE with GI Bleed
Pre Rx Post Rx(5 min)
Massive PE with GI Bleed
Pre Rx Post Rx
Catheter Directed Rx: Right
• 1990 – 2008 publications
• 95 studies, 594 patients
• Clinical success – 86.5%
• Procedural complications
– Minor – 7.9%
– Major – 2.4%
Kuo W T et al
JVIR 2009; 20:1431
Catheter-directed Therapy for the Treatment of
Massive Pulmonary Embolism: Systematic Review
and Meta-analysis of Modern Techniques
7 – Year Review(N=102)
Avgerinos E., et alJVS Ven Lym Dis 2017;5:303l
C54
E. Avgerinos et al
JVS Ven Lym Dis 2017;5:303-11
Pulmonary Embolism- 14 Massive
- 88 Submassive
CDI- 60 USAT
- 36 Standard CDT
Age 59.2 yrs. (ave.)
49% Male
Dose rtPA 28 mg. (ave.)
Assoc. FactorMajor
Bleed
CDI
Failure p-value
Age ≥ 70 yrs. 17%* 24%*** 0.019
**0.121
Massive PE 21%* 50%***0.052
**0.001
Absolute contra. 43%* 71%***0.006
**0.001
Major Bleed/Failure
E. Avgerinos et al
JVS Ven Lym Dis 2017;5:303-11
Predictors of failure and complications of catheter-directed
interventions for pulmonary embolism of failure and
complications of catheter-directed interventions for pulm
Assoc. FactorMajor
Bleed
CDI
Failure p-value
Age ≥ 70 yrs. 17% - 0.019
Massive PE 21%* 50%***0.052
**0.001
Absolute contra. 43%* 71%***0.006
**0.001
Major Bleed/Failure
E. Avgerinos et al
JVS Ven Lym Dis 2017;5:303-11
Predictors of failure and complications of catheter-directed
interventions for pulmonary embolism
Perhaps Massive PE should have immediate IVC
filter and 50mg rt-PA ……or emergent operative
thromboembolectomy, depending upon results
of head CT…as part of CTA of chest
Initial Therapy
1. Significant immediate and long term benefit of removing
large burden thrombus from Pulmonary Arteries
2. Increased bleeding risk with systemic TNK (PEITHO trial
….. But in older patients)
3. Reduced bleeding with lower dose rtPA, equal efficacy
4. Bleeding risk increased in:
– Patients simultaneously anticoagulated
– Older patients (≥75 …..83% maj. bleeds in ATTRACT > 65yr.
100% maj. bleeds in patients > 60yr.)
– Low body weight patients
– Studies Show –
Pulmonary Embolism
Massive and Submassive PE
Reduce/Eliminate
RV Outflow
Obstruction AnticoagulationRV Dysfct Normal
Cardiac Echo
Elevated Normal
BNP/Troponins
Pulmonary Embolism
– Risk Stratification –
Hemodynamically Unstable Hemodynamically Stable
Pulmonary Embolism
InovaHeart and Vascular Institute
Thank You!