current status of thrombolysis for venous thromboembolism...lytic rx vs. anticoagulation •...

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!