Thrombolysis in acute pulmonary embolism

Dr James Edwards Royal Prince Alfred Hospital

Evidence Review in Emergency Medicine Wollongong March 3rd 2016 Ma

E

Case

A 66 yo male, previous well presents with SOB and pleuritic chest pain. Noted to have mild hypoxia, HR

110 and BP 100/70. Hs Troponin 30

CTPA shows a large saddle embolus. Bedside echo shows mod RV dilatation.

Management

a) Heparin b) Heparin and thrombolysis

c) Embolectomy d) Novel oral anticoagulant

e) Catheter directed fragmentation and/or thrombolysis

Pathophysiology

Rationale

Thrombolysis vs anticoagulation

Balance of risks

Bleeding

Recurrent PE

Death

Pulmonary hypertension

Risk stratification

High risk Low Intermediate

sPESI score age > 80

history of cancer chronic cardiac or lung disease

HR >110 BP< 100 Sa02 <90

High risk (massive) PE

thrombolyse if shocked bedside echo if very unstable to rule in

no thrombolysis for undifferentiated shock

Intermediate risk (sub-massive) PE

Not shocked but presence of RV dysfunction

Does thrombolysis reduce mortality in intermediate

risk PE?

Thrombolysis for Pulmonary Embolism and Risk of All-Cause Mortality, Major Bleeding, and Intracranial Hemorrhage. A Meta- analysis Chatterjee S et al.

JAMA. 2014 Jun 18;311(23):2414-21

16 trials 2115 patients

mortality benefit with thrombolytics (2.17% vs 3.89%)

NNT 59

increase in major bleeding with thrombolytics (9.24% vs 3.42%) NNH 11

increase in ICH with thrombolytics (1.46% vs 0.19%)

NNH 78

Odds of Mortality in Patients With Intermediate-Risk Pulmonary Embolism Treated With Thrombolytic

Therapy vs Anticoagulation

Thrombolysis for Pulmonary Embolism and Risk of All-Cause Mortality, Major Bleeding, and Intracranial Hemorrhage. A Meta- analysis Chatterjee S et al. JAMA. 2014 Jun 18;311(23):2414-21

Intermediate-Risk Pulmonary Embolism Treated With Thrombolytic Therapy vs Anticoagulation

Outcome (no of studies) No.of events/patients, absolute event rate NNT P value

Thrombolytic Anticoagulation

All-cause mortality (8) 12/866 (1.39) 26/889 (2.92) NNT =65 .03 Major bleeding (8) 67/866 (7.74) 20/889 (2.25) NNH =18 <.001

Thrombolysis for Pulmonary Embolism and Risk of All-Cause Mortality, Major Bleeding, and Intracranial Hemorrhage. A Meta- analysis Chatterjee S et al. JAMA. 2014 Jun 18;311(23):2414-21

Impact of the efficacy of thrombolytic therapy on the mortality of patients with acute submassive

pulmonary embolism: a meta-analysis. Nakamura et al. J Thromb Haemost. 2014 Jul;12(7):1086-95

6 studies 1510 patients

no significant differences were found in all-cause death between the thrombolytic and heparin (2.3% vs. 3.7%)

30 day mortality 3%

Impact of the efficacy of thrombolytic therapy on the mortality of patients with acute submassive pulmonary embolism: a meta-analysis. Nakamura et al. J Thromb Haemost. 2014 Jul;12(7):1086-95

PEITHO study

Fibrinolysis for patients with intermediate-risk pulmonary embolism. Meyer G, et al. The New England Journal of

Medicine. 2014. 370(15):1402-1411

PEITHO

Double blind, RCT

76 centres/13 countries

Intermediate risk PE (RV dysfunction and trop rise)

N= 1005

tenecteplase (weight based) plus heparin (n=506) placebo plus heparin (n= 499)

Fibrinolysis for patients with intermediate-risk pulmonary embolism. Meyer G, et al. The New England Journal of Medicine. 2014. 370(15):1402-1411

Outcomes

Primary

All-cause mortality or haemodynamic decompensation at 7 days

Tenecteplase 2.6% vs. placebo 5.6% (OR 0.44; 95% CI 0.23-0.87; P=0.02; NNT 33)

All-cause mortality

At 7 days: tenecteplase 1.2% vs. placebo 1.8%

(OR 0.65; 95% CI 0.23-1.85; P=0.42)

At 30 days: tenecteplase 2.4% vs. placebo 3.2% (OR 0.73; 95% CI 0.34-1.57; P=0.42)

Fibrinolysis for patients with intermediate-risk pulmonary embolism. Meyer G, et al. The New England Journal of Medicine. 2014. 370(15):1402-1411

Bleeding risk

Extracranial bleeding occurred in 32 patients (6.3%) in the tenecteplase group and 6 patients (1.2%) in the placebo

group (P<0.001)

Stroke occurred in 12 patients (2.4%) in the tenecteplase group and was haemorrhagic in 10 patients; 1 patient (0.2%) in the placebo group had a stroke, which was

hemorrhagic (P=0.003).

Fibrinolysis for patients with intermediate-risk pulmonary embolism. Meyer G, et al. The New England Journal of Medicine. 2014. 370(15):1402-1411

Subgroup analysis

Fibrinolysis for patients with intermediate-risk pulmonary embolism. Meyer G, et al. The New England Journal of Medicine. 2014. 370(15):1402-1411

Take home messages from PEITHO

No short term mortality benefit

Significant bleeding risk with thrombolysis especially age >75

TOPCOAT

Treatment of submassive pulmonary embolism with tenecteplase or placebo: cardiopulmonary outcomes at 3

months: multicenter double-blind, placebo- controlled randomized trial. Kline J. et al.. J Thromb Haemost. 2014.

12(4):459-468

TOPCOAT trial

multicentre, RCT83 pat 83 patients

placebo vs tenecteplase intermediate risk as determined by echo/biomarkers

LMWH rather than unfractionated in placebo

Primary outcome

Composite adverse outcome

Within 5 days PE related -death, haemodynamic compromise

Treatment complication

At 90 days pulmonary hypertension, poor quality of life, exercise intolerance

Improvement in tenecteplase group vs placebo

15% vs. 37% had at least 1 adverse outcome (P=0.017, NNT 5)

Take Home message

complicated composite outcome Is an improvement in self reported exercise

tolerance enough of a reason to give thrombolytics? Probably not

What dose of thrombolytic?

MOPETT study

Moderate pulmonary embolism treated with thrombolysis.

Sharifi M. Am J Cardiol. 2013 Jan 15;111(2):273-7

MOPETT trial

Single centre study, RCT Low dose thrombolysis n=61 and heparin n= 60

Alteplase 0.5mg/kg (max 50mg) with 10mg bolus and then

rest over 2 hour

Moderate (?Intermediate) risk

>70% involvement of thrombus in ≥ 2 lobar or either the left or right main pulmonary arteries

High probability V/Q scan with V/Q mismatch in ≥2 lobes

Primary outcomes

Pulmonary hypertension at 28 months thrombolysis16% (9/58) vs. heparin 57% (32/56)

(P<0.001; NNT 2)

Pulmonary hypertension or recurrent PE at 28 months tthrombolysis 16% (9/58) vs. heparin 63% (35/56)

(P<0.001; NNT 2)

Secondary outcomes

No difference in mortality No bleeding occurred in either group!

Take Home messages

Thrombolysis reduces the pulmonary arterial systolic pressure and this persisted for 2

years but is it clinically significant?

Less bleeding than other studies ? safer dose

PERFECT trial

Pulmonary Embolism Response to Fragmentation, Embolectomy, and Catheter Thrombolysis

(PERFECT): Initial Results From a Prospective Multicenter Registry Chest. 2015;148(3):667-673

PERFECT Trial

multi-centre registry of 101 consecutive patients

not randomised

high (n=28) and intermediate (n=73) risk

low dose tPA or urokinase for intermediate risk

high risk PE were treated with catheter-directed mechanical or pharmacomechanical thrombectomy

Outcomes

6/101 deaths (4/28 high and 2/73 intermediate risk)

no major procedure-related complications,

major haemorrhages, or strokes

8/9 patients with absolute contraindications to systemic tPA survived

The future?

A 46 yo male, previous well presents with SOB and pleuritic chest pain. Noted to have mild hypoxia, HR 110

and BP 100/70. Hs Troponin 30

CTPA shows a large saddle embolus. Bedside echo shows mod RV dilatation.

Management a) Heparin

b) Heparin and thrombolysis c) Embolectomy

d) Novel oral anticoagulant e) Catheter directed fragmentation and/or thrombolysis

A 76 yo male, previous well presents with SOB and pleuritic chest pain. Noted to have mild hypoxia, HR 110

and BP 100/70. Hs Troponin 30

CTPA shows a large saddle embolus. Bedside echo shows mod RV dilatation.

Management a) Heparin

b) Heparin and thrombolysis c) Embolectomy

d) Novel oral anticoagulant e) Catheter directed fragmentation and/or thrombolysis

A 66 yo male, previous well presents with SOB and pleuritic chest pain. Noted to have mild hypoxia, HR 110

and BP 100/70. Hs Troponin 30

CTPA shows a large saddle embolus. Bedside echo shows mod RV dilatation.

Management a) Heparin

b) Heparin and thrombolysis c) Embolectomy

d) Novel oral anticoagulant e) Catheter directed fragmentation and/or thrombolysis

Take home messages

PE risk is a spectrum

In regards to thrombolysis in intermediate PE;

Age over 75, the risks probably outweigh the benefits

Under 75 (especially under 65), thrombolysis should be

considered within the context of bleeding risk

Ideal dose and role for catheter directed thrombolysis not clear

Shared decision making process with your colleagues (respiratory, haematology, ICU) and the patient prior to

decision to thrombolyse