Treatment of submassive pulmonary embolism

Is thrombolysis the best treatment??

Gulf Thoracic MeetingAbu Dhabi, UAE

MArch 18-20, 2010

Egyptian Society of Chest Diseases & Tuberculosis The 55th International Conference

25-28 March 2014Cairo, Egypt

Majdy M IdreesSaudi Arabia

Financial disclosure

•Honoraria for lecturing for Actelion, BSP, pfizer, AstraZeneca, MSD & GSK

•Research grant from pfizer & Actelion

•Multi-national RCT sponsored by Actelion, BSP, and pfizer

The 55th ESCT conference

“Venous thrombosis is always a severe disease and is often fatal, because fragments of the thrombi may detach and occlude branches of the pulmonary artery... the occlusion of the main branches of the pulmonary artery causes a striking rise of the blood pressure in these vessels. This rise, which the right heart might fight in order to ensure circulation, may sometimes lead to cardiac arrest.”

Picot 1884 Lecons de Clinique Médicale

The 55th ESCT conference

“In acute diseases, coldness of the

extremities,,

“is a very bad sign”

The aphorisms of Hippocrates

The 55th ESCT conference

•74-year-old lady presented with progressive shortness of breath (WHO functional class IV) over 10-day period

•She had one attack of syncope 2 days before her presentation

•Recent surgery (appendectomy 3 weeks earlier)

The 55th ESCT conference

•BP 155/88, PR 92/min, O2 sat 84% on r/a and

92% on 4 L/min•Physical examination revealed Rt. heart strain

•Doppler US negative •EKG revealed sinus tachycardia with T wave

inversion in the anterior precordial leads•NT-pro BNP 4200

The 55th ESCT conference

Echocardiography:•Dilated RV•Severe TR

•sPAP 84 mmHg•Small posterior PE

The 55th ESCT conference

The 55th ESCT conference

CT angiogram..•PE occluding the

main right PA•RV:LV > 1

Management issues:

.1How severe is this patient’s PE?

.2What is the risk of mortality? Risk-stratifying

.3Is the pathobiology different from massive PE?

.4What is the “best” management approach?

The 55th ESCT conference

RV Dysfunction

SeverityEmbolism sizeCardiopulmonary Status

100

70

30

10

0

Mor

talit

ySudden Death

Cardiac Arrest

Shock

Outcome in pulmonary embolism

Infliction Point Our patient

Goldhaber 1993 23 2 8.7%

Grifoni 2000 61 3 5%

Hamel 2001 64 0 0%

Giannitsis 2000 26 2 7.7%

Viellard-Baron 2002 32 1 3%

Pruszczyk 2003 64 8 12.5%

Pruszczyk 2003 51 10 19.6%

Kucher 2003 19 2 10.5%

340 28 8.2%

Outcomes in hemodynamically-stable, RV-strained PE treated with Heparin

Study Year Number PE Death % Mortality

Massive Pulmonary EmbolismWell-understoodObstructive shock

Sub-massive Pulmonary Embolism

Poorly understood

Different pathophysiology

The 55th ESCT conference

Hemodynamic – PE

-10

0

10

20

120

100

80

60

40

m PAP

Progressive PR occlusion

RAP

Systemic Arterial Pressure

COP RV Pressure

Total OcclusionZero Occlusion

Pre

ssur

e (m

mH

g)

Guyton Cir Res 1954; 2:326-332

PE: Vascular resistance vs. obstruction

0 30

20

30

10

10 20 Miller index

PVR

•• • •

•••

•

•

••

•

°

°

°

°°

°

°

°•

•

••

•

•

••

•

••

Petitpretz Circ 1984; 70:861-866.

Thrombolytic therapy in massive PE

• Randomized trial• Aimed for 40 patients• Patients with massive PE (SBP<90)• IV bolus of SK Vs Heparin

The study was prematurely Terminated.

Throm Thrombolysis 1995

Sur

viva

l

0

20

40

60

80

100

Heparin

Streptokinase

4

Thrombolytic therapy in massive PE

J Throm Thrombolysis 1995

4

Conclusion:Although a small study, it strongly support the current indication for thrombolytic therapy in massive PE.

UPET ’73 Urokinase 73 73 2.7% (2) 8.2% (6)

Marini ’88 Urokinase 20 10 0% 0%

PIOPED ’90 rt-PA 9 4 11.1% (1) 0%

Levine ’90 rt-PA 33 25 3.0% (1) 0%

PAIMS 2 ’92 rt-PA 20 16 10% (2) 6.3% (1)

Goldhaber ’93 rt-PA 46 55 0% 3.6% (2)

Konstantinides ’02 rt-PA 118 138 3.4% (4) 2.2% (3)

Total 319 321 3.1% (10) 3.7% (12)

Non-shock mortality thrombolytic therapy

Study Lytic Heparin Lytic % (N) Heparin % (N)

Patients Mortality

American Journal of Cardiovascular Drugs 2004, 4(2):69-74

Thrombolytic therapy in patients with non-shock pulmonary embolism?

• Randomized, DB, multicenter trial• 256 pt• PE confirmed by HP V/Q scan, spiral CT or angiogram• Normal BP• RV dysfunction (echo, ECG or RHC)

Primary endpoint:• In-hospital mortality• Worsening circulation• Need for additional therapy

Secondary endpoint:• 30-days mortality• Recurrent PE

Com

posit

e PE

P

0

5

10

15

20

25

Heparin

Alteplase

Heparin TPA

11%

24.6%

Thrombolytic Therapy in patients with non-shock pulmonary embolism?

Am J of Cardiovascular Drugs, 4 (2) 2004 , 69-74

P = 0.0058

In-h

ospi

tal

Mor

talit

y

5

4

3

2

1

0

2.4%

2.1%

P = NS

Non-shock PE: Pathobiology

Observations: • Clinical observation• Lack of response to anti-obstructive lytic

treatment

Science: • Inflammatory neurohormonal mediators’

release bilateral pulmonary vasoconstriction, bilateral V/Q mismatch PVR RV dysfunction

Stein M, Prog Cardiovasc Dis 1974; 17:167-174Malik AB, Physiol Rev 1983; 63: 1114-1207 Alpert JS, Chest 1978; 73: 795-797

Methods:

• Inhaled Iloprost used in 11 patients with Submassive PE, who refused to receive thrombolytic therapy

• NYHA III to IV for duration between 1-14 day• Helical CT angiogram was confirmatory• Echocardiography was used to evaluate the RV

•All patients were stable hemodynamically

• Beside anticoagulation, all patients received inhaled Iloprost, 2.5-5 µg every 4 hours for 3 weeks.

Novel approach for the management of sub-massive pulmonary embolism

Idrees et al. Ann Thorac Med 2012; 7(3):157-161.

SMC fibroblasts monoc T-cellsPMN

vasodilation

Prostanoids

matrixsecretion

TNFIFNIL-2

burstelastaseleuko-trienes

NFkBTNFIL-1IL-10

anti-coagulation

platelets

anti-proliferation

MAPKiNOS

Vessels LeukocytesPlatelets

Olschewski et al. Pharmacol Ther, 2004

Novel approach for the management of sub-massive pulmonary embolism

End points: • Improvement in echocardiographic parameters

for right ventricular strain/PH

• Functional class improvement• Improvement in dyspnea score• Exercise improvement• Biomarker (Pro BNP)• Improvement in oxygenation• Mortality

Idrees et al, ATM, Submitted

Results

Pre IloprostPost Iloprost

sPAP NT - Pro 6MWT Dyspnea NYHA BNP Score

Idrees et al, ATM, Submitted

P < 0.003

lll +

l +

Vlll

ll

P = 0.03

155 m

520 m

P = 0.01

1620

420

P < 0.001P = 0.01

38

89

100

80

60

40

20

1800

1500

1200

900

600

300

0

600 -- 450 --

300 --

150 --0

X

VIII

VI

IV

II

0

IV

III

II

I

0

Novel approach for the management of sub-massive pulmonary embolism

Idrees et al, ATM, Submitted

Conclusion:

• In sub-massive pulmonary embolism, directing therapy towards decreasing PVR is effective in improving the hemodynamics derangement associated with this condition.

• This strategy might turn to be the most effective approach for treating this condition and probably safer than thrombolytic therapy.

• However, these conclusion should be confirmed in a large, randomized, placebo-controlled study

Take Home Messages

The 55th ESCT conference

Summary

•Pulmonary embolism could be a fatal disease•Diagnostic-Therapeutic approach based on risk

stratification is probably the most important step in the management

o RV Dysfunctiono Shock

o Cardiac arresto Sudden arrest

Summary

Thrombolytic therapy in M-PE:

• Accelerated clot lysis• Hemodynamic improvement• May improve

Recurrent embolism CTEPHQuality of life Symptoms Mortality

Thrombolytic therapy in SM-PE:• Controversial issue• Administrating early in the course of sub-

massive pulmonary embolism prevents worsening of the disease

In SM-PE• Directing therapy towards PVR rather than clotting lysis might be

the ideal approach in this patients’ population• Need to be tested in randomized clinical studies

Thank you

Egyptian Society of Chest Diseases & Tuberculosis The 55th International Conference

25-28 March 2014Cairo, Egypt