peitho presentation slides · pulmonaryembolismthrombolysisstudy *...

Pulmonary Embolism Thrombolysis Study an inves6gator-‐ini6ated, inves6gator-‐sponsored trial

The PEITH Inves,gators

ClinicalTrials.gov # NCT00639743 EudraCT # 2006-005328-18

Ra6onale: risk-‐adjusted treatment of acute PE

Thrombolysis?

Primary To inves,gate the clinical benefits (efficacy) of thrombolysis with tenecteplase over placebo in normotensive pa,ents with acute intermediate-‐risk PE (both treatment arms receive standard heparin an,coagula,on)

Secondary To assess the safety of tenecteplase in pa,ents with intermediate-‐risk PE

PEITHO: Objec6ves

•  All-‐cause mortality or •  Hemodynamic collapse within 7 days of randomiza,on, defined as: need for cardiopulmonary resuscita,on or systolic BP < 90 mm Hg for ≥15 min or drop by ≥ 40 mm

Hg for ≥15 min with end organ hypoperfusion (cold extremi,es, urinary output < 30 mL/h, mental confusion)

or need for catecholamines to maintain adequate organ

perfusion and a systolic BP of >90 mm Hg

PEITHO: Primary outcome

Secondary end points: •  All-‐cause mortality within 7 days of randomiza,on •  Hemodynamic collapse within 7 days of randomiza,on •  Confirmed symptoma,c pulmonary embolism recurrence within 7 days •  All-‐cause mortality within 30 days of randomiza,on

Safety endpoints •  Non-‐intracranial major bleeding within 7 days •  Total strokes (intracranial hemorrhage or ischemic stroke) within 7 days •  Serious adverse events (SAE) within 30 days

PEITHO: Secondary efficacy and safety outcomes

All end points were adjudicated by an independent 3-‐member Clinical Events CommiJee (CEC)

Day 2 Day 7 Day 30

R

DOUBLE BLIND

VKA

Sec

onra

y O

utom

es, S

AE

Prim

ary

Out

com

e, S

econ

dary

Out

com

es

Confirmed acute

symptoma6c PE

Absence of hemodynamic

collapse

Confirmed RV dysfunc6on + myocardial

injury

UFH infusion UFH, LMWH or Fondaparinux

UFH infusion

TNK

Placebo

VKA UFH bolus i.v.

<2 h

UFH, LMWH or Fondaparinux

S Konstantinides for the PEITHO Steering Committee. Am Heart J 2012;163:33-38.e1

PEITHO: Overview of study design

ClinicalTrials.gov # NCT00639743 EudraCT # 2006-005328-18

PEITHO: Analyzed popula6on

*all ITT patients received study medication

Safety population*

ITT Population

Randomized (N=1006)

Tenecteplase Placebo

The PEITHO Investigators

1 ICF unavail. 500

499

499 506

506

506

First Pa6ent In: November 2007; Last Pa6ent Out: August 2012

Tenecteplase (n=506)

Placebo (n=499)

Age (y,) mean+SD 66.5+14.7 65.8+15.9

Age (y), median (Q1-‐Q3) 70.0 (57.0-‐78.0) 70.0 (58.0-‐78.0)

Sex (female/male) 264/242 268/231

Weight (kg), mean+SD 82.5+17.9 82.6+18.2

Systolic blood pressure (mm Hg), mean+SD 130.8+18.3 131.3+18.5

Diastolic blood pressure (mm Hg), mean+SD 78.6+12.6 79.2+12.1

Heart rate (beats per min), mean+SD 94.5+17.1 92.3+16.7

Respiratory rate (resp per min), mean+SD 21.8+5.8 21.6+5.7

Chronic obstruc,ve pulmonary disease (%) 26 (5.1) 34 (6.8)

Chronic heart failure (%) 21 (4.2) 26 (5.2)

Previous VTE (%) 126 (24.9) 147 (29.5)

Known malignant tumor (%) 41 (8.1) 32 (6.4)

Surgery or trauma in previous 30 days (%) 31 (6.1) 27 (5.4)

PEITHO: Baseline characteris6cs



Placebo (n=499)

Confirma6on of PE (%)

CT scan 480 (94.9) 472 (94.6)

High-‐probability lung scan 31 (6.1) 35 (7.0)

Pulmonary angiography 6 (1.2) 8 (1.6)

At least one of the above 506 (100) 499 (100)

Confirma6on of RV dysfunc6on

Echocardiography

Echocardiography + Spiral CT

278 (54.9)

154 (30.4)

255 (51.1)

172 (34.5) Spiral CT 74 (14.6) 72 (14.4)

At least one of the above 506 (100) 499 (100)

Confirma6on of myocardial injury

Troponin I or T elevated 505 (99.8) 499 (100)

PEITHO: Diagnos6c and risk stra6fica6on tests


PEITHO outcomes


Placebo (n=499) P value

n (%) n (%)

All-‐cause mortality or hemodynamic collapse within 7 days of randomiza6on

13 (2.6) 28 (5.6) 0.015

ITT population The PEITHO Investigators

PEITHO: Primary efficacy outcome

1.00 0

0.23 0.44

2.00 Odds ra,o

Thrombolysis superior

0.88



n (%) n (%) All-‐cause mortality within 7 days

6 (1.2) 9 (1.8) 0.43

Hemodynamic collapse within 7 days

8 (1.6) 25 (5.0) 0.002

Need for CPR 1 5

Hypotension / blood pressure drop

8 18

Catecholamines 3 14

Resulted in death 1 6


PEITHO: Analysis of primary efficacy outcome



n (%) n (%) PE recurrence 1 (0.2) 5 (1.0) 0.12

Intuba6on / mechanical ven6la6on

8 (1.6) 15 (3.0) 0.13

Open-‐label thrombolysis 4 (0.8) 23 (4.6) <0.001


PEITHO: Other clinical outcomes (within 7 days)



n (%) n (%) Non-‐intracranial major bleeding 32 (6.3) 6 (1.5) <0.001

Severe 16 2 Moderate 16 4

ISTH major bleeding 58 (11.5) 12 (2.4) <0.001

Type of bleeding

Fatal 1 0

Intracranial/hemorrhagic stroke 10 1

Extracranial major 4 1

Hemoglobin drop >2g/dL 46 11

Transfusion of >2 units 10 0

Minor bleeding 165 (32.6) 43 (8.6) <0.001


PEITHO: Safety outcomes (within 7 days of randomiza6on)



n (%) n (%) All strokes by day 7 12 (2.4) 1 (0.2) 0.003

Hemorrhagic 10 1 Ischemic 2 0

Serious adverse events (SAE) 29 (5.7) 39 (7.8) 0.19


PEITHO: Safety outcomes (2)



n (%) n (%) All-‐cause mortality 12 (2.4) 16 (3.2) 0.42 From hemodynamic collapse 1 3 From recurrent PE 1 3 From respiratory failure 0 3

From stroke 5 1

From bleeding 2 0

Other cause 3 6


PEITHO: Causes of death (within 30 days of randomiza6on)

1.00 0

0.12 0.33

2.00 Odds ra,o

0.85

1.00 0

0.23 0.63

2.00 Odds ra,o

1.66

PEITHO: Primary end point according to age

Age ≤ 75 years

Age >75 years



%

≤ 75 years >75 years

N 335 344 164 162

Death or hemodynamic collapse (primary EP)

Stroke without primary EP (not leading to death or hemodynamic collapse)

PEITHO: Efficacy versus safety according to age

placebo placebo TNK TNK

PEITHO: Conclusions

v  In pa,ents with intermediate-‐risk pulmonary embolism, intravenous bolus tenecteplase significantly reduced the primary end point of death or hemodynamic collapse within 7 days of randomiza,on.

v The results of PEITHO jus,fy the concept of risk stra,fica,on of normotensive pa,ents with acute PE.

v They confirm the no,on that early “advanced” (recanaliza,on) treatment prevents clinical deteriora,on in pa,ents with evidence of right ventricular dysfunc,on and myocardial injury.

v  In PEITHO, the benefits of thrombolysis came at the cost of a significantly increased risk of major, par,cularly intracranial, hemorrhage.

v The pa,ent’s age should be taken into account when weighing the expected benefits versus risks of systemic thrombolysis in clinical prac,ce.

PEITHO: Organiza6on

•  Irene M. Lang Austria •  Franck Verschuren Belgium •  Hélène Bouvaist France •  Thierry Danays (non-‐vo,ng) France •  Nicolas Meneveau France •  Gerard Pacouret France •  Mustapha Sebbane France •  Jan Beyer-‐Westendorf Germany •  Claudia Dellas Germany •  Klaus Empen Germany •  Anneqe Geibel Germany •  Chris,an Kupaq Germany •  Sebas,an Schellong Germany •  Holger Thiele Germany •  Benjamin Brenner Israel

•  Giancarlo Agnelli Italy •  Cecilia Becarni Italy •  Nazzareno Galiè Italy •  Maqeo Rugoloqo Italy •  Aldo Salvi Italy •  Piotr Pruszczyk Poland •  Adam Torbicki Poland •  Ana Franca Portugal •  Antoniu Petris Romania •  Gabriel Tatu-‐Chitoiu Romania •  Branislav Stefanovic Serbia •  Ma,ja Kozak Slovenia •  David Jiménez Castro Spain •  Nils Kucher Switzerland •  Samuel Z. Goldhaber United States

Co-‐Chairmen (Principal Inves6gators) •  Stavros Konstan,nides, Germany/Greece •  Guy Meyer, France

Trial Sta6s6cian •  Eric Vicaut, France

Data Safety Monitoring Board •  Thomas Meinertz, Germany (Chair) •  Frans van de Werf, Belgium •  Arnaud Perrier, Switzerland

Cri6cal Events Adjudica6on CommiJee •  Mareike Lankeit, Germany (Chair) •  Philippe Girard, France •  Olivier Sanchez, France

Steering CommiJee Members

Sponsor’s Representa6ve: • Philippe Gallula, France

Carl C. Kaulfersch Austria Alexandre Ghuysen Belgium Serge Moqe Belgium Bernard Charbonnier France Francis Couturaud France Emile Ferrari France Jose Roul Gerald France Mar,al Hamon France Xavier Jacob France Khalifé Khalifé France Marcel Laurent France Chris,ne Lorut France Florence Parent France Jeannot Schmidt France Jacques Pierre Schwob France Gabriel Steg France Bernard Tardy France Mathias M. Borst Germany Leonhard Bruch Germany Chris,ne Espinola-‐Klein Germany Dirk Habedank Germany Andreas Hartmann Germany Uwe Janssens Germany Volkhard Kurowski Germany F. Joachim Meyer Germany Chris,an Opitz Germany

Michael Kapeliovich Israel Iolanda Enea Italy Maria Grazia Modena Italy Leonardo Goffredo Pancaldi Italy Giuseppe di Pasquale Italy Giancarlo Piovaccari Italy Viqorio Pengo Italy Rosa Maria Salvi Italy Bozena Sobkowicz Poland Jerzy Lewczuc Poland Marianna Janion Poland Jarosław D. Kasprzak Poland Targonski Ryszard Poland Lech Polonski Poland Zbigniew Gaciong Poland Tiago Judas Portugal Alexandru Cris,an Nechita Romania Lucian Petrescu Romania Calin Pop Romania Mircea Vladoianu Romania Goran Koraćević Serbia Biljana Putniković Serbia Carlos Escobar Cervantes Spain Mikel Oribe Ibanez Spain Xosé Pérez Fernandez Spain María José Rodríguez Spain Christophe Wyss Switzerland

PEITHO: Inves6gators PEITHO Inves6gators

PEITHO: Acknowledgements

Special thanks to: •  Laurence Guery, France •  Erich Bluhmki, Germany •  Gudrun Heinrichs, Germany •  Anke Hallmann, Germany •  Anja Kronenberg, Germany •  Raoul Stahrenberg, Germany •  Jeanneqe Veuhoff, Germany •  Cinzia Nir, Italy •  Marco Villa, Italy •  Maciej Kostrubiec, Poland

Study CRO •  Pierrel Research

PEITHO: Inclusion criteria

1)  Age ≥ 18 years 2)  Acute PE confirmed by: ù

a)  lung scan, or b)  spiral CT, or c)  pulmonary angiogram

3)  RV dysfunction plus myocardial injury:

a) echocardiography or CT PLUS b) positive troponin I or T test

PEITHO: Key exclusion criteria

v Hemodynamic collapse at presenta,on (high-‐risk PE); v  Known significant bleeding risk v  Administra,on of thromboly,c agents within the 4 previous days v  Vena cava filter inser,on or pulmonary thrombectomy within the 4

previous days v  Known coagula,on disorder (including vitamin K antagonist) v  Treatment with an inves,ga,onal drug under another study protocol in

the 7 previous days v  Previous enrollment in this study v  Any other condi,on that the inves,gator feels would place the pa,ent at

increased risk of the inves,ga,onal therapy is ini,ated

Weight (kg) Dose in mg Dose in units Dose in ml <60 30 mg 6000 U 6 ml >60 to <70 35 mg 7000 U 7 ml >70 to <80 40 mg 8000 U 8 ml >80 to <90 45 mg 9000 U 9 ml >90 50 mg 10000 U 10 ml

Weight-‐adapted bolus of TNK (or placebo)



n (%) n (%) Death by day 7 6 (1.2) 9 (1.8) 0.43 From hemodynamic collapse 1 3 From recurrent PE 0 3 From stroke 4 0

From bleeding 1 0

Other cause 0 3


PEITHO: Causes of death (within 7 days of randomiza6on)

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