Pulmonary Embolism Thrombolysis Study an investigator-initiated, - - PowerPoint PPT Presentation

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Pulmonary Embolism Thrombolysis Study

an investigator-initiated, investigator-sponsored trial

The PEITH Investigators

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

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Rationale: risk-adjusted treatment of acute PE Thrombolysis?

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Primary

To investigate the clinical benefits (efficacy) of thrombolysis with tenecteplase* over placebo in normotensive patients with acute intermediate-risk PE (both treatment arms receive

standard heparin anticoagulation)

Secondary

To assess the safety of tenecteplase* in patients with intermediate-risk PE

PEITHO: Objectives

* Tenecteplase is not approved medication for use in pulmonary embolism in the United States or Europe.

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• All-cause mortality or
• Hemodynamic collapse

within 7 days of randomization, defined as:

need for cardiopulmonary resuscitation

• r

systolic BP < 90 mm Hg for ≥15 min or drop by ≥ 40 mm Hg for ≥15 min with end organ hypoperfusion (cold extremities, urinary output < 30 mL/h, mental confusion)

• r

need for catecholamines to maintain adequate organ perfusion and a systolic BP of >90 mm Hg

PEITHO: Primary outcome

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Secondary end points:

• All-cause mortality within 7 days of randomization
• Hemodynamic collapse within 7 days of randomization
• Confirmed symptomatic pulmonary embolism recurrence within 7 days
• All-cause mortality within 30 days of randomization

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 Committee (CEC)

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Day 2 Day 7 Day 30

R

DOUBLE BLIND VKA

Seconray Outomes, SAE Primary Outcome, Secondary Outcomes

Confirmed acute symptomatic PE Absence of hemodynamic collapse Confirmed RV dysfunction + myocardial injury

UFH infusion UFH, LMWH or Fondaparinux UFH infusion

Tenecteplase

(weight-adapted bolus)

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

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PEITHO: Analyzed population

*all ITT patients received study medication

Safety population* ITT Population Randomized (N=1006) Tenecteplase Placebo

The PEITHO Investigators

500 499 499 506 506 506

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

1 ICF unavail.

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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 obstructive 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 characteristics

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Tenecteplase

(n=506)

Placebo

(n=499)

Confirmation 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) Confirmation of RV dysfunction 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) Confirmation of myocardial injury Troponin I or T elevated 505 (99.8) 499 (100)

PEITHO: Diagnostic and risk stratification tests

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PEITHO outcomes

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Tenecteplase (n=506) Placebo (n=499) P value n (%) n (%)

All-cause mortality or hemodynamic collapse within 7 days of randomization 13 (2.6) 28 (5.6) 0.015

ITT population

The PEITHO Investigators

PEITHO: Primary efficacy outcome

1.00 0.23 0.44 2.00 Odds ratio

Thrombolysis superior

0.88

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Tenecteplase (n=506) Placebo (n=499) P value 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

ITT population

The PEITHO Investigators

PEITHO: Analysis of primary efficacy outcome

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Tenecteplase

(n=506)

Placebo

(n=499)

P value n (%) n (%) PE recurrence 1 (0.2) 5 (1.0) 0.12 Intubation / mechanical ventilation 8 (1.6) 15 (3.0) 0.13 Open-label thrombolysis 4 (0.8) 23 (4.6) <0.001

ITT population

The PEITHO Investigators

PEITHO: Other clinical outcomes (within 7 days)

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Tenecteplase (n=506) Placebo (n=499) P value n (%) n (%)

Non-intracranial bleeding Major 32 (6.3) 6 (1.5) <0.001 Minor 165 (32.6) 43 (8.6) <0.001 ISTH major bleeding 58 (11.5) 12 (2.4) <0.001 Type of bleeding Fatal 1 Intracranial/hemorrhagic stroke 10 1 Extracranial major 4 1 Hemoglobin drop >2g/dL 46 11 Transfusion of >2 units 10

ITT population

The PEITHO Investigators

PEITHO: Safety outcomes (within 7 days of randomization)

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Tenecteplase (n=506) Placebo (n=499) P value n (%) n (%)

All strokes by day 7 12 (2.4) 1 (0.2) 0.003 Hemorrhagic 10 1 Ischemic 2 Serious adverse events (SAE) 29 (5.7) 39 (7.8) 0.19

ITT population

The PEITHO Investigators

PEITHO: Safety outcomes (2)

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Tenecteplase (n=506) Placebo (n=499) P value 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 3 From stroke 5 1 From bleeding 2 Other cause 3 6

ITT population

The PEITHO Investigators

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

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1.00 0.12 0.33 2.00 Odds ratio 0.85 1.00 0.23 0.63 2.00 Odds ratio 1.66

PEITHO: Primary end point according to age

Age ≤ 75 years Age >75 years

ITT population

The PEITHO Investigators

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ITT population

The PEITHO Investigators

% ≤ 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

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PEITHO: Conclusions

 In patients with intermediate-risk pulmonary embolism, intravenous bolus tenecteplase significantly reduced the primary end point of death or hemodynamic collapse within 7 days of randomization.  The results of PEITHO justify the concept of risk stratification of normotensive patients with acute PE.  They confirm the notion that early “advanced” (recanalization) treatment prevents clinical deterioration in patients with evidence of right ventricular dysfunction and myocardial injury.  In PEITHO, the benefits of thrombolysis came at the cost of a significantly increased risk of major, particularly intracranial, hemorrhage.  The patient’s age should be taken into account when weighing the expected benefits versus risks of systemic thrombolysis in clinical practice.

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PEITHO: Organization

• Irene M. Lang

Austria

• Franck Verschuren

Belgium

• Hélène Bouvaist

France

• Thierry Danays (non-voting)

France

• Nicolas Meneveau

France

• Gerard Pacouret

France

• Mustapha Sebbane

France

• Jan Beyer-Westendorf

Germany

• Claudia Dellas

Germany

• Klaus Empen

Germany

• Annette Geibel

Germany

• Christian Kupatt

Germany

• Sebastian Schellong

Germany

• Holger Thiele

Germany

• Benjamin Brenner

Israel

• Giancarlo Agnelli

Italy

• Cecilia Becattini

Italy

• Nazzareno Galiè

Italy

• Matteo Rugolotto

Italy

• Aldo Salvi

Italy

• Piotr Pruszczyk

Poland

• Adam Torbicki

Poland

• Ana Franca

Portugal

• Antoniu Petris

Romania

• Gabriel Tatu-Chitoiu

Romania

• Branislav Stefanovic

Serbia

• Matija Kozak

Slovenia

• David Jiménez Castro

Spain

• Nils Kucher

Switzerland

• Samuel Z. Goldhaber

United States

Co-Chairmen (Principal Investigators)

• Stavros Konstantinides, Germany/Greece
• Guy Meyer, France

Trial Statistician

• Eric Vicaut, France

Data Safety Monitoring Board

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

Critical Events Adjudication Committee

• Mareike Lankeit, Germany (Chair)
• Philippe Girard, France
• Olivier Sanchez, France

Steering Committee Members

Sponsor’s Representative:

• Philippe Gallula, France

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Carl C. Kaulfersch Austria Alexandre Ghuysen Belgium Serge Motte Belgium Bernard Charbonnier France Francis Couturaud France Emile Ferrari France Jose Roul Gerald France Martial Hamon France Xavier Jacob France Khalifé Khalifé France Marcel Laurent France Christine 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 Christine Espinola-Klein Germany Dirk Habedank Germany Andreas Hartmann Germany Uwe Janssens Germany Volkhard Kurowski Germany

• F. Joachim Meyer

Germany Christian Opitz Germany Michael Kapeliovich Israel Iolanda Enea Italy Maria Grazia Modena Italy Leonardo Goffredo Pancaldi Italy Giuseppe di Pasquale Italy Giancarlo Piovaccari Italy Vittorio 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 Cristian 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: Investigators

PEITHO Investigators

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PEITHO: Acknowledgements

Special thanks to:

• Laurence Guery, France
• Erich Bluhmki, Germany
• Gudrun Heinrichs, Germany
• Anke Hallmann, Germany
• Anja Kronenberg, Germany
• Raoul Stahrenberg, Germany
• Jeannette Veuhoff, Germany
• Elena Forlanelli, Italy
• Miriam Mazzoleni, Italy
• Cinzia Nitti, Italy
• Marco Villa, Italy
• Maciej Kostrubiec, Poland

Study CRO

• Pierrel Research

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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

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PEITHO: Key exclusion criteria

 Hemodynamic collapse at presentation (high-risk PE);

 Known significant bleeding risk  Administration of thrombolytic agents within the 4 previous days  Vena cava filter insertion or pulmonary thrombectomy within the 4 previous days  Known coagulation disorder (including vitamin K antagonist)  Treatment with an investigational drug under another study protocol in the 7 previous days  Previous enrollment in this study  Any other condition that the investigator feels would place the patient at increased risk of the investigational therapy is initiated

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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)

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Tenecteplase (n=506) Placebo (n=499) P value n (%) n (%) Death by day 7 6 (1.2) 9 (1.8) 0.43

From hemodynamic collapse 1 3 From recurrent PE 3 From stroke 4 From bleeding 1 Other cause 3

ITT population

The PEITHO Investigators

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