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Pulmonary Embolism Thrombolysis Study an investigator-initiated, investigator-sponsored trial
The PEITH Investigators
ClinicalTrials.gov # NCT00639743 EudraCT # 2006-005328-18
Rationale: risk-adjusted treatment of acute PE
Thrombolysis?
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.
• All-cause mortality or • Hemodynamic collapse within 7 days of randomization, defined as: need for cardiopulmonary resuscitation or 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) 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 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)
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
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
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.
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
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
PEITHO outcomes
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
0.23 0.44
2.00 Odds ratio
Thrombolysis superior
0.88
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
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)
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 0
Intracranial/hemorrhagic stroke 10 1
Extracranial major 4 1
Hemoglobin drop >2g/dL 46 11
Transfusion of >2 units 10 0
ITT population The PEITHO Investigators
PEITHO: Safety outcomes (within 7 days of randomization)
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 0
Serious adverse events (SAE) 29 (5.7) 39 (7.8) 0.19
ITT population The PEITHO Investigators
PEITHO: Safety outcomes (2)
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 0 3
From stroke 5 1
From bleeding 2 0
Other cause 3 6
ITT population The PEITHO Investigators
PEITHO: Causes of death (within 30 days of randomization)
1.00 0
0.12 0.33
2.00 Odds ratio
0.85
1.00 0
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
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
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.
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
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
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
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
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
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)
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 0 3 From stroke 4 0
From bleeding 1 0
Other cause 0 3
ITT population The PEITHO Investigators
PEITHO: Causes of death (within 7 days of randomization)