PEITHO - Clinical Trial Results

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PEITHO - Clinical Trial Results
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?
PEITHO: Objectives
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
* Tenecteplase is not approved medication for use in pulmonary embolism in the United States or Europe.
PEITHO: Primary outcome
• 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: Secondary efficacy and safety outcomes
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
All end points were adjudicated by an independent
3-member Clinical Events Committee (CEC)
Tenecteplase
(weight-adapted bolus)
Absence of
hemodynamic
collapse
Confirmed RV
dysfunction +
myocardial
injury
UFH, LMWH or
Fondaparinux
UFH infusion
DOUBLE
BLIND
<2 h
VKA
R
Placebo
UFH infusion
UFH
bolus i.v.
ClinicalTrials.gov # NCT00639743
EudraCT # 2006-005328-18
UFH, LMWH or
Fondaparinux
VKA
Day 2
Day 7
Seconray Outomes, SAE
Confirmed
acute
symptomatic
PE
Primary Outcome, Secondary Outcomes
PEITHO: Overview of study design
Day 30
S Konstantinides for the PEITHO Steering Committee. Am Heart J 2012;163:33-38.e1
PEITHO: Analyzed population
Tenecteplase
506
Placebo
Randomized
(N=1006)
500
1 ICF unavail.
506
ITT Population
499
506
Safety population*
499
*all ITT patients received study medication
First Patient In: November 2007; Last Patient Out: August 2012
The PEITHO Investigators
PEITHO: Baseline characteristics
Tenecteplase
Placebo
(n=506)
66.5+14.7
65.8+15.9
70.0 (57.0-78.0)
70.0 (58.0-78.0)
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)
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)
Age (y,) mean+SD
Age (y), median (Q1-Q3)
Sex (female/male)
Previous VTE (%)
(n=499)
PEITHO: Diagnostic and risk stratification tests
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)
Echocardiography
278 (54.9)
255 (51.1)
Echocardiography + Spiral CT
Spiral CT
154 (30.4)
74 (14.6)
172 (34.5)
72 (14.4)
At least one of the above
506 (100)
499 (100)
505 (99.8)
499 (100)
Confirmation of RV dysfunction
Confirmation of myocardial injury
Troponin I or T elevated
PEITHO outcomes
PEITHO: Primary efficacy outcome
Tenecteplase
(n=506)
n
(%)
All-cause mortality or
hemodynamic collapse
within 7 days of
randomization
0.23
0.44
0
13
(2.6)
Placebo
(n=499)
n
(%)
28
(5.6)
P value
0.015
0.88
1.00
Odds ratio
2.00
Thrombolysis superior
ITT population
The PEITHO Investigators
PEITHO: Analysis of primary efficacy outcome
All-cause mortality
within 7 days
Hemodynamic collapse
within 7 days
Tenecteplase
(n=506)
n
(%)
6
(1.2)
8
(1.6)
Placebo
(n=499)
n
(%)
9
(1.8)
25
Need for CPR
1
5
Hypotension / blood
pressure drop
Catecholamines
8
18
3
14
Resulted in death
1
6
ITT population
(5.0)
P value
0.43
0.002
The PEITHO Investigators
PEITHO: Other clinical outcomes (within 7 days)
Tenecteplase
(n=506)
Placebo
P value
(n=499)
n
1
(%)
(0.2)
n
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
PE recurrence
ITT population
The PEITHO Investigators
PEITHO: Safety outcomes (within 7 days of randomization)
Tenecteplase
(n=506)
n
(%)
Placebo
(n=499)
n
(%)
P value
Non-intracranial bleeding
Major
Minor
ISTH major bleeding
32
165
(6.3)
(32.6)
6
43
(1.5)
(8.6)
<0.001
<0.001
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 (2)
Tenecteplase
(n=506)
n
(%)
All strokes by day 7
12
Hemorrhagic
Ischemic
Serious adverse events (SAE)
10
2
29
ITT population
Placebo
(n=499)
n
(%)
P value
(2.4)
1
(0.2)
0.003
(5.7)
1
0
39
(7.8)
0.19
The PEITHO Investigators
PEITHO: Causes of death (within 30 days of randomization)
All-cause mortality
Tenecteplase
(n=506)
n
(%)
12
(2.4)
Placebo
(n=499)
n
(%)
16
(3.2)
From hemodynamic collapse
From recurrent PE
From respiratory failure
1
1
0
3
3
3
From stroke
5
1
From bleeding
2
0
Other cause
3
6
ITT population
P value
0.42
The PEITHO Investigators
PEITHO: Primary end point according to age
Age ≤ 75 years
0.12
0.33
0.85
0
1.00
Odds ratio
2.00
Age >75 years
0.23
0
ITT population
0.63
1.66
1.00
Odds ratio
2.00
The PEITHO Investigators
PEITHO: Efficacy versus safety according to age
≤ 75 years
>75 years
%
Death or
hemodynamic collapse
(primary EP)
Stroke without primary EP
(not leading to death or
hemodynamic collapse)
placebo
N 335
ITT population
TNK
placebo
TNK
344
164
162
The PEITHO Investigators
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
Co-Chairmen (Principal Investigators)
Data Safety Monitoring Board
•
•
•
•
•
Stavros Konstantinides, Germany/Greece
Guy Meyer, France
Trial Statistician
•
Eric Vicaut, France
Critical Events Adjudication Committee
•
•
•
Sponsor’s Representative:
•
Thomas Meinertz, Germany (Chair)
Frans van de Werf, Belgium
Arnaud Perrier, Switzerland
Philippe Gallula, France
Mareike Lankeit, Germany (Chair)
Philippe Girard, France
Olivier Sanchez, France
Steering Committee Members
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Irene M. Lang
Franck Verschuren
Hélène Bouvaist
Thierry Danays (non-voting)
Nicolas Meneveau
Gerard Pacouret
Mustapha Sebbane
Jan Beyer-Westendorf
Claudia Dellas
Klaus Empen
Annette Geibel
Christian Kupatt
Sebastian Schellong
Holger Thiele
Benjamin Brenner
Austria
Belgium
France
France
France
France
France
Germany
Germany
Germany
Germany
Germany
Germany
Germany
Israel
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Giancarlo Agnelli
Cecilia Becattini
Nazzareno Galiè
Matteo Rugolotto
Aldo Salvi
Piotr Pruszczyk
Adam Torbicki
Ana Franca
Antoniu Petris
Gabriel Tatu-Chitoiu
Branislav Stefanovic
Matija Kozak
David Jiménez Castro
Nils Kucher
Samuel Z. Goldhaber
Italy
Italy
Italy
Italy
Italy
Poland
Poland
Portugal
Romania
Romania
Serbia
Slovenia
Spain
Switzerland
United States
PEITHO: Investigators
PEITHO Investigators
Carl C. Kaulfersch
Alexandre Ghuysen
Serge Motte
Bernard Charbonnier
Francis Couturaud
Emile Ferrari
Jose Roul Gerald
Martial Hamon
Xavier Jacob
Khalifé Khalifé
Marcel Laurent
Christine Lorut
Florence Parent
Jeannot Schmidt
Jacques Pierre Schwob
Gabriel Steg
Bernard Tardy
Mathias M. Borst
Leonhard Bruch
Christine Espinola-Klein
Dirk Habedank
Andreas Hartmann
Uwe Janssens
Volkhard Kurowski
F. Joachim Meyer
Christian Opitz
Austria
Belgium
Belgium
France
France
France
France
France
France
France
France
France
France
France
France
France
France
Germany
Germany
Germany
Germany
Germany
Germany
Germany
Germany
Germany
Michael Kapeliovich
Iolanda Enea
Maria Grazia Modena
Leonardo Goffredo Pancaldi
Giuseppe di Pasquale
Giancarlo Piovaccari
Vittorio Pengo
Rosa Maria Salvi
Bozena Sobkowicz
Jerzy Lewczuc
Marianna Janion
Jarosław D. Kasprzak
Targonski Ryszard
Lech Polonski
Zbigniew Gaciong
Tiago Judas
Alexandru Cristian Nechita
Lucian Petrescu
Calin Pop
Mircea Vladoianu
Goran Koraćević
Biljana Putniković
Carlos Escobar Cervantes
Mikel Oribe Ibanez
Xosé Pérez Fernandez
María José Rodríguez
Christophe Wyss
Israel
Italy
Italy
Italy
Italy
Italy
Italy
Italy
Poland
Poland
Poland
Poland
Poland
Poland
Poland
Portugal
Romania
Romania
Romania
Romania
Serbia
Serbia
Spain
Spain
Spain
Spain
Switzerland
PEITHO: Acknowledgements
Study CRO
•
Pierrel Research
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
PEITHO: Inclusion criteria
1) Age ≥ 18 years
2) Acute PE confirmed by:
ù
a)
b)
c)
lung scan, or
spiral CT, or
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-adapted bolus of TNK (or placebo)
Weight (kg)
<60
>60 to <70
>70 to <80
>80 to <90
>90
Dose in mg
30 mg
35 mg
40 mg
45 mg
50 mg
Dose in units
6000 U
7000 U
8000 U
9000 U
10000 U
Dose in ml
6 ml
7 ml
8 ml
9 ml
10 ml
PEITHO: Causes of death (within 7 days of randomization)
Death by day 7
Tenecteplase
(n=506)
n
(%)
6
(1.2)
Placebo
(n=499)
n
(%)
9
(1.8)
From hemodynamic collapse
From recurrent PE
From stroke
1
0
4
3
3
0
From bleeding
1
0
Other cause
0
3
ITT population
P value
0.43
The PEITHO Investigators

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