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

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)

PEITHO: Overview of study design Confirmed acute symptomatic Tenecteplase PE Primary Outcome, Secondary Outcomes (weight-adapted bolus) Seconray Outomes, SAE Absence of hemodynamic UFH, LMWH or UFH infusion collapse Fondaparinux DOUBLE BLIND Confirmed RV VKA <2 h dysfunction + R myocardial injury Placebo UFH, LMWH or UFH infusion Fondaparinux VKA UFH bolus i.v. Day 2 Day 7 Day 30 ClinicalTrials.gov # NCT00639743 EudraCT # 2006-005328-18 S Konstantinides for the PEITHO Steering Committee. Am Heart J 2012;163:33-38.e1

PEITHO: Analyzed population Tenecteplase Placebo Randomized 506 500 (N=1006) 1 ICF unavail . 506 499 ITT Population 506 499 Safety population* *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) (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: Diagnostic and risk stratification tests Tenecteplase Placebo (n=506) (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 278 (54.9) 255 (51.1) Echocardiography + Spiral CT 154 (30.4) 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 outcomes

PEITHO: Primary efficacy outcome Tenecteplase Placebo (n=506) (n=499) P value n (%) n (%) All-cause mortality or hemodynamic collapse 13 (2.6) 28 (5.6) 0.015 within 7 days of randomization 0.23 0.44 0.88 0 1.00 2.00 Odds ratio Thrombolysis superior ITT population The PEITHO Investigators

PEITHO: Analysis of primary efficacy outcome Tenecteplase Placebo (n=506) (n=499) P value n (%) n (%) All-cause mortality 6 (1.2) 9 (1.8) 0.43 within 7 days Hemodynamic collapse 8 (1.6) 25 (5.0) 0.002 within 7 days Need for CPR 1 5 Hypotension / blood 8 18 pressure drop Catecholamines 3 14 Resulted in death 1 6 ITT population The PEITHO Investigators

PEITHO: Other clinical outcomes (within 7 days) Tenecteplase Placebo P value (n=506) (n=499) n (%) n (%) PE recurrence 1 (0.2) 5 (1.0) 0.12 Intubation / mechanical 8 (1.6) 15 (3.0) 0.13 ventilation Open-label thrombolysis 4 (0.8) 23 (4.6) <0.001 ITT population The PEITHO Investigators

PEITHO: Safety outcomes (within 7 days of randomization) Tenecteplase Placebo (n=506) (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 (2) Tenecteplase Placebo (n=506) (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: Causes of death (within 30 days of randomization) Tenecteplase Placebo (n=506) (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: Primary end point according to age Age ≤ 75 years 0.12 0.33 0.85 0 1.00 2.00 Odds ratio Age >75 years 0.23 0.63 1.66 0 1.00 2.00 Odds ratio ITT population 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 TNK placebo TNK N 335 344 164 162 ITT population 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 Thomas Meinertz, Germany (Chair) • • Guy Meyer, France Frans van de Werf, Belgium • • • Arnaud Perrier, Switzerland Trial Statistician Eric Vicaut, France • Critical Events Adjudication Committee • Mareike Lankeit, Germany (Chair) Sponsor’s Representative: • Philippe Girard, France Philippe Gallula, France • Olivier Sanchez, France • Steering Committee Members • Irene M. Lang Austria • Giancarlo Agnelli Italy • Franck Verschuren Belgium • Cecilia Becattini Italy Hélène Bouvaist France • Nazzareno Galiè Italy • Thierry Danays (non-voting) France • Matteo Rugolotto Italy • • Nicolas Meneveau France • Aldo Salvi Italy • Gerard Pacouret France • Piotr Pruszczyk Poland • Mustapha Sebbane France • Adam Torbicki Poland Jan Beyer-Westendorf Germany • Ana Franca Portugal • • Claudia Dellas Germany • Antoniu Petris Romania • Klaus Empen Germany • Gabriel Tatu-Chitoiu Romania • Annette Geibel Germany • Branislav Stefanovic Serbia • Christian Kupatt Germany • Matija Kozak Slovenia Sebastian Schellong Germany • David Jiménez Castro Spain • Holger Thiele Germany • Nils Kucher Switzerland • Benjamin Brenner Israel • Samuel Z. Goldhaber United States •