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 •
Recommend
More recommend
