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Pulmonary Embolism Who Should Receive Thrombolysis? Stavros V. Konstantinides, MD, FESC Professor, Clinical Trials in Antithrombotic Therapy Center for Thrombosis und Hemostasis, University of Mainz, Germany stavros.konstantinides@unimedizin-mainz.de Professor of Cardiology Democritus University of Thrace, Greece 2

Disclosures Lecture fees (moderate): Bayer HealthCare, Boehringer Ingleheim, Daiichi Sankyo, Pfizer – Bristol-Myers Squibb Consultancy fees (moderate): Bayer HealthCare, Boehringer Ingleheim, Daiichi Sankyo, Pfizer – Bristol-Myers Squibb Institutional research support: Bayer HealthCare

Risk-adjusted management of acute PE What is intermediate-risk (submassive) PE? Do we need “revascularization/reperfusion” for intermediate-risk PE? Is thrombolysis safe for everybody? What alternative/additional options do we have? What are the implications of the recent trials? 4

Resolution of RV dysfunction with alteplase Echocardiography (paradoxical septal wall) rtPA + Heparin Heparin alone S Konstantinides, Am J Cardiol 1998;82:966-970

pes Resolution of RV dysfunction with tenecteplase Time course of R/L end-diastolic dimension ratio p =0.04 p = ns p= 0.043 pes C Becattini et al. Thromb Res 2010

Elevated early risk beyond massive PE? Parameter Tests / Findings RV Dysfunction RV dilatation, hypokinesis or pressure overload on echocardiography RV dilatation on spiral CT [BNP or NT-proBNP elevation] [ right heart pressures at RHC] Myocardial injury Cardiac troponin T or I positive [H-FABP] [Myoglobin]

Thrombolysis for submassive PE (2002) 30% P=0.001 Alteplase (n=118) 32 (23.2%) Placebo (n=138) 20% Incidence P=0.7 P=0.2 P=0.33 P=0.85 9 (7.6%) 10% 8 (5.8%) 4 (3.4%) 3 (2.2%) 3 (2.5%) 3 (2.5%) 3 (2.2%) 1 (0.7%) Death CPR Shock Intubation Emergency Thrombolysis S Konstantinides. N Engl J Med 2002;347:1143

RV dysfunction on CT: LOW positive predictive value Meta analysis (27 studies, 4767 patients) Cut-off for RV:LV >1.0 (6 studies; 1678 pts) OR for 30-d death, 2.81 (1.78-4.42) Hemodynamically stable pts (6 studies; n=2254) OR for 30-d death, 1.64 (1.06-2.52) OR for 3-month death, 5.14 (1.4-18.19) 30-d PE-related death (7 studies) OR, 7.7 (3.53-17.14) NPV, 99%; PPV, 5% C Becattini. Eur Respir J 2014; Epub ahead of print

Biomarkers (cTn) in PE: LOW positive predictive value Author Pts (n) Marker Ref. value* Positive (%) NPV (%) PPV (%) Giannitsis, 2000 56 Trop T 0.10 32 97 44 Konstantinides, 2002 106 Trop I 0.07 41 98 14 0.04 37 12 Janata, 2003 0.09 11 99 34 Pruszczyk, 2003 64 0.01 50 100 25 * in ng/mL N Kucher and S Z Goldhaber. Circulation 2003;108:2191

+? Going further: Biomarkers combined with imaging RV Dysfunction Parameter Tests / Findings RV Dysfunction RV dilatation, hypokinesis or pressure overload on echocardiography RV dilatation on spiral CT [BNP or NT-proBNP elevation] [ right heart pressures at RHC] Myocardial injury Cardiac troponin T or I positive [H-FABP] [Myoglobin] +?

Complication risk (OR, 95% CI) Biomarkers combined with imaging (2005) Patient group Complication risk (OR, 95% CI) Troponin T-negative (<0.04 ng/ml) ------- Troponin-positive, echo-negative 3.70 (0.76-18.18) P=0.107 Troponin-negative, echo-positive 5.56 (0.97-32) P=0.055 Both troponin- and echo-positive 10.00 (2.14-46.80) P=0.004 ~ 15% of all PE patients L Binder, S Konstantinides. Circulation 2005;112:1573-1579

Risk-adjusted management of acute PE What is intermediate-risk PE? Do we need “revascularization” for intermediate-risk PE? Is thrombolysis safe for everybody? What alternative/additional options do we have? What are the implications of the trials? 13

PEITHO: Design Primary Outcome, Secondary Outcomes Confirmed acute symptomatic PE Primary Outcome, Secondary Outcomes TNK Absence of hemodynamic collapse Seconray Outomes, SAE UFH, LMWH or Fondaparinux UFH infusion Long-term Follow-up <2 h DOUBLE BLIND Confirmed RV dysfunction + myocardial injury VKA R Placebo UFH, LMWH or Fondaparinux UFH infusion UFH bolus i.v. VKA Day 2 Day 7 Day 30 Day 180 S Konstantinides for the PEITHO Steering Committee. Am Heart J 2012;163:33-38.e1 14

PEITHO: Analyzed population Rivaroxaban clinical development PEITHO: Analyzed population Tenecteplase Placebo Randomized (N=1006) 506 500 1 ICF unavail. ITT Population 506 499 Safety population* 506 499 EINSTEIN PE: patient flow This slide shows the patient flow in the EINSTEIN PE study. *all ITT patients received study medication First Patient In: November 2007; Last Patient Out: August 2012 The PEITHO Investigators. N Engl J Med 2014;370(15):1402-1411 15

Thrombolysis superior PEITHO: Primary efficacy outcome Tenecteplase (n=506) Placebo (n=499) P value n (%) All-cause mortality or hemodynamic collapse within 7 days of randomization 13 (2.6) 28 (5.6) 0.015 0.23 0.44 0.88 Verified against source data tables sent for the NEJM publication 1.00 2.00 Odds ratio Thrombolysis superior ITT population The PEITHO Investigators. N Engl J Med 2014;370(15):1402-1411 16 16 16

PEITHO: Secondary efficacy outcomes Tenecteplase (n=506) Placebo (n=499) P value 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 18 Catecholamines 3 14 Resulted in death Verified against source data tables sent for the NEJM publication ITT population The PEITHO Investigators. N Engl J Med 2014;370(15):1402-1411 17 17 17

PE risk assessment: What did we learn? ‘Intermediate-risk patient’, not just ‘intermediate-risk PE’ Acute pressure overload (RV dysfunction) Preexisting cardiovascular disease Other serious comorbidity (cancer) Recurrent PE (residual DVT) Presence of a PFO Presence of a PFO Presence of a PFO Poor prognosis

Original and simplified pulmonary embolism severity index (PESI)

Original and simplified pulmonary embolism severity index (PESI)

Classification of early mortality risk aPESI Classes III to V indicate moderate to very high 30-day mortality risk; sPESI >1 point(s) indicate high 30-day mortality risk. bEchocardiographic criteria of RV dysfunction include RV dilatation and/or an increased end-diastolic RV/LV diameter ratio (in most studies, the reported threshold value was 0.9 or 1.0); hypokinesia of the free RV wall; decreased tricuspid annulus plane systolic excursion (TAPSE); or combinations of the above. On computed tomographic (CT) angiography (four-chamber views of the heart), RV dysfunction is defined as an increased end-diastolic RV–LV diameter ratio (with a threshold of 0.9 or 1.0). cMarkers of myocardial injury (e.g. elevated cardiac troponin I or T concentrations in plasma), or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic peptide concentrations in plasma). dNeither calculation of the PESI (or sPESI) nor laboratory testing is considered necessary in patients with hypotension or shock. ePatients in the PESI class I-II, or with sPESI of 0, and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests, are also to be classified into the intermediate-low risk category. This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index

Risk-adjusted management of acute PE What is intermediate-risk PE? Do we need “revascularization” for intermediate-risk PE? Is thrombolysis safe for everybody? What alternative/additional options do we have? What are the implications of the trials? 22

PEITHO: Safety outcomes (within 7 days of randomization) Tenecteplase (n=506) Placebo (n=499) P value n (%) Non-intracranial bleeding Major 32 (6.3) 6 (1.5) <0.001 Minor 165 (32.6) 43 (8.6) Strokes by day 7 12 (2.4) 1 (0.2) 0.003 Hemorrhagic 10 Ischemic 2 Verified against source data tables sent for the NEJM publication ITT population The PEITHO Investigators. N Engl J Med 2014;370(15):1402-1411 23 23 23

PEITHO 6-month follow-up: all-cause mortality Tenecteplase (n=486) Placebo (n=474) P value N (%) n All-cause mortality within 180 days 35 (7.0) 30 (6.1) 0.57 The PEITHO Investigators; ESC 2014 24 24 24

PEITHO 6-month follow-up: day 31 – day 180 Tenecteplase (n=486) Placebo (n=474) P value n (%) All-cause mortality between day 30 and 180 23 (4.7) 14 (3.0) 0.15 Cancer 9 4 Stroke 1 Bleeding 2 Respiratory failure / pneumonia Sudden unexplained death Unknown Other 3 5 The PEITHO Investigators; ESC 2014 25 25 25

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) Verified against source data tables sent for the NEJM publication placebo TNK placebo TNK N 335 344 164 162 ITT population The PEITHO Investigators. N Engl J Med 2014;370(15):1402-1411 26 26 26 26

Reduced-dose thrombolysis ? 121 patients with „moderate“ PE Thrombus in >2 lobar arteries plus >2 symptoms/signs of PE No RV dysfunction required Patients received <50% of rtPA dose Pulmonary hypertension or PR recurrence in 16% of thrombolyzed pts vs. 63% of controls (P<0.001). No major or minor bleeds! M. Sharifi. Am J Cardiol 2013;111:273-277

Reduced-dose thrombolysis ? After the dose reduction [by 50%] of tenecteplase in patients 75 years of age or older, there were no cases of intracranial hemorrhage (0 of 97) as opposed to 8.1% (3 of 37) before protocol amendment…. PW Armstrong. N Engl J Med 2013 ;368:1379-1387

Ultrasound-assisted, catheter-directed thrombolysis Ultrasound- accelerated, reversible disaggregation of uncrosslinked fibrin, (microsonic core wire containing ultrasound elements); Infusion of recombinant tissue plasminogen activator (5.2 F, multi-sidehole infusion catheter) 6F sheath for unilateral, 10 F for bilateral insertion Engelberger RP and Kucher N. Eur Heart J 2014;35:758-764

Ultrasound-assisted, catheter-directed thrombolysis Engelberger RP and Kucher N. Eur Heart J 2014;35:758-764

Courtesy Drs Piazza and Goldhaber

Risk-adjusted management of acute PE What is intermediate-risk PE? Do we need “revascularization” for intermediate-risk PE? Is thrombolysis safe for everybody? What alternative/additional options do we have? What are the implications of the recent trials? 36

Risk-adjusted management algorithm aIf echocardiography has already been performed during diagnostic work-up for PE and detected RV dysfunction, or if the CT already performed for diagnostic work–up has shown RV enlargement (RV/LV (left ventricular) ratio ≥0.9, a cardiac troponin test should be performed except for cases in which primary reperfusion is not a therapeutic option (e.g. due to severe comorbidity or limited life expectancy of the patient). bMarkers of myocardial injury (e.g. elevated cardiac troponin I or T concentrations in plasma), or of heart failure as a result of (right) ventricular dysfunction (elevated natriuretic peptide concentrations in plasma). If a laboratory test for a cardiac biomarker has already been performed during initial diagnostic work-up (e.g. in the chest pain unit) and was positive, then an echocardiogram should be considered to assess RV function, or RV size should be (re)assessed on CT. cPatients in the PESI Class I-II, or with sPESI of 0, and elevated cardiac biomarkers or signs of RV dysfunction on imaging tests, are also to be classified into the intermediate-low risk category. This might apply to situations in which imaging or biomarker results become available before calculation of the clinical severity index. These patients are probably no candidates for home treatment. dThrombolysis, if (and as soon as) clinical signs of haemodynamic decompensation appear; surgical pulmonary embolectomy or percutaneous catheter-directed treatment may be considered as alternative options to systemic thrombolysis, particularly if the bleeding risk is high. eMonitoring should be considered for patients with confirmed PE and a positive troponin test, even if there is no evidence of RV dysfunction on echocardiography or CT. fThe simplified version of the PESI has not been validated in prospective home treatment trials; inclusion criteria other than the PESI were used in two single-armed (non-randomized) management studies.

Recommendations: acute phase treatment

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is NOT a controversy anymore Thrombolysis in PE is NOT a controversy anymore