Τι ςυμβαίνει μετά από την οξεία πνευμονική εμβολή;

Τι ςυμβαίνει μετά από την οξεία πνευμονική εμβολή; Σταφροσ Β. Κωνςταντινίδησ, MD, PhD, FESC Καθηγητήσ Καρδιολογίασ Δημοκρίτειο Πανεπιςτήμιο Θράκησ skonst@med.duth.gr Professor, Clinical Trials in Antithrombotic Therapy Center for Thrombosis und Hemostasis, University of Mainz, Germany stavros.konstantinides@unimedizin-mainz.de

Τι συμβαίνει μετά από την οξεία ΠΕ; 1. Κίλδπλνο ππνηξνπήο θιεβηθήο ζξνκβνεκβνιηθήο λόζνπ 2. Η ζσζηή δηάξθεηα αληηπεθηηθήο αγσγήο 3. Λύζε ησλ ζξόκβσλ ή αλάπηπμε CTEPH; 4. Αλάγθε γηα πνηνηηθά θιηληθά δεδνκέλα CTEPH, chronic thromboembolic pulmonary hypertension; PE, pulmonary embolism; VTE, venous thromboembolism. 2

Cumulative incidence (%) VTE recurrence: early versus late Cohort data 1980s 1990s Cumulative incidence (%) Projected annual incidence rate (%) 30 25 20 2 weeks 2 55 3 months 6.4 30 6 months 8 18 2 years 17 8.5 15 10 5 0 0 1 2 3 4 5 6 7 8 Duration of follow-up (years) Prandoni P et al. Ann Intern Med 1996;125:1 7. 5 years 24 4.8 8 years 30 3.8 Prandoni P et al. Ann Intern Med 1996;125:1 7. Prandoni P et al. Haematologica 1997;82:423 8. 3

Recurrence and bleeding rates during first 6 months (on treatment): historical data Cohort data 1980s 1990s (Olmsted County, MN, USA) VTE recurrence Major bleeding Heit JA et al. Blood 2011;118:4992 9. 4

Recurrence and bleeding rates during first 6 months (on treatment): recent trials (EINSTEIN DVT and PE pooled analysis) Rivaroxaban (N=4150) Enoxaparin/VKA (N=4131) n % n % First symptomatic recurrent VTE 86 2.1 95 2.3 Fatal PE 2 <0.1 1 <0.1 Death (PE cannot be excluded) 10 0.2 11 0.3 DVT and PE 1 <0.1 2 <0.1 DVT only 32 0.8 45 1.1 PE only 41 1.0 36 0.9 Hazard ratio 0.66 0.89 1.19 0 Rivaroxaban superior p=0.41 for superiority (two-sided) 1.00 ITT population DVT, deep vein thrombosis; ITT intent-to-treat; VKA, vitamin K antagonist. Prins MH et al. Thromb J 2013;11:21. Rivaroxaban non-inferior 1.75 p<0.0001 for non-inferiority (one-sided) Rivaroxaban inferior 5

Factors predisposing to early recurrence Poor quality of anticoagulation (failure to achieve therapeutic aptt and INR) Cancer aptt, activated partial thromboplastin time; INR, international normalized ratio. Heit JA et al. Blood 2011;118:4992 9. 6

Recurrence and bleeding risk of tumor patients 842 patients after VTE: 181 of them had a known tumor Tumor (%) No tumor (%) HR (95% CI) VTE recurrence at 12 months 20.7 6.8 3.2 (1.9 5.4) Major bleeding at 12 months 12.4 4.9 2.2 (1.2 4.1) CI, confidence interval; HR, hazard ratio. Prandoni P et al. Blood 2002;100:3484 8. 7

Cumulative incidence (%) VTE recurrence: early versus late Cohort data 1980s 1990s Cumulative incidence (%) Projected annual incidence rate (%) 30 25 20 2 weeks 2 55 3 months 6.4 30 6 months 8 18 2 years 17 8.5 15 10 5 0 0 1 2 3 4 5 6 7 8 Duration of follow-up (years) Prandoni et al. Ann Intern Med 1996;125:1 7. 5 years 24 4.8 8 years 30 3.8 Prandoni P et al. Ann Intern Med 1996;125:1 7. Prandoni P et al. Haematologica 1997;82:423 8. 8

Late VTE recurrence Data obtained from several cohorts Heit JA. Am J Hematol 2012(Suppl 1);S63 7. 9

Risk of late recurrence: provoked versus unprovoked first episode Idiopathic Unprovoked 19.4% Secondary Non-surgical risk 8.8% Surgery 0% Prandoni P et al. Haematologica 2007;92:199 205 Meta-analysis Provoked surgical: 0.7%/year Provoked non-surgical: 4.2%/year Unprovoked: 7.4%/year Baglin T et al. Lancet 2003;362:523 26 Iorio A et al. Arch Intern Med 2010;170:1710 6. 10

Risk factors for late recurrence: no validated recurrence score exists Strong/established Unprovoked (vs provoked) VTE More than one VTE event Ongoing hormonal therapy Elevated D-dimer levels after/during VKA treatment Weaker/controversial Male sex Location: PE/proximal DVT vs distal DVT Age Family history of VTE Obesity (increased BMI) Cancer Antiphospholipid syndrome Hereditary thrombophilia BMI, body mass index. Heit JA. Am J Hematol 2012(Suppl 1)S63 7. Zhu T et al. Arterioscler Thromb Vasc Biol 2009;29:298 310. 11

Example: Is male sex a risk factor for recurrence? Lijfering WM et al. Blood 2009:114:2031 6. 12

Risk of VTE recurrence: provoking factors versus thrombophilia Prospective cohort study including 570 patients (29% PE) Thrombophilia in 29% (factor V Leiden: 16%; factor II mutation: 4%) 19.4% Unprovoked HR 1.5 (0.8 2.8) Thrombophilia Non-surgical risk 8.8% No thrombophilia Surgery 0% Unprovoked VTE indicates thrombophilia including and beyond the defects known today Baglin et al. Lancet 2003;362:523 6. 13

Risk and prognosis of VTE recurrence: localization of first event PE versus DVT Outcome After DVT (3 months) After PE Number of patients included (60 studies: 13 cohort, 56 RCT) n=10050 n=3422 Recurrent VTE (3 months) 3.2 (2.4-4.1)% 3.6 (2.3-5.0)% Recurrent PE (3 months) 1.3 (1.0-1.7)% 3.0 (2.5-3.7)% Fatal VTE 0.3 (0.2-0.5)% 1.3 (0.9-1.7)% Case fatality rate 9% 30% M Carrier. Ann Intern Med 2010; 152:578-589

Risk and prognosis of VTE recurrence: localization of first event PE versus DVT Outcome (adjusted) HR (95% CI) for presentation with intial PE versus isolated DVT 30-day events 1-year events 3-year events Recurrent PE 0.67 (0.22-2.02) 0.87 (0.44-1.71) 1.11 (0.63-1.96) Recurrent VTE 0.94 (0.52-1.69) 0.91 (0.63-1.33) 0.85 (0.62-1.18) Major bleeding 1.17 (0.77-1.76) 0.96 (0.67-1.38) 1.07 (0.77-1.49) Total mortality 3.22 (2.18-4.79) 1.52 (1.20-1.93) 1.43 (1.16-1.76) FA Spencer. Arch Intern Med 2008;168:425-430

Τι συμβαίνει μετά από την οξεία ΠΕ; 1. Κίλδπλνο ππνηξνπήο θιεβηθήο ζξνκβνεκβνιηθήο λόζνπ 2. Η ζσζηή δηάξθεηα αληηπεθηηθήο αγσγήο 3. Λύζε ησλ ζξόκβσλ ή αλάπηπμε CTEPH; 4. Αλάγθε γηα πνηνηηθά θιηληθά δεδνκέλα 16

VKA: 6 weeks versus 6 months n=902 patients enrolled At 2-year follow-up: 18.1% recurrence in the 6-week group versus 9.5% in the 6-month group (OR: 2.1; 95% CI: 1.4 3.1) Major bleeding rates similar OR, overall response. Schulman S et al. N Engl J Med 1995;332:1661 5. 17

VKA: indefinite after all unprovoked VTEs? Benefits AND risks Recurrence rate reduced by 90% Major bleeding: 3.8%/year Study terminated prematurely at 2 years Kearon C et al. N Engl J Med 1999;340:901 7. 18

VKA: indefinite after second episode? n=277 patients enrolled, randomized to 6 months vs indefinitely At 4-year follow-up: 20.7% recurrence in the 6-month group vs 2.6% in the continuing group (RR: 8.0; 95% CI: 2.5 25.9) 2.7% major bleeding in the 6-month group versus 8.6% in the continuing group (RR: 0.3; 95% CI: 0.1 1.1) RR, relative risk. Schulman S et al. N Engl J Med 1997;336:393 8. 19

ESC recommendations: treatment duration Recommendation Class Level First event, transient risk factor: VKA for 3 months Idiopathic /unprovoked event: VKA for at least 3 months Idiopathic event, low bleeding risk, stable anticoagulation: consider long-term treatment In PE with cancer, LMWH for 3 6 months; then long-term therapy with VKA or LMWH I I IIb IIa I A A B B C ESC, European Society of Cardiology; LMWH, low-molecular-weight heparin. Torbicki A et al. Eur Heart J 2008:2276 315. Available at: www.escardio.org. 20

Cumulative event rate (%) Extended anticoagulation with rivaroxaban effective: EINSTEIN-EXT results No. at risk 10 9 8 7 6 5 4 3 2 1 0 Number needed to treat to prevent 1 primary efficacy outcome: 15 Placebo (n=594) HR=0.184 (95% CI 0.086 0.391) RRR=82% p<0.0001 Rivaroxaban (n=602) 0 30 60 90 120 150 180 210 240 270 300 330 360 Time to event (days) Rivaroxaban 602 590 583 573 552 503 482 171 138 132 114 92 81 Placebo 594 582 570 554 521 467 444 164 138 133 110 93 85 ITT population. RRR, relative risk reduction. Bauersachs R et al. N Engl J Med 2010;363:2499 510 21

Extended anticoagulation with rivaroxaban safe: EINSTEIN-EXT results Placebo (n=590) Rivaroxaban (n=598) Major bleeding 0 4 (0.7%)* Bleeding contributing to death 0 0 Bleeding in a critical site 0 0 Associated with fall in hemoglobin 2 g/dl and/or transfusion Gastrointestinal bleeding 0 3 (0.5%) Menorrhagia 0 1 (0.2%) *p=0.11 Number needed to harm: approximately 139. Safety population. Bauersachs R et al. N Engl J Med 2010;363:2499 510 22

Extended anticoagulation effective and safer: new oral anticoagulants Efficacy: EINSTEIN-EXT Bauersachs R et al. N Engl J Med 2010;363:2499 510. Efficacy: RE-SONATE Schulman S et al. N Engl J Med 2013;368:709 18. Safety: AMPLIFY-EXT Agnelli G et al. N Engl J Med 2013;368:699 708. Safety: RE-MEDY Schulman S et al. N Engl J Med 2013;368:709 18. Major bleeds: 0.8% (placebo) vs 0.2% (2.5 mg bid) vs 0.1% (5 mg bid) bid, twice daily. 23

Extended anticoagulation necessary: Recurrence risk resumes after discontinuation (RE-SONATE) Estimated cumulative risk* (%) 12 Study drug Follow-up after termination of study drug 10 8 6 4 2 Dabigatran 150 mg bid Placebo Patients at risk Dabigatran 150 mg BID Placebo 0 0 3 6 9 12 15 18 Months after randomization 681 662 667 615 651 586 591 537 557 502 503 461 186 171 *Symptomatic DVT or symptomatic or fatal PE, or death of unclear cause. Schulman S et al. N Engl J Med 2013;368:709 18. 24

What else may happen after PE? Arterial events and the continuum of thrombosis Myocardial infarction and stroke after DVT and PE HR DVT vs control HR PE vs control DVT (n=25 199) DVT population control (n=97 773) Adjusted RR (95% CI)* PE (n=16 925) PE population control (n=65 793) Adjusted RR (95% CI)* Follow-up: 1 year 2 20 years 1 year 2 20 years 1 year 2 20 years 1 year 2 20 years 1 year 2 20 years 1 year 2 20 years Acute MI or stroke 380 2388 806 10 009 1.88 (1.66 2.12) 1.26 (1.20 1.31) 254 1133 611 7559 2.73 (2.36 3.16) 1.31 (1.23 1.39) Acute MI 176 1157 447 5107 1.60 (1.35 1.91) Stroke 209 1367 371 5504 2.19 (1.85 2.60) 1.18 (1.11 1.26) 1.31 (1.23 1.39) 144 597 383 3918 2.60 (2.14 3.14) 113 608 237 4069 2.93 (2.34 3.66) 1.32 (1.21 1.43) 1.29 (1.18 1.40) Ischemic stroke 92 587 195 2267 1.85 (1.44 2.37) 1.36 (1.24 1.48) 45 272 118 1707 2.34 (1.66 3.31) 1.34 (1.18 1.52) Data are number of events, unless otherwise specified. *Adjusted for sex, age, and year of VTE diagnosis. Sørensen HT et al. Lancet 2007;370:1773 9. 25

Τι συμβαίνει μετά από την οξεία ΠΕ; 1. Κίλδπλνο ππνηξνπήο θιεβηθήο ζξνκβνεκβνιηθήο λόζνπ 2. Η ζσζηή δηάξθεηα αληηπεθηηθήο αγσγήο 3. Λύζε ησλ ζξόκβσλ ή αλάπηπμε CTEPH; 4. Αλάγθε γηα πνηνηηθά θιηληθά δεδνκέλα 26

Incomplete resolution of thrombi after PE: frequent Author Patients (n) Design Follow-up Imaging method Persistent thrombi B Cosmi 1 173 Prospective 9 months CT (n=80), Lung scan (n=93) 15% by CT 28% by lung scan O Sanchez 2 254 Prospective 12 months Lung scan 29% M Nijkeuter 3 268 Meta-analysis 8 days to 6 months Lung scan (2 studies: 187) CT (2 studies: 81) Up to 65% after 3 months 1. Cosmi B et al. Intern Emerg Med 2011;6:521 8. 2. Sanchez O et al. J Thromb Haemost 2010;8:1248 55. 3. Nijkeuter M et al. Chest 2006;129:192 7. 27

Is CTEPH a consequence of unresolved PE? DVT Embolus in transit Acute PE CTEPH As many as 75% of patients with CTEPH report a history of previous symptomatic DVT or PE (data from 679 patients) International CTEPH Registry. Pepke-Zaba J et al. Circulation 2011;124:1973 81. 28

The thromboembolic concept Image used courtesy of M Madani

Cumulative incidence of CTEPH after PE CTEPH incidence in survivors of PE: frequent (?) 0.04 3.8% at 2 years 0.03 3.1% at 1 year 0.02 0.01 1.0% at 6 months 0 0 1 2 3 4 5 6 7 8 9 10 11 Time (years) Pengo V et al. N Engl J Med 2004;350:2257 64. 30

Risk of developing CTEPH after PE: unknown Author Patients (n) Design Follow-up (echo screening) (months) CTEPH confirmed, n (%) PEA D Poli 1 239 P 36 1 (0.4) 0 FA Klok 2 866 (308 idiopathic) S Surie 3 110 R F Dentali 4 91 (49 idiopathic) C Becattini 5 259 (135 idiopathic) R P 34 36 (questionnaire) P? 6 12 4, all pre-existing (0.57) 0 on screening! 0 0 0 8 (8.8): incomplete confirmation! P 46 2 (0.8) 1 M Miniati 6 320 P 25 4 (1.3)? V Pengo 7 223 (83 idiopathic) P 94 7 (3.1) a 2? Total 2108 22 (1) 3 0 a Cumulative incidence of CTEPH at 1 year. PEA, pulmonary endarterectomy; P, prospective; R P, retrospective inclusion, prospective follow-up. 1. Poli D et al. J Throm Thrombolysis 2010;30:294 9. 2. Klok FA et al. Haematologica 2010;95:970 5. 3. Surie S et al. Thromb Res 2010;125:e202 5. 4. Dentali F et al. Thromb Res 2009;124:256 8. 5. Becattini C et al. Chest 2006;130:172 5. 6. Miniati M et al. Medicine 2006;85:253 62. 7. Pengo V et al. N Engl J Med 2004;350:2257 64. 31

Τι συμβαίνει μετά από την οξεία ΠΕ; 1. Κίλδπλνο ππνηξνπήο θιεβηθήο ζξνκβνεκβνιηθήο λόζνπ 2. Η ζσζηή δηάξθεηα αληηπεθηηθήο αγσγήο 3. Λύζε ησλ ζξόκβσλ ή αλάπηπμε CTEPH; 4. Αλάγθε γηα πνηνηηθά θιηληθά δεδνκέλα 32

True incidence determines value of screening: 1st scenario 1000 patients after PE 900 will have no CTEPH 100 will have CTEPH If echo 60% accurate 540 true negative 360 false positive 60 true positive 40 false negative Out of 420 positive echos, 16% will be true positive Thomas Bayes (1702 1761) 33

True incidence determines value of screening: 2nd scenario 1000 patients after PE 990 will have no CTEPH 10 will have CTEPH If echo 60% accurate 590 true negative 400 false positive 6 true positive 4 false negative Out of 406 positive echos, only 6 (1.4%) will be true positive!! Thomas Bayes (1702 1761) 34

Long-term follow-up after acute PE: A prospective multicenter follow-up cohort study Study objectives To determine, over a 2-year follow-up period, the incidence of CTEPH or post-pe impairment after an index episode of acute PE Co-primary outcomes 1. Confirmed diagnosis of CTEPH at any time during 2-year-follow-up; 2. Post-PE impairment at >1 follow-up visit: deterioration (compared with the previous visit or to findings at discharge) by at least one category in 1 of a (echocardiographic) parameters plus deterioration in 1 of b (clinical, functional, or laboratory) parameters Main secondary outcomes 1. Overall and disease-specific mortality 2. Rehospitalization 3. Evidence of PH on echocardiography 4. Pulmonary vascular disturbance on cardiopulmonary exercise testing 5. Generic and disease-specific QoL after PE Number of patients/ sites 1000/15 Trial phase Observational Estimated FPI / LPO June 2014 end 2017 FPI, first patient in; LPO, last patient out; PH, pulmonary hypertension; QoL, quality of life. 35

FOCUS follow-up protocol Enrollment Discharge 3 months 12 months 24 months Enrollment informed consent X Medical history X Demographic data X Clinical examination X X X X Confirmation of PE (imaging) X Echocardiography X X X X X Cardiopulmonary exercise testing X X X Laboratory diagnostic and safety tests X X X X Treatment(s) for index PE and prophylaxis X X X X X Hemodynamic collapse X Death X X X X Rehospitalization X X X Stroke X X X X Symptomatic recurrent DVT/PE X X X X Major bleeding/clinically relevant non-major bleeding X X X X Functional status X X X Diagnostic workup for CTEPH X X X Generic QoL (EQ-5D questionnaire) X X X Disease-specific quality of life (PEmb-QoL questionnaire) X X X 36

FOCUS and FOCUS BioSeq importance of the largest ever after PE biobank In-hospital Follow-up 0 (ml) 3 months (ml) 6 months (ml) 12 months (ml) 24 months (ml) EDTA 9 9 9 9 9 Serum 7.5 7.5 7.5 7.5 7.5 Citrate 9 9 9 9 9 DNA 8.5 8.5 8.5 8.5 8.5 RNA/miRNA 2.5 2.5 2.5 2.5 2.5 Urine 5 5 5 5 5 Biobanking 41.5 41.5 41.5 41.5 41.5 Biobanking 41.5 83 124.5 166 207.5 37

FOCUS and FOCUS BioSeq: importance of the largest ever after PE biobank Decentralized Centralized Sample collection Sample entry Sample shipment Final sample entry and storaging Measurement: Measurement: protein quantity protein activity FOCUS BioSeq substudy v Sample pre-processing DNA and RNA isolation Microarray analyses Sequencing analyses Sample storaging Quality control 38

Σύνοψη και συμπεπάσματα Ο δηαξθήο θίλδπλνο ππνηξνπήο κεηά από κε πξνθιεζείζα ΠΕ δηθαηνινγεί ηελ αληηπεθηηθή αγσγή επ αόριζηον, πξόβιεκα ήηαλ όκσο σο ηώξα ν αηκνξξαγηθόο θίλδπλνο κε ηνπο αληαγσληζηέο βηηακίλεο Κ. Η βειηησκέλε αζθάιεηα κε ηα λέα από ηνπ ζηόκαηνο αληηπεθηηθά ζα επιμηκύνει ηη διάρκεια αληηπεθηηθήο αγσγήο ζην κέιινλ, εθ όζνλ ηα απνηειέζκαηα ησλ κειεηώλ επηβεβαησζνύλ ζηελ θιηληθή πξάμε. Η αηειήο ιύζε πλεπκνληθώλ ζξόκβσλ κεηά από ΠΕ είλαη ζύλεζεο θαηλόκελν, αιιά ε παζνγέλεζε θαη ε ζπρλόηεηα ηεο τρόνιας θρομβοεμβολικής πνεσμονικής σπέρηαζης παξακέλνπλ ζε κεγάιν βαζκό αδηεπθξίληζηεο θαη ρξεηάδνληαη πςειήο πνηόηεηαο θιηληθά δεδνκέλα κε ζπζηεκαηηθή πξννπηηθή παξαθνινύζεζε κεγάινπ αξηζκνύ κε επηιεγκέλσλ αζζελώλ κε ΠΕ. 39