Optimal Management of Intermediate-Risk Pulmonary Embolism

Transcription

1 Optimal Management of Intermediate-Risk Pulmonary Embolism Stavros V. Konstantinides, MD, PhD, FESC Professor, Clinical Trials in Antithrombotic Therapy Center for Thrombosis und Hemostasis, University of Mainz, Germany Professor of Cardiology Democritus University of Thrace, Greece

2 Disclosures Advisory boards / Lecture fees (moderate): Boehringer Ingelheim Bayer HealthCare Pfizer Bristol-Myers Squibb

3 Management of intermediate risk: the questions 1) What options do we have to treat PE? 2) What is intermediate-risk PE? 3) What is the recommended evidence-based treatment for intermediate-risk PE?

4 1) Systemic thrombolysis 2 h

5 Thrombolytic regimens for PE Streptokinase Urokinase Alteplase Reteplase Tenecteplase 250,000 U over 30 min followed by 100,000 U/h over h Accelerated: 1.5 Mio. U over 2 h 4,400 U/kg KG over 10 min, followed by 4,400 U/kg/h over h Accelerated: 3 Mio. U over 2 h 100 mg over 2 h Accelerated: 0.6 mg/kg over 15 min (off-label) in AMI dose: TIPES study

6 What did the guidelines say in 2008? Recommendation Class Level Thrombolytic therapy in patients with high-risk PE presenting with cardiogenic shock and/or persistent arterial hypotension Surgical pulmonary embolectomy if thrombolysis is absolutely contraindicated or has failed Catheter embolectomy or fragmentation of proximal pulmonary arterial clots may be an alternative to surgical treatment I I IIb A C C

7 Thrombolysis for PE: very recent epidemiological data Nationwide Inpatient Sample USA ,110,320 patients discharged with diagnosis of PE (ICD-9-CM) 72,230 (3.4%) unstable (shock, ventilated) 21,390 (30%) received thrombolytics In patients who received thrombolysis: All-cause mortality: RR, 0.31 ( ) PE-related death: RR, 0.20 ( ) PD Stein. Am J Med. 2012;125: Epub 2012 Feb 10.

8 Thrombolysis for PE: very recent epidemiological data Nationwide Inpatient Sample ,237,600 patients with PE 49,500 (2.2%) received thrombolysis: 29% of unstable, 1.3% of stable patients In patients who received thrombolysis: Intracerebral haemorrhage in 430 cases (0.9%) PD Stein. Am J Med. 2012;125:50-6. Epub 2011 Nov 24

9 Thrombolysis for non-high-risk PE?

10 What did the guidelines say in 2008? Recommendation Class Level Anticoagulation should be initiated without delay in patients with high or intermediate clinical probability of PE while diagnostic workup is still ongoing I C LMW heparin or fondaparinux for most patients I A Thrombolysis generally NOT recommended (1B) may be considered in selected cases IIb B

11 Thrombolysis for non-high-risk PE? What about normotensive patients? In RIETE, 432 of 15,944 (2.7%) patients received thrombolysis Propensity score adjustment matched-pair analysis (217 pairs) Effect of thrombolysis on 90-day all-cause mortality: OR, 2.32; 95% CI, A Riera-Mestre. J Thromb Haemost 2012 Mar 15 [Epub ahead of print]

12 PEITHO results expected March 2013 Poland Belgium Germany France Portugal Austria Slovenia Romania Spain Italy Serbia Israel

13 2) Intervention

14 PE catheter interventions: meta-analysis (35 studies) Thrombus fragmentation, rheolytic thrombectomy, suction thrombectomy, rotational thrombectomy Clinical success* Major complications Minor complications N = % 2% 8% * stabilisation of haemodynamic parameters, resolution of hypoxia, survival RP Engelberger and N Kucher. Circulation 2011;124:2139 WT Kuo. J Vasc Interv Radiol. 2009;20:

15 What did the guidelines say in 2008? Recommendation Class Level Thrombolytic therapy in patients with high-risk PE presenting with cardiogenic shock and/or persistent arterial hypotension Surgical pulmonary embolectomy if thrombolysis is absolutely contraindicated or has failed Catheter embolectomy or fragmentation of proximal pulmonary arterial clots may be an alternative to surgical treatment I I IIb A C C

16 Ultrasound-assisted thrombolysis Without Ultrasound Fibrin strands prevent drug from penetrating thrombus and binding to plasminogen receptor sites With Ultrasound Destabilisation of fibrin strands, enabling penetration of drug into thrombus Ultrasound + Thrombolysis Ultrasound pressure waves force drug into thrombus, resulting in rapid removal of thrombus even at low drug dose Courtesy Prof. Nils Kucher, Bern, CH

17 Ultrasound-assisted thrombolysis Improvement in right ventricular enlargement Subannular RV/LV ratio Pre to Post RV/LV Ratio N= 24 mean rt-pa dose 33 ± 15 mg over 20 hours P < RV/LV Ratio ± ± 0.13 Pre RV/LV Baseline CT Post RV/LV Follow-up CT at 38 ± 14 hours Engelhardt TC, et al. Thromb Res 2011;128:149-54

18 The Ekosonic endovascular system Ekosonic Control Unit Ekosonic Mach4 Endovascular Device 5 fr Intelligent side-hole drug delivery catheter Ongoing trials in patients with non-high-risk PE: NCT in Europe (randomized) NCT in the US (single-arm) Ultrasound MicroSonic Core Courtesy Prof. Nils Kucher, Bern, CH

19 3) Anticoagulation

20 Anticoagulation for pulmonary embolism: NOAC Current standard of care LMWH or Fonda s.c.* VKA Day 1 Day 5 11 At least 3 months RE-COVER (published) HOKUSAI-VTE (NCT ongoing) Switching LMWH s.c. dabigatran bid / edoxaban od Day 1 Day 5 11 At least 3 months Single oral drug EINSTEIN-DVT/PE (published) rivaroxaban 15 mg bid for 3 weeks, then 20 od AMPLIFY (NCT ongoing) apixaban 10 mg bid for 1 week, then 5 bid Day 1 At least 3 months *Or UFH or fondaparinux S Konstantinides and SZ Goldhaber. Eur Heart J 2012; in press

21 Dabigatran in VTE treatment RE-COVER Predefined treatment period of 6 months Symptomatic VTE RE-COVER N=2,564 Parenteral anticoagulant Dabigatran etexilate 150 mg bid R Symptomatic VTE RE-COVER II N=2,554 ~53% Parenteral anticoagulant VKA target INR 2.5 (INR range 2 3) Day 1 Day 6 1. Schulman S, et al. N Engl J Med 2009;361: ; 2. RE-COVER-II Study Information. Trial ID: NCT Available at:

22 30-day observation period Rivaroxaban for acute DVT/PE: EINSTEIN Objectively confirmed DVT without symptomatic PE Objectively confirmed PE with or without symptomatic DVT N=~2,900 R N=~3,300 EINSTEIN DVT/PE Treatment period of 3, 6 or 12 months Rivaroxaban 15 mg bid Enoxaparin 1.0 mg/kg bid for at least 5 days, followed by VKA to start 48 hours, target INR 2.5 (INR range 2 3) Day 1 Day 21 Rivaroxaban 20 mg od

23 EINSTEIN-PE: Primary efficacy outcome Rivaroxaban (n=2,419) Warfarin (n=2,413) n (%) n (%) First symptomatic recurrent VTE 50 (2.1%) 44 (1.8%) Recurrent DVT 18 (0.7%) 17 (0.7%) Non-fatal PE 22 (0.9%) 19 (0.8%) Fatal PE 2 1 Unexplained death where PE could not be ruled out 8 (0.3%) 5 (0.2%) Odds ratio 2.00 Rivaroxaban superior Rivaroxaban non-inferior Rivaroxaban inferior P=0.003 for non-inferiority HR Büller for the EINSTEIN Investigators. N Engl J Med 2012; published online March 26

24 Single drug approach for severe PE as well? Anatomical extent of PE Rivaroxaban n=2,419 N (%) Standard Tx n=2,413 Limited: <25% of vasculature of a single lobe 309 (12.8) 299 (12.4) Intermediate 1392 (57.5) 1424 (59.0) Extensive: multiple lobes and >25% of entire pulmonary vasculature 597 (24.7) 576 (23.9) Not assessable 121 (5.0) 114 (4.7) HR Büller for the EINSTEIN Investigators. N Engl J Med 2012; published online March 26

25 Management of intermediate risk: the questions 1) What options do we have to treat PE? 2) What is intermediate-risk PE? 3) What is the recommended evidence-based treatment for intermediate-risk PE?

26 The large group of normotensive PE patients >95%

27 What did the guidelines say in 2008?

28 1 st definition (hypothesis) Intermediate risk PE = Subclinical right ventricular dysfunction

29 Tools for assessment of RV dysfunction ECG Right heart catheterization Echocardiography CT scan Laboratory biomarkers

30 Echocardiographic findings in acute PE Echo criteria RV dilatation (RV>LV, or RVEDD >30 mm) RV free wall hypokinesia Paradoxical septal wall Pulmonary hypertension (RV-RA gradient >30 mm Hg, or pulmonary acceleration time <80 ms) S Konstantinides. Curr Opin Cardiol 2005; N Engl J Med 2008

31 O Sanchez. Eur Heart J 2008;29: Echocardiography in normotensive patients: Value? Meta-analysis: relative risk of in-hospital death Negative predictive value: 60 (55-65)% Positive predictive value: 58 (53-63)%

32 Incidence Echo alone does NOT indicate poor prognosis 30% Alteplase (n=118) Placebo (n=138) P= (23.2%) 20% 10% P=0.7 4 (3.4%) 3 (2.2%) 0 P=0.2 1 (0.7%) P= (2.5%) 8 (5.8%) P= (2.5%) 3 (2.2%) 9 (7.6%) 0 Death CPR Shock Intubation Emergency Thrombolysis S Konstantinides. N Engl J Med 2002;347:1143

33 Imaging of RV dysfunction on CT: similar information Prospective multicenter validation (457 pts with PE): RV dilatation: RV:LV >0.9 present in 66% of patients sensitivity, 92%; NPV, 100% Independent predictor of adverse outcome: HR, 3.5; 95% CI, ; P= C Becattini, S Konstantinides. Eur Heart J 2011;32:

34 Intermediate-risk PE: imaging Echocardiography is valuable for assessing and for followup of right ventricular function in PE It is valuable for management of high-risk patients. It is debatable whether echo -or CT- alone can identify intermediate risk among normotensive patients. Neither imaging method has been shown to identify candidates for advanced treatment in the absence of haemodynamic instability.

35 Tools for assessment of RV dysfunction ECG Right heart catheterization Echocardiography CT scan Laboratory biomarkers

36 C Becattini. Circulation 2007;116: Troponins associated with mortality in PE: meta-analysis 20 studies; n=1,985 pts ( ): Troponin in 31%

37 Troponins in PE: LOW positive predictive value Author Pts (n) Marker Ref. value* Positive (%) NPV (%) PPV (%) Giannitsis, 2000 Konstantinides, 2002 Konstantinides, Trop T Trop I Trop T Janata, Trop T Pruszczyk, Trop T * in ng/ml N Kucher. Circulation 2003;108:2191

38 D Jiménez. Chest 2009; 136: Troponins and mortality: normotensive PE patients n=318 hemodynamically stable patients Log rank p=0.008 cardiac troponin (I) is NOT an indepenedent predictor of overall mortality D Jiménez. Eur Respir J 2008;31:847 Meta analysis: 9 studies 1366 patients with symptomatic PE Pts normotensive at diagnosis cardiac troponin levels did NOT adequately distinguish between high risk and low risk

39 FA Klok. Am J Respir Crit Care Med 2008;178: Natriuretic peptides and mortality in PE: meta-analysis Data from 13 studies; n=1,132 pts: BNP/NT-proBNP in 51%

40 BNP, probnp in PE: LOW positive predictive value Author Pts (n) Marker ten Wolde, BNP Kucher, BNP Krüger, BNP Kucher, NT-proBNP Pruszczyk, NT-proBNP Binder, NT-proBNP Ref. value 21.7 pmol/l 50 pg/ml 90 pg/ml 500 pg/ml pg/ml 1,000 pg/ml Positive (%) NPV (%) PPV (%) N Kucher. Circulation 2003;108:2191

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

42 Biomarkers combined with imaging: early evidence Patient group Complication risk (OR, 95% CI) Troponin T-negative (<0.04 ng/ml) Troponin-positive, echo-negative Troponin-negative, echo-positive Both troponin- and echo-positive ~ 15% of all PE patients 3.70 ( ) P= ( ) P= ( ) P=0.004 L Binder, S Konstantinides. Circulation 2005;112:

43 Biomarkers combined with imaging: additive value Echo + GDF-15 Echo + H-FABP M Lankeit., S Konstantinides. Am J Respir Crit Care Med 2008;177: C Dellas, S Konstantinides. J Am Coll Cardiol 2010;55:2150

44 Intermediate-risk PE: biomarkers Biomarkers such as cardiac troponins and natriuretic peptides are associated with a poor prognosis. It is debatable whether biochemical markers alone can identify intermediate risk among normotensive patients. No biochemical marker has been shown to identify candidates for advanced treatment in the absence of haemodynamic instability. Biomarker combination models are still of theoretical value.

45 Tools for risk stratification of PE: a critical look S Konstantinides and SZ Goldhaber. Eur Heart J 2012; in press

46 2 nd Hypothesis Intermediate risk PE beyond subclinical right ventricular dysfunction

47 Further determinants of an adverse early outcome Preexisting cardiovascular disease Acute pressure overload (RV dysfunction) Other serious comorbidity (cancer) Recurrent PE (residual DVT) Presence of a PFO Poor prognosis

48 Pulmonary Embolism Severity Index (PESI) Low-risk, 0 points (30 to 36% of patients) High-risk, 1 or more points D Jiménez. Arch Intern Med 2010;170:1383

49 M Lankeit, Chest 2012;141: spesi good for excluding intermediate risk Single-center prospective cohort study: 526 patients In-hospital mortality: 7.6% [ %] Low-risk category Pts Death Sensitivity (all-cause death) NPV (all causedeath) spesi 165 (31%) 0 100% 100% Echo-biomarker model 207 (39%) 7 (3.4%) 82.5% 96.6%

50 Management of intermediate risk: the questions 1) What options do we have to treat PE? 2) What is intermediate-risk PE? 3) What is the recommended evidence-based treatment for intermediate-risk PE?

51 Biomarkers + echo identify candidates for thrombolysis? Thrombolysis?

52 PEITHO - International randomized thrombolysis trial Poland Belgium Germany France Portugal Austria Slovenia Romania Spain Italy Serbia Israel

53 Primary Outcome, Secondary Outcomes Seconray Outomes, SAE Long-term Follow-up Confirmed acute symptomatic PE PEITHO - Design TNK Absence of hemodynamic collapse UFH infusion UFH, LMWH or Fondaparinux <2 h Confirmed RV dysfunction + myocardial injury DOUBLE BLIND R Placebo VKA UFH infusion UFH, LMWH or Fondaparinux 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

54 PEITHO FINAL Status (July 31, 2012) GLOBAL: cumulative Jul Jun May Apr Mar Feb Jan 2012 Dec Nov Oct Sep Aug Jul Jun May Apr Mar Feb Jan 2011 Dec Nov Oct Sep Aug Jul Jun May Apr Mar Feb Jan 2010 Dec Nov Oct Sep Aug Jul Jun May Apr Mar Feb Jan 2009 Dec Nov Oct Sep Aug Jul Jun May Apr Mar Feb Jan 2008 Dec Nov planned actual 1006

55 Intermediate-risk PE: Conclusions and outlook (1) Right ventricular dysfunction is an important - but not the only - determinant of prognosis in acute pulmonary embolism. In normotensive patients, echocardiographic and CT parameters, several biomarkers, and clinical parameters, have individually been correlated with poor prognosis. PEITHO, a large European randomized trial, will soon determine whether definition of intermediate-risk PE by imaging + biomarker may have implications for acute management, i.e. set the indication for early thrombolysis.

56 Intermediate-risk PE: Conclusions and outlook (2) Future risk stratification scores and strategies may need to include clinical data (comorbidity) and define a smaller proportion of patients at truly elevated risk for advanced early treatment (thrombolysis, intervention). It will need to be determined whether new oral anticoagulants can be given from the beginning also to patients with intermediate-risk PE.

57 EARLY DEATH RISK PE classification update : like this? EARLY DEATH RATE Hypotension, instability Clinical RISK MARKERS Normotensive, high clinical risk (score?) Imaging/biochemical RV dysfunction (echo, CT) Positive biomarker (troponin, BNP) HIGH >15% (+) ACUTE TREATMENT Thrombolysis (intervention, surgery) + + Thrombolysis? 8-10% NON- HIGH 1-2% Monitoring; initial A/C inhospital <1% - - (-) - Early discharge

58 Or perhaps as simple as this? EARLY DEATH RISK EARLY DEATH RATE Hypotension, instability Clinical RISK MARKERS Normotensive, high clinical risk (score?) Imaging/biochemical RV dysfunction (echo, CT) Positive biomarker (troponin, BNP) HIGH >15% (+) ACUTE TREATMENT Thrombolysis (intervention, surgery) NON- HIGH 1-8% - (+) Initial A/C inhospital <1% - - (-) - Early discharge

59 Thank you