1. Thrombolysis in Submassive PE Adam Oster Grand Rounds April 4, 2002

2. Guiding Questions Should we identify normotensive PE patients with RV dysfunction (submassive PE)? Should these patients be considered for thrombolytic therapy?

3. Patient Subgroups HEMODYNAMICALLY UNSTABLE HEMODYNAMICALLY STABLE PULMONARY EMBOLUS DIAGNOSED OR SUSPECTED WITH SIGNS OF ORGAN HYPOPERFUSION (INCL. CARDIAC ARREST) EVIDENCE OF RIGHT HEART STRAIN NO EVIDENCE OF RIGHT HEART STRAIN WITHOUT SIGNS OF HYPO PERFUSION

4. Outline Studies demonstrating the natural history of PE with RV dysfunction Trials evaluating thrombolytics in PE with RV dysfunction *Special topics –evidence for thrombolytics in PE with shock and during CPR for PE-related arrest –role of TTE by EPs

5. History Randomised trials comparing thrombolytics to heparin –UPET 1970 -- prospective, Randomised. –USET –PIOPED 1990 –Levine et al. 1990 –PAIMS 2. 1992 –Goldhaber et al. 1993 Non-randomized –Dalla-Volta, 1993 –Konstantanindes, 1997 –Hamel, 2001

6. Should we attempt to identify normotensive PE patients with right heart strain?

7. Pathophysiology Review Normal RV has a narrow range over which it can compensate for acute increases in afterload. The pericardium has a limited ability to distend. Increased RV afterload elevation in RV wall pressures dilation and hypokinesis of the RV wall shift of intraventricular septum towards left ventricle (tricuspid regurgitation) and decreased LV output.

8. Grifoni et al. Short-Term Clinical Outcome of Patient With Acute Pulmonary Embolism, Normal Blood Pressure and Echocardiographic Right Ventricular Dysfunction. Circulation, 101. 2000, Prospective clinical outcome study –209 consecutive patients with documented PE –all patients had an TTE within 1 hr of admission –patients stratified into one of four groups –results only for in-hospital period

9. Grifoni et al, Circulation, 2000. 4 groups –Shock (N=28,13.4%) SBP<100 with signs of organ hypoperfusion –Hypotensive without signs of shock (N=19, 9.1%) –Normotensive with RV strain (N=65, 31.1%) –Normotensive without RV strain (N=97, 46.4%)

10. Grifoni et al, Circulation, 2000. Patients with hypotension/shock (22%, N=47) –Mortality 19% Normotensive without evidence of RV strain (46.5%, n=97) –0 PE-related deaths Normotensive with RV strain (31.1%, N=65) –10% (n=6) clinically deteriorated due to PE recurrence –5% (n=3) PE-related deaths

11. Grifoni et al, Circulation, 2000. Positive predictive value of echocardiography was low NPV was 100% good tool for screening low risk patients The detection of RV dysfunction defines a subset of patients with short-term risk of PE-related mortality.

12. Ribeiro et al. Echocardiography Doppler in Pulmonary Embolism: Right Ventricular Dysfunction as a Predictor of Mortality Rate. American Heart Journal, 134. 1997. RV dysfunction at diagnosis of PE is a predictor of mortality –126 ‘consecutive’ PE patients assessed by TTE on day of diagnosis –stratified into 2 groups based on severity of RV systolic dysfunction on TTE –(A) normal to mildly hypokinetic and –(B) moderate to severely hypokinetic –Follow-up TTE within 1 year

13. Ribeiro et al. American Heart Journal, 1997. 56 patients in group A and 70 in group B –baseline characteristics similar (except over twice as many with symptoms >14days (sig.), malignancy and CHF (NS)in B) In-hospital PE mortality all in group B (n=9), p=0.002 1 year overall mortality rate 15.1% (n=19) –group A, 7.1% (n=4) mortality, all non-PE. –group B, 27.7 % (n=15) mortality, 9 due to PE (p=0.04) Group B –RR for in-hospital death 6.0 (95% CI 1.1 to 111.5) –RR for death within 1 year 2.4 (95% CI 1.2 to 4.5) *(malignancy RR 3.0).

14. Ribeiro et al. American Heart Journal, 1997. Subgroup analysis of patients without cancer (n=101) –In-hospital mortality Group A 0% Group B 7.7% (N=4/52) –1 year cumulative mortality Group A 2%, (N=1) Group B 9.8%, (N=5)

15. Should patients with RV dysfunction be considered for thrombolytic therapy?

16. Goldhaber, S. et al. Alteplase versus Heparin in Acute Pulmonary Embolism: Randomised Trial Assessing Right-Ventricular Function and Pulmonary Perfusion. The Lancet. 1993, no 8844. vol 341. Thrombolysis plus heparin is better than heparin alone in reversing echo evidence of RV dysfunction –Prospective and randomized, non-consecutive. –99 hemodynamically stable PE patients –PE confirmed by high probability V/Q and/or pulmonary angiogram –excluded if at high risk of adverse hemorrhage. –all had TTE assessments of right ventricular wall motion at baseline, then repeated at 3 and 24 hours. –Angiograms were obtained at baseline and at 24h

17. Goldhaber et al. The Lancet. 1993. 46 patients randomized to rt-PA followed by heparin and 55 to heparin alone Endpoints; mortality, recurrent PE and major bleeding (72h) Followed for 14 days for adverse outcomes (PE recurrence or death), or longer if in hospital. 72 hrs for bleeding.

18. Goldhaber et al. The Lancet. 1993. Results –follow-up echo (89 patients) rtPA group vs heparin –3 hrs -- greater improvement in RV wall motion (p=0.01) –24 hrs -- 39% improved, 2% worse vs 17% improved and 17% worse vs 17% improvement and 17% worse in heparin group (p=0.005) –follow-up angiogram at 24hrs (95 patients) rtPA vs heparin -- mean absolute improvement in pulmonary perfusion of 14.6% vs 1.5% in heparin (p<0.0001).

19. Goldhaber et al. The Lancet. 1993 Subgroup analysis –patients with right ventricular hypokinesis on echo (N=36) rtPA -- 89% improvement, 6% worsened heparin -- 44% improvement, 28% worsened (p=0.03) Deaths –2 in heparin group (1 refractory CA and 1 with CI to tPA) Recurrent PEs –rtPA -- none –heparin -- 5 (2 fatal) Significant hemorrhage –heparin -- 1 –rtPA -- 3

20. Goldhaber et al. The Lancet. 1993. Conclusions –rtPA group improved right heart function at 24 hours improvement in pulmonary perfusion decrease in recurrent PEs lower rate of death Strong points randomization and similarities between groups echo and angiogram readers blinded to treatment and timing in relation to therapy Limitations non-blinded to clinicians and open-labeled no long -term morbidity or mortality data

21. Konstantinides, et al. Association Between Thrombolytic Treatment and the prognosis of hemodynamically Stable Patients with Major Pulmonary Embolism: Results of a Multicenter Registry. Circulation, 96. 1997 Early thrombolysis favorably affects in-hospital clinical outcome. –Multicentred, registry study –719 consecutive patients analyzed; 73% PE confirmed by one or more imaging study –evidence of either increased right ventricular afterload or pulmonary hypertension based on TTE or cath. –all patients “hemodynamically stable” also included patients who were hypotensive (SBP<90) without signs of shock and those on low dose (<5mcg/kg/min) dopamine.

22. Konstantinides, et al. Circulation. 1997 primary end-point -- overall 30-day mortality secondary endpoints -- PE recurrence, major bleeding

23. Konstantinides, et al. Circulation. 1997 Treatment decisions made at discretion of physician 23.5% (n=169) received thrombolytic therapy within 24h of diagnosis followed by heparin remaining patients treated with heparin alone –unless the physician thought that they required thrombolytics after the first 24h of heparin.

24. Konstantinides, et al. Circulation. 1997 Findings overall 30d mortality higher in heparin group 11.1% vs 4.7% (p=0.016). thrombolytic treatment was found by multivariate analysis to be the only independent predictor of survival (OR 0.46 for in-hospital death) 95% CI 0.21 to 1.00 thrombolytic group; –lower rates of recurrent PE (7.7 vs. 18.7, p=0.001) –higher rates of major bleeding events (21.9 vs 7.8, p=0.001) ICH and deaths due to bleeding were the same in the two groups

25. Konstantinides, et al. Circulation. 1997 Subgroup analysis –patients with a dilated right ventricle on echo 30 day mortality in (N=380) 10% compared with 4.1% in those without (p=0.018), a 58% reduction in mortality. 58% reduction in mortality in patients treated with thrombolytics (4.7% vs 11.1% heparin, p=0.16)

26. Konstantinides, et al. Circulation. 1997 Limitations –study design; non-randomised, heterogeneous thrombolytic regimens many patients had clinical signs of disease severity more with chronic lung disease in UF heparin group choice of treatment was at the discretion of the physician –selection bias is likely distribution of many clinical variables were statistically different between the two groups (esp. age, pre-existing CHF, higher in heparin) major end point analyses required multivariate regression model to account for the unequal distribution of clinical variables

27. Konstantinides, et al. Circulation. 1997 40% of patients thrombolysed had contraindications to lytics 25% in the heparin group ‘crossed over’ and received thrombolytics. This data was not reported.

28. Hamel et al. Thrombolysis or Heparin Therapy in Massive Pulmonary Embolism With Right Ventricular Dilation. Chest, 2001. Vol. 120:1. There is a benefit to thrombolysis over heparin in stable PE patients with RVD –Retrospective, cohort study of 153 consecutive patients –PE confirmed by, V/Q or angiography –RV function evaluated by TT E on admission –64 patients in each treatment group were matched on the basis of RV/LV diameter ratio –perfusion scans repeated on day 7 to 10 or earlier if recurrent PE suspected

29. Hamel et al. Chest, 2001. Inclusion criteria –included PIOPED criteria for high prob. V/Q –Pulmonary vascular obstruction >40% on V/Q or Miller index of 20/34 –RV to LV ratio of >0.6* in absence of LV or Mv disease Exclusion criteria –SBP <90 –contraindications to thrombolysis –inotropes –syncope prior to presentation

30. Hamel et al. Chest, 2001. thrombolysis versus heparin –higher mean relative improvement in lung scan at 7-10 days (54% vs 42%, p=0.01) –>50% relative improvement in lung scan perfusion defect seen in 57% (vs 37%) –at day 7-10 follow-up scan, average defect equal between two groups

31. Hamel et al. Chest, 2001. PE recurrence –rates were the same in both groups, 4.7% (N=3). Mortality –4 (6.3%) in thrombolytic and 0 in heparin (NS) Bleeding events –6 severe, 3 intracranial; significantly higher in thrombolytic group. 4 died as a result. (15.6%, N=10 vs 0, p=0.001)

32. Hamel et al. Chest, 2001. Retrospective, case-controlled, consecutive patients small numbers Two groups comparable at baseline for historic factors, RV dysfunction, LS defect and all free of signs of PE severity –LS defect, RV/LV ratio and higher PAP higher in thrombolysis group (not significant) heterogeneous treatment regimen in thrombolytic group

33. Levine et al. A Randomised Trial of a Single Bolus Dosage Regimen of Recombinant Tissue Plasminogen Activator in Patients with Acute Pulmonary Embolism. Chest. 1990. 98:1473. rt-PA will benefit pulmonary perfusion in patients with PE and demonstrated perfusion deficits –Inclusion -- ‘symptomatic’ patients with either high probability V/Q or angiographically proven PE and no contraindications to thrombolytics. –Excluded if hypotensive or hemodynamically unstable –All patients received heparin bolus. Then randomized to either rt- PA (0.6mg/kg, given as a bolus over 2min) or placebo. –10 day study period

34. Levine et al. Chest. 1990 End-points were >50% improvement in perfusion defect over baseline and major bleeding events; –intracranial, retroperitoneal, requires transfusion >2U or fall in Hgb >20g/L

35. Levine et al. Chest. 1990 58 patients randomized (33 to rt-PA) and groups were comparable for baseline characteristics. Comparison lung scans (at 24h and 7days) available for 57 –At 24 hours rt-PA group -- 34.4% demonstrated a greater than 50% improvement in perfusion scan (12% improved >50% in the placebo group (p=0.017). Mean absolute improvement of 9.7% in rt-PA (5.2% in placebo, p=0.07)

36. Levine et al. Chest. 1990 At 7 days –no statistically significant difference in lung scan resolution No recurrent PEs in either group No major bleeding episodes

37. Dalla-Volta, S. et al. : Alteplase Combined With Heparin Versus Heparin in the Treatment of Acute Pulmonary Embolism. Plasminogen Activator Italian Multicentre Study 2 (PAIMS 2). Journal of the American College or Cardiology 1992. 20; 520. tPA will result in more rapid improvement in angiographic and hemodynamic variables. –Open, parallel, multicenter, randomized trial, N=36. –PE confirmed by angiogram with PA pressures recorded. –all patients hemodynamically stable –excluded if contraindications to thrombolytics –all patients received bolus UF heparin then Randomised to rt-PA or heparin –follow-up angiogram at end of randomized treatment (2hrs), subset had lung scans at 7 and 30d.

38. Dalla-Volta, S. et al. JACC. 1993 Interim data analyzed for first 32 patients randomized study terminated due to >3 SD (p<0.01) in the difference between the angiographic index of the two groups patients treated with rt-PA –decrease in Miller Score (mean 28.3 to 24.8) at 2 hours –decrease in mean PA pressure (mean of 30.2mmHg to 21.4mmHg, p<0.01). –CI increased from 2.1 to 2.4 L/min/m2, p<0.01 patients treated with heparin –no change in Miller Score or CI –increase in PA pressure, p<0.001.

39. Dalla-Volta, S. et al. JACC. 1993 Patient Subset with 7 and 30day follow-up perfusion scans –No difference in Miller Scores (p<0.05) Bleeding complications –14/20 in tPA had, 3 were severe (Hb decreased by >50g/L) –6/16 and 2 severe in heparin group (NS) Deaths –2 in tPA group (ICH, tamponade).

40. Summary of Studies To-Date Grifoni -- RVD confers increased risk of death and PE recurrence. Ribeiro -- extent of RVD correlates with early and late death Levine -- early improvement in scan but no benefit at 7 days Goldhaber -- improved short-term hemodynamics and lower rate of short-term rec. PE and death. Randomised, non-blinded. Konstantinides -- lower rate of mortality in subgroup of pts with RVD and thrombolysis. *Non-randomized, groups sig. different at baseline. Dalla-Volta negative for mortality Hammel no better survival (mortality higher in thrombolysis group) and higher rate of serious bleeding.

41. Take Home RV dysfunction proportionately increases the risk of death in PE (8% to 14%) Severity of RV dysfunction correlates with worse prognosis TTE can identify low-risk population Thrombolytic therapy results in prompt (approx 24h) improvement in RV function, PA pressures and lung scan deficit Any benefit to thrombolysis does not appear to be present after ?24hrs. Likely does not decrease risk of recurrent PEs

42. Thrombolytics in Severe Shock or During CPR in Fulminant Pulmonary Embolism? Fulminant PE can produce CA in approx. 40% of cases Mortality ranges from 65% to 95% Multiple purported mechanisms –RV strain, AMI, arrhythmia. –PEA or asystole

43. Patient Subgroups HEMODYNAMICALLY UNSTABLE HEMODYNAMICALLY STABLE PULMONARY EMBOLUS DIAGNOSED OR SUSPECTED WITH SIGNS OF ORGAN HYPOPERFUSION (INCL. CARDIAC ARREST) EVIDENCE OF RIGHT HEART STRAIN NO EVIDENCE OF RIGHT HEART STRAIN WITHOUT SIGNS OF HYPO PERFUSION

44. Jerjes-Sanchez C. et al. Streptokinase and Heparin versus Heparin Alone in Massive Pulmonary Embolism: A Randomised Controlled Trial. Journal of Thrombosis and Thrombolysis. 1995. Prospective and Randomised trial, N=8 –all had “massive” PE and in cardiogenic shock high prob. V/Q, with abnormal RH echo or >9 obstructed segments on V/Q autopsy in 3 –no significant baseline differences between the two groups, except time elapsed from onset of symptoms to randomization (2.5 vs 34.75hrs) –100% survival in streptokinase plus heparin group –100% mortality in heparin group –no bleeding complications

45. Thrombolytics in Severe Shock or During CPR in Fulminant Pulmonary Embolism? Ruiz Bailen M. et al., Thrombolysis During Cardiopulmonary Resuscitation in Fulminant Pulmonary Embolism: A Review. Critical Care Medicine. 2001. Vol 29, No. 11. –single cases and small series demonstrate promising outcomes when PE suspected clinically. Kurkciyan et al. 2000 –retrospective, N=42 (thrombolysis 21, 21 no treatment) »9.5% survival in thrombolysis vs 4.5% in no treatment »ROSC in 81% vs 33.3% Survival from 9.5% to 100% (Sienblenlist, 1990; Sigmund, 1991; Hopf, 1991; Bittiger, 1991; Scheeren, 1994)

46. Moore, et al. Determination of Left Ventricular Function by Emergency Physician Echocardiography of Hypotensive Patients. Academic Emergency Medicine, vol. 9, no. 3, 2002. Prospective, observational study, convenience sample of 51. EPs with prior US training underwent focused echo training inclusion: symptomatic hypotension exclusion: trauma, CPR, ECG of AMI EPs estimation of EF –compared with cardiologist; correlation coefficient of 0.86 –between cardiologists 0.84 EP categorization of EF, –agreement 84% (kappa 0.61)

47. Relationship between degree of RV dysfunction and degree of perfusion scan deficits Wolfe, 1994. N=90 –degree of perfusion deficit greater in patients with RVD (54% vs 30%, p<0.001) all patients with recurrent PE in group with initial RVD, p<0.01 Ribiero, 1998 –correlation between RVD and perfusion scan deficit but wide CI. Miller, 1998. N=64 –failed to demonstrate a correlation between RVD and perfusion deficit