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Whats New in the Treatment of Pulmonary EmbolismDecember 2009

David Garcia, MDAssociate ProfessorUniversity of New Mexico

OutlineCan we identify PE patients at low risk of adverse outcomes?

How long should patients with PE be treated with warfarin?

When is thrombolysis appropriate?

Risk-stratifying PE patientsMortality among patients with PE is high 17% in one studyMany clinicians believe that a subset of patients with PE could be safely treated out of hospitalHow to identify patients at high or low risk of adverse outcomes

PE Severity Index (PESI)Aujesky, et al. Archives Internal Medicine. 2006;166:169-175

INDEPENDENT PREDICTORS OF 30-DAY MORTALITY IN THE DERIVATION SAMPLE AND POINTS ASSIGNED TO THE RISK SCOREPredictorsB-Coefficients(95% C1)Points AssignedDemographic characteristicsAge, per yr0.03 (0.02-0.03)Age, in yrMale sex0.17 (0.02-0.32)+10Co-morbid illnessesCancer0.87 (0.71-1.03)+30Heart failure0.31 (0.14-0.49)+10Chronic lung disease0.30 (0.12-0.47)+10Clinical findingsPulse > 110/min0.60 (0.44-0.76)+20Systolic blood pressure < 100mm Hg0.86 (0.67-1.04)+30Respiratory rate > 30/min0.41 (0.23-0.58)+20Temperature < 36 C0.42 (0.25-0.59)+20Altered mental status *1.50 (1.30-1.69)+60Arterial oxygen saturation < 90%0.58 (0.37-0.79)+20Point total and risk class:< 65 class I; 66-85 class II; 86-105 class III; 106-125 class IV; > 125 class V.

Validation Cohort 30-Day Mortality and Adverse Events Within Risk Strata Derived From the PESI Prediction Rule * PESIn = 10,354n = 953

n = 599n = 43I19.4 (18.720.2)1.1 (0.71.7)

12.3 (9.715.0) 0II21.5 (20.722.3)3.1 (2.54.0)

23.7 (20.327.1)1.4 (0.53.3)III21.7 (20.922.5)6.5 (5.57.6)

28.9 (25.232.5) 6.9 (3.913.0)IV16.4 (15.717.1)10.4 (9.011.9)

21.5 (18.224.8) 10.1 (4.915.3)V21 (20.321.8)24.5 (22.726.9)

13.5 (10.816.3) 19.7 (11.128.4)Jimenez et al Chest 2007 vol. 132(1):P 7-8.% in risk class*% dead* % in risk class* % dead** Parentheses are 95% CI

Although not yet the U.S. standard of care, medium-quality evidence supports out-of-hospital PE treatment in selected patients1.Wells PS. A randomized trial comparing 2 low-molecular-weight heparins for the outpatient treatment of deep vein thrombosis and pulmonary embolism. Arch Intern Med. 2005;165:733-738

2.Kovacs MJ. Outpatient treatment of pulmonary embolism with dalteparin. Thrombosis & Haemostasis. 2000;83:209-211

3.Kearon C. Comparison of fixed-dose weight-adjusted unfractionated heparin and low-molecular-weight heparin for acute treatment of venous thromboembolism. Jama. 2006;296:935-942

4.Buller HR. Subcutaneous fondaparinux versus intravenous unfractionated heparin in the initial treatment of pulmonary embolism. N Engl J Med. 2003;349:1695-1702

Outpatient VTE ProtocolClinical Exclusionary Criteria*AbsoluteActive bleeding or positive stool guiacThrombocytopenia benefit

RV dysfunction, elevated laboratory markers (e.g. troponin)Evidence not definitiveControversy persists

Odds of short-term death in patients with elevated (vs. normal) troponin levels

Troponin ITroponin TBecattini C, et al. Prognostic value of troponins in acute pulmonary embolism: a meta-analysis. Circulation. 2007 Jul 24;116(4):427-33.

Right Ventricular Dysfunction (RVD): a risk factor for mortality(-) RVD(+) RVDRibeiro 9756 (0)70 (4)Grifoni 0097 (0)65 (5)Viellard-Baron 0163 (3)32 (3)Total216 (0.9)167 (4)No. of patients (% mortality)Dalen, JE. Arch Int Med 2002, 162:2521-2523

Alteplase for PESexy, recombinant clot-busting technology Improves V/Q scans, reduces angiographic clot burden, lowers pulmonary artery & RV pressuresMore active than simple anticoagulation

Heparins for PE Room to improve?For patients with PE treated with heparin (or LMWH) + warfarin, the overall in-hospital mortality due to PE is 2.2%.1,2

1 Douketis, et al. Risk of fatal PE in pts with treated venous thromboembolism JAMA 1998, 279:458-462.2 Carson, et al. The clinical course of pulmonary embolism NEJM 1992, 326:1240-1245..

Thrombolytic Therapyand BleedingYearCommentNo.patientsICH(%)Fatal Bleed (%)Levine95VTE review223-2.2Dalen97PE review5592.11.6Kanter97PE review3121.9-Goldhaber99PE registry3043.0-Hamel01PE cohort644.7-Konstantinides03PE - RCT118

Other ideas that made senseAnti-arrhythmic drugs to suppress PVCs post-MI

Hormone replacement therapy to stroke and ACS in postmenopausal women

Thrombolysis for PE with RVD: a randomized, controlled trial.

256 patientsHemodynamically stable(+) RV dysfunctionHeparin 5000/1000 + alteplasen=118Heparin 5000/1000 + placebon=138RANDOMIZED,DOUBLE-BLIND*Primary end point:in-hospital death + escalation of treatment

Escalation of TreatmentEndotracheal Intubation

Catecholamine Infusion

Cardiopulmonary Resuscitation

Secondary Thrombolysis

Event-free SurvivalKonstantinides, S et al. NEJM 2003, 347(15): 1143-1150.50607080901000051015202530heparin + alteplaseheparin + placeboP=0.005

In-Hospital Clinical Events (%)Konstantinides, S et al. NEJM 2003, 347(15): 1143-1150.EventHeparin + alteplase(n=118)Heparin + placebo(n=138)PPrimary endpoint11.024.60.006

31Rates of CPR, ET intubation, vasopressor use NOT DIFFERENT.In-Hospital Clinical Events (%)Konstantinides, S et al. NEJM 2003, 347(15): 1143-1150.EventHeparin + alteplase(n=118)Heparin + placebo(n=138)PPrimary endpoint11.024.60.006Death3.42.20.71Endotracheal Intubation2.52.20.85Catecholamine Infusion2.55.80.33CPR00.71.0

32Rates of CPR, ET intubation, vasopressor use NOT DIFFERENT.In-Hospital Clinical Events (%)Konstantinides, S et al. NEJM 2003, 347(15): 1143-1150.EventHeparin + alteplase(n=118)Heparin + placebo(n=138)PPrimary endpoint11.024.60.006Death3.42.20.71Endotracheal Intubation2.52.20.85Catecholamine Infusion2.55.80.33CPR00.71.0Secondary Thrombolysis7.6(n=9)23.2(n=32)0.001

33Rates of CPR, ET intubation, vasopressor use NOT DIFFERENT.MAPPET-3Konstantinides, S et al. NEJM 2003, 347(15): 1143-1150.Did the placebo patients really deteriorate more frequently than the alteplase patients?

Thrombolysis for PE with RVD: a randomized, controlled trial.256 patientsHemodynamically stable(+) RV dysfunctionheparin+ alteplasen=118heparin + placebon=138RANDOMIZED,DOUBLE-BLIND**Investigators contemplating open-label alteplase were permitted to break the randomization code!

In-Hospital Clinical Events (%)Konstantinides, S et al. NEJM 2003, 347(15): 1143-1150.EventHeparin + alteplase(n=118)Heparin + placebo(n=138)PPrimary endpoint11.024.60.006Death3.42.20.71Endotracheal Intubation2.52.20.85Catecholamine Infusion2.55.80.33CPR00.71.0Secondary Thrombolysis7.6(n=9)23.2(n=32)0.001

36Rates of CPR, ET intubation, vasopressor use NOT DIFFERENT.Thrombolytic Therapyand BleedingYearCommentNo.patientsICH(%)Fatal Bleed (%)Levine95VTE review223-2.2Dalen97PE review5592.11.6Kanter97PE review3121.9-Goldhaber99PE registry3043.0-Hamel01PE cohort644.7-Konstantinides03PE - RCT11800

MAPPET 3:ConclusionsPatients in the heparin + placebo arm received alteplase more often than patients in the heparin + alteplase arm.

Patients with RV dysfunction given a suboptimal heparin regimen + placebo have an in-hospital mortality rate of only 2.2%!

Overall ConclusionsRisk prediction models allow clinicians to identify PE patients at high (or low) risk of death.

LMWH and fonda preferred over UFH.

Further prospective studies are needed to confirm the hypothesis that selected low risk patients can be treated entirely out-of-hospital.

Duration must be individualized but latest guidelines lean toward extended therapy

Currently available evidence does not support the routine use of thrombolytic agents among patients with submassive PE.