Slide 2 Whats New in the Treatment of Pulmonary Embolism
December 2009 David Garcia, MD Associate Professor University of
New Mexico Slide 3 Outline Can we identify PE patients at low risk
of adverse outcomes? How long should patients with PE be treated
with warfarin? When is thrombolysis appropriate? Slide 4
Risk-stratifying PE patients Mortality among patients with PE is
high 17% in one study Many clinicians believe that a subset of
patients with PE could be safely treated out of hospital How to
identify patients at high or low risk of adverse outcomes Slide 5
PE Severity Index (PESI) Aujesky, et al. Archives Internal
Medicine. 2006;166:169-175 Slide 6 INDEPENDENT PREDICTORS OF 30-DAY
MORTALITY IN THE DERIVATION SAMPLE AND POINTS ASSIGNED TO THE RISK
SCORE Predictors B-Coefficients (95% C1)Points Assigned Demographic
characteristics Age, per yr0.03 (0.02-0.03)Age, in yr Male sex0.17
(0.02-0.32)+10 Co-morbid illnesses Cancer0.87 (0.71-1.03)+30 Heart
failure0.31 (0.14-0.49)+10 Chronic lung disease0.30 (0.12-0.47)+10
Clinical findings Pulse > 110/min0.60 (0.44-0.76)+20 Systolic
blood pressure < 100mm Hg0.86 (0.67-1.04)+30 Respiratory rate
> 30/min0.41 (0.23-0.58)+20 Temperature < 36 C0.42
(0.25-0.59)+20 Altered mental status *1.50 (1.30-1.69)+60 Arterial
oxygen saturation < 90%0.58 (0.37-0.79)+20 Point total and risk
class: 125 class V. Slide 7 Validation Cohort 30-Day Mortality and
Adverse Events Within Risk Strata Derived From the PESI Prediction
Rule ** PESIn = 10,354n = 953n = 599n = 43 I 19.4 (18.720.2)1.1
(0.71.7)12.3 (9.715.0)0 II 21.5 (20.722.3)3.1 (2.54.0)23.7
(20.327.1)1.4 (0.53.3) III 21.7 (20.922.5)6.5 (5.57.6)28.9
(25.232.5)6.9 (3.913.0) IV 16.4 (15.717.1)10.4 (9.011.9)21.5
(18.224.8)10.1 (4.915.3) V 21 (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 Slide 8 Although not yet the U.S. standard of care,
medium-quality evidence supports out-of- hospital PE treatment in
selected patients 1.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 Slide 9
Outpatient VTE Protocol Clinical Exclusionary Criteria* Absolute
Active bleeding or positive stool guiac Thrombocytopenia75yrs
Acquired or congenital hypercoagulable state Based on compedium of
RCTs and observational studies Slide 10 Psychosocial and/or
Socioeconomic Exclusionary Factors from Outpatient VTE Treatment
History of non-compliance with medicines History of substance abuse
Language barrier Inability to pay for LMWH Inaccessibility to
clinic or telephone Unstable home environment Incompetence to
assume responsibility for self- care or inability for
family/friend/nurse to administer care Above are relative
exclusionary risk factors Slide 11 Product Dosing heparin aPTT or
anti-Xa 1.5-2.5 x control (use nomogram) OR (unfract.) give
weight-based SC dosing (see Kearon et al. JAMA 2006) enoxaparin 1.0
mg/kg sc. every 12 hrs OR 1.5 mg/kg sc. once a day tinzaparin 175
anti Xa IU/kg once daily dalteparin 200 anti Xa IU/kg once daily OR
100 anti Xa IU/kg every 12 hrs fondaparinux 7.5 mg SC q.d. Acute
Treatment of DVT Slide 12 ACCP Consensus Conference on
Antithrombotic Therapy In patients with acute DVT and submassive
PE, initial treatment with LMWH or fondaparinux recommended over
unfractionated heparin Kearon et al. Chest 2008. Slide 13 DVT
treatment: LMWH vs. IV UFH Major Bleeding (n=3674) Recurrent
Thromboembolism (n=3566) OR, 0.57 (P=0.047) OR, 0.71 (P =0.25) OR,
0.85 (P=0.28) OR, 0.87 (P =0.40) 0.01 0.1 1 10 100 Favors LMWH
Favors UFH Odds Ratio Favors LMWH Favors UFH Odds Ratio Primary
Studies Duroux, 1991 (nadroparin) Hull, 1992 (tinzaparin) Prandoni,
1992 (nadroparin) Lopaciuk, 1992 (nadroparin) Simonneau, 1993
(enoxaparin) Lindmarker, 1994 (daltiparin) Levine, 1996
(enoxaparin) Koopman, 1995 (nadroparin) Fiessinger, 1996
(dalteparin) Luomanmaki, 1998 (dalteparin) Columbus, 1997
(riviparin) Gould ANN INT MED 1999 Slide 14 LMWH vs. UFH in
treatment of PE symptomatic VTE at end of treatment Quinlan Ann Int
Med 2004 Slide 15 UFH in the REAL WORLD 311 patients being bridged
with UFH to warfarin Once aPTT in range, next 2 measurements were
therapeutic only 29% of the time Therapeutic range maintained for 4
consecutive days only 7% of the patients 54% had at least one
prolonged interruption of their infusion Hylek et al. Arch Int Med
2003 163(5):621-7. Slide 16 Are all provoked clots the same? Baglin
et al. Lancet. 2003 Aug 16;362(9383):523-6. Unprovoked (n=192)
Non-surgical RF: cast, immobilization, estrogen, travel (n=279)
Surgery (n=86) Slide 17 Risk factors for recurrence Factor Relative
Risk DVT isolated to calf (vs. proximal)0.5 Low d-dimer 1 month
after VKA stopped0.4 Asian ethnicity0.8 One or more prior VTE
episodes1.5 Antiphospholipid antibody2.0 Protein C or Protein S
deficiency1.5 Male gender (vs. female)1.6 Residual thrombosis in
proximal veins1.5 Kearon et al Chest 2008 133: 454S-545S Slide 18
Major Bleeding during Extended Treatment with Warfarin Study
Events/patient-yrs (% / yr) (% / yr) DURAC 2 4/355 (1.1%) LAFIT
(total) 4/268 (1.5%) ELATE 8/872 (0.9%) PROLONG 1/154 (0.6%) Total
24/1843 (1.3%) Slide 19 Hylek, EM. Slide 20 Hylek, EM Slide 21 My
Approach Treat Proximal DVT or PE (unprovoked) at least 3- 6 months
Ensure the patient is up-to-date on age-appropriate cancer
screening and perform careful physical exam and review of systems.
Ensure the patient is up-to-date on age-appropriate cancer
screening and perform careful physical exam and review of systems.
Discuss risks/benefits of extended therapy with all patients.
Discuss risks/benefits of extended therapy with all patients.
Encourage extended therapy for patients who: Encourage extended
therapy for patients who: are male have had previous VTE had PE
(rather than DVT) as their index event have poor cardiopulmonary
reserve have stable INR values Test young patients for
antiphospholipid syndrome. Test young patients for antiphospholipid
syndrome. Consider d-dimer testing and/or repeat ultrasound if
other factors equivocal. Consider d-dimer testing and/or repeat
ultrasound if other factors equivocal. Slide 22 When are
thrombolytic agents appropriate for patients with PE? Hypotension,
shock Consensus that risk > benefit RV dysfunction, elevated
laboratory markers (e.g. troponin) Evidence not definitive
Controversy persists Slide 23 Odds of short-term death in patients
with elevated (vs. normal) troponin levels Troponin I Troponin T
Becattini C, et al. Prognostic value of troponins in acute
pulmonary embolism: a meta-analysis. Circulation. 2007 Jul
24;116(4):427-33. Slide 24 Right Ventricular Dysfunction (RVD): a
risk factor for mortality (-) RVD(+) RVD Ribeiro 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 Slide 25 Alteplase for PE Sexy, recombinant
clot-busting technology Improves V/Q scans, reduces angiographic
clot burden, lowers pulmonary artery & RV pressures More active
than simple anticoagulation Slide 26 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..
Slide 27 Thrombolytic Therapy and Bleeding YearComment No. patients
ICH (%) Fatal Bleed (%) Levine95 VTE review 223-2.2 Dalen97 PE
review 5592.11.6 Kanter97 PE review 3121.9- Goldhaber99 PE registry
3043.0- Hamel01 PE cohort 644.7- Konstantinides 03 PE - RCT 118
Slide 28 Other ideas that made sense Anti-arrhythmic drugs to
suppress PVCs post-MI Hormone replacement therapy to stroke and ACS
in postmenopausal women Slide 29 Thrombolysis for PE with RVD: a
randomized, controlled trial. 256 patients Hemodynamically stable
(+) RV dysfunction Heparin 5000/1000 + alteplase n=118 Heparin
5000/1000 + placebo n=138 RANDOMIZED, DOUBLE-BLIND* Primary end
point: in-hospital death + escalation of treatment Slide 30
Escalation of Treatment Endotracheal Intubation Catecholamine
Infusion Cardiopulmonary Resuscitation Secondary Thrombolysis Slide
31 Event-free Survival Konstantinides, S et al. NEJM 2003, 347(15):
1143-1150. 50 60 70 80 90 100 0 0 51015202530 heparin + alteplase
heparin + placebo P=0.005 Slide 32 In-Hospital Clinical Events (%)
Konstantinides, S et al. NEJM 2003, 347(15): 1143-1150.
EventHeparin + alteplase (n=118) Heparin + placebo (n=138) P
Primary endpoint11.024.60.006 Slide 33 In-Hospital Clinical Events
(%) Konstantinides, S et al. NEJM 2003, 347(15): 1143-1150.
EventHeparin + alteplase (n=118) Heparin + placebo (n=138) P
Primary endpoint11.024.60.006 Death3.42.20.71 Endotracheal
Intubation2.52.20.85 Catecholamine Infusion2.55.80.33 CPR00.71.0
Slide 34 In-Hospital Clinical Events (%) Konstantinides, S et al.
NEJM 2003, 347(15): 1143-1150. EventHeparin + alteplase (n=118)
Heparin + placebo (n=138) P Primary endpoint11.024.60.006
Death3.42.20.71 Endotracheal Intubation2.52.20.85 Catecholamine
Infusion2.55.80.33 CPR00.71.0 Secondary Thrombolysis 7.6 (n=9) 23.2
(n=32) 0.001 Slide 35 MAPPET-3 Konstantinides, S et al. NEJM 2003,
347(15): 1143-1150. Did the placebo patients really deteriorate
more frequently than the alteplase patients? Slide 36 Thrombolysis
for PE with RVD: a randomized, controlled trial. 256 patients
Hemodynamically stable (+) RV dysfunction heparin + alteplase n=118
heparin + placebo n=138 RANDOMIZED, DOUBLE-BLIND* *Investigators
contemplating open-label alteplase were permitted to break the
randomization code! Slide 37 In-Hospital Clinical Events (%)
Konstantinides, S et al. NEJM 2003, 347(15): 1143-1150.
EventHeparin + alteplase (n=118) Heparin + placebo (n=138) P
Primary endpoint11.024.60.006 Death3.42.20.71 Endotracheal
Intubation2.52.20.85 Catecholamine Infusion2.55.80.33 CPR00.71.0
Secondary Thrombolysis 7.6 (n=9) 23.2 (n=32) 0.001 Slide 38
Thrombolytic Therapy and Bleeding YearComment No. patients ICH (%)
Fatal Bleed (%) Levine95 VTE review 223-2.2 Dalen97 PE review
5592.11.6 Kanter97 PE review 3121.9- Goldhaber99 PE registry
3043.0- Hamel01 PE cohort 644.7- Konstantinides 03 PE - RCT 11800
Slide 39 MAPPET 3: Conclusions Patients 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%! Slide 40 Overall Conclusions Risk 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.
