Transcript Slide 1

What’s New in the Treatment of
Pulmonary Embolism
December 2009
David Garcia, MD
Associate Professor
University of New Mexico
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?
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
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 SCORE
B-Coefficients
(95% C1)
Points Assigned
Age, per yr
0.03 (0.02-0.03)
Age, in yr
Male sex
0.17 (0.02-0.32)
+10
Cancer
0.87 (0.71-1.03)
+30
Heart failure
0.31 (0.14-0.49)
+10
Chronic lung disease
0.30 (0.12-0.47)
+10
Pulse > 110/min
0.60 (0.44-0.76)
+20
Systolic blood pressure < 100mm Hg
0.86 (0.67-1.04)
+30
Respiratory rate > 30/min
0.41 (0.23-0.58)
+20
Temperature < 36 C
0.42 (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
Predictors
Demographic characteristics
Co-morbid illnesses
Clinical findings
Point 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 *
% in risk class*
% dead*
% in risk class*
% dead*
PESI
n = 10,354
n = 953
n = 599
n = 43
I
19.4 (18.7–20.2)
1.1 (0.7–1.7)
12.3 (9.7–15.0)
0
II
21.5 (20.7–22.3)
3.1 (2.5–4.0)
23.7 (20.3–27.1)
1.4 (0.5–3.3)
III
21.7 (20.9–22.5)
6.5 (5.5–7.6)
28.9 (25.2–32.5)
6.9 (3.9–13.0)
IV
16.4 (15.7–17.1)
10.4 (9.0–11.9)
21.5 (18.2–24.8)
10.1 (4.9–15.3)
V
21 (20.3–21.8)
24.5 (22.7–26.9)
13.5 (10.8–16.3)
19.7 (11.1–28.4)
* Parentheses are 95% CI
Jimenez et al Chest 2007 vol. 132(1):P 7-8.
Although not yet the U.S. standard of care,
medium-quality evidence supports out-ofhospital 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
Outpatient VTE Protocol
Clinical Exclusionary Criteria*
Absolute
• Active bleeding or positive
stool guiac
• Thrombocytopenia <100K
• Major surgery/trauma or
CVA <2 weeks
• Phlegmasia
• Symptomatic PE
• Severe renal dysfunction
• Recent GI bleeding
• Hypertensive emergency
• History of heparin sensitivity
or HIT
• Active or major comorbid
illness
Relative
• History of familial bleeding
disorder
• Morbid obesity
• Iliofemoral DVT
• Pregnancy
• Underlying liver disorder
• Age > 75yrs
• Acquired or congenital
hypercoagulable state
Based on compedium of RCT’s and observational studies
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 selfcare or inability for family/friend/nurse to
administer care
Above are relative exclusionary risk factors
Acute Treatment of DVT
Product
heparin
(unfract.)
enoxaparin
Dosing
aPTT or anti-Xa 1.5-2.5 x control (use nomogram) OR
give weight-based SC dosing (see Kearon et al. JAMA 2006)
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.
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.
DVT treatment:
LMWH vs. IV UFH
Major Bleeding
(n=3674)
Recurrent Thromboembolism
(n=3566)
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)
0.01
Favors
LMWH
Gould ANN INT MED 1999
0.1
OR, 0.57
(P=0.047)
OR, 0.85
(P=0.28)
OR, 0.71
(P =0.25)
OR, 0.87
(P =0.40)
1
Odds Ratio
10
Favors
UFH
100
0.01
Favors
LMWH
0.1
1
Odds Ratio
10
Favors
UFH
100
LMWH vs. UFH in treatment of PE –
symptomatic VTE at end of treatment
Quinlan Ann Int Med 2004
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.
Are all “provoked”
clots the same?
Unprovoked (n=192)
Non-surgical RF:
cast, immobilization,
estrogen, travel (n=279)
Surgery (n=86)
Baglin et al. Lancet. 2003 Aug 16;362(9383):523-6.
Risk factors for recurrence
Factor
Relative
Risk
DVT isolated to calf (vs. proximal)
Low d-dimer 1 month after VKA stopped
Asian ethnicity
0.5
0.4
0.8
One or more prior VTE episodes
Antiphospholipid antibody
Protein C or Protein S deficiency
1.5
2.0
1.5
Male gender (vs. female)
Residual thrombosis in proximal veins
1.6
1.5
Kearon et al Chest 2008 133: 454S-545S
Major Bleeding during
Extended Treatment with Warfarin
Study
Events/patient-yrs
(% / 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%)
Hylek, EM.
Hylek, EM
My Approach
Treat Proximal DVT or PE (unprovoked) at least 36 months
•
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.
•
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.

Consider d-dimer testing and/or repeat ultrasound if other factors equivocal.
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
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.
Right Ventricular Dysfunction
(RVD): a risk factor for mortality
No. of patients (% mortality)
(-) RVD
(+) RVD
Ribeiro ‘97
56 (0)
70 (4)
Grifoni ‘00
97 (0)
65 (5)
Viellard-Baron ‘01
63 (3)
32 (3)
216 (0.9)
167 (4)
Total
Dalen, JE. Arch Int Med 2002, 162:2521-2523
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
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 Therapy
and Bleeding
Year
Comment
No.
patients
ICH
(%)
Fatal
Bleed (%)
Levine
‘95
VTE review
223
-
2.2
Dalen
‘97
PE review
559
2.1
1.6
Kanter
‘97
PE review
312
1.9
-
Goldhaber
‘99
PE registry
304
3.0
-
Hamel
‘01
PE – cohort
64
4.7
-
Konstantinides
‘03
PE - RCT
118
Other ideas that
“made sense”
• Anti-arrhythmic drugs to suppress PVC’s
post-MI
• Hormone replacement therapy to stroke
and ACS in postmenopausal women
Thrombolysis for PE with RVD: a
randomized, controlled trial.
256 patients
Hemodynamically stable
(+) RV dysfunction
RANDOMIZED,
DOUBLE-BLIND*
Heparin “5000/1000”
+ alteplase
n=118
Heparin “5000/1000”
+ placebo
n=138
Primary end point:
in-hospital death + “escalation of treatment”
“Escalation of Treatment”
• Endotracheal Intubation
• Catecholamine Infusion
• Cardiopulmonary Resuscitation
• “Secondary” Thrombolysis
Event-free Survival
Konstantinides, S et al. NEJM 2003, 347(15): 1143-1150.
100
heparin + alteplase
90
80
P=0.005
70
heparin + placebo
60
50
0
0
5
10
15
20
25
30
In-Hospital Clinical Events (%)
Konstantinides, S et al. NEJM 2003, 347(15): 1143-1150.
Event
Primary endpoint
Heparin +
alteplase
(n=118)
11.0
Heparin +
placebo
(n=138)
24.6
P
0.006
In-Hospital Clinical Events (%)
Konstantinides, S et al. NEJM 2003, 347(15): 1143-1150.
Event
Heparin +
alteplase
(n=118)
Heparin +
placebo
(n=138)
P
Primary endpoint
11.0
24.6
0.006
Death
3.4
2.2
0.71
Endotracheal Intubation
2.5
2.2
0.85
Catecholamine Infusion
2.5
5.8
0.33
0
0.7
1.0
CPR
In-Hospital Clinical Events (%)
Konstantinides, S et al. NEJM 2003, 347(15): 1143-1150.
Event
Heparin +
alteplase
(n=118)
Heparin +
placebo
(n=138)
P
Primary endpoint
11.0
24.6
0.006
Death
3.4
2.2
0.71
Endotracheal Intubation
2.5
2.2
0.85
Catecholamine Infusion
2.5
5.8
0.33
0
0.7
1.0
7.6
(n=9)
23.2
(n=32)
0.001
CPR
Secondary
Thrombolysis
MAPPET-3
Konstantinides, 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 patients
Hemodynamically stable
(+) RV dysfunction
heparin
+ alteplase
n=118
RANDOMIZED,
DOUBLE-BLIND*
heparin
+ placebo
n=138
*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.
Event
Heparin +
alteplase
(n=118)
Heparin +
placebo
(n=138)
P
Primary endpoint
11.0
24.6
0.006
Death
3.4
2.2
0.71
Endotracheal Intubation
2.5
2.2
0.85
Catecholamine Infusion
2.5
5.8
0.33
0
0.7
1.0
7.6
(n=9)
23.2
(n=32)
0.001
CPR
Secondary
Thrombolysis
Thrombolytic Therapy
and Bleeding
Year Comment
No.
patients
ICH
(%)
Fatal
Bleed (%)
Levine
‘95
VTE review
223
-
2.2
Dalen
‘97
PE review
559
2.1
1.6
Kanter
‘97
PE review
312
1.9
-
Goldhaber
‘99
PE registry
304
3.0
-
Hamel
‘01
PE – cohort
64
4.7
-
Konstantinides
‘03
PE - RCT
118
0
0
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%!
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.