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Clot Controversies: Thrombolysis and VTE Prophylaxis. Timothy A. Morris, M.D. Professor of Medicine Division of Pulmonary and Critical Care Medicine University of California, San Diego. “A.S.”. 68 y.o. man obese, smoker, inactive, inguinal hernia Lost weight Quit smoking Exercise program - PowerPoint PPT Presentation
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Clot Controversies: Thrombolysis and VTE Prophylaxis
Timothy A. Morris, M.D.Professor of Medicine
Division of Pulmonary and Critical Care MedicineUniversity of California, San Diego
“A.S.”
• 68 y.o. man– obese, smoker, inactive, inguinal hernia
Lost weightQuit smokingExercise programElective inguinal hernia repair
• “I want to do everything!”
Elective Inguinal Hernia Repair
• Uneventful operative course• No prophylaxis
Disaster
• 5 days post-op– Sudden cardiac arrest– No neurological recovery– Dx: massive PE
PE Epidemiology
600,000 annual incidence of clinically recognized thromboembolism
True incidence may be three to ten times this amount.
Unsuccessful Pre-Hospital Resuscitation
Aortic Aneurysm
6%
Other15%
Pulmonary Embolism
10%
Heart disease
69%
Silfvast. J Int Med. 1991;229:331-5
Mortality From “Massive” PE
7%14%
23%
60%
0%
20%
40%
60%
80%
Mortality
high PAP+RVP low MAP shock CPR
PE deaths other deaths
Kasper, et al. J Am Coll Cardiol, 1997
Ante-Mortem Dx of PE
0%
20%
40%
60%
80%
100%
Goldhaber 1982
Rubenstein1988
Karwinski1989
Stein 1995
Unsuspected Diagnosed
Ages: freq distrib
5 15 25 35 45 55 65 75 85 950
25
50
75
100
Age at time of death (+/- 5 years)
Frequency
Screening isn’t effective
• Asymptomatic DVT are less detectable• Outcome studies show no effect of pre-
discharge screening
Why doesn’t everybody prophylax?
Illusion of individual observation
I’ve always done just fine without…• seatbelts• giving up smoking• fire escapes• DVT prophylaxis
Who gets DVTs and PEs
Risk Stratification
Pathophysiology: Etiologies
• Venous stasis• Endothelial damage• Hypercoagulability
Venous Stasis
• bed rest, immobility• surgery (esp. for age >40 and time >30 min)• congestive heart failure• venous obstruction (especially previous
DVTs)• obesity (most prevalent factor in Framingham
study)
Endothelial Damage
• previous DVTs• trauma • hip or knee replacement
– Local inflammation– Torsion on vessel
Hypercoagulability
• estrogen in pharmacologic doses• Factor V Leiden• Protein C or S deficiency• Lupus “anticoagulant”• Cancer• Ortho surg: mediators from marrow.
– Contralateral leg DVT in 15-20% of cases
FVL and Hip/Knee Replacement
0%
20%
40%
60%
80%
100%
All DVT Prox DVT
Incidence of DVT
FVL (+) FVL (-)
Ryan, Ann Intern Med 1998
Risk Categories.
Low Risk
• Minor surgery– No risk factors for DVT– Age under 40
Moderate Risk
• Minor surgery– Risk factors for DVT
• Surgery– Age 40-60
High Risk
• Surgery– Age > 60– Age 40-60 + risk factors for DVT
Highest Risk
• Major surgery– Multiple risk factors for DVT
• Hip or knee arthroplasty• Hip fracture surgery• Major trauma• Spinal cord injury
Risk of DVT and PE
80%
20%10% 5%
0%
20%
40%
60%
80%
calf DVT prox DVT PE fatal PElow risk
mod riskhigh risk
highest risk
• General medical patients 10-26%1,2
• Stroke 11- 75%3
• Myocardial infarction (MI) 17-34%3
• Spinal cord injury 6 -100%3
• Congestive heart failure 20- 40%4
• Medical intensive care 25- 42%1,5,6
Incidence of VTE*
• 1. Cade 1982. 2. Belch et al., 1981. 3. Nicolaides et al., 1997. 4. Anderson et al., 1950. 5. Dekker et al., 1991. 6. Hirsh et al., 1995.
Prevention of DVT and PE:Medicine Patients
DVT in the ICU
• 100 ICU patients followed for DVT1
• Screened with DUS (upper and lower)– On ICU admission– Twice weekly– One week after discharge
1. Hirsch, et al JAMA 1995
DVT in 100 ICU pts
no clot, 67
prox LE DVT, 16
only calf DVT, 12UE DVT, 4
UE and calf DVT, 1
DVT in MICU patients
• 2/3 were off prophylaxis
• 70% were positive on the first test– 43% of them had been in house > 5 days
• All 5 UE clots were associated with IV catheters
Fatal PE in Medical Patients
• 400 consecutive autopsies reviewed– Incidence of PE?
• 200 consecutive admissions reviewed– Mortality?– Fatal PE (autopsy proven)?
Baglin et al. J Clin Path 1997
Fatal PE in Med Pts
Consecutive autopsies
7%4%
Fatal PE other PE
Consecutive medical admits
6%
10%
Died: PE Died: no PEBaglin et al. J Clin Path 1997
What type of prophylaxis?
Prophylaxis
• Mechanical: venous compression
• Pharmaceutical: anticoagulants
Venous compression
• “TEDS” stockings: custom-made
• Intermittent pneumatic compression stockings (IPC)– Safe: leg ischemia is a relative contraindication– Convenient– Effective: 48% RR for prox DVT
Mechanical Prophylaxis
• OR of 0.28 for DVT in ICU1
– Five pooled trails
• No comparative trials b/w IPC and TEDS
• Very few adverse effects
1. Attia J et al Arch Int Med 2001
Anticoagulants
• consider risk factors for thrombosis• consider bleeding risk
Clinical Decisions
Thrombosis Bleeding
Antithrombotic Drugs
• AT3 mediated– UH– LMWH– pentasaccharide
• Direct Thrombin Inhibitors– Hirudin-like drugs– Synthetic drugs
• Factor depleting Drugs– Ancrod– Warfarin
Thrombin + Fibrinogen
Thrombin
Fibrinogen
Antithrombin
Thrombin or Factor Xa
Antithrombin 3
Antithrombin + Heparin
Thrombin or Factor Xa
Antithrombin 3
Heparin
Heparin
• Polysaccharide
• Specific pentasaccharide necessary to interact with Antithrombin-3
• Function changes with size
Heparin
Domain 1
Domain 2
Domain 3Mol. Wt.
5400
Heparin Domains
“Inhibits”:
7500
Xa
Xa > IIa
IIa > Xa
Pentasaccharide, found in only 1/3 of molecules
Low Molecular Weight Heparins
• Depolymerize heparin
• Produce smaller chains
Antithrombin + Heparin
Thrombin or Factor Xa
Antithrombin 3
Heparin
Antithrombin + LMWH
Thrombin or Factor Xa
Antithrombin 3
LMWH
Antithrombin + Pentasaccharide
Factor Xa
Antithrombin 3
Pentasaccharide
Domain 1
Domain 2
Domain 3Mol. Wt.
5400
Heparin Domains
“Inhibits”:
7500
Xa
Xa > IIa
IIa > Xa
Pentasaccharide, found in only 1/3 of molecules
Heparin
Heparin
Sizes of Heparin Preparations
heparin
12K-15K(5K-30K)
tinzaparin
4.5K(3K-6K)
dalteparin
5K(2K-9K)
enoxaparin
4.5K(3K-8K)
Fonadaparinux
• Acute MI: Low-dose UFH 2
• Stroke: Low-dose UFH or LMWH 1,2
• Medical ICU: Low-dose UFH3
• Med pts Low-dose UFH or LMWH 1,2
– with risk factors:
1. Nicolaides et al., 1998; 2. Clagett et al., 1997; Cade et al, 1982
ACCP Consensus
Clinical trials:What to measure?
• Sensitive screening tests?– High number of occurrences– Clinical effect less certain
• Clinical outcome?– Importance is self-evident– Symptomatic VTE is relatively uncommon
Prophylaxis for Medical Inpatients
0%
1%
2%
3%
4%
5%
6%
heparin 5000u bid (n=216) enoxaparin 20 mg qd(n=207)
DVT on routine FGN uptake
Bergmann. Thrombosis and Hemostasis. 76(4) 529-34 1996
ns
Prophylaxis for MICU Patients
29%
13%
0%
5%
10%
15%
20%
25%
30%
35%
placebo heparin 5000u tid
DVT on serial I125 screening
Cade. Crit Care Med 1982
RR 0.65
Prophylaxis for Medical Inpatients
0.00%0.10%
0.20%0.30%
0.40%0.50%0.60%
0.70%0.80%
0.90%
heparin 5000u tid (n=710)
fraxiparin 36 mg qd(n=726)
Clinically Evident VTE
Harenberg. Hemostasis 26:127-139. 1996
ns
Prophylaxis for Medical (ID) Patients
5.30%5.60%
0.42%0.48%
0%
1%
2%
3%
4%
5%
6%
7%
control heparin 5000 u bid
Mortality
Mortality Autopsy proven PE
Garlund et al. Lancet 1996
P = NS
After heparin stopped
Prophylaxis for Medical (ID) Patients
5.30%5.60%
0.42%0.48%
1.20%2.00%
0%1%2%3%4%5%6%7%8%9%
control heparin 5000 u bidClinically important events
Mortality Autopsy proven PE Non fatal PE/DVT
Garlund et al. Lancet 1996
P = 0.012
After heparin stopped
n % n % n%
No. of patients assessed for VTE 288 100 287 100 291100
Any thromboembolic event 43 14.9 43 15.0 165.5*
DVT only 40 13.9 42 14.6 165.5
Proximal DVT 14 4.9 13 4.5 51.7**
Symptomatic DVT 2 0.7 3 1.0 10.3
PE only 2 0.7 0 0.0 00.0
DVT and PE 1 0.3 1 0.3 00.0
:*Relative Risk (RR) = 0.37, P = 0.0002; **RR = 0.35, P = 0.037
Enoxaparin 40 mg vs. placebo VTE during treatment
Placebo EnoxaparinEnoxaparin
20 mg 40 mg
Prophylaxis for Medical Inpatients
0%
2%
4%
6%
8%
10%
12%
14%
16%
placebo (n=288) enoxaparin 40 mg qd(n=291)
DVT on routine venogram
Samama. New England Journal of Medicine. 341(11) 793-800 1999
P < 0.001
3.8%
9.3% 1.70%
4.90%
0%2%4%
6%8%
10%12%
14%16%
Placebo EnoxDVT on Routine Venogram
Proximal DVT
Other DVT
Prophylaxis for Medical Inpatients
13.2%
5.2%
0.70%
0.30%
1.00%
0.00%
2.00%3.40%
0%2%4%
6%8%
10%12%
14%16%
Placebo Enox
MajorBleeding
PE +/- DVT
SymptomaticDVT
AsymptomaticDVT
Prophylaxis for Medical Inpatients
n % n%
No. of patients assessed for VTE 1833 100 1848100
Symptomatic DVT (proximal or distal) or…Symptomatic nonfatal PE or…Fatal PE or…Asymptomatic proximal DVT or…Sudden death 73 4.96 42
2.77
Relative Risk (RR) = 0.55, P = 0.0015
Dalterparin 5000u vs. placebo VTE during treatment
PlaceboDalteparin
2.77%4.96%
0.49%0.16%0%1%2%3%4%5%6%
PlaceboDalteparin
MajorBleeding
SymptomaticDVT,PE orsudden death
Prophylaxis for Medical Inpatients
Is UH Less Predictable Than LMWH?
Anti-Xa Activity After One Subcutaneous Injection
00.050.1
0.150.2
0.250.3
0.350.4
0.45
0 0.75 1.5 3 5 8 12 18 24
UH 5000U Enox 40mg
IU/ml
Hours
Bara. Thrombosis Research. 1993
Anti-thrombin Activity After One S.Q. Injection
00.010.020.030.040.050.060.070.08
0 0.75 1.5 3 5 8 12 18 24
UH 5000U Enox 40mg
IU/ml
Hours
Bara. Thrombosis Research. 1993
Is Heparin Less Effective Than LMWH?
Metaanalysis of UH vs LMWH for Prophylaxis in General Surgery*
Outcome Assessment Blinded to Drug Type? Results
Yes LMWH = UFH
NoLMWH superior (overestimated by 35%)
*Jüni P et al. The Hazards of Scoring the Quality of Clinical Trials for Meta-analysis.JAMA. 1999;282:1054-1060.
Prophylaxis for Medical Inpatients
0.00%
0.10%
0.20%
0.30%
0.40%
0.50%
0.60%
0.70%
0.80%
heparin 5000u tid (n=780)
nadroparin 3400u qd(n=810)
Clinically Evident VTE
Harenberg. Hemostasis 26:127-139. 1996
ns
Efficacy: VTE during Prophylaxis in Med Patients
• THE-PRINCE1 enox vs hep– No sig difference
• Prime2 enox vs hep– No sig difference
1. Kleber et al. Am Heart J. 2003;145:614-21.2. Lechler et al. The Prime Study Group. Haemostasis. 1996;26 Suppl 2:49-56.
Is Heparin Less Safe Than LMWH?
Safety: Bleeding during Prophylaxis in Med Patients
• THE-PRINCE1 enox vs hep– No sig difference
• Prime2 enox vs hep– No sig difference
1. Kleber et al. Am Heart J. 2003;145:614-21.2. Lechler et al. The Prime Study Group. Haemostasis. 1996;26 Suppl 2:49-56.
Safety Meta-analysis: UFH vs LMWH1
UH LMWH p
Major bleeding 8/815 (1.0%)
9/1169 (0.8%)
NS
Thrombocytopenia 5/815 (0.6%)
5/1169 (0.4%)
NS
1. Alikhan et al. Thromb Haemost. 2003;89:590-1.
Heparin-induced thrombocytopenia
HIT: UH vs LMWH for VTE Rx
0.01 0.1 1 10 100
Total
Kirchmaier 1998
Breddin 2001Thery 1992
Kakkar 2003Albada 1989Levine 1996
Prandoni 2004Harenberg 2000
Merli 2001Koopman 1996
Fiessinger 1996Lopaciuk 1992Prandoni 1992
Favors UH OR Favors LMWH
Heparin Induced Thrombocytopenia
HeparinPF-4
Heparin Induced Thrombocytopenia
HeparinPF-4
PF-4
Heparin
Heparin Induced Thrombocytopenia
LMWHPF-4
PF-4
LMW
H
Sizes of Heparin Preparations
heparin
12K-15K(5K-30K)
tinzaparin
4.5K(3K-6K)
dalteparin
5K(2K-9K)
enoxaparin
4.5K(3K-8K)
HeparinFonadaparinux
Heparin Induced Thrombocytopenia
PF-4
PF-4
Pentasaccharides
Filter Placement
• Very high risk patients in whom other therapy is contraindicated
• No protection against symptomatic DVT
• No evidence of the need for long term anticoagulation after placement.
Prophylaxis for Mod Risk Pts
• IPC
• LDUH
• LMWH
• IVC
• Why the heck not?
• Good option
• Good option
• Only if risk of VTE and bleeding is high
Fatal PE
Unsuspected, 47.5%
Treated, 21.3%
Other Anticoag, 10.4%
Diagnosed, 0.6%
Suspected, 20.5%
Was prophylaxis appropriate?
4.9%
56.9%
38.2%
0%
10%
20%
30%
40%
50%
60%
70%
No opportunity Appropriate Not appropriate
Prophylaxis Order Sheet
Acute Thrombo-embolus
Fatal PE During Anticoagulation
0.50%
2.30%
0%
1%
2%
3%
DVT PE
Presenting Condition
Douketis. JAMA 1998; 279:458-62
Mortality From “Massive” PE
7%14%
23%
60%
0%
20%
40%
60%
80%
Mortality
high PAP+RVP low MAP shock CPR
PE deaths other deaths
Kasper, et al. J Am Coll Cardiol, 1997
PE Without Prior Heart/Lung Disease
0
1
2
3
4
5
6
0 20 40 60 80
Percent Obstruction by Angiography
Cardiac Index
McIntyre, Sasahara. Am J Card, 1971
Experimental PA Obstruction
0
20
40
60
80
100
120
Control RV HTN RV failure Neoinfused
torr
0
0.5
1
1.5
2
2.5
3L/min
PA Systolic
RVEDP
SystemicBP
CardiacOutput
Experimental PA Obstruction
0102030405060708090
Control RV HTN RV failure Neoinfused
0
0.5
1
1.5
2
2.5
3RCA drivingpressure(torr)
CardiacOutput(L/min)
RVmyocardialblood flow(ml/min/g)
RVischemia
Vlahakes. Circulation 1981
PE Without Prior Heart/Lung Disease
0 80
0
1
2
3
4
5
6
7
0 20 40 60 80 100
Percent Obstruction by Angiography
Cardiac Index
McIntyre, Sasahara. Am J Card, 1971
Fast vs Slow Thrombolysis
4
5
6
0 2 4 6 8 10 12 14
Hrs
Cardiac Output (L/min)
TPA (2 hr inf) STK (12 hr inf)
Thrombolytics:Intracranial Bleed1
1. Dalen, Arch Int Med 1997
0.00%
0.50%
1.00%
1.50%
2.00%
2.50%
Hep: ICB Lytic: ICB Lytic: Fatal ICB
Thrombolytics in Massive PE?
• Mortality rate of massive PE = 28%
• Mortality rate for thrombolytics = 1.6%
• Hemodynamic benefit vs risk of ICH?
“Submassive PE”
• Hemodynamically stable• Randomized to
– Heparin alone– tPA (100mg) + heparin
• “Blinded”– Unless someone really wanted to look
• Sponsored by makers of tPA
Konstantinides et al: Heparin plus Alteplase Compared with Heparin Alone in Patients with Submassive Pulmonary Embolism. NEJM 347(15):1143-1150 October 10, 2002
Heparin vs tPA + Heparin
• Heparin: increase in composite endpoint.– in-hospital death– clinical deterioration/ escalation of treatment,
• catecholamine infusion,• secondary thrombolysis,• endotracheal intubation, • cardiopulmonary resuscitation, or • emergency surgical embolectomy or by catheter.
Konstantinides et al: Heparin plus Alteplase Compared with Heparin Alone in Patients with Submassive Pulmonary Embolism. NEJM 347(15):1143-1150 October 10, 2002
Heparin vs tPA + Heparin
• Heparin: increase in composite endpoint.– in-hospital death – ns (heparin better)– clinical deterioration/ escalation of treatment,
• catecholamine infusion ns• secondary thrombolysis p = 0.001 tPA better• endotracheal intubation ns • cardiopulmonary resuscitation ns• emergency embolectomy ns
Konstantinides et al: Heparin plus Alteplase Compared with Heparin Alone in Patients with Submassive Pulmonary Embolism. NEJM 347(15):1143-1150 October 10, 2002
When do PE pts crash?
• After day 1• Throughout the first week
Do RVs fail several days after presentation?
Konstantinides et al: Heparin plus Alteplase Compared with Heparin Alone in Patients with Submassive Pulmonary Embolism. NEJM 347(15):1143-1150 October 10, 2002
When do patients Rx’d for PE die?
0
2
4
6
8
10
12
14
Death from PE
ER 0-3 3-7 8-14 15-21 22-30 >30
Days After Admission
Morgenthaler, Ryu. Mayo Clin Proc. 1995;70:417-424.
IVC filters
Siskin, 2005
Conclusions
• VTE Prophylaxis– Range of acceptable choices– Make conscious decision
• PE Thrombolysis– No RCTs to definitively guide therapy– Balance clinical risk with potential clinical benefit
• Shock, etc.
– Consider all applicable strategies• IVC?
• Other support?
• Surgery?