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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


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


Antithrombin 3

Heparin

Antithrombin + LMWH


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


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


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


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


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


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.


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


HeparinPF-4

PF-4

Heparin


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


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.


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


When do PE pts crash?

• After day 1• Throughout the first week

Do RVs fail several days after presentation?


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?