Stroke and VTE:A Deadly Combination

Amjad AlMahameed, MD, MPH, FACPDivision of Cardiology

Beth Israel Deaconess Medical CenterBoston, MA

Historical and Projected Stroke Deaths

Historical Data

Projected Data

Projected values are the product of future age-race-sex–specific mortality rates and US Census Bureau projections

Stroke 2003

50% of early post stroke

deaths have PE on autopsy studies

VTE in stroke patients has worse prognosis than nonstroke pts:

50% present as sudden deathMost patients do not have clinical evidence of DVT

VTE and Death in Stroke patients

up to 25% of early post

stroke deaths are secondary

to PE

Stroke 2000

Did u know?

Peak PE Incidence

(1st week post

stroke)

PE is the most

common cause of

Death

(week 2-4 poststroke)

33% had DVT on

venogram after 9 weeks

Stroke

Day 2 Day 7 Day 10 Week 2 Week 4 Week 9

39% had PE on

screening VQ scans

VTE is Common After StrokeThe Risk of VTE Extends Beyond the Acute Illness Phase

Stroke 2000

DVT After Acute Stroke EPIDEMIOLOGY

Arch Phys Rehab 1992, Lancet 1987, Ann intern Med 1996, Arch Neurol 1992, Stroke 1991 and 2001

Usually the paralyzed leg Commonly asymptomatic

1/3 proximal

2/3 below knee

Risk increases with: Severity of paralysis, older age, and presence of A fib

Incidence exceeds that following general

surgery and equivalent TKA/THA

Barriers to PE Diagnosis in Stroke Patients

• Elderly population

• Nonspecific signs and symptoms

• Patients inability to complain (Dysphasia, mental obtundation, cognitive impairment)

• Coexistence with pneumonia: 40% in autopsy studies. None was diagnosed antemortem

• Provider bias towards overlooking complaints made by the elderly

Stroke 2000

Consequences of ALL Proximal DVT After Stroke

All PE (silent & clinical)

50%

Clinical PE37%

Large PE10%

Fatal PE 10-15%

Stroke 2000

Consequences of Asymptomatic Below-Knee (BK) DVT After Stroke

ProximalProximalExtensionExtension

20%20%

Silent PE 33%Usually small sizePE, not massive

Asymptomatic below the knee DVT is not as benign as once thought!!

Clinically Apparent ButUntreated DVT

Post ThromboticSyndrome 30-90%

Fatal PE37%

Stroke 2000

The Incidence of VTE Post Craniotomy

• Brain tumors: 1/10,000 in the US

• Yearly 13,000 pts die from brain tumor in the US

• VTE is the most frequent complication following VTE is the most frequent complication following craniotomy for brain tumorscraniotomy for brain tumors

• Incidence of symptomatic VTE after craniotomy in one study: 7.5% for primary tumors and 19% for metastatic tumors

Chan. J Thrombosis and thrombolysis, 1999, Goldhaber. Stroke 2000

VTE in the Acute Treatment Phase After Spinal Cord Injury

PE is the third most common cause of

death in this population (2)

The risk of fatal PE after SCI has NOT decreased over the past 25 years (3)

(1) Brach 1977, Rossi 1980, Myllynen 1985, Petaja 1989, Geerts 1994(2) Waring 1991, De Vivo 1999(3) De Vivo 1999

In the absence of thromboprophylaxis, objective evidence of

DVT 67-100% (1)

The risk of VTE post neurological events (stroke, spinal cord injury/surgery, and

craniotomy) is even higher in the presence of other risk factors for VTE

Risk Factors for VTE (DVT/PE)

ACQUIREDACQUIRED• Previous thrombosis

• Immobilization (age dependent)

• Major surgery, multiple trauma

• Orthopedic surgery

• Venous Instrumentation

• Malignancy

• Age

• Hormones

• Antiphospholipid synd

• Medically Ill (CHF, AMI, Shock)

• Heparin thrombocytopenia

• Travel

• Factor V Leiden (APC Resistance)

• Antithrombin (formerly AT III)

• Protein C

• Protein S

• Prothrombin G20210A mutation

• Dysfibrinogenemia

• Plasminogen

• Homocysteine

• Factor VIII (?) and XI

INHERITEDINHERITED

Risk Factors For Venous Thrombosis

• Association between atherosclerotic disease and Spontaneous venous thrombosis is reported

• Risk factors for ATHEROSCLEROSIS are also risk factors for VENOUS THROMBOSIS:

- Obesity

- HTN

- Cigarette smoking

• Previous thrombosis

• Immobilization (age dependent)

• Major surgery, multiple trauma

• Orthopedic surgery

• Venous Instrumentation

• Malignancy

• Age

• Hormones

• Antiphospholipid synd

• Medically Ill (CHF, AMI, Shock)

• Heparin thrombocytopenia

• Travel

• Factor V Leiden (APC Resistance)

• Antithrombin (formerly AT III)

• Protein C

• Protein S

• Prothrombin G20210A mutation

• Dysfibrinogenemia

• Plasminogen

• Homocysteine

• Factor VIII (?) and XI

ACQUIRED INHERITED

Primary Prevention Strategies

Prevention of Venous Thromboembolism

• Low dose heparin• Adjusted dose heparin• LMWH• Warfarin• Danaparoid• Refludan• Dextran, Aspirin• Fondaparinux• Ximelagatran?

• Elastic stockings• IPC• Early ambulation• IVC filter• External pneumatic plantar

compression

PharmacologicPharmacologic NonpharmacologicNonpharmacologic

Current Strategies:Mechanical Prophylaxis

• Intermittent pneumatic compression (IPC)

• Pneumatic plantar compression (foot pump)

Clot Formation

In real life: poor compliance

Contraindications for Use of PCD

Severe PAD (ABI < 0.4)

Diabetic neuropathy with sensory loss

Dermatological diseases

Presence of acute DVT at time of application

Kay 1986, Merret 1993, CLOTS 2001

Outcome: DVT during scheduled treatment period

0.43 [0.14-1.38]1.00 [0.21-4.67]

OR 95% CITreatment Control OR 95% CIStudy

Muir 2000 7/65 7/32Prasad 1982 6/13 6/13

Total (95% CI) 13/78 13/45

0.1 0.2 1 5 10

Favor Treatment Favor Control

Physical Methods vs. Control for prevention of DVT in Stroke

0.59 [0.24-1.48]

Less DVTs with prophylaxis

Cochrane review

Physical Methods vs. Control for prevention of DVT in Stroke

Favor Treatment Favor Control

5.06 [0.96-26.78]5.06 [0.96-26.78]

Outcome: death from any cause during scheduled treatment period

0.1 0.2 1 5 10

Muir 2000 9/13 4/13

Total (95% CI) 9/13 4/13

OR 95% CITreatment Control OR 95% CIStudy

Less deaths with prophylaxis

Cochrane review

Systematic Review of Trials Comparing LMWH w UFH in Acute Ischemic Stroke: Effects on DVT

Results expressed as Peto odds ratio (OR) with a fixed-effects model. OR <1 suggests LMWH superior to UFH.

Enoxaparin vs. standard UFH

Hilbom 1998 14/106 24/106

Subtotal 14/106 24/106

Total (95% CI) 55/414 65/291

0.53 (0.26-1.06)0.53 (0.26-1.06)

0.52 (0.35-0.79)

0.1 0.2 6 10

Counsell C, Sandercock P (Cochrane Review)

Less DVT with LMWH vs. UFH

VTE Prophylaxis Post Trauma, SCIs and Craniotomy

Leg DVT in Trauma Patients

Fisher, J Ortho Trauma 1995, Kaufman, Angiology 1983, Geerts, NEJM 1996, KUDSK, Am J Surgery 1989 Geerts Injury 1996

RRR for LMWH vs. UFH

All DVT: 30% reduction (p=0.01)

Proximal DVT: 58% reduction (p=0.01)

Incidence w/o prophylaxis Incidence w prophylaxis

US studiesUp to 30%

Venography28-63%

Enoxaparin31% (40/129)

UFH44% (60/136)

UFH 5000 q 8 hrs and IPC vs. Lovenox 30 mg q 12 hrs in Acute SCI

• 1995-1998, 27 acute SCI centers in USA and Canada

• Patients > 15 years

• Traumatic SCI (C2-T12)within 72 hours

• American Spinal Injury Association (ASIA) impairment classification A, B, and C

• Bleeding (SC, ICH, other site), Coagulopathy, GI bleed within 2 weeks

• Pregnancy

• Inability to use IPC, perform US or venography, administer Heparin or contrast agents

• Uncontrolled HTN, S Creat. > 2.0, requirement for AC, Spinal surgery planned in 2 weeks, use of ASA, NSAIDS, or Ketorolac

Exclusion CriteriaInclusion Criteria

Spinal Cord Injury Thromboprophylaxis Investigators, J Trauma 2003;54:1116-1126

2 Weeks Acute Treatment Phase

VTE: termination from the study

2 weeks(bilateral venography + DUS)

6 Weeks Rehabilitation Phase

No VTE

No VTEEnoxaparin 40 mg q.d.

UFH 5000 U q 8h + ICP

8 weeks(DUS)

STUDY DESIGN

Randomization

< 72 hours After injury

UFH 5000 U q 8h + ICP

Enoxaparin 30 mg q 12 h

246 pts

230 pts

Spinal Cord Injury Thromboprophylaxis Investigators, J Trauma 2003;54:1116-1126

Outcome UFH + IPC Enoxaparin P Value

(n = 49) (%) (n = 58) (%) All VTE 31 (63.3) 38 (65.5) 0.81

DVT 22 (44.9) 35 (60.3) 0.11

PE 9 (18.4) 3 (5.2) 0.03

Symptomatic DVT 1 (2.0) 1 (1.7) -

Fatal PE 0 (0.0) 0 (0.0) -

Efficacy Outcomes in Assessable Patients with Adequate Proximal and Distal Diagnostic Imaging or Evidence of PE (N = 107)

Spinal Cord Injury Thromboprophylaxis Investigators, J Trauma 2003;54:1116-1126

FactorOdds Ratio

(95% CI) P Value

Age (per yr) 1.06 (1.03-1.1) <0.01

Age Category

( > 50 vs. < 50 )

7.21 (2.0-25.95) <0.01

Time from injury to 1st dose of study

medication

1.56 (0.98-2.47) 0.05

Days to venography 1.26 (0.97-1.63) 0.05

Analysis of Selected Risk Factors of VTE Despite Use of ProphylaxisIn Assessable Patients with Adequate Proximal and Distal Venography

Or Positive Proximal US or Evidence of PE

Spinal Cord Injury Thromboprophylaxis Investigators, J Trauma 2003;54:1116-1126

Outcome UFH + IPC Enoxaparin P Value

(n = 249) (%) (n = 230) (%) Major Bleeding 13 (5.3) 6 (2.6) 0.14

Minor Bleeding 44 (17.9) 34 (14.8) 0.43

Discontinuation

b/c of bleeding

9 (3.7) 6 (2.6) 0.51

Deaths 2 (0.8) 2 (0.9) 0.95

Safety Events during Acute Treatment in theRandomized Population (N = 476)

Spinal Cord Injury Thromboprophylaxis Investigators, J Trauma 2003;54:1116-1126

LMWH for VTE prophylaxis after Craniotomy and Spinal Surgery

307 patients post elective craniotomy or spinal surgery97% had brain tumors

All received graduated compression stockings

Enoxaparin 40 mg/d

RANDOMIZED

Placebo

DVT: 17% DVT: 32%42% RRR

NEJM 1998;339:80-85

Multimodality Prophylaxis After Craniotomy for Brain Tumors

150 pts All had PCD

And GCS

Rabdomized

Enoxaparin 40 mg/d

UFH 5000 q 12 hrs

Pre-discharge Venous US

Symptomatic VTE: 0%Asymptomatic VTE: 9.3% (10/14 had calf DVT)

Chest 2002;122;1933-1937

Strategies for decreasing the Incidence of VTE after Acute Ischemic Stroke, SCI,

and Post craniotomy

• Effective and optimal in-patient prophylaxis

• ? Extended out of hospital prophylaxis

• ? Early diagnosis of subclinical VTE (screening serial US, D-Dimer, MRV)

• ? Multi-modality approach

• Prompt diagnosis and treatment of clinically apparent VTE (saves life and prevents recurrence)