Stroke and VTE : A Deadly Combination Amjad AlMahameed, MD, MPH, FACP Division of Cardiology Beth Israel Deaconess Medical Center Boston, 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 death Most 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 post stroke) 33% had DVT on venogram after 9 weeks Stroke Day 2 Day 7Day 10Week 2Week 4Week 9 39% had PE on screening VQ scans VTE is Common After Stroke The 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 legCommonly 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 PE 37% Large PE 10% Fatal PE 10-15% Stroke 2000

Consequences of Asymptomatic Below-Knee (BK) DVT After Stroke ProximalExtension20% Silent PE 33% Usually small size PE, not massive Asymptomatic below the knee DVT is not as benign as once thought!!

Clinically Apparent But Untreated DVT Post Thrombotic Syndrome 30-90% Fatal PE 37% 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 craniotomy for brain tumorsVTE is the most frequent complication following craniotomy 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 % (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) ACQUIRED 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 INHERITED

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 ACQUIREDINHERITED

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 PharmacologicNonpharmacologic

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 [ ] 1.00 [ ] OR 95% CITreatmentControlOR 95% CIStudy Muir 20007/65 7/32 Prasad 19826/13 6/13 Total (95% CI)13/78 13/ Favor Treatment Favor Control Physical Methods vs. Control for prevention of DVT in Stroke 0.59 [ ] Less DVTs with prophylaxis Cochrane review

Physical Methods vs. Control for prevention of DVT in Stroke Favor Treatment Favor Control 5.06 [ ] Outcome: death from any cause during scheduled treatment period Muir /13 4/13 Total (95% CI) 9/13 4/13 OR 95% CITreatmentControlOR 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 /10624/106 Subtotal 14/10624/106 Total (95% CI) 55/414 65/ ( ) 0.52 ( ) 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 prophylaxisIncidence w prophylaxis US studies Up to 30% Venography 28-63% Enoxaparin 31% (40/129) UFH 44% (60/136)

UFH 5000 q 8 hrs and IPC vs. Lovenox 30 mg q 12 hrs in Acute SCI , 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 Criteria Inclusion Criteria Spinal Cord Injury Thromboprophylaxis Investigators, J Trauma 2003;54:

2 Weeks Acute Treatment Phase VTE: termination from the study 2 weeks (bilateral venography + DUS) 6 Weeks Rehabilitation Phase No VTE Enoxaparin 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:

Outcome UFH + IPC Enoxaparin P Value (n = 49) (%) (n = 58) (%) All VTE31 (63.3)38 (65.5)0.81 DVT22 (44.9)35 (60.3)0.11 PE9 (18.4)3 (5.2)0.03 Symptomatic DVT1 (2.0)1 (1.7)- Fatal PE0 (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:

Factor Odds Ratio (95% CI) P Value Age (per yr)1.06 ( )<0.01 Age Category ( > 50 vs. < 50 ) 7.21 ( )<0.01 Time from injury to 1 st dose of study medication 1.56 ( )0.05 Days to venography1.26 ( )0.05 Analysis of Selected Risk Factors of VTE Despite Use of Prophylaxis In 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:

Outcome UFH + IPC Enoxaparin P Value (n = 249) (%) (n = 230) (%) Major Bleeding13 (5.3)6 (2.6)0.14 Minor Bleeding44 (17.9)34 (14.8)0.43 Discontinuation b/c of bleeding 9 (3.7)6 (2.6)0.51 Deaths2 (0.8)2 (0.9)0.95 Safety Events during Acute Treatment in the Randomized Population (N = 476) Spinal Cord Injury Thromboprophylaxis Investigators, J Trauma 2003;54:

LMWH for VTE prophylaxis after Craniotomy and Spinal Surgery 307 patients post elective craniotomy or spinal surgery 97% 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;

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)