Stroke: Year in Review 2007 South Carolina Society of Health-System Pharmacists Spring Symposium April D. Miller, PharmD South Carolina College of Pharmacy-

Stroke: Year in Review 2007Stroke: Year in Review 2007

South Carolina Society of Health-System South Carolina Society of Health-System Pharmacists Spring SymposiumPharmacists Spring Symposium

April D. Miller, PharmDApril D. Miller, PharmDSouth Carolina College of Pharmacy-South Carolina College of Pharmacy-

USC CampusUSC Campus

True or FalseTrue or False

Warfarin therapy is generally Warfarin therapy is generally contraindicated in atrial contraindicated in atrial

fibrillation patients greater fibrillation patients greater than 75 years of age due to than 75 years of age due to

fall and bleeding riskfall and bleeding risk

Which of the following agents Which of the following agents can be used for DVT can be used for DVT

prophylaxis in patients with prophylaxis in patients with ischemic stroke?ischemic stroke?

A: EnoxaparinA: EnoxaparinB: Unfractionated heparinB: Unfractionated heparinC: FondaparinuxC: FondaparinuxD: AbciximabD: Abciximab

ObjectivesObjectives

Discuss new evidence for antiplatelet and Discuss new evidence for antiplatelet and anticoagulant therapy for stroke preventionanticoagulant therapy for stroke prevention

Present evidence on the use of DVT Present evidence on the use of DVT prophylaxis in stroke patientsprophylaxis in stroke patients

Explain recent studies on non-Explain recent studies on non-pharmacologic issues in stroke carepharmacologic issues in stroke care

Epidemiology of StrokeEpidemiology of Stroke

33rdrd leading cause of death in United States leading cause of death in United States

Approximately 550,000 cases per yearApproximately 550,000 cases per year

Leading cause of disability Leading cause of disability

National Vital Statistics Reports 2007

Disability Due to StrokeDisability Due to Stroke

0

10

20

30

40

50

60

70

80

Require Assistancewith ADLs

Require Assistancewith Ambulation

Impaired VocationalCapacity

% o

f S

trok

e S

urvi

vors

31% 20%

71%

Heart and Stroke Facts: 1996 Statistical Supplement

Antithrombotics and Primary Antithrombotics and Primary Stroke Prevention GuidelinesStroke Prevention Guidelines

““Antithrombotic therapy (warfarin or Antithrombotic therapy (warfarin or aspirin) is recommended to prevent stroke aspirin) is recommended to prevent stroke in patients with non-valvular atrial in patients with non-valvular atrial fibrillation according to assessment of their fibrillation according to assessment of their absolute stroke risk, estimated bleeding absolute stroke risk, estimated bleeding risk, patient preferences, and access to risk, patient preferences, and access to high quality anticoagulation monitoring.” high quality anticoagulation monitoring.” (Class I, Level A evidence)(Class I, Level A evidence)

Stroke 2006;37:1583-1633

Majority of elderly patients do not receive Majority of elderly patients do not receive warfarin therapy warfarin therapy

Study aim: Determine risk versus benefit Study aim: Determine risk versus benefit of warfarin in an elderly populationof warfarin in an elderly population

Lancet 2007;370:493-503

BAFTABAFTA

Study design: prospective, randomized, Study design: prospective, randomized, open-label with blind endpoint assessmentopen-label with blind endpoint assessment

Primary objective is compare frequency:Primary objective is compare frequency:– Fatal and non-fatal hemorrhagic or ischemic Fatal and non-fatal hemorrhagic or ischemic

strokestroke– Intracranial hemorrhageIntracranial hemorrhage– Clinically significant arterial embolismClinically significant arterial embolism

Lancet 2007;370:493-503

BAFTABAFTA

PatientsPatients– Inclusion criteria:Inclusion criteria:

Age > 75 (mean age 81.5 years)Age > 75 (mean age 81.5 years)Atrial fibrillation diagnosed by ECG within 2 yearsAtrial fibrillation diagnosed by ECG within 2 years

– Exclusion criteriaExclusion criteriaRheumatic heart diseaseRheumatic heart diseaseMajor, non-traumatic hemorrhage or ICH within 5 Major, non-traumatic hemorrhage or ICH within 5 yearsyearsPeptic ulcer disease or esophageal varicesPeptic ulcer disease or esophageal varicesBP > 180/110BP > 180/110

Lancet 2007;370:493-503

BAFTABAFTA

Interventions: Aspirin 75mg (n= 488) daily Interventions: Aspirin 75mg (n= 488) daily versus warfarin (n= 485) with target INR 2-3 x versus warfarin (n= 485) with target INR 2-3 x 5.5 years5.5 years– Frequency or method of INR monitoring not altered by Frequency or method of INR monitoring not altered by

studystudy

Results: Results: – Ischemic stroke: Warfarin 1.6% versus Aspirin 3.4% Ischemic stroke: Warfarin 1.6% versus Aspirin 3.4%

RR: 0.46, ARR: 1.8%, NNT: 56, P=0.003RR: 0.46, ARR: 1.8%, NNT: 56, P=0.003

– Major hemorrhage: Warfarin 1.9% versus Aspirin 2%, Major hemorrhage: Warfarin 1.9% versus Aspirin 2%, P=0.74P=0.74

Lancet 2007;370:493-503

BAFTABAFTA

Discussion: Discussion: – Selection bias for low-risk stroke patientsSelection bias for low-risk stroke patients– Patients potentially at lower risk for bleedingPatients potentially at lower risk for bleeding

Conclusion:Conclusion:– Warfarin is effective and safe for stroke Warfarin is effective and safe for stroke

prevention in elderly patients with atrial prevention in elderly patients with atrial fibrillationfibrillation

Lancet 2007;370:493-503

Background: Up to 75% of patients with Background: Up to 75% of patients with hemiplegia post-stroke develop DVT and hemiplegia post-stroke develop DVT and 20% develop PE20% develop PE– Unfractionated Heparin and Low Molecular Unfractionated Heparin and Low Molecular

Weight Heparin (LMWH) are shown to be Weight Heparin (LMWH) are shown to be beneficialbeneficial

– Optimal agent unknownOptimal agent unknownLancet 2007;369:1347-55

PREVAIL: DVT ProphylaxisPREVAIL: DVT Prophylaxis

Study design: Prospective, randomized, Study design: Prospective, randomized, open-label trialopen-label trial– Randomization stratified based on stroke Randomization stratified based on stroke

severity (severe- NIHSS severity (severe- NIHSS >> 14, less severe 14, less severe NIHSS < 14)NIHSS < 14)

Primary endpoint: cumulative occurrence Primary endpoint: cumulative occurrence of confirmed venous thromboembolismof confirmed venous thromboembolismSecondary endpoints: ICH, Secondary endpoints: ICH, thrombocytopenia, adverse events thrombocytopenia, adverse events

Lancet 2007;369:1347-55

PREVAIL: DVT ProphylaxisPREVAIL: DVT Prophylaxis

Interventions initiated within 48 hours of Interventions initiated within 48 hours of stroke symptoms and continued ~10days:stroke symptoms and continued ~10days:– Enoxaparin 40mg SC daily (n=604) OREnoxaparin 40mg SC daily (n=604) OR– Unfractionated heparin 5000 units SC q12h Unfractionated heparin 5000 units SC q12h

(n=609)(n=609)

ResultsResults– Frequency of VTE at day 14Frequency of VTE at day 14

Enoxaparin 10% versus UFH 18%Enoxaparin 10% versus UFH 18%

P= 0.0001, RRR= 43%, ARR= 8%, NNT= 13P= 0.0001, RRR= 43%, ARR= 8%, NNT= 13

Lancet 2007;369:1347-55

PREVAIL: DVT ProphylaxisPREVAIL: DVT Prophylaxis

PREVAIL: DVT ProphylaxisPREVAIL: DVT Prophylaxis

ResultsResults– Bleeding at end of treatment + 48hBleeding at end of treatment + 48h

Enoxaparin and UFH = 8%Enoxaparin and UFH = 8%

– Extracranial hemorrhage incidence slightly Extracranial hemorrhage incidence slightly increased in enoxaparin group (1% n= 7 increased in enoxaparin group (1% n= 7 versus 0)versus 0)

Lancet 2007;369:1347-55

PREVAIL: DVT ProphylaxisPREVAIL: DVT Prophylaxis

Important considerationsImportant considerations– 95% of DVTs detected were asymptomatic 95% of DVTs detected were asymptomatic

and detected routine venography and detected routine venography – Comparison with BID unfractionated heparinComparison with BID unfractionated heparin

ConclusionsConclusions– Enoxaparin more effective for DVT Enoxaparin more effective for DVT

prophylaxis in ischemic strokeprophylaxis in ischemic stroke– Increased incidence of clinically significant Increased incidence of clinically significant

bleeding with enoxaparinbleeding with enoxaparinLancet 2007;369:1347-55

NEJM 2007;357:2262-8

Pooled analysis of 3 prior studies (93 Pooled analysis of 3 prior studies (93 patients total)patients total)– DECIMALDECIMAL– DESTINYDESTINY– HAMLETHAMLET

Lancet Neurol 2007;6:215-22

Patient OutcomesPatient Outcomes

2%

14%

19%

29%

2%

31%

5%

4%

71%

22%

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

1

2

MRS-2 MRS-3 MRS-4 MRS-5 Death

Su

rge

ryC

on

serv

ativ

e

Lancet Neurol 2007;6:215-22

Stroke 2008;39:30-35

Northern Manhattan StudyNorthern Manhattan StudyMetabolic Syndrome and Ischemic Stroke RiskMetabolic Syndrome and Ischemic Stroke Risk

Upcoming StudiesUpcoming Studies

FASTER: Fast Assessment of Stroke and FASTER: Fast Assessment of Stroke and TIA to prevent Early RecurenceTIA to prevent Early Recurence– Use of clopidogrel, aspirin and simvastatin to Use of clopidogrel, aspirin and simvastatin to

reduce subsequent stroke in patients reduce subsequent stroke in patients presenting with TIApresenting with TIA

SELESTIAL: Trial of insulin to control SELESTIAL: Trial of insulin to control blood sugar after acute stroke using MRI blood sugar after acute stroke using MRI endpointsendpoints

http://www.clinicaltrials.gov

Upcoming StudiesUpcoming Studies

PRoFESS: Prevention Regimen for PRoFESS: Prevention Regimen for Effectively avoiding Second StrokesEffectively avoiding Second Strokes– Aspirin/dipyridamole versus clopidogrelAspirin/dipyridamole versus clopidogrel

CLEAR stroke: Combined approach to CLEAR stroke: Combined approach to Lysis utilizing eptifibatide and rt-TPA in Lysis utilizing eptifibatide and rt-TPA in acute ischemic stroke acute ischemic stroke

http://www.clinicaltrials.gov

True orTrue or FalseFalse

Warfarin therapy is generally Warfarin therapy is generally contraindicated in atrial contraindicated in atrial

fibrillation patients greater fibrillation patients greater than 75 years of age due to than 75 years of age due to

fall and bleeding riskfall and bleeding risk

Which of the following agents Which of the following agents can be used for DVT can be used for DVT

prophylaxis in patients with prophylaxis in patients with ischemic stroke?ischemic stroke?

A: EnoxaparinA: EnoxaparinB: Unfractionated HeparinB: Unfractionated HeparinC: FondaparinuxC: FondaparinuxD: AbciximabD: Abciximab

ReferencesReferencesMinino AM, Heron MP, Murphy SL, et al. Deaths: Final data for 2004. National Vital Minino AM, Heron MP, Murphy SL, et al. Deaths: Final data for 2004. National Vital Statistics Reports; 55 (19). Hyattsville, MD: National Center for Health Statistics Statistics Reports; 55 (19). Hyattsville, MD: National Center for Health Statistics 2007.2007.Heart and Stroke Facts: 1996 Statistical supplement. Dallas: American Heart Heart and Stroke Facts: 1996 Statistical supplement. Dallas: American Heart Association 1996.Association 1996.Goldstein LB, Adams R, Alberts MJ, et al. Primary prevention of ischemic stroke. Goldstein LB, Adams R, Alberts MJ, et al. Primary prevention of ischemic stroke. Stroke 2006;37:1583-1633.Stroke 2006;37:1583-1633.Mant J, Hobbs R, Fletcher K et al. Warfarin versus aspirin for stroke prevention with Mant J, Hobbs R, Fletcher K et al. Warfarin versus aspirin for stroke prevention with atrial fibrillation (BAFTA): a randomised controlled trial. Lancet 2007;370: 493-503atrial fibrillation (BAFTA): a randomised controlled trial. Lancet 2007;370: 493-503Sherman DG, Albers GW, Bladin C, et al. The efficacy and safety of enoxaparin Sherman DG, Albers GW, Bladin C, et al. The efficacy and safety of enoxaparin versus unfractionated heparin for the prevention of VTE after acute ischemic stroke versus unfractionated heparin for the prevention of VTE after acute ischemic stroke (PREVAIL study): an open-label randomised comparison. Lancet 2007;369:1347-55(PREVAIL study): an open-label randomised comparison. Lancet 2007;369:1347-55Handke M, Harloff A, Olschewski M, et al. Patent foramen ovale and cryptogenic Handke M, Harloff A, Olschewski M, et al. Patent foramen ovale and cryptogenic stroke in older patients. N Eng J Med 2007;357:2262-8stroke in older patients. N Eng J Med 2007;357:2262-8Vahedi K, Hofmejer J, Juettler E, et al. Early decompressive surgery in malignant Vahedi K, Hofmejer J, Juettler E, et al. Early decompressive surgery in malignant infarction of the MCA: a pooled analysis of three randomised trials. Lancet Neurol infarction of the MCA: a pooled analysis of three randomised trials. Lancet Neurol 2007;6:215-22.2007;6:215-22.Boden-Albala B, Sacco RL, Lee HS. Metabolic syndrome and ischemic stroke risk. Boden-Albala B, Sacco RL, Lee HS. Metabolic syndrome and ischemic stroke risk. Stroke 2008;39:30-35Stroke 2008;39:30-35

Stroke: Year in Review 2007Stroke: Year in Review 2007

South Carolina Society of Health-System South Carolina Society of Health-System Pharmacists Spring SymposiumPharmacists Spring Symposium

April D. Miller, PharmDApril D. Miller, PharmDSouth Carolina College of Pharmacy-South Carolina College of Pharmacy-

USC CampusUSC Campus