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STROKE PREVENTION- A REALITY     IN THIS MILLENNIUM       Prof. A.V. SRINIVASAN,       MD, DM, Ph.D, F.A.A.N, F.I.A.N.    ...
Cerebrovascular                Prevention Is survival a mere stroke of Luck?“My Opinions are founded on knowledge but modi...
INTRODUCTION Perceptual Sense(Observation) Word Sense (Recording) Common Sense (Thinking)     Will lead you to get - C...
Cerebrovascular disease –        Mind boggling facts World wide incidence: 2/1000 population/annum 1 Incidence in people...
Annual risk CVD, MI, vascular death    following TIA, minor CVD• CVD                                           6.7 %• MI  ...
Common Stroke Mimics   Hypoglycemia   Post ictal state   Drug overdose   Concussion with neck injury   Migrainous acc...
Drugs used for stroke    prevention…    ACE inhibitors   Lipid lowering agent     Anti-platelets
Prevention ofCerebrovascular Events      with Perindopril:           New Evidence
Why ACE inhibitors in stroke        prevention ? Blood pressure lowering effect Prevention of endothelial dysfunction P...
Objective of PROGRESSWhether in patients with…                             Stroke               OR     TIA                ...
Patient selection criteria                                      Evidence of                                      Stroke / ...
Patient selection criteria                                               Young            Diabetic                        ...
Baseline characteristics Characteristic                                   Perindopril + indapamide   Placebo              ...
Total stroke                                                                             28%                              ...
Stroke subtype (1)                            Fatal /                      Non fatal /                             disabli...
Stroke subtype (2)                                      Ischaemic          Haemorrhagic                                   ...
Hypertensives / normotensives                                                 Stroke                              Hyperten...
Treatment acceptability                                                                       Active group    Causes of wi...
PROGRESS results showed… Perindopril+ indapamide substantially  reduced risk of secondary stroke and  other vascular even...
Summarise… ACE inhibitors are beneficial in the  prevention of stroke All stroke patients, hypertensive as well as  norm...
Which ACE inhibitor ?    Treatment                                  Number-needed-to-treat     Perindopril-               ...
Statins: Stroke Prevention andSurvival Benefits
Primary Prevention of Ischemic Stroke     A Guideline From the American Heart        Association/American Stroke          ...
JUPITER & STROKE   JUPITER is the first large-scale, prospective    study to examine the role of statin therapy in    ind...
JUPITER                 JUPITERTrial Design Multi-National Randomized Double Blind Placebo Controlled                     ...
JUPITER: Results                 No. of patients with any stroke       70                                    64       60  ...
JUPITER: Results             No. of patients with non-fatal stroke       60                                    58       50...
JUPITER: Results              No. of patients with fatal stroke      6                                    6               ...
JUPITER: Results             No. of patients with ischemic stroke        50                                   47        45...
Primary Prevention of        Stroke:What do the previousstatins trials suggest?
WOSCOPS STUDY: Statin: Pravastatin 40 mg        AFCAPS/TexCAPS STUDY: n=6595                           Statin: Lovastatin ...
A meta-analysis of WOSCOPS+AFCAPS/TexCAPS+MEGA             •Stroke reduction by 14% (statistically non-             signif...
Summary Stroke is one of the leading cause of  death worldwide. Guidelines recommends the use of statins  for primary as...
Symptomatic Carotid        Endarterectomy ASA 2006         Secondary Stroke Recs• Ipsilateral severe (70% to 99%) carotid ...
Urgent EndarterectomySurgery within 2 weeks is suggested rather than delaying surgery(Class IIa, Evidence B).Rothwell PM. ...
Carotid Angioplasty and Stenting   ASA 2006 Secondary Stroke               Recs• CAS may be considered (Class IIb, Evidenc...
Atrial Fibrillation    ASA 2006 Recommendations• For patients with ischemic stroke or TIA withpersistent or paroxysmal (in...
Stroke Prevention:        Non-cardioembolic   ASA 2006 RecommendationsFor patients with noncardioembolic ischemicstroke or...
Stroke Prevention: Non-          cardioembolic   ASA 2006 Recommendations• Acceptable options for initial therapy    (Clas...
Antiplatelet Therapy ASA 2006 Recommendations• Compared to aspirin alone, both the combination ofaspirin and extended-rele...
Secondary Stroke Prevention     ASA 2006 Recommendations• Insufficient data are available to make evidence-based recommend...
Secondary Stroke Prevention  ASA 2006 Recommendations• The addition of aspirin to clopidogrel increasesthe risk of hemorrh...
MATCH: Safety Outcomes  • Excess life-threatening bleeding events with  combination versus clopidogrel monotherapy:       ...
Secondary Stroke Prevention ASA 2006 Recommendations• For patients who have an ischemiccerebrovascular event while taking ...
Stroke and PregnancyASA 2006 Secondary Stroke Recs• High-risk thromboembolic conditions consider:   - adjusted-dose UFH th...
Postmenopausal HormonesASA 2006 Secondary Stroke RecsFor women with ischemic stroke or TIA,postmenopausal hormone therapy ...
Women’s Health Initiative   • 16,608 postmenopausal women, 50-79 years,   with an intact uterus at baseline were recruited...
Other CircumstancesASA 2006 Secondary Stroke Recs• Dissections• PFO and hyperhomocysteinemia• Hypercoagulable states• Sick...
Level A Recommendations• Antihypertensive treatment• Glucose control to reduce microvascularcomplications of diabetes• Sta...
Carotid Angioplasty and Stenting  ASA 2006 Secondary Stroke Recs• CAS may be considered (Class IIb, Evidence B).   - Steno...
Other CircumstancesASA 2006 Secondary Stroke Recs• Dissections• PFO and hyperhomocysteinemia• Hypercoagulable states• Sick...
Level A Recommendations• Antihypertensive treatment• Glucose control to reduce microvascularcomplications of diabetes• Sta...
PROGNOSTIC PEARLS   Flaccid Paralysis for more than 96 hrs   When tendon reflexes recover without return of voluntary   ...
CVD – Prevention or Cure?While number of curative methods are    available, preventive therapy is undoubtedly the main str...
Dedicated to my family formaking everything worthwhile
READ not to contradict or confuteNor to Believe and Take for Grantedbut TO WEIGH AND CONSIDERTHANK YOUMy sincere thanks to...
Stroke prevention a reality in this millennium
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Stroke prevention a reality in this millennium

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Stroke prevention a reality in this millennium

  1. 1. STROKE PREVENTION- A REALITY IN THIS MILLENNIUM Prof. A.V. SRINIVASAN, MD, DM, Ph.D, F.A.A.N, F.I.A.N. Emeritus Professor The Tamilnadu Dr. M.G.R. Medical University Former Head Institute of Neurology, Madras Medical College 21-08-10
  2. 2. Cerebrovascular Prevention Is survival a mere stroke of Luck?“My Opinions are founded on knowledge but modified by experience”
  3. 3. INTRODUCTION Perceptual Sense(Observation) Word Sense (Recording) Common Sense (Thinking)  Will lead you to get - Clinical Sense “ He who cannot forgive others destroys the bridge over which he himself must pass” - Annoy
  4. 4. Cerebrovascular disease – Mind boggling facts World wide incidence: 2/1000 population/annum 1 Incidence in people aged 45 – 84 years: about 4/1000 1 Incidence in India: was 36/100,000 for the year 1998-1999 3 in a study in Calcutta Incidence of mortality due to stroke (India: WHO study): 73/100,000 per year2CVD is the most disabling of all neurologic diseases.50% of survivors have a residual neurologic deficit. Greater than 25% require chronic care. 1.A practical approach to management of stroke patients; 1996; 360-384 2. Epidemology of cerebrovascular disorders in India; 1999; 4-19 3. Neuroepidemiology 2001;20:201-207 If you think you can or you can’t You are always right
  5. 5. Annual risk CVD, MI, vascular death following TIA, minor CVD• CVD 6.7 %• MI 2.5 %• Death 7.2 %• CVD, MI, Vascular death 8.6 %• CVD, MI, Death 10.3 % Experience can be defined as yesterday’s answer to today’s problems
  6. 6. Common Stroke Mimics Hypoglycemia Post ictal state Drug overdose Concussion with neck injury Migrainous accompaniment Encephalopathies with focal signs Hyponatremia Subdural hematoma, Empyema Focal Encephalitis: Herpes Being ignorant is not so much a shame as being unwilling to learn
  7. 7. Drugs used for stroke prevention… ACE inhibitors Lipid lowering agent Anti-platelets
  8. 8. Prevention ofCerebrovascular Events with Perindopril: New Evidence
  9. 9. Why ACE inhibitors in stroke prevention ? Blood pressure lowering effect Prevention of endothelial dysfunction Prevention of progression of atherosclerosis Favourable alteration of the fibrinolytic balance Prevention of cardiac remodelling Clinical evidence…
  10. 10. Objective of PROGRESSWhether in patients with… Stroke OR TIA Perindopril + Indapamide Risk of stroke & vascular events WHO – ISH initiated the studyPROGRESS collaborative group. Lancet 2001;358:1033-41.
  11. 11. Patient selection criteria Evidence of Stroke / TIA > 2 weeks and < 5 years of event …but without a definite indication / contraindication to treatment with an ACE inhibitorPROGRESS collaborative group. Lancet 2001;358:1033-41.
  12. 12. Patient selection criteria Young Diabetic Non-diabetic IncludedHypertensive Normotensive OldPROGRESS collaborative group. Lancet 2001;358:1033-41.
  13. 13. Baseline characteristics Characteristic Perindopril + indapamide Placebo N = 3051 N = 3054 Mean age (yrs) 64 64 Females (%) 30 30 Stroke history  Ischaemic stroke (%) 71 71  Haemorrhagic stroke (%) 11 11  TIA (%) 22 22  Duration since event (months) 8 8 Diabetes (%) 13 12 CAD (%) 16 16 Mean BP (mmHg) 147/86 147/86 Hypertension (%) 48 48 Antihypertensive therapy (%) 50 51PROGRESS collaborative group. Lancet 2001;358:1033-41.
  14. 14. Total stroke 28% 28% Placebo group risk risk reduction Risk reduction (%) reduction 38% Active group 0 1 2 3 4 YearsPROGRESS collaborative group. Lancet 2001;358:1033-41.
  15. 15. Stroke subtype (1) Fatal / Non fatal / disabling stroke disabling stroke 24 33 Risk reduction (%)PROGRESS collaborative group. Lancet 2001;358:1033-41.
  16. 16. Stroke subtype (2) Ischaemic Haemorrhagic stroke stroke 24 50 Risk reduction (%)PROGRESS collaborative group. Lancet 2001;358:1033-41.
  17. 17. Hypertensives / normotensives Stroke Hypertensives Normotensives 27 32 Risk reduction (%)PROGRESS collaborative group. Lancet 2001;358:1033-41.
  18. 18. Treatment acceptability Active group Causes of withdrawal (%) Placebo 23 21 8 8 2 2 0.9 0.4 All causes Voluntary Cough HypotensionPROGRESS collaborative group. Lancet 2001;358:1033-41.
  19. 19. PROGRESS results showed… Perindopril+ indapamide substantially reduced risk of secondary stroke and other vascular events Irrespective of  Age  Blood pressure level  Other diseases  Background medication PROGRESS collaborative group. Lancet 2001;358:1033-41.
  20. 20. Summarise… ACE inhibitors are beneficial in the prevention of stroke All stroke patients, hypertensive as well as normotensives should receive an ACE inhibitor All CAD patients, diabetic patients, who are at-risk of developing stroke should receive an ACE inhibitor Which ACE inhibitor ?
  21. 21. Which ACE inhibitor ? Treatment Number-needed-to-treat Perindopril- 23 to prevent based therapy 1 stroke in 5 years Ramipril-based 67 to prevent therapy 1 stroke in 5 years JNC – 7 reference only to perindoprilStroke 2002;33:862-875. JNC-7, JAMA May 2003 – Vol.289; No.19: 2560-2571.
  22. 22. Statins: Stroke Prevention andSurvival Benefits
  23. 23. Primary Prevention of Ischemic Stroke A Guideline From the American Heart Association/American Stroke Association Stroke Council It is recommended that patients with known CAD and high-risk hypertensive patients even with normal LDL cholesterol levels be treated with lifestyle measures and a statin (Class I, Level of Evidence A). Stroke 2006;37;1583-1633
  24. 24. JUPITER & STROKE JUPITER is the first large-scale, prospective study to examine the role of statin therapy in individuals with low to normal LDL-C levels, but with increased cardiovascular risk identified by elevated CRP Nearly half of all cardiovascular events occur in patients who are apparently healthy and who have low or normal levels of LDL-C hsCRP predicts cardiovascular disease independent of LDL-C levels
  25. 25. JUPITER JUPITERTrial Design Multi-National Randomized Double Blind Placebo Controlled Trial of Rosuvastatin in the Prevention of Cardiovascular Events Among Individuals With Low LDL and Elevated hsCRP Rosuvastatin 20 mg (N=8901)No Prior CVD or DM Men >50, Women >60 LDL <130 mg/dL 4-week Placebo (N=8901) hsCRP >2 mg/L run-in Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica, Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands, Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland, United Kingdom, Uruguay, United States, Venezuela Ridker et al, Circulation 2003;108:2292-2297.
  26. 26. JUPITER: Results No. of patients with any stroke 70 64 60 48% 50 Reduction 40 33 * 30 20 10 0 Rosuvastatin Placebo n=8901 n=8901 Circulation 2010;121:143-150* p< 0.002 vs. placebo
  27. 27. JUPITER: Results No. of patients with non-fatal stroke 60 58 50 48% 40 Reduction 30 * 30 20 10 0 Rosuvastatin Placebo n=8901 n=8901 Circulation 2010;121:143-150* p< 0.003 vs. placebo
  28. 28. JUPITER: Results No. of patients with fatal stroke 6 6 50% 5 Reduction 4 3 3 2 1 0 Rosuvastatin Placebo n=8901 n=8901Circulation 2010;121:143-150
  29. 29. JUPITER: Results No. of patients with ischemic stroke 50 47 45 51% 48% 40 35 Reduction 30 * 23 25 20 15 10 5 0 Rosuvastatin Placebo n=8901 n=8901 Circulation 2010;121:143-150* p< 0.004 vs. placebo
  30. 30. Primary Prevention of Stroke:What do the previousstatins trials suggest?
  31. 31. WOSCOPS STUDY: Statin: Pravastatin 40 mg AFCAPS/TexCAPS STUDY: n=6595 Statin: Lovastatin 10-40 mg Results: Stroke 11% n=6605 Results: Stroke 18%MEGA STUDY: JUPITER STUDY:Statin: Pravastatin 10-20 mg Statin: Rosuvastatin 20 mgn=7730 n=17802Results: Stroke 17% Results: Stroke 48% Circulation 2010;121:143-150
  32. 32. A meta-analysis of WOSCOPS+AFCAPS/TexCAPS+MEGA •Stroke reduction by 14% (statistically non- significant)A meta-analysis of these 3 trials along with JUPITER •Stroke reduction by 25% (statistically significant)Analysis of JUPITER only:Stroke reduction by 48% (statistically non-significant)
  33. 33. Summary Stroke is one of the leading cause of death worldwide. Guidelines recommends the use of statins for primary as well as secondary prevention of stroke. JUPITER trial has established that rosuvastatin is the most effective statin in preventing stroke in high risk population.
  34. 34. Symptomatic Carotid Endarterectomy ASA 2006 Secondary Stroke Recs• Ipsilateral severe (70% to 99%) carotid stenosis,CEA is recommended (Class I, Evidence A).• Ipsilateral moderate (50% to 69%) carotid stenosis,CEA is recommended depending on age, gender,comorbidities, and the severity of symptoms (Class I,Evidence A).• Stenosis <50%, there is no indication for CEA (ClassIII, Evidence A).
  35. 35. Urgent EndarterectomySurgery within 2 weeks is suggested rather than delaying surgery(Class IIa, Evidence B).Rothwell PM. Lancet 2004;363(9413):915-24
  36. 36. Carotid Angioplasty and Stenting ASA 2006 Secondary Stroke Recs• CAS may be considered (Class IIb, Evidence B). - Stenosis (>70%) difficult to access surgically - Medical conditions that greatly increase the risk for surgery, or - When other circumstances exist such asradiation-induced stenosis or restenosis afterCEA.• CAS is reasonable when performed by operators with morbidity and mortality rates of 4% to 6% (Class IIa, Evidence B).
  37. 37. Atrial Fibrillation ASA 2006 Recommendations• For patients with ischemic stroke or TIA withpersistent or paroxysmal (intermittent) AF,anticoagulation with adjusted-dose warfarin (target INR2.5, range 2.0 to 3.0) is recommended (Class I,Evidence A).• For patients unable to take oral anticoagulants,aspirin 325 mg per day is recommended (Class I,Evidence A).
  38. 38. Stroke Prevention: Non-cardioembolic ASA 2006 RecommendationsFor patients with noncardioembolic ischemicstroke or TIA, antiplatelet agents arerecommended rather than oral anticoagulation toreduce the risk of recurrent stroke and othercardiovascular events (Class I, Evidence A).
  39. 39. Stroke Prevention: Non- cardioembolic ASA 2006 Recommendations• Acceptable options for initial therapy (Class IIa, Evidence A). - aspirin (50-325 mg qd) - the combination of aspirin and extended-release dipyridamole (25/200 mg bid) - clopidogrel (75 mg qd)
  40. 40. Antiplatelet Therapy ASA 2006 Recommendations• Compared to aspirin alone, both the combination ofaspirin and extended-release dipyridamole andclopidogrel are safe.• The combination of aspirin and extended-releasedipyridamole is suggested instead of aspirin alone(Class IIa, Level A).• Clopidogrel is suggested instead of aspirin alonebased on direct comparison trials(Class IIb, Level B).
  41. 41. Secondary Stroke Prevention ASA 2006 Recommendations• Insufficient data are available to make evidence-based recommendations regarding choices betweenantiplatelet options other than aspirin. Selection of anantiplatelet agent should be individualized based onpatient risk factor profiles, tolerance, and other clinicalcharacteristics.
  42. 42. Secondary Stroke Prevention ASA 2006 Recommendations• The addition of aspirin to clopidogrel increasesthe risk of hemorrhage and is not routinelyrecommended for stroke or TIA patients (ClassIII, Evidence A).• For patients allergic to aspirin, clopidogrel isrecommended (Class IIa, Evidence B).
  43. 43. MATCH: Safety Outcomes • Excess life-threatening bleeding events with combination versus clopidogrel monotherapy: 96 (2.6%) vs. 49 (1.3%); p<0.0001 • Excess minor bleeds with combination therapy versus clopidogrel alone: 120 (3.2%) vs. 39 (1.0%); p<0.0001Diener H-C et al. Lancet 2004;364:331-7
  44. 44. Secondary Stroke Prevention ASA 2006 Recommendations• For patients who have an ischemiccerebrovascular event while taking aspirin,there is no reliable evidence that increasing thedose of aspirin provides additional benefit.Although alternative antiplatelet agents areoften considered for these patients, no singleagent or combination has been specificallyevaluated in patients who have had an eventwhile receiving aspirin.
  45. 45. Stroke and PregnancyASA 2006 Secondary Stroke Recs• High-risk thromboembolic conditions consider: - adjusted-dose UFH throughout pregnancy, - adjusted-dose LMWH with Factor Xa monitoring - UFH or LMWH until week 13, followed bywarfarin until mid-3rd trimester, then UFH orLMWH in last trimester (Class IIb, EvidenceC).• Lower risk conditions - UFH or LMWH in the first trimester followed by - low-dose aspirin for the remainder of the pregnancy (Class IIb, Evidence C).
  46. 46. Postmenopausal HormonesASA 2006 Secondary Stroke RecsFor women with ischemic stroke or TIA,postmenopausal hormone therapy (with estrogenwith or without a progestin) is not recommended(Class III, Evidence A).
  47. 47. Women’s Health Initiative • 16,608 postmenopausal women, 50-79 years, with an intact uterus at baseline were recruited by 40 U.S. clinical centers for the period 1993- 1998. • Received conjugated equine estrogens, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, in 1 tablet (n = 8506) or placebo (n = 8102). • After a mean of 5.2 years of follow-up, the trial was stopped because of high rates of invasive breast cancer and the global index statistic supported risks exceeding benefits.Rossouw et al. JAMA 2002;288(3):321-33
  48. 48. Other CircumstancesASA 2006 Secondary Stroke Recs• Dissections• PFO and hyperhomocysteinemia• Hypercoagulable states• Sickle cell disease• Cerebral venous thrombosis• Anticoagulation after cerebral hemorrhage
  49. 49. Level A Recommendations• Antihypertensive treatment• Glucose control to reduce microvascularcomplications of diabetes• Statins to reduce LDL to <100 or <70 for high-risk patients (sympt CHD or athero)• CEA for sympt 50-99%• NO CEA for <50% sympt stenosis• Warfarin at INR 2.5 for Afib. (ASA if unable)• Antiplatelet for noncardioembolic• NO combination clopidogrel and ASA
  50. 50. Carotid Angioplasty and Stenting ASA 2006 Secondary Stroke Recs• CAS may be considered (Class IIb, Evidence B). - Stenosis (>70%) difficult to access surgically - Medical conditions that greatly increase the risk for surgery, or - When other circumstances exist such asradiation-induced stenosis or restenosis afterCEA.• CAS is reasonable when performed by operators with morbidity and mortality rates of 4% to 6% (Class IIa, Evidence B).
  51. 51. Other CircumstancesASA 2006 Secondary Stroke Recs• Dissections• PFO and hyperhomocysteinemia• Hypercoagulable states• Sickle cell disease• Cerebral venous thrombosis• Anticoagulation after cerebral hemorrhage
  52. 52. Level A Recommendations• Antihypertensive treatment• Glucose control to reduce microvascularcomplications of diabetes• Statins to reduce LDL to <100 or <70 for high-risk patients (sympt CHD or athero)• CEA for sympt 50-99%• NO CEA for <50% sympt stenosis• Warfarin at INR 2.5 for Afib. (ASA if unable)• Antiplatelet for noncardioembolic• NO combination clopidogrel and ASA
  53. 53. PROGNOSTIC PEARLS Flaccid Paralysis for more than 96 hrs When tendon reflexes recover without return of voluntary movement – prognosis poor Recovery of sensory less in usual to a degree. Postion sense recovers but not pain and temperature Recovery from Dysphasia is never complete Dysarthria usual improves and Dysphagia never improves Diplopia due to brain stem is usually permanent Conjugate gaze – recovers Vertigo improves but hearing loss is permanent Pseudobulbar palsy permanent “ByNature All Men/W en are alike but om byEducation widelydifferent”
  54. 54. CVD – Prevention or Cure?While number of curative methods are available, preventive therapy is undoubtedly the main strategy in the management of CVD Lijec Vjesn. 2003 Nov-Dec;125(11-12):322-8 The sign wasn’t placed there By the Big Printer in the sky
  55. 55. Dedicated to my family formaking everything worthwhile
  56. 56. READ not to contradict or confuteNor to Believe and Take for Grantedbut TO WEIGH AND CONSIDERTHANK YOUMy sincere thanks to Serdia pharmaceuticals

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