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Stroke PROTECT

Stroke PROTECT. Statins and Lifestyle Modification Approaches. Presentation Overview. Recurrent stroke risk factors Stroke prevention evidence – practice gap Rationale for Statin intervention in stroke prevention PROTECT program results [Statin utilization]

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Stroke PROTECT

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  1. Stroke PROTECT Statins and Lifestyle Modification Approaches

  2. Presentation Overview • Recurrent stroke risk factors • Stroke prevention evidence – practice gap • Rationale for Statin intervention in stroke prevention • PROTECT program results [Statin utilization] • Rationale for lifestyle modification approaches in stroke prevention • PROTECT program results [lifestyle modification compliance]

  3. Recurrent Stroke Predictors Hankey, Cerebrovasc Dis 2003

  4. Modifiable Stroke Risk Factors • Behaviors • Cigarette smoking • Heavy alcohol use • Physical inactivity Medical Conditions • Prior TIA or stroke • Hypertension • Cardiac disease • Atrial fibrillation • Hyperlipidemia • Diabetes mellitus • Carotid stenosis • Elevated homocysteine

  5. Risk Factor Control: Impact on Stroke Prevention • >750,000 strokes annually in the US • Preventable strokes • Hypertension 369,000 • Hypercholesterolemia 150,000 • Tobacco Use 91,500 • Atrial Fibrillation 47,000 • Heavy Alcohol Use 35,200 --Modified from Gorelick, Neuroepidemiology 1997

  6. The Evidence – Practice Gap in Implementing 2o Prevention in Stroke Patients • Coverdell Acute Stroke Registries Pilot Data • 4 states, 7474 consecutive admissions, 2001-02 Lipid profile done 42% Antithrombotic at discharge 89% Warfarin for atrial fibrillation* 67% Smoking cessation counseling 24% *(Among patients with no MD documented contraindication) --Frankel et al, Intl Stroke Conf, 2/03

  7. The Evidence – Practice Gap in Implementing 2o Prevention in Stroke Patients • UHC Ischemic Stroke Benchmarking Project • 35 Academic Medical Centers, 1206 consecutive admissions, 2001 Antithrombotic at discharge 89% Warfarin for atrial fibrillation* 57% Smoking cessation counseling 40% Patient educated about stroke 32% *(Among patients with no MD documented contraindication)

  8. UCLA Stroke PROTECT Program • Focused on achieving 4 behavioral goals + 4 pharmacologic goals in all cervicocephalic atherothrombotic disease patients prior to hospital discharge • Use of program tools including preprinted orders, simple guidelines, and prospective monitoring of treatment use • Started in 2002 and current template of care at UCLA

  9. Stroke PROTECT Program Goals Appropriate Hospital Initiation and Maintenance of : Antithrombotic ACE Inhibitor/ ARB Statin Thiazide diuretic Exercise Education Diet Education Smoking Cessation Awareness of Stroke Warning signs

  10. Stroke Prevention approaches in 2003 Traditional interventions: • BP control, smoking cessation, diet etc • proven efficacy but sub-optimal application Emerging strategies: • targeting the atherosclerotic plaque

  11. Targeting “the Plaque” • Atherosclerosis is responsible for the majority of ischemic strokes • Destabilization of the atheromatous plaque is a forerunner of ischemic stroke • This plaque is now the main focus for new directions in prevention and treatment of cerebrovascular atherosclerosis

  12. Overlap of Vascular Disease in Patients With Atherothrombosis Ischemic stroke Unstable angina MI PAD Platelet adhesion, activation, and aggregation Plaque rupture Thrombus formation Vascular events (MI, stroke, or CV death) Ness J, Aronow WS. J Am Geriatr Soc. 1999;47:1255-1256. Schafer AI. Am J Med. 1996;101:199-209.

  13. Thrombus P l a t e l e t s Atherosclerotic Plaque Stable Unstable Lumen Endothelium Lipid Rich Core ThickFibrous Cap Thin Fibrous Cap Falk E et al. Circulation. 1995;92:657–671.

  14. Statins and Stroke

  15. Statin Types *Utilizes P450 CYP 3A4; ‡CYP 2C9; †dose note utilize CYP

  16. Mechanisms Through Which Statins may Confer Stroke Protection • Lipoprotein alterations • Improved endothelial function • Plaque stabilization • Anti-thrombosis • Attenuation of the inflammatory cytokine responses that accompany cerebral ischemia • Antioxidant properties that ameliorate ischemic oxidative stress on the brain

  17. Statin Effect on Carotid Plaque Composition Crisby, Circulation 2001

  18. Pravastatin Effect on Human Carotid Plaques--Crisby et al, Circulation 2001;103:926-933 Collagen content differences in endarterectomy specimens Bright field sections / Sirius red stain

  19. Statin Effect and Aortic Plaque • Retrospective non-randomized study • Effect of treatment [statins, warfarin, or antiplatelets] on the incidence of stroke and other emboli in 519 patients with severe thoracic aortic plaque • Each patient taking each class of therapy was matched for age, gender, previous embolic event, hypertension, diabetes, congestive failure, and atrial fibrillation to an individual not taking that medication. Tunick, P A et al Am J Cardiol 2002

  20. Statins and Aortic Plaque Contd • Embolic event in 111 patients (21%) • Multivariate analysis showed that statin use was independently protective against recurrent events (p = 0.0001). • Matched analysis also showed a protective effect of statins (p = 0.0004; absolute risk reduction 17%, relative risk reduction 59%, number needed to treat [n = 6]) • No protective effect was found for warfarin or antiplatelet drugs.

  21. Statin Effect and Cerebral Small Vessel Disease • Transcranial Doppler sonography (TCD) was used to examine acetazolamide reactivity as a marker of cerebral vasoreactivity in patients with subcortical small-vessel disease before and after pravastatin treatment. • 16 patients (mean age 68+/-10 years) with subcortical small-vessel disease, cerebral vasomotor reactivity was tested using TCD insonating the middle cerebral artery. • Cerebral blood flow velocity (CBFV) increase after bolus injection of 1 g acetazolamide was determined before and after 2-month treatment with pravastatin 20 mg daily. Sterzer, P et at Stroke 2001

  22. Statin Effect and Cerebral Small Vessel Disease Contd • Relative CBFV increase was significantly greater after pravastatin treatment (41.9+/-23.7% versus 55.7+/-18.3%, P=0.004) • No associations were found between the effect of pravastatin on vasomotor reactivity and pretreatment levels or changes of LDL cholesterol • Provides the first evidence for a significant improvement of cerebral vasomotor reactivity by statin therapy in patients with cerebral small-vessel disease

  23. Statins and Stroke Prevention:Meta-Analysis • Prevention of stroke in patients at risk for MI • 4 trials, 6808 patients • Stroke rates Placebo 3.1% Statin 2.7% RR 15% • Prevention of stroke in MI survivors • 8 trials, 11710 patients • Stroke rates Placebo 5.6% Statin 4.1% RR 27% --Crouse et al, Arch Int Med 1997

  24. Heart Protection Study • 20,536 patients • High risk for CHD • Total cholesterol > 135 mg/dl • 6000 patients with LDL  115 mg/dl • No clear indication for lipid Rx • 40 mg simvastatin vs placebo

  25. PRIOR DISEASE at BASELINE

  26. AGE & SEX at BASELINE

  27. Heart Protection Study - Results

  28. TOTAL & LDL CHOLESTEROL at BASELINE

  29. HEART PROTECTION STUDY: STROKE INCIDENCE SIMVASTATIN PLACEBO Rate ratio & 95% CI (10269) (10267) STATIN better PLACEBO better Type Ischaemic 290 409 Haemorrhagic 51 53 Unknown 103 134 Severity Fatal 96 119 Severe 42 51 Moderate 107 155 Mild 138 189 Unknown 61 71 ALL STROKES 444 585 25% SE 5 reduction (4.3%) (5.7%) (2P<0.00001) 0.4 0.6 0.8 1.0 1.2 1.4

  30. SIMVASTATIN: MAJOR VASCULAR EVENT by YEAR 30 25 PLACEBO 20 15 SIMVASTATIN 10 5 0 0 1 2 3 4 5 6 Years of follow-up 5(3) 20(4) 35(5) 46(5) 54(7) People suffering events (%) Benefit/1000 (SE): 60(18) SIMVASTATIN

  31. SIMVASTATIN 40mg daily: Safety monitoring

  32. SIMVASTATIN: Main conclusions • 40mg daily simvastatin safely reducesthe risk of heart attack, of stroke, and of revascularisation by about one-third • 5 years of statin treatment typically prevents these “major vascular events” in about: 100 of every 1000 people with previous MI 80 " " " other CHD 70 " " " cerebrovascular disease 70 " " " other arterial disease 70 " " " diabetes (age 40+) • irrespective of cholesterol level(or age, or sex, or other treatments)

  33. HPS – Study Limitations [Stroke Perspective] • Stroke – secondary endpoint • Absence of data on how patients with different subtypes of ischemic stroke fared in the trial. • Absence of data on the incidence of recurrent stroke in those individuals who suffered primary strokes or TIAs

  34. ASCOT (LLA)Primary Objective To compare the effects on the combined outcome of nonfatal MI (including silent MI) and fatal CHD of atorvastatin 10 mg with those of placebo in hypertensive patients with TC levels of 250 mg/dL

  35. Secondary and Tertiary End Points Secondary • Primary outcome without silent MI • All-cause mortality • CV mortality • Fatal + nonfatal stroke • Fatal + nonfatal heart failure • Total coronary end points • All CV events and procedures Tertiary • Silent MI • Unstable angina • Chronic stable angina • Peripheral vascular disease • Development of diabetes • Development of renal impairment • Major study end points in specific subpopulations

  36. Patient Population: LLA Eligibility criteria • SBP 160 mm Hg and/or DBP 100 mm Hg (untreated) or SBP 140 mm Hg and/or DBP 90 mm Hg (treated) • TC 6.5 mmol/L (250 mg/dL) and TGs 4.5 mmol/L (400 mg/dL) • 40-79 years of age • 3+ CVD risk factors • No history of CHD

  37. Termination of ASCOT Trial • The DSMB in September 2002 reported that in the lipid arm of ASCOT there was a highly significant reduction in the primary end pointas well as a significant reduction in stroke • The DSMB recommended that the double-blind cholesterol lowering study treatment arm be terminated since the results were outside of the stopping rules of the trial • The Steering Committee endorsed the recommendation of the DSMB, and the lipid arm was closed after a median follow-up period of 3.3 years

  38. ASCOT LLA: Patient Population Risk Factor Profile All patients in ASCOT have hypertension plus 3 risk factors for CHD Patients with risk factor (%) Data on file

  39. Baseline Characteristics Atorvastatin (n=5168) Placebo (n=5137) Characteristic Age* (years) Male (%) Caucasian (%) SBP* (mm Hg) DBP* (mm Hg) TC* (mmol/L [mg/dL]) LDL-C* (mmol/L [mg/dL]) TG* (mmol/L [mg/dL]) HDL-C* (mmol/L [mg/dL]) Number of risk factors* 63.1 ± 8.5 81.1 94.6 164.2 ± 17.7 95.0 ± 10.3 5.5 ± 0.8 (213 ± 31) 3.4 ± 0.7 (131 ± 27) 1.7 ± 0.9 (150 ± 80) 1.3 ± 0.4 (50 ± 27) 3.7 ± 0.9 63.2 ± 8.6 81.3 94.7 164.2 ± 18.0 95.0 ± 10.3 5.5 ± 0.8 (213 ± 31) 3.4 ± 0.7 (131 ± 27) 1.6 ± 0.9 (142 ± 80) 1.3 ± 0.4 (50 ± 27) 3.7 ± 0.9 *Mean ± SD

  40. Reductions in Total and LDL Cholesterol Atorvastatin 10 mg Placebo 6 200 1.3 mmol/L 1.1 mmol/L Total cholesterol (mmol/L) (mg/dL) 150 4 100 2 0 1 2 3 150 4 125 (mg/dL) 3 LDL cholesterol (mmol/L) 1.2 mmol/L 1.0 mmol/L 100 2 75 1 LLA Close-out 0 1 2 3 Years

  41. ASCOT Results

  42. Secondary End Point: Fatal and Nonfatal Stroke Atorvastatin 10 mg Number of events 89 Placebo Number of events 121 27% reduction HR = 0.73 (0.56-0.96) p=0.0236

  43. ASCOT - Summary and Conclusions In hypertensive patients at modest risk of CHD, and normal to moderately elevated cholesterol levels, atorvastatin is associated with: • A highly significant reduction in the primary end point of CHD (36%, p=0.0005) • Significant reductions in the secondary end points of stroke (27%, p=0.0236)

  44. ASCOT - Conclusions (continued) • Risk reductions in CHD events were unrelated to baseline cholesterol levels • Were the trial to have continued to its planned duration of 5 years, it is estimated that atorvastatin would have reduced CHD incidence by approximately 50% • Implications for future lipid-lowering guidelines, particularly with reference to hypertensive patients

  45. Statins and Stroke - 2003 • FDA New Labeling • April 17, 2003 • Indicated for patients with “stroke or evidence of cerebrovascular disease” • Pending • SPARCL Trial – Atorvastatin • 4730 patients with previous stroke or TIA, no CHD • Baseline LDL level between 100 to 190 mg/dl • Placebo vs 80 mg atorvastatin • Primary Outcome: Stroke • Recruitment completed. Follow-up is expected to conclude by 10/04

  46. PROTECT Inpatient Algorithm

  47. Impact of PROTECT on Treatment Discharge Rates

  48. Frequency of Indications for Statin Therapy in 50 Ischemic Stroke and TIA Patients – Ovbiagele et al 2003

  49. Secondary Stroke Prevention Treatment Discontinuation Rates at Follow-up • Various randomized trials of antithrombotic agents in secondary stroke prevention have included data on follow-up dropout rates. • However, there is a paucity of published data on discontinuation rates following initiation of lifestyle interventions targeted at reducing future stroke risk e.g. smoking cessation etc in stroke patients

  50. Medical Regimen Follow-up • Continuation of the therapies [medication and lifestyle] targeting the underlying disease process markedly improves clinical outcome in stroke patients with atherosclerosis. {recent trials} • The beneficial therapies prescribed need to be strongly reinforced during patient follow-up.

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