STATINS POST STROKE: HOW MUCH IS ENOUGH?

1
STATINS POST STROKE HOW MUCH IS ENOUGH?

• Case presentation
• General Medicine Rotation
• Rajwant Minhas
• Oct 2011

2
Outline

• Learning Objectives
• Case
• Background Stroke
• Overview of statin therapy
• Clinical Question
• Assessment
• Plan
• Monitoring
• Follow up

3
Learning Objectives

• Have an understanding of stroke and hemorrhagic
  transformation
• Discuss benefit vs. harm of using statins post
  stroke
• Review of SPARCL trial

4
Patient Information

• VB 58 yo (53, 88.6 kg) IBW 51.9 kg
• Caucasian F
• Admitted Oct 13, 2011
• Vitals
• Temp 36.6 C, BP 191/93 mm Hg, HR 71
• RR 20, O2 Sat 99
• C/C Ischemic Stroke
• HPI
• Felt unsteady for a day
• Left hand doing its own thing, unable to control
• Left arm tingling, numbness
• Confusion
• Nausea

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Patient Information
PMH MPTA
NIDDM X 1 year HTN X 15 years Dyslipidemia x 3 wks Metformin 500 mg BID Gliclazide ER 30 mg OD Atenolol 25 mg BID Ramipril 10 mg OD Atorvastatin 10 mg OD
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Patient Information

• Allergies NKDA
• FH Father and mother died of stroke
• SH
• Caffeine 1-2 cups coffee/day
• No alcohol
• No smoking
• AAT
• Lives with husband
• Low fat diet

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Current Medications
HTN Amlodipine 10 mg OD Ramipril 5 mg BID HCTZ 25 mg PO daily Captopril 12.5 mg if SBPgt180 mm Hg, DBP gt 100 mm Hg
NIDDM Metformin 500 mg PO BID CC Gliclazide 80 mg PO OD
HA Morphine 10 mg/ml 2.5-5mg SC Q3H PRN Acetaminophen 650 mg PO Q4H
Dyslipidemia Atorvastatin 80 mg OD (? to 40 mg OD on Oct 20)
Nausea Dimenhydrinate 25-50 mg Q4H PRN
Anxiety Lorazepam SL 0.5 mg Q6H PRN
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Review of Systems

• CVS Oct 19 BP 139/83, HR 61
• GI/GU/Renal Oct 19 SCr84, BUN5, eGFR101
• Liver/Spleen/Endo Oct 16 A1C 7.1
• Oct 15 Oct 21
• Bilirubin 12 14
• GGTP 27 35
• AST 27 37
• ALT 29 41
• ALP 71 88
• Oct 16
• TG 1.1
• Cholesterol 3.4
• LDL 2.0
• HDL 0.9
• TC/HDL 3.78

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Diagnostic Tests
Oct 13 Head CT Right posterior parietal lobe infarct
Oct 13 ECG Marked sinus bradycardia with non-specific ST-T wave abnormalities
Oct 14 Angiography CT Evolving hemorrhage within subacute right parietal infarct, no evidence of carotid artery stenosis or intracranial inclusion
Oct 17 Head CT Evolving hemorrhagic stroke, no change in amount
Oct 18 Echo Normal left ventricular size systolic function, no cardiac source of embolus seen
Oct 18 Carotid doppler study No significant carotid stenosis
Oct 19 Holter monitor No AF, bradycardia in sleep
Oct 22 Test for Inherited Thrombophilia Functional protein C, protein S, Antithrombin III test, dRVVT screen ratio, lupus anticoagulant, Factor V, Factor V Leiden mutation negative
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Medical Problem List

• Ischemic stroke with hemorrhagic transformation
• HTN
• Diabetes
• Headache
• Dyslipidemia

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Drug Related Problems

• Potential VB is at risk of stroke recurrence
  secondary to not receiving high dose Atorvastatin
  and would benefit from reassessment of her
  therapy.
• Potential VB is at risk of stroke recurrence
  secondary to not receiving anti-platelet therapy
  and would benefit from reassessment of her
  therapy once repeat CT scan shows resolution of
  stroke and no further bleeding.
• Potential VB is at risk of stroke recurrence
  secondary to not receiving therapy for low HDL.

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Background Stroke

• .

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Hemorrhagic Transformation (HT)

• Could be symptomatic with clinical worsening or
  asymptomatic
• Antithrombotics, anticoagulants thrombolytic
  agents ? the likelihood of serious HT
• Early use of ASA small ? in the risk of clinical
  detectable hemorrhage
• HT in patients with cerebellar infarct
  significantly ? the risk of deterioration
• With the use of CT, 1 prospective study
  determined that 5 of infarctions spontaneously
  developed symptomatic hemorrhagic transformations
  from frank hematomas.

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Goals of Therapy

• VBs goal
• Restore functioning of her left arm
• Prevent another stroke, MI
• Healthcare teams goal
• Minimize brain damage
• Prevent complications aphasia, paralysis, memory
  loss
• Reduce risk of recurrence
• Restore baseline function of VB
• Minimize adverse drug events

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Clinical Question

• P In a 58 yo Caucasian female with ischemic
  stroke transformed to hemorrhagic stroke
• I Is Atorvastatin 80 mg OD better than
• C Atorvastatin 40 mg OD
• O In preventing future stroke

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What Do We Know About Statins?

• Meta Analysis Statins ? primary stroke incidence
  in hyperlipidemic patients both with without
  CHD (RR0.75 0.77 respectively).
• Heart Protection Study Simvastatin 40mg ? the
  rate of 1 and/or 2 (fatal or non-fatal) stroke
  in patients with CHD (4.3 vs. 5.7 placebo,
  NNT72) regardless of baseline lipid levels (but
  not those with pre-existing stroke)

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Benefit vs. Harm of Statins
Benefit Harm
Reduces cell loss due to cell death Anti-inflammatory effects Enhances fibrinolysis Inhibits blood coagulation Weakens endothelial walls of cerebral vessels by lowering cholesterol
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SPARCL Trial Stroke Prevention by Aggressive
Reduction in Cholesterol Levels

• P Patients after a recent stroke or TIA with
  normal cholesterol levels (LDL 2.6-4.9 mmol/L)
  no known hx of CHD
• I Atorvastatin 80 mg OD
• C Placebo
• O Efficacy of high dose Atorvastatin for the
  prevention of stroke recurrence (fatal and non
  fatal)

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SPARCL Background

• Statins ? stroke in patients at risk for CVD or
  CHD
• Prior stroke or TIA ? risk for future CV events
• Prior stroke or TIA No trials conducted to
  evaluate statin use for secondary prevention

Goal To evaluate whether high-dose statin
treatment ? risk of stroke in patients with a
recent stroke or TIA no hx of CHD

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Inclusion Exclusion Criteria
Inclusion Criteria Exclusion Criteria
gt18 who had an ischemic or hemorrhagic stroke (included if deemed to be at risk for ischemic stroke or CHD) or TIA 1-6 months before randomization Baseline LDL-C 2.6 to 4.9 mmol/L No known CHD Ambulatory Modified Rankin score lt 3 Patients with Atrial Fibrillation Other cardiac sources of embolism Subarachnoid hemorrhage
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SPARCL Study design
Stroke or TIA in 6 months,no known CHD, LDL-C
100190 mg/dL
Atorvastatin 80 mg daily n 2365
Placebo n 2366
Randomized Double blind, ITT
Primary end point Time to first fatal/nonfatal
strokeSecondary end points Major coronary or CV
events
Follow-up 5 years (until gt540 primary end
points)
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Baseline Characteristics
Characteristic Atorvastatin (N 2365) Placebo (N 2366)
Male () 60.3 59
Age (years) 63 62.5
BMI 27.5 27.4
Systolic BP (mm Hg) 138.9 138.4
Lipid profile (mg/dL)
LDL-C 132.7 (3.4 mmol) 133.7
HDL-C 50.0 50.0
Total Cholesterol 211.4 212.3
Trigylcerides 144.2 143.2
Risk factors ()
Systemic HTN 62.4 61.4
DM 16.7 16.9
Current smoker 19.1 19.3
Former smoker 40.7 38.8
.
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Baseline Characteristics
Entry event-no. () Atorvastatin (N2365) Placebo (N2366)
Stroke 1655 (70.0) 1613(68.2)
Ischemic 1595 (67.4) 1559(65.9)
Hemorrhagic 45(1.9) 48(2.0)
Other type or not determined 15(0.6) 6(0.3)
TIA 708(29.9) 752(31.8)
Unknown 2(0.1) 1(lt0.1)
Time since entry event-days 87.1 84.3
Ischemic stroke or TIA in gt97 of patients
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Baseline Characteristics
Concomitant therapy no. () Atorvastatin N () Placebo N ()
Antiplatelets excluding heparin 2067 (87.4) 2063 (87.2)
ACE inhibitor 683 (28.9) 667 (28.2)
Dihydropyridine derivative 350 (14.8) 359 (15.2)
ß-blocker 414 (17.5) 422 (17.8)
ARB 110 (4.7) 102 (4.3)
Vitamin K antagonist 139 (5.9) 154 (6.5)
Prior Statin Therapy 57 (2.4) 63 (2.7)

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High-dose Statin Treatment Reduces Fatal/nonfatal
Stroke
Primary outcome
Placebo
NNT 46 patientsfor 5 years
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16 RRR HR 0.84 (0.710.99) P 0.03
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Fatal/ nonfatal stroke()
Atorvastatin
8
4
0
0
1
2
3
4
5
6
Time since randomization (years)
Prespecified adjustment for baseline factors
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Results
Endpoints Atorvastatin (N2366) Placebo (N2366) ARR RRR NNT/4.9 yrs P value unadjusted
1 Nonfatal or fatal stroke 11.2 (265 events) 13.1 (311 events) 1.9 15 53 0.05
2 TIA 6.5 8.8 2.3 26 43 0.004
2 Major Coronary Event 3.4 5.1 1.7 33 59 0.006
2 Major CV Event 14.1 17.2 3.1 18 32 0.005
2 Death (any cause) 9.1 8.9 0.2 2 NS 0.77
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Magnitude of Benefit

• 1 less secondary stroke for q 53 patients treated
  X 4.9 years.
• Reduction in TIA NNT 43
• Major Coronary Events NNT59
• Major CV events NNT32
• NO reduction in overall mortality, not powered
  to assess risk of death

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Adverse Events
Variable Atorvastatin (N2365) Placebo (N2366)
Any adverse event 2199 (93.0) 2156(91.1)
Any serious adverse event 988 (41.8) 975 (41.2)
Any SAE resulting in discontinuation of study tx 415 (17.5) 342 (14.5)
Myalgia Myopathy Rhabdomyolsis 129(5.5) 7(0.3) 2(0.1) 141(6.0) 7(0.3) 3(0.1)
Accidental injury Infection HTN Pain Depression HA Back pain Diarrhea 487 (20.6) 414 (17.5) 395(16.7) 357(15.1) 296(12.5) 272(11.5) 266(11.2) 238(10.1) 447 (18.9) 439(18.6) 443(18.7) 388(16.4) 298(12.6) 271(11.5) 241(10.2) 187(7.9)
ALT or AST gt3xULN at 2 consecutive measurements 51(2.2) plt0.001 11(0.5)
CK gt10xULN at 2 consecutive measurements 2(0.1) 0


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Post Hoc Analysis

• Atorvastatin group
• ? Risk of hemorrhagic stroke (HR 1.66, 95 CI
  1.08-2.55)
• ? Risk of ischemic stroke (HR 0.78, 95 CI
  0.66-0.94).
• ? Risk unclassified stroke (HR 0.55, 95 CI 0.21
  to 1.40)
• Statins may be associated with an? the risk of
  hemorrhagic stroke in all patients with prior
  stroke or prior hemorrhagic stroke
• Epidemiologic evidence Inverse association b/w
  total cholesterol levels brain hemorrhage

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Magnitude of Harm

• 1 more hemorrhagic stroke for q 112 patients
  (2.3) vs. 33 (1.4) in placebo group treated
  with Atorvastatin 80mg x4.9 years.
• Also ?d in those with previous CV hx
• HPS 1.3 Simvastatin 40mg vs. 0.7 placebo

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Investigators Conclusion

• In patients with a recent stroke or TIA,
  treatment with Atorvastatin 80 mg/day ? the
  overall incidence of strokes and of
  cardiovascular events despite a small increase in
  the incidence of hemorrhagic stroke.

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Limitations

• Extrapolation to patients with Afib other
  cardiac sources of embolism
• Non-significant ? in non-fatal stroke
• Comparison to lower doses of Atorvastatin?
• Benefit vs. harm (Atorvastatin 10mg800 80mg
  1050 per yr)
• Difference in stroke severity?
• (preliminary data presented by Goldstein at the
  ANA 131st Meeting suggests ? stroke severity)
• Open label statin use Atorvastatin group 11.4,
  Placebo 25.4
• Treatment assignment of 9 patients ( 3 in
  Atorvastatin group, 6 placebo) revealed to study
  physician
• Serious adverse events not defined

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Assessment

• VB would benefit from statin therapy
• Benefit gt risk
• Start anti-platelet therapy when follow-up CT
  scan show resolution of hemorrhage and rules out
  no further bleeding

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Plan Drug Non-drug Measures

• Continue with Atorvastatin 40 mg
• Reinitiate ASA 81 mg once follow-up CT scan
  results show resolution of hemorrhage and no
  further bleeding
• Diet (? saturated fats refined sugars)
• Weight loss (Actual weight 88.6 kg, IBW51.9
  kg)
• Exercise

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Monitoring

• SEs HA, dyspepsia, N,V, diarrhea, muscle
  soreness, tenderness or pain
• Lipid level monitoring in 4 weeks
• Liver enzyme monitoring in 12 weeks
• Serum transaminases CK monitoring q 6-12 months

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Discharge Medications

• Lipitor 40 mg OD
• Ramipril 5 mg BID
• HCTZ 25 mg OD
• Amlodipine 10 mg OD
• Metformin 500 mg BID
• Gliclazide 80 mg OD

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Follow up

• F/U with Neurologist in 6 months
• Repeat CT Oct 28 previous areas of hemorrhage
  resolving
• FD to initiate therapy for low HDL

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Outline

• Learning Objectives
• Case
• Background Stroke
• Overview of statin therapy
• Clinical Question
• Assessment
• Plan
• Monitoring
• Follow up

39
References

• Mascitelli, Luca et al. Letter to the editor.
  Hemorrhagic stroke in the SPARCL study . Stroke.
  200839e180, published online before print
  October 2 2008, doi 10.1161/STROKEAHA.108.532309
  
• The Stroke Prevention by Aggressive Reduction in
  Cholesterol Levels (SPARCL) Investigators
  High-dose atorvastatin after stroke or transient
  ischemic attack. N Engl J Med 2006, 355549559
• Rx Files. An Overview of SPARCL Stroke
  Prevention by Aggressive Reduction in Cholesterol
  Levels. updated 2006 Nov cited 2011 Oct 28
  Available from http//www.rxfiles.ca/rxfiles/uplo
  ads/documents/Lipid-QandA-SPARCL.pdf