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STATINS POST STROKE:
HOW MUCH IS ENOUGH?
Case presentation
General Medicine Rotation
Rajwant Minhas
Oct 2011
Outline
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Learning Objectives
Case
Background Stroke
Overview of statin therapy
Clinical Question
Assessment
Plan
Monitoring
Follow up
Learning Objectives
• Have an understanding of stroke and
hemorrhagic transformation
• Discuss benefit vs. harm of using statins
post stroke
• Review of SPARCL trial
Patient Information
• VB 58 yo (5’3”, 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:
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Felt unsteady for a day
Left hand doing its own thing, unable to control
Left arm tingling, numbness
Confusion
Nausea
Patient Information
PMH
MPTA
•NIDDM X 1 year
Metformin 500 mg BID
Gliclazide ER 30 mg OD
•HTN X 15 years
Atenolol 25 mg BID
Ramipril 10 mg OD
•Dyslipidemia x 3 wks
Atorvastatin 10 mg OD
Patient Information
• Allergies: NKDA
• FH: Father and mother died of stroke
• SH:
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Caffeine: 1-2 cups coffee/day
No alcohol
No smoking
AAT
Lives with husband
Low fat diet
Current Medications
HTN
Amlodipine 10 mg OD
Ramipril 5 mg BID
HCTZ 25 mg PO daily
Captopril 12.5 mg if SBP>180 mm Hg, DBP > 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
Review of Systems
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CVS: Oct 19: BP =139/83, HR = 61
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GI/GU/Renal: Oct 19: SCr=84, BUN=5, eGFR=101
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Liver/Spleen/Endo: Oct 16: A1C 7.1
Bilirubin
GGTP
AST
ALT
ALP
Oct 15
Oct 21
12
27
27
29
71
14
35
37
41
88
Oct 16
TG
Cholesterol
LDL
HDL
TC/HDL
1.1
3.4
2.0
0.9
3.78
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
Medical Problem List
• Ischemic stroke with hemorrhagic
transformation
• HTN
• Diabetes
• Headache
• Dyslipidemia
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.
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.
Goals of Therapy
• VB’s goal:
– Restore functioning of her left arm
– Prevent another stroke, MI
• Healthcare team’s goal
– Minimize brain damage
– Prevent complications: aphasia, paralysis, memory
loss
– Reduce risk of recurrence
– Restore baseline function of VB
– Minimize adverse drug events
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
What Do We Know About Statins?
• Meta Analysis: Statins ↓ primary stroke incidence in
hyperlipidemic patients both with & without CHD
(RR:0.75 & 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,
NNT=72) regardless of baseline lipid levels (but not
those with pre-existing stroke)
Benefit vs. Harm of Statins
Benefit
•Reduces cell loss due
to cell death
Harm
•Enhances fibrinolysis
•Inhibits blood coagulation
•Anti-inflammatory effects
•Weakens endothelial walls of cerebral
vessels by lowering cholesterol
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)
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
Inclusion & Exclusion Criteria
Inclusion Criteria
•>18 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
Exclusion Criteria
•Patients with Atrial
Fibrillation
•Other cardiac sources of
embolism
•Baseline LDL-C = 2.6 to 4.9 mmol/L
•No known CHD
•Ambulatory: Modified Rankin score < 3
•Subarachnoid
hemorrhage
SPARCL: Study design
Stroke or TIA in ≤6 months,
no known CHD, LDL-C 100–190 mg/dL
Atorvastatin 80 mg daily
n = 2365
Randomized
Double blind, ITT
Placebo
n = 2366
Primary end point: Time to first fatal/nonfatal stroke
Secondary end points: Major coronary or CV events
Follow-up: ~5 years (until >540 primary end points)
Baseline Characteristics
Atorvastatin
(N = 2365)
Placebo
(N = 2366)
60.3
59
63
62.5
BMI
27.5
27.4
Systolic BP (mm Hg)
138.9
138.4
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
Systemic HTN
62.4
61.4
DM
16.7
16.9
Current smoker
19.1
19.3
Former smoker
40.7
38.8
Characteristic
Male (%)
Age (years)
Lipid profile (mg/dL)
Risk factors (%)
.
Baseline Characteristics
Entry event-no. (%)
Atorvastatin
(N=2365)
Placebo
(N=2366)
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(<0.1)
Time since entry event-days
87.1
84.3
*Ischemic stroke or TIA in >97% of patients
Baseline Characteristics
Concomitant therapy – no. (%)
Atorvastatin
N (%)
Placebo
N (%)
Antiplatelets excluding
heparin
ACE inhibitor
Dihydropyridine derivative
2067 (87.4)
2063 (87.2)
683 (28.9)
350 (14.8)
667 (28.2)
359 (15.2)
β-blocker
ARB
Vitamin K antagonist
414 (17.5)
110 (4.7)
139 (5.9)
422 (17.8)
102 (4.3)
154 (6.5)
Prior Statin Therapy
57
(2.4)
63
(2.7)
High-dose Statin Treatment Reduces
Fatal/nonfatal Stroke
Primary outcome
16
NNT = 46
patients
for 5 years
16% RRR*
HR 0.84 (0.71–0.99)
P = 0.03
12
Fatal/
nonfatal
stroke
(%)
Placebo
Atorvastatin
8
4
0
0
1
2
3
4
5
Time since randomization (years)
*Prespecified adjustment for baseline factors
6
Results
Endpoints
Atorvastati
n%
(N=2366)
Placebo %
(N=2366)
ARR% RRR
%
NNT/4.9
yrs
P value *
unadjust
ed
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
Magnitude of Benefit
• 1 less secondary stroke for q 53 patients
treated X 4.9 years.
• Reduction in TIA:
• Major Coronary Events:
• Major CV events:
NNT= 43
NNT=59
NNT=32
• NO reduction in overall mortality, not powered
to assess risk of death
Adverse Events
Variable
Atorvastatin (N=2365)
Placebo (N=2366)
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 >3xULN at 2 consecutive measurements
51(2.2) p<0.001
11(0.5)
CK >10xULN at 2 consecutive measurements
2(0.1)
0
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
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
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.
Limitations
1. Extrapolation to patients with Afib & other cardiac sources of embolism
2. Non-significant ↓ in non-fatal stroke
3. Comparison to lower doses of Atorvastatin?
Benefit vs. harm (Atorvastatin 10mg=$800; 80mg= $1050 per yr)
4. Difference in stroke severity?
(preliminary data presented by Goldstein at the ANA 131st Meeting
suggests ↓ stroke severity)
5. Open label statin use: Atorvastatin group: 11.4%, Placebo: 25.4%
6. Treatment assignment of 9 patients ( 3 in Atorvastatin group, 6
placebo) revealed to study physician
7. Serious adverse events not defined
Assessment
• VB would benefit from statin therapy
• Benefit > risk
• Start anti-platelet therapy when follow-up
CT scan show resolution of hemorrhage
and rules out no further bleeding
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, IBW=51.9 kg)
• Exercise
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
Discharge Medications
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Lipitor 40 mg OD
Ramipril 5 mg BID
HCTZ 25 mg OD
Amlodipine 10 mg OD
Metformin 500 mg BID
Gliclazide 80 mg OD
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
Outline
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Learning Objectives
Case
Background Stroke
Overview of statin therapy
Clinical Question
Assessment
Plan
Monitoring
Follow up
References
1.
Mascitelli, Luca et al. Letter to the editor. Hemorrhagic stroke in the
SPARCL study . Stroke. 2008;39:e180, published online before print
October 2 2008, doi: 10.1161/STROKEAHA.108.532309
2.
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, 355:549–559
3.
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/uploads/documents/LipidQandA-SPARCL.pdf