atorvastatin

SPARCL TRIAL: HIGH-DOSE SPARCL TRIAL: HIGH-DOSE

ATORVASTATIN AFTER STROKE OR ATORVASTATIN AFTER STROKE OR

TRANSIENT ISCHEMIC ATTACKTRANSIENT ISCHEMIC ATTACK

PRESENTED BY:

TING CHUONG WEI

KENNY GOH WEI CHUAN

CHEN SIAW MING

12-12-2007

Atherosclerosis TimelineAtherosclerosis Timeline

Phase I: Initiation

LDL-C plays a major role in initiating the development of atherosclerotic plaque.

Libby P. In: Heart Disease: A Textbook of Cardiovascular Medicine. 6th ed. Philadelphia, Pa: WB Saunders Co; 2001:995-1009; Libby P. J Intern Med. 2000;247:349-358.

Media

Intima

Phase II: Progression

Disease progression results in the remodeling of the vascular wall so that the size of the lumen does not change significantly.

LDL-C

Phase III: Complication

Extensive lipid accumulation and a greater inflammatory component can pose the threat of plaque rupture.

Lumen Unstable

Stable

Mechanism of Action of Statins Mechanism of Action of Statins Cholesterol Synthesis PathwayCholesterol Synthesis Pathway

acetyl CoA

HMG-CoA

mevalonic acid

mevalonate pyrophosphate

isopentenyl pyrophosphate

geranyl pyrophosphate

farnesyl pyrophosphate

squalene

cholesterol

dolicholsubiquinones

HMG-CoA synthase

HMG-CoA reductase

Squalene synthase

StatinsX

Mechanisms Through Which Statins may Mechanisms Through Which Statins may

Confer Stroke ProtectionConfer Stroke Protection

Lipoprotein alterations

Prevent atherosclerosis

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

WHAT IS THE BACKGROUND AND RATIONALE WHAT IS THE BACKGROUND AND RATIONALE BEHIND THIS STUDY?BEHIND THIS STUDY?

Patients with prior stroke/TIA are at risk for future

cardiovascular (CVS) events.

Statins stroke incidence in patients at risk for CVS

disease, however, stroke risk reduction with statin

therapy has not been demonstrated in patients with a

history of stroke or TIA.

This study was designed to evaluate whether high-dose

statin treatment reduces risk of stroke in patients with a

recent stroke or TIA and no history of coronary heart

disease

SPARCL Investigators. N Engl J Med. 2006;355:549-59.

PPRIMARY RIMARY HHYPOTHESIS OF THE STUDYYPOTHESIS OF THE STUDY

Treatment with 80 mg of atorvastatin per

day would reduce the risk of fatal or

nonfatal stroke among patients with a

history of stroke or TIA.


DEFINITIONDEFINITION

STROKE - focal clinical signs of central nervous

system dysfunction of vascular origin that lasted

for at least 24 hours.

TRANSIENT ISCHEMIC ATTACK (TIA) – the loss of

cerebral or ocular for less than 24 hours,

presumably owing to atherosclerotic causes.


6670 SELECTED FOR SCREENING VISIT

STUDY DESIGNSTUDY DESIGN


4731 UNDERWENT

RANDOMIZATION

1939 EXCLUDED

1591 = DID NOT MEET ENRTY CRITERIA

250 = WITHDREW CONSENT

54 = EXCLUDED FOR OTHER

ADMINISTRATION REASONS

44 = HAD AN ADVERSE EVENT OR REACHED AN END POINT DURING SCREENING POINT

STUDY DESIGNSTUDY DESIGN


Stroke or TIA in ≤6 months,no known CHD, LDL-C 100–190 mg/dL

N = 4731

Atorvastatin 80 mg dailyn = 2365

Placebon = 2366

Randomized Double blind

Primary end point: Fatal/nonfatal strokeSecondary end points: Major coronary or CV events

Median follow-up: ~ 4.9 years

SAFETY ASSESMENTS FOR THIS STUDY SAFETY ASSESMENTS FOR THIS STUDY

INCLUDE……INCLUDE……

Full clinical laboratory assessments were

performed

Electrocardiograms were obtained

Drug safety also assed by an evaluation of the

type, frequency, severity, and duration of any

reported adverse event

And also basis of vital signs, physical

examination, laboratory test.


QS1: DID THE STUDY ASK A CLEARLY

FOCUSED QUESTION?

PICO CHARACTERISTICS

POPULATION The patients Were men and women over 18 years old who

had an ischemic or hemorrhagic stroke or a

TIA 1-6 months before randomization. had to be ambulatory with a modified Rankin

Score of more than 3. LDL cholesterol level of at least 100 mg/dL and

not more than 190mg/dL.

INTERVENTION • Administration of atorvastatin 80mg daily. Follow-up visit were scheduled 1, 3 and 6

months after enrollment and every 6 months

thereafter

YES , from PICO chart

PICO CHARACTERISTICS

COMPARISON •Treatment group is compared with the placebo group

OUTCOME •Primary end point:

Fatal and non-fatal strokeSecondary end-point:Stroke and TIA Major coronary events (death from cardiac causes, nonfatal MI

or resuscitation after cardiac arrest)Major cardiovascular event (stroke + any major coronary

events)Acute coronary events (major coronary events or unstable

angina)Revascularization procedures (Coronary, Carotid or Peripheral)Any cardiovascular event (Any of the former + clinically

significant peripheral vascular disease)Any coronary events (Acute coronary event + coronary

revascularization procedures, unstable angina or ischemia

requiring emergency hospitalization)

QS2: WAS THIS RANDOMIZED CONTROL-

TRIAL AND WAS IT APPROPRIATE?

YES, this trial is a Randomized Control-Trial (RCT) to

study the comparison of risk reduction incidence of fatal

and non-fatal stroke among the patients receiving 80 mg

of atorvastatin per day with placebo over median follow

up 4.9 years.

This RCT is an appropriate research design because this

is a clinical question and is the most reliable form of

scientific event.


QS3. WERE THE PARTICIPANTS

APPROPRIATELY ALLOCATED TO

INTERVENTION AND CONTROL GROUPS?

• YES, after the patients given written informed consent, they are

randomly assigned to double-blind therapy with either 80 mg of

atorvastatin per day or placebo.

• Patients who were taking lipid-altering drug had to stop these

medication 30 days before the screening phase of the study.

• Both groups were well balanced. The baseline characteristics as in

Table 1 were similar in the 2 groups. Both groups were well

matched with respect relevant clinical parameters.

Table 1: Baseline characteristics of patients


• The subjects were men and women > 18 years old who had

an ischemic or hemorrhagic stroke or a TIA 1 to 6 months

before randomization.

• The mean LDL-C, HDL-C and triglyceride were similar in the

both groups at baseline.

• Patient with hemorrhagic stroke were included if they were

deemed by the investigator to be at risk for ischemic or

coronary heart disease.

• After randomization, the patients in both groups also took

other medications.


• Patient who had a stroke or TIA within 1 - 6 months before

study entry.

• Had low-density lipoprotein (LDL) cholesterol levels of 100-

190 mg/dL (2.6-4.9 mmol/L).

• Had no known coronary heart disease.

Inclusion criteria:


Exclusion Criteria:

• Atrial filbrillation

• Other cardiac sources of embolism

• Subarachnoid hemorrhage

Table 1: Baseline characteristics of patients

Atorvastatinn = 2365

Placebon = 2366

Male (%) 60 59

Age (years) 63 63

Systolic BP (mm Hg) 139 138

Lipid profile (mg/dL)

LDL-C 133 134

HDL-C 50 50

Triglycerides 144 143

Risk factors (%)

Hypertension 62 61

Diabetes 17 17

Current smoker 19 19

Former smoker 41 39


Table 2: Entry events

Atorvastatin Placebo

n (%) n (%)

Entry event*

Stroke

Ischemic

Hemorrhagic

Other type or not

determined

16551595

4515

(70)(67)

(2)(0.6)

16131559

486

(68)(66)

(2)(0.3)

TIA 708 (30) 752 (32)

Unknown 2 (0.1) 1 (<0.1)

*Ischemic stroke or TIA in >97% of patients

N = 4731


Table 3: Concomitant medications

Atorvastatin n (%)

Placebo n (%)

Concomitant therapy

Antiplatelet agent 2067 (87) 2063 (87)

ACE inhibitor 683 (29) 667 (28)

Dihydropyridine derivative 350 (15) 359 (15)

β-blocker 414 (18) 422 (18)

ARB 110 (5) 102 (4)

Vitamin K antagonist, including warfarin 139 (6) 154 (7)

Prior statin therapy 57 (2) 63 (3)

BACK

N = 4731


QS4. WERE THE PARTICIPANTS, STAFF AND

STUDY PERSONNEL BLIND TO PARTICIPANTS

STUDY GROUP?

• YES, eligible patients were randomly assigned to double-

blind therapy with either 80 mg of atorvastatin per day or

placebo.

• All patients were counseled to follow the National

Cholesterol Education Program Step 1 (or similar) diet

throughout the study.


• If LDL-C level below 40 mg/dL (1.0 mmol/L) in patient

treated with atorvastatin, the investigator for a randomly

chosen placebo patient was notified. And LDL-C level were

remeasured in both patients.

• Only nine of patients (3 assigned to atorvastatin group and

6 assigned to placebo group) was revealed to the study

physician. And they were unblinded to their study physician

during the study.


QS5. WERE ALL THE PARTICIPANTS WHO

ENTERED TO THE TRIAL ACCOUNTED FOR ITS

CONCLUSION?

• YES.

• Complete follow-up achieved for 96% atorvastatin (2365

patients) vs. 95% placebo groups (2253 patients), all

randomized patients analyzed by intention to treat.


QS6. WERE THE PARTICIPANTS IN ALL GROUPS

FOLLOWED UP AND DATA COLLECTED IN THE

SAME WAY?

• Yes. At the end of the study the median period of follow-up

was 4.9 years

• Both groups were treated in exactly the same way with

follow-up visits at 1, 3, and 6 months after enrolment and

every six months thereafter.


QS7. DID THE STUDY HAVE ENOUGH PARTICIPANTS TO MINIMIZE THE PLAY OF CHANCE?

• Yes. The design of the study provide 90% power to detect

an absolute 25% reduction in the 4.9 years (median follow

up) primary outcome measure between treatment groups

and placebo group, with a two-sided 5% level of

significance (p<0.05).

• These conditions were met the study was sufficiently

powered to make reliable conclusions.


QS 8: WHAT WAS THE MAIN RESULT AND

HOW WERE THE RESULTS PRESENTED?

• Primary outcome: fatal and non-fatal stroke

Total

participants

Participants

with fatal and

non-fatal

stroke

Participants

without fatal

and non-fatal

stroke

%

Atorvastatin 2365 265 2100 EER

= 265/2365

x100%

= 11.2%

Placebo 2366 311 2055 CER

= 311/2366

x 100%

= 13.1%


ARR = CER – EER

= 13.1% - 11.2%

= 1.9% ~ 2%

Interpretation:

• Treatment with atorvastatin (80mg per day) reduces the

risk of fatal and non-fatal stroke by 2%.

• In every 100 persons treated with atorvastatin, 2 persons

can avoid fatal and non-fatal stroke due to the treatment of

atorvastatin.

Absolute Risk Reduction (ARR)


RRR = 1 – EER/CER

= 1 – 11.2/13.1

= 0.145

= 14.5%

Interpretation

• The treatment reduces the probability of fatal and

non-fatal stroke by 14.5%.

Relative Risk Reduction (RRR)


NNT = 1/ARR

= 1/0.019

= 52.63 ~ 53

Interpretation

• In order to avoid 1 case of fatal or non-fatal stroke, 53

persons need to be treated.

Number Needed to Treat (NNT)


Time since randomization (years)

High-dose statin treatment reduces fatal/nonfatal stroke


Fatal/ nonfatal stroke

(%)

00 1 2 3 4 5 6

16

12

8

4

14.5% RRRHR 0.84 (0.71–0.99)P = 0.03

Placebo

Atorvastatin

NNT = 53 patientsfor median f/u 4.9 years

Primary outcome

Secondary outcomes:

Outcomes EER (%) CER (%) ARR (%) NNT

1. Stroke or TIA 15.9 20.1 4.2 24

a. TIA 6.5 8.8 2.3 44

2. Major coronary

events

3.4 5.1 1.7 59

3. Major CVS event 14.1 17.2 3.1 33

4. Acute coronary

events

4.3 6.4 2.1 48

5. Any coronary

events

5.2 8.6 3.4 29

6. Revascularization 4.0 6.9 2.9 34

7. Any CVS event 22.4 29.0 6.6 15

8. Death 9.1 8.9 The result is

statically not

significant (P

= 0.98)

-

High-dose statin reduces majorcardiovascular events


*Cardiac death, MI, resuscitatedcardiac arrest, and stroke

00

30

20

10

1 2 3 4 5 6


Major CVS events*

(%)

18% RRRHR 0.80 (0.69–0.92)P = 0.002

Placebo

Atorvastatin

NNT = 33 patientsfor median 4.9 years

Reductions in major coronary events

SPARCL Investigators. N Engl J Med. 2006;355:549-59. *Cardiac death, MI, resuscitated cardiac arrest

00

10

6

2

1 2 3 4 5 6


Major coronary events*

(%)

33% RRRHR 0.65 (0.49–0.87)P = 0.003

Placebo

Atorvastatin

8

4

Treatment effect on stroke and TIA

Hazard ratio


HR* (95% CI)

0.84 (0.71–0.99)

0.57 (0.35–0.95)

0.87 (0.73–1.03)

0.77 (0.67–0.88)

0.74 (0.60–0.91)

Primary outcome

Stroke (total)

Fatal

Nonfatal

Secondary outcomes

Stroke or TIA

TIA

P

0.03

0.03

0.11

<0.001

0.004

0.3 1.0 1.7

N = 4731Aggressive statin therapy

Better Worse

Stroke Types Total Atorvastatin

Group

Placebo

Group

Ischemic stroke 492 218 274

Hemorrhagic stroke 88 55 33

Unclassified stroke 19 7 12

• The incident of fatal hemorrhagic stroke did not

differ significantly between groups (17 in

atorvastatin and 18 in placebo group).


SAFETY ASSESSMENT: ADVERSE EVENTS


Atorvastatin Placebo

n (%) n (%)

Musculoskeletal AE

Myalgia 129 (5.5) 141 (6.0)

Myopathy7 (0.3) 7 (0.3)

Rhabdomyolysis 2 (0.1) 3 (0.1)

ALT or AST > 3x ULN 51 (2.2) 11 (0.5)

Creatine kinase >10x ULN 2 (0.1) 0

N = 4731

ADVERSE EVENTS

Outcomes EER CER ARR NNH

Serious adverse effect -

elevation in alanine or

aspartate aminotransferase

> 3 times upper limit of

normal

2.2 0.5 1.7 58


• discontinuation of study treatment due to adverse effect

reported in 17.5% atorvastatin vs. 14.5% placebo patients.

Median follow up: 4.9 years

Dosage: 2 tablets daily (1 tablet 40 mg)

Cost: 1 tablet (40mg) = ~ RM 5

Total Cost of Drug Expenditure required for beneficial effect:

Dosage x 365 days x years of follow up x price of the

drugs x NNT

= 2 x 365 days x 4.9 years x RM 5 x 53

= RM 947,905RM 17,885 is

needed per person


QS9: WHAT OTHER FACTORS NEED TO BE CONSIDERED?

• Other concomitant medications eg. Aspirin, beta-

blockers?

• Costs?

• Risk of recurrent hemorrhage??

• Different lifestyle and diet among the participants?

• Safety?


APPLICABLE?

• Translating trial results into clinical practice is often

difficult, and application of the SPARCL results may be

very hard. Physicians treating a patient with recent

stroke but without known coronary heart disease may

have difficulty prescribing a presumably lifelong drug

such as high-dose atorvastatin, which may have harmful

side effects.

COMMENTS

• Statin hepatotoxicity is dose-related, information about the

specific liver enzyme elevations that occurred in these

studies should be provided.

• Further reassurance to the safety of this approach is

needed.

• Atorvastatin reduces the risk of nonfatal stroke from 11.8%

to 10.4% over a period of median follow up 4.9 years, but it

does so without improving survival.

CONCLUSION

Based on the findings in this journal:

• In patient with a recent stroke or TIA, without known

coronary heart disease, treatment with 80mg of

atorvastatin per day decreased the risk of stroke, major

coronary events and revascularization procedures.

• The results support the initiation of atorvastatin treatment

soon after a stroke or TIA.

• However, some factors need to be considered, for

example, risk of recurrent hemorrhage, before the

initiation of treatment.


THANK YOU!!!!

atorvastatin

Health & Medicine

coronary heart

major coronary

sparcl investigators

randomized

recurrent

revascularization

unstable angina

recent stroke