Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering – MIRACL: Rationale and Results...

Myocardial Ischemia Reduction with Aggressive Cholesterol

Lowering – MIRACL:Rationale and Results

A Slide Lecture Kit

Acute coronary syndromes

Acute Coronary Syndrome

No ST Elevation ST Elevation

Unstable Angina Myocardial InfarctionNon Qw MI Qw MI

Non ST Elevation MI

Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062.

Outcomes in primary prevention, stable and unstable coronary disease

Dea

th/n

on

fata

l MI (

%)

Months of follow-up

Unstable angina/non-Q-wave MI (FRISC II)

16

12

8

4

0

0 2 4 6 8 10 12

Stable angina (SAPAT)

Wallentin L et al. Lancet 2000;356:9–16.Juul-Moller S et al. Lancet 1992;340:1421–1425.Shepherd J et al. N Engl J Med 1995;333:1301–1307.

Primary prevention (WOSCOPS)

Unstable angina: prognosis

• Patients with unstable angina have a far worseshort-term prognosis than do patients with stable angina

• Despite recent advances in therapy, the relative risk of death or nonfatal MI in patients with unstable angina versus those with stable disease is higher over the first year

Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062.Wallentin L et al. Lancet 2000;356:9–16.Juul-Moller S et al. Lancet 1992;340:1421–1425.

Early secondary prevention trials only focussed on long-term event reductions in stable patients

1.00

0.95

0.90

0.85

0.80

0.00

0 1 2 3 4 5 6

Pro

po

rtio

n a

liv

e

Risk reduction, 30%Log-rank p=0.0003

Simvastatin

Placebo

4S

0

0

Fa

tal

CH

D/n

on

fata

lM

I (%

)

5

10

15

20

1 2 3 4 5 6 7

Risk reduction, 24%p<0.001

Pravastatin

Placebo

LIPID

0 1 2 3 4 5 6

15

10

5

0

Fa

tal

CH

D/n

on

fata

lM

I (%

)

Risk reduction, 24%p=0.003

Pravastatin

Placebo

CARE

Years4S Study Group. Lancet 1994;344:1383–1389.Sacks FM et al. N Engl J Med 1996;335:1001–1009.LIPID study group. N Engl J Med 1998;339:1349–1357.

MIRACL: addressed a treatment gapAcute coronary

event

MIRACL

4S3

AFCAPS / TexCAPS/WOSCOPS

CARE1/LIPID2

4 moNo history of CAD Unstable CAD

Randomization:24–96 h

3 mo

t=0

6 moRandomization:

CARE - 3–20 moLIPID - 3–36 mo

Randomization:>6 mo

Stable CAD

Primary prevention Secondary prevention

Schwartz GG et al. Am J Cardiol 1998;81:578–581.Duration of follow-up: 15.0 years; 26.1 years; 35.4 years.

MIRACL: central hypothesis

Early, rapid, and profoundcholesterol lowering therapy with

atorvastatin can reduce early recurrent ischemic events in patients with unstable

angina or non-Q-wave acute MI

Schwartz GG et al. Am J Cardiol 1998;81:578–581.

MIRACL: inclusion criteria

• Unstable Angina– Hospitalization with 15 min or more chest pain or discomfort within

24 h of admission, together with one of the following:–Dynamic or interval ECG changes–New wall motion changes on echo and/or positive perfusion

defect–Abnormally elevated Troponin-T or -I

• Absence of new/presumed new Q-waves (30 m sec)

• Non-Q-wave MI– Hospitalization with chest pain (15 min or more) within 24 h– Elevated CK or Troponin (>2 x ULN)

Schwartz GG et al. Am J Cardiol 1998;81:578–581.Data on file, Pfizer Inc.

MIRACL: exclusion criteria

• Serum cholesterol levels >7 mmol/L (>8 mmol/L in Poland and South Africa)

• Coronary revascularization planned/anticipated

• Recent Q-wave MI <1 month

• Recent CABG (<3 months) or PTCA (<6 months)

• LBBB or paced ventricular rhythm; severe CHF

• Concurrent lipid-lowering therapy (except niacin)


MIRACL: exclusion criteria (cont’d)

• Vitamin E (except at doses 400 IU daily)

• Drugs associated with rhabdomyolysis

• Severe anemia; renal or hepatic dysfunction

• Brittle type 1 diabetes

• Pregnancy/lactation


MIRACL: study design

• Randomized, double-blind, placebo-controlled

• Intention-to-treat

• 16-week follow-up

• 3086 patients

• Enrollment: June 1997–September 1999

• Last patient completed in January 2000


MIRACL: study design (cont’d)

Hospitalizationfor

unstable anginaor non-Q MI

n=3086Randomized

24–96 hoursafter admission

Placebo + diet

Atorvastatin 80 mg + diet

16 weeks

Assessments conducted at weeks 0, 2, 6 and 16


MIRACL: primary efficacy measure

Time to first event:• Death (any cause)

• Nonfatal MI

• Resuscitated cardiac arrest

• Worsening angina with new objective evidence of ischemia requiring urgent rehospitalization


MIRACL: secondary efficacy measures

• Occurrence of

– Individual components of the primary efficacy measure

– Stroke

– Myocardial revascularization (CABG or PTCA)

– Worsening congestive heart failure

– Worsening angina without new objective evidence of ischemia

• Percent change from baseline in lipids (TC, LDL-C, HDL-C, TG) at end of study


MIRACL: statistical assumptions/analyses

• Overall primary end point rate = 13%

• Sample size = 3000 (80% power to detect 25% reduction in primary end points)

• Due to interim analyses, significance level = 0.049 for primary efficacy measure

• All analyses by intention to treat

• All end points adjudicated by blinded committee

• Time-to-event analysis: Cox Proportional Hazards

• End point occurrence: Cochran-Mantel-Haenszel

• Lipid analyses: ANCOVA

Data on file, Pfizer Inc.

• Investigators at 122 sites in 19 countries

• Committees– Steering– Blinded End point– Data Monitoring and Safety

• Core laboratories– ECG– Clinical chemistry

• Investigators at 122 sites in 19 countries

• Committees– Steering– Blinded End point– Data Monitoring and Safety

• Core laboratories– ECG– Clinical chemistry

MIRACL: study organization


MIRACL: study organization (cont’d)

Co-Principal Investigators• Anders Olsson, MD• Gregory Schwartz, MD

Steering Committee• Anders Olsson, MD• Gregory Schwartz, MD• Michael Ezekowitz, MD• Peter Ganz, MD• Michael Oliver, MD• David Waters, MD• Andreas Zeiher, MD

St. Louis Core ECG Lab• Bernard Chaitman, MD

Data Monitoring and Safety Committee• Eliott Rapaport, MD (Chair)• Paul Armstrong, MD• Antonio Gotto Jr, MD• Stuart Pocock, PhD

End point Committee• Peter Stone, MD (Chair)• Merill Knudtson, MD• Jean-Marc LaBlanche, MD• Herbert Levine, MD• Christopher O’Connor, MD• Blair O’Neill, MD


MIRACL: baseline characteristicsDemographics

Placebo AtorvastatinCharacteristic (n=1548) (n=1538)

Gender

Male, n (%) 1020 (65.9) 992 (64.5)

Female, n (%) 528 (34.1) 546 (35.5)

Race

White, n (%) 1324 (85.5) 1317 (85.6)Black, n (%) 44 (2.8) 51 (3.3)Asian, n (%) 58 (3.7) 40 (2.6)Other, n (%) 122 (7.9) 130 (8.5)

Age (years), Median 65 66

Min–Max 26–94 30–93

Mean (SE) 65 (0.30) 65 (0.30)


MIRACL: baseline characteristicsDemographics (cont’d)

Placebo AtorvastatinCharacteristic [n (%)] (n=1548) (n=1538)

Current smokers 430 (27.8) 429 (27.9)

Past MI 392 (25.3) 382 (24.8)Q-wave 191 (12.3) 180 (11.7)

Revascularization 173 (11.2) 153 (9.9)CABG 121 (7.8) 112 (7.3)PTCA 52 (3.4) 41 (2.7)

Inclusion eventUnstable angina 705 (45.5) 726 (47.2)Non-Q-wave acute MI 843 (54.5) 812 (52.8)


MIRACL: concurrent medicationsaccording to treatment group

Medications during and/or following Placebo Atorvastatinhospitalization for Index Event [n (%)] (n=1548) (n=1538)

Aspirin 1412 (91.2) 1400 (91.0)Platelet GPIIb/IIIa RAs 19 (1.2) 14 (0.9)Other antiplatelet agents 176 (11.4) 176 (11.3)Heparin 1154 (74.6) 1147 (74.6)Oral anticoagulants (coumarites) 129 (8.3) 119 (7.7)Fibrinolytic agents 137 (8.9) 109 (7.1) Nitrates 1396 (90.2) 1389 (90.3)Beta-blockers 1200 (77.5) 1192 (77.5)Calcium-channel blockers 745 (48.1) 735 (47.8)ACE inhibitors or ARBs 769 (49.7) 746 (48.5)Digoxin 171 (11.1) 182 (11.8)


Baseline End of studyMean of both groups Placebo Atorvastatin

mg/dL mg/dL (% change)

Total cholesterol 206 217 147 (+ 7%) (- 27%)

LDL cholesterol 124 135 72(+ 12%) (- 40%)

HDL cholesterol 46 46 48(+ 4%) ( + 5%)

Triglycerides 182 187 139(+ 9%) (- 16%)

MIRACL: plasma lipids


MIRACL: primary efficacy measure

Relative risk = 0.84p=0.048

Atorvastatin

Placebo

0

5

10

15

0 4 8 12 16Time since randomization (weeks)

Cu

mu

lati

ve I

nci

den

ce (

%)

Time to first occurrence of:• Death (any cause)• Nonfatal MI• Resuscitated cardiac arrest• Worsening angina with new

objective evidence requiring urgent rehospitalization

17.4%

14.8%


MIRACL: worsening angina with new objective evidence of ischemia requiring urgent rehospitalization

0

3

6

9

0 4 8 12 16

Time since randomization (weeks)

Cu

mu

lati

ve I

nci

den

ce (

%)


Atorvastatin

Placebo 8.4%

6.2%


MIRACL: occurrence of primary end point events

*p=0.02

0.25 0.50 0.75 1.00 1.25 1.50 1.75 2.00Atorvastatin better Placebo better

Relative risk

Death

Nonfatal Acute MI

ResuscitatedCardiac Arrest

Worsening angina with newobjective evidence of ischemiarequiring urgent rehospitalization

*


* Patients may experience more than one revascularization and/or more than one secondary clinical end point.

† p=0.045 vs placebo; ‡ p=0.021 vs placebo

MIRACL: occurrence of secondaryclinical end points

Placebo AtorvastatinSecondary end point [n (%)] (n=1548) (n=1538)

Revascularization* 250 (16.1) 254 (16.5)Catheter based 143 (9.2) 150 (9.8)CABG 110 (7.1) 106 (6.9)

Fatal + Nonfatal Stroke 24 (1.6) 12 (0.8)†

Nonfatal stroke 22 (1.4) 9 (0.6)‡

New or worsening CHF 43 (2.8) 40 (2.6)Worsening angina w/o new objectiveevidence of ischemia 106 (6.8) 91 (5.9)


MIRACL: fatal or nonfatal stroke

0

0.5

1

1.5

2

0 4 8 12 16

Time since randomization (weeks)

Cu

mu

lati

ve I

nci

den

ce (

%)


Atorvastatin

Placebo 1.6%

0.8%


MIRACL: compliance with intended treatment

Placebo Atorvastatin(n=1548) (n=1538)

Mean duration of compliance 99 days 98 days

Premature discontinuation 10.3% 11.2%

Reasons for discontinuation:nonfatal AE 1.5% 2.1%nonfatal ischemic event 0.6% 0.5%other 8.2% 8.6%

No. of patients lost to follow-up 4 8


MIRACL: safety

Placebo Atorvastatin(n=1548) (n=1538)

Elevated liver transaminases 0.6% 2.5%(>3xULN on 2 occasions)

Myositis 0% 0%(with CPK >10xULN on 2 occasions)

Any serious adverse event 8.0% 9.0%


MIRACL: conclusions

• Early, rapid, and profound cholesterol lowering therapy with atorvastatin reduced early recurrent ischemic events in patients with unstable angina or non-Q-wave acute MI

• Atorvastatin reduced the incidence of recurrent ischemic events within 16 weeks

• Treatment was generally well tolerated


Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering – MIRACL: Rationale and Results...

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