Download Myocardial Ischemia Reduction with Aggressive

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
Non ST Elevation MI
Unstable Angina
Myocardial Infarction
Non Qw MI
Qw MI
Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062.
Outcomes in primary prevention, stable and
unstable coronary disease
Death/nonfatal MI (%)
16
12
Unstable angina/non-Q-wave MI (FRISC II)
8
Stable angina (SAPAT)
Primary prevention (WOSCOPS)
4
0
0
2
4
6
Months of follow-up
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.
8
10
12
Unstable angina: prognosis
• Patients with unstable angina have a far worse
short-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.
4S
1.00
Fatal CHD/nonfatal
MI (%)
Proportion alive
Early secondary prevention trials only focussed on
long-term event reductions in stable patients
Simvastatin
0.95
Placebo
0.90
0.85
Risk reduction, 30%
Log-rank p=0.0003
0.80
0.00
1
2
3
Fatal CHD/nonfatal
MI (%)
0
4
5
LIPID
20
Placebo
15
10
Pravastatin
5
Risk reduction, 24%
p<0.001
0
6
0
1
2
CARE
15
10
Placebo
Pravastatin
5
Risk reduction, 24%
p=0.003
0
0
1
2
3
Years
4S 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.
4
5
6
3
4
5
6
7
MIRACL: addressed a treatment gap
Acute coronary
event
No history of CAD
Unstable CAD
Stable CAD
4 mo
AFCAPS / TexCAPS/
WOSCOPS
t=0
MIRACL
CARE1/LIPID2
3 mo
4S3
6 mo
Randomization:
24–96 h
Primary prevention
Duration of follow-up: 15.0 years; 26.1 years; 35.4 years.
Schwartz GG et al. Am J Cardiol 1998;81:578–581.
Randomization:
CARE - 3–20 mo
LIPID - 3–36 mo
Randomization:
>6 mo
Secondary prevention
MIRACL: central hypothesis
Early, rapid, and profound
cholesterol 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)
Schwartz GG et al. Am J Cardiol 1998;81:578–581.
Data on file, Pfizer Inc.
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
Schwartz GG et al. Am J Cardiol 1998;81:578–581.
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
Schwartz GG et al. Am J Cardiol 1998;81:578–581.
Data on file, Pfizer Inc.
MIRACL: study design (cont’d)
n=3086
Hospitalization
Randomized
for
unstable angina 24–96 hours
or non-Q MI
after admission
Placebo + diet
Atorvastatin 80 mg + diet
16 weeks
Assessments conducted at
weeks 0, 2, 6 and 16
Schwartz GG et al. Am J Cardiol 1998;81:578–581.
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
Schwartz GG et al. Am J Cardiol 1998;81:578–581.
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
Schwartz GG et al. Am J Cardiol 1998;81:578–581.
Data on file, Pfizer Inc.
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.
MIRACL: study organization
• Investigators at 122 sites in 19 countries
• Committees
– Steering
– Blinded End point
– Data Monitoring and Safety
• Core laboratories
– ECG
– Clinical chemistry
Schwartz GG et al. Am J Cardiol 1998;81:578–581.
Data on file, Pfizer Inc.
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 on file, Pfizer Inc.
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 characteristics
Demographics
Characteristic
Placebo
(n=1548)
Atorvastatin
(n=1538)
1020 (65.9)
528 (34.1)
992 (64.5)
546 (35.5)
1324 (85.5)
44 (2.8)
58 (3.7)
122 (7.9)
65
26–94
65 (0.30)
1317 (85.6)
51 (3.3)
40 (2.6)
130 (8.5)
66
30–93
65 (0.30)
Gender
Male, n (%)
Female, n (%)
Race
White, n (%)
Black, n (%)
Asian, n (%)
Other, n (%)
Age (years), Median
Min–Max
Mean (SE)
Data on file, Pfizer Inc.
MIRACL: baseline characteristics
Demographics (cont’d)
Placebo
(n=1548)
Atorvastatin
(n=1538)
Current smokers
430 (27.8)
429 (27.9)
Past MI
Q-wave
392 (25.3)
191 (12.3)
382 (24.8)
180 (11.7)
Revascularization
CABG
PTCA
173 (11.2)
121 (7.8)
52 (3.4)
153 (9.9)
112 (7.3)
41 (2.7)
Inclusion event
Unstable angina
Non-Q-wave acute MI
705 (45.5)
843 (54.5)
726 (47.2)
812 (52.8)
Characteristic [n (%)]
Data on file, Pfizer Inc.
MIRACL: concurrent medications
according to treatment group
Medications during and/or following
hospitalization for Index Event [n (%)]
Aspirin
Platelet GPIIb/IIIa RAs
Other antiplatelet agents
Heparin
Oral anticoagulants (coumarites)
Fibrinolytic agents
Nitrates
Beta-blockers
Calcium-channel blockers
ACE inhibitors or ARBs
Digoxin
Data on file, Pfizer Inc.
Placebo
(n=1548)
Atorvastatin
(n=1538)
1412 (91.2)
19 (1.2)
176 (11.4)
1154 (74.6)
129 (8.3)
137 (8.9)
1396 (90.2)
1200 (77.5)
745 (48.1)
769 (49.7)
171 (11.1)
1400 (91.0)
14 (0.9)
176 (11.3)
1147 (74.6)
119 (7.7)
109 (7.1)
1389 (90.3)
1192 (77.5)
735 (47.8)
746 (48.5)
182 (11.8)
MIRACL: plasma lipids
Baseline
Mean of both groups
End of study
Placebo
mg/dL
Total cholesterol
206
mg/dL (% change)
217
HDL cholesterol
Triglycerides
Data on file, Pfizer Inc.
147
(+ 7%)
27%)
LDL cholesterol
Atorvastatin
124
46
182
(-
135
72
(+ 12%)
(- 40%)
46
48
(+ 4%)
( + 5%)
187
139
(+ 9%)
(- 16%)
MIRACL: primary efficacy measure
Cumulative Incidence (%)
Placebo
15
17.4%
14.8%
Atorvastatin
10
Time to first occurrence of:
• Death (any cause)
• Nonfatal MI
• Resuscitated cardiac arrest
• Worsening angina with new
objective evidence requiring
urgent rehospitalization
5
Relative risk = 0.84
p=0.048
0
0
4
8
12
Time since randomization (weeks)
Data on file, Pfizer Inc.
16
Cumulative Incidence (%)
MIRACL: worsening angina with new objective evidence
of ischemia requiring urgent rehospitalization
9
8.4%
Placebo
6.2%
6
Atorvastatin
3
Relative risk = 0.74
p=0.02
0
0
4
8
12
Time since randomization (weeks)
Data on file, Pfizer Inc.
16
MIRACL: occurrence of primary end point events
Death
Nonfatal Acute MI
Resuscitated
Cardiac Arrest
Worsening angina with new
objective evidence of ischemia
requiring urgent rehospitalization
0.25
*
0.50
0.75
*p=0.02
1.00
Atorvastatin better
1.25
1.75
Placebo better
Relative risk
Data on file, Pfizer Inc.
1.50
2.00
MIRACL: occurrence of secondary
clinical end points
Secondary end point [n (%)]
Revascularization*
Catheter based
CABG
Fatal + Nonfatal Stroke
Nonfatal stroke
New or worsening CHF
Worsening angina w/o new objective
evidence of ischemia
Placebo
(n=1548)
250
143
110
24
22
43
(16.1)
(9.2)
(7.1)
(1.6)
(1.4)
(2.8)
106 (6.8)
Atorvastatin
(n=1538)
254
150
106
12
9
40
(16.5)
(9.8)
(6.9)
(0.8)†
(0.6)‡
(2.6)
91 (5.9)
* 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
Data on file, Pfizer Inc.
Cumulative Incidence (%)
MIRACL: fatal or nonfatal stroke
2
Placebo
1.5
1
Atorvastatin
0.5
1.6%
0.8%
Relative risk = 0.50
p=0.045
0
0
4
8
12
Time since randomization (weeks)
Data on file, Pfizer Inc.
16
MIRACL: compliance with intended treatment
Placebo
(n=1548)
Atorvastatin
(n=1538)
99 days
98 days
Premature discontinuation
10.3%
11.2%
Reasons for discontinuation:
nonfatal AE
nonfatal ischemic event
other
1.5%
0.6%
8.2%
2.1%
0.5%
8.6%
4
8
Mean duration of compliance
No. of patients lost to follow-up
Data on file, Pfizer Inc.
MIRACL: safety
Elevated liver transaminases
(>3xULN on 2 occasions)
Myositis
(with CPK >10xULN on 2 occasions)
Any serious adverse event
Data on file, Pfizer Inc.
Placebo
(n=1548)
Atorvastatin
(n=1538)
0.6%
2.5%
0%
0%
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
Data on file, Pfizer Inc.