A to Z: Phase Z, Early Intensive verses Delayed
Simvastatin in Acute Coronary Syndromes
Purpose
To compare early initiation of an intensive statin regimen with delayed
initiation of a less intensive regimen in patients with an acute
coronary syndrome (ACS).
Reference
de Lemos JA, Blazing MA, Wiviott SD et al. Early Intensive vs a
Delayed Conservative Simvastatin Strategy in Patients With Acute
Coronary Syndromes Phase Z of the A to Z Trial. JAMA
2004;292:1307-1316.
A to Z: Phase Z, Early Intensive verses Delayed
Simvastatin in Acute Coronary Syndromes
- TRIAL DESIGN -
Design
Multicenter, randomized, double-blind, placebo-controlled
Patients
4497 patients, aged 21-80 years, with non-ST-segment-elevation ACS
or ST-elevation MI and total cholesterol ≤ 250 mg/dL. Patients
receiving statin therapy, or scheduled for CABG or PCI within two
weeks, or increased ALT or creatinine were excluded
Follow up and primary endpoint
Primary endpoint: composite of cardiovascular death, non-fatal MI,
readmission for ACS and stroke. Median follow-up: 721 days.
Treatment
Placebo (4 months) then simvastatin 20 mg/day or simvastatin 40
mg/day (1 month) then simvastatin 80 mg/day
A to Z: Phase Z, Early Intensive verses Delayed
Simvastatin in Acute Coronary Syndromes
- TRIAL DESIGN continued-
Baseline characteristics
Placebo + 20 mg/day Simvastatin 40/80
simvastatin mg/day
N=2232 N=2265
Age (mean) 61 61
Male 75% 76%
ST-segment elevation MI 40% 40%
Non-ST-segment elevation ACS 60% 60%
Total cholesterol (mean mg/dL) 184 185
A to Z: Phase Z, Early Intensive verses Delayed
Simvastatin in Acute Coronary Syndromes
- RESULTS -
The primary efficacy outcome (cardiovascular death, MI, readmission for ACS
and stroke) occurred in 16.7% of patients on placebo/simvastatin compared
with 14.4% in patients receiving 40/80 mg/day simvastatin (p=0.14)
Secondary endpoints of cardiovascular death and congestive heart failure were
reduced in the 40/80 mg/day simvastatin group (p=0.05 and p=0.04
respectively)
No significant difference in all-cause mortality, MI, readmission for ACS, stroke
and coronary revascularization
No significant difference in primary endpoint at four months (placebo-controlled
comparison period)
From four months, primary endpoint reduced from 9.3% in placebo/simvastatin
group to 6.8% in the 40/80 mg simvastatin group (p=0.02)
A to Z: Phase Z, Early Intensive verses Delayed
Simvastatin in Acute Coronary Syndromes
- RESULTS continued -
A to Z: Phase Z, Early Intensive verses Delayed
Simvastatin in Acute Coronary Syndromes
- RESULTS continued -
Breakdown of secondary and tertiary endpoints
Placebo + 20 Simvastatin 40/80
Hazard Ratio
mg/day simvastatin mg/day P Value
(95% CI)
N=2232 N=2265
All-cause mortality 130 (6.7%) 104 (5.5%) 0.79 (0.61,1.02) 0.08
Cardiovascular- 109 (5.4%) 83 (4.1%) 0.75 (0.57,1.00) 0.05
related death
MI 155 (7.4%) 151 (7.1%) 0.96 (0.77,1.21) 0.74
Readmission for ACS 102 (5.0%) 103 (4.9%) 0.99 (0.76,1.31) 0.97
Stroke 35 (1.8%) 28 (1.3%) 0.79 (0.48,1.30) 0.36
Coronary 124 (6.2%) 119 (5.9%) 0.93 (0.73,1.20) 0.60
revascularization
Congestive heart 98 (5.0%) 72 (3.7%) 0.72 (0.53,0.98) 0.04
failure
A to Z: Phase Z, Early Intensive verses Delayed
Simvastatin in Acute Coronary Syndromes
- RESULTS continued -
Cholesterol levels (mg/dL)
Time from randomization
Total Cholesterol Baseline 1 Month 4 Months 8 Months 24 Months
Placebo + 20 184 (165-506) 198 (176-223) 202 (180-227) 152 (134-172) 157 (138-176)
mg/day
simvastatin
Simvastatin 185 (163-205) 138 (119-157) 132 (116-153) 135 (118-155) 138 (122-158)
40/80 mg/day
P-value <0.001 <0.001 <0.001 <0.001
LDL Cholesterol
Placebo + 20 111 (95-131) 122 (104-143) 124 (106-147) 77 (64-95) 81 (66-96)
mg/day
simvastatin
Simvastatin 112 (94-130) 68 (54-84) 62 (48-77) 63 (50-79) 66 (54-82)
40/80 mg/day
P-value <0.001 <0.001 <0.001 <0.001
A to Z: Phase Z, Early Intensive verses Delayed
Simvastatin in Acute Coronary Syndromes
- SUMMARY -
Early initiation of aggressive simvastatin regimen resulted in trend towards
reduction in major cardiovascular events
Cardiovascular death, MI and readmission for acute coronary syndrome
reduced, but not significantly, in patients receiving aggressive simvastatin
regimen
Total and LDL cholesterol levels decreased over 24 months with simvastatin
40/80 mg/day treatment. Cholesterol levels rose during placebo phase, then fell
in second phase of treatment with placebo/simvastatin 20 mg/day