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					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

				
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posted:1/2/2011
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