1. Statin Landmark Trials Across the Spectrum of Risk: Secondary CV Prevention

2. TNT: Study Design Treating to New Targets
Patient Population
Clinically evident CHD
LDL-C 130250 mg/dL following up to 8-week washout and 8-week open-label run-in with atorvastatin 10 mg
Atorvastatin 10 mg
LDL-C target: 100 mg/dL
10,001 Patients
Primary End Point
Atorvastatin 80 mg
LDL-C target: 75 mg/dL
TNT randomized 10,001 patients to either atorvastatin 10 mg with a goal of an average LDL-C of 100 mg/dL versus atorvastatin 80 mg with an average LDL-C of 80 mg/dL after an 8-week open-label run-in on atorvastatin 10 mg. The primary end point was time to first occurrence of a major CV event (CHD death, nonfatal non–procedure-related MI, resuscitated cardiac arrest, fatal or nonfatal stroke). Patients were followed for 5 years.
During the open-label period, the LDL-C level was reduced by 35% from a mean of 152 mg/dL (3.9 mmol/L) to a mean of 98 mg/dL (2.6 mmol/L). After randomization, mean LDL-C levels during the study were 77 mg/dL (2 mmol/L) among patients receiving atorvastatin 80 mg and 101 mg/dL (2.6 mmol/L) among those receiving atorvastatin 10 mg .
LaRosa JC, Grundy, Waters DD, et al; for the Treating to New Targets (TNT) Investigators. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;352:
Time to first occurrence of a major cardiovascular event (CHD death, nonfatal non–procedure-related MI, resuscitated cardiac arrest, fatal or nonfatal stroke)
5 years
LaRosa JC et al. N Engl J Med. 2005;352:

3. TNT Primary Efficacy Outcome Measure: Major CV Events*
Treating to New Targets (TNT) Study
TNT Primary Efficacy Outcome Measure: Major CV Events*
LaRosa 2005, p7, Fig 3
0.14
HR = 0.78 (95% CI, 0.69–0.89)
P < .001
0.12
Atorvastatin 10 mg (n = 5006)
LDL-C 101 mg/dL (2.6 mmol/L)
0.10
0.08
Cumulative Incidence of Major Cardiovascular Events, %
0.06
Atorvastatin 80 mg (n = 4995)
LDL-C 77 mg/dL (2.0 mmol/L)
0.04
The high-dose group experienced a significant relative reduction in cumulative incidence of major CV events of 22% compared with the low-dose group (HR = 0.78; 95% CI, ; P < 0.001). This reflects a composite outcome of death from CHD, nonfatal non–procedure-related MI, resuscitation after cardiac arrest, or fatal or nonfatal stroke.
LaRosa JC, Grundy, Waters DD, et al; for the Treating to New Targets (TNT) Investigators. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;352:
0.02
Relative risk reduction = 22%
Time, years
*CHD death, nonfatal non–procedure-related MI, resuscitated cardiac arrest, fatal or nonfatal stroke.
LaRosa JC et al. N Engl J Med. 2005;352:

4. TNT: Primary and Secondary Efficacy Outcomes
LaRosa 2005, p8, Table 2
Primary Efficacy Measure HR
P Value
Major CV event
0.78
.001
CHD death
0.80
.09
Nonfatal non–procedure-related MI
0.78
.004
Resuscitated cardiac arrest
0.96
.89
Fatal/nonfatal stroke
0.75
.02
Secondary Efficacy Measures
Any cardiovascular event
0.81
<.001
Major coronary event*
0.80
.002
Any coronary event
The high-dose atorvastatin regimen was associated with significant risk reductions for components of both the primary efficacy measure—nonfatal non–procedure-related MI, fatal or nonfatal stroke; and the secondary efficacy measures—any CV event, major or any coronary events, cerebrovascular events, and hospitalization for CHF.
LaRosa JC, Grundy, Waters DD, et al; for the Treating to New Targets (TNT) Investigators. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;352:
0.79
<.001
Cerebrovascular event
0.77
.007
Hospitalization for CHF
0.74
.01
Peripheral arterial disease
0.97
.76
All-cause mortality
1.01
.92
Atorvastatin 80 mg Better
Atorvastatin 10 mg Better
*CHD death, nonfatal non–procedure-related MI, resuscitated cardiac arrest.
LaRosa JC et al. N Engl J Med. 2005;352:

5. TNT: Time to First Fatal or Nonfatal Stroke
Time (years)
0.01
0.02
0.04
0.03
HR = 0.75 (95% CI )
P=0.02
Relative RR = 25%
Atorvastatin 10 mg
Atorvastatin 80 mg
Proportion of patients experiencing events
In the TNT trial, atorvastatin 80 mg reduced the outcome of fatal and nonfatal stroke by 25% relative risk (HR = 0.75; 95% CI, ; P = 0.02) compared with atorvastatin 10 mg.
LaRosa JC, Grundy, Waters DD, et al; for the Treating to New Targets (TNT) Investigators. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;352:
LaRosa JC et al. N Engl J Med. 2005;352:

6. Elevated Liver Enzymes*
TNT: Safety Profile 10
P<0.001
8.1 8
5.8
P =0.72 6
4.8
4.7
% of Patients 4
P<0.001 2
1.2
0.2
(n=406)
(n=289)
(n=241)
(n=234)
(n=60)
(n=9)
The rate of treatment-related adverse events was higher in the atorvastatin 80 mg group (8.1%) than in the 10 mg group (5.8%) (P < 0.001). There was no difference in the rate of treatment-related myalgia between atorvastatin 80 mg (4.8%) and atorvastatin 10 mg (4.7%) (P = NS). The rate of elevated liver enzymes was higher (1.2%) in the atorvastatin 80 mg group than in the atorvastatin 10 mg group (0.2%) (P < 0.001).
LaRosa JC, Grundy, Waters DD, et al; for the Treating to New Targets (TNT) Investigators. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;352:
Treatment-Related
Adverse Events
Treatment-Related
Myalgia
Elevated Liver Enzymes*
Atorvastatin 80 mg (n=4,995)
Atorvastatin 10 mg (n=5,006)
Persistent = 2 consecutive measurements.
LaRosa JC et al. N Engl J Med. 2005;352:

7. Simvastatin 20 mg; titration to 40 mg for TC >190 mg/dL
IDEAL (Incremental Decrease in End Points Through Aggressive Lipid Lowering): Study Design
Patient Population
Previous hospitalization with definite acute MI or a history of definite MI
Eligibility for statin therapy according to respective national guidelines at discharge
Atorvastatin 80 mg
8888 Patients
Primary End Point
Simvastatin 20 mg; titration to 40 mg for TC >190 mg/dL
TNT randomized 10,001 patients to either atorvastatin 10 mg with a goal of an average LDL-C of 100 mg/dL versus atorvastatin 80 mg with an average LDL-C of 80 mg/dL after an 8-week open-label run-in on atorvastatin 10 mg. The primary end point was time to first occurrence of a major CV event (CHD death, nonfatal non–procedure-related MI, resuscitated cardiac arrest, fatal or nonfatal stroke). Patients were followed for 5 years.
During the open-label period, the LDL-C level was reduced by 35% from a mean of 152 mg/dL (3.9 mmol/L) to a mean of 98 mg/dL (2.6 mmol/L). After randomization, mean LDL-C levels during the study were 77 mg/dL (2 mmol/L) among patients receiving atorvastatin 80 mg and 101 mg/dL (2.6 mmol/L) among those receiving atorvastatin 10 mg .
LaRosa JC, Grundy, Waters DD, et al; for the Treating to New Targets (TNT) Investigators. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;352:
Time to occurrence of a major cardiovascular event (CHD death, nonfatal acute MI, resuscitated cardiac arrest)
4.8 years
Open label with blinded end-point evaluation
Pedersen TR et al. JAMA. 2005;294:

8. IDEAL: Primary and Secondary End Points
Major coronary events – primary end point
Major CV events – secondary end point 16 16
Simvastatin
Atorvastatin
Simvastatin
Atorvastatin
13% RRR 12
11% RRR 12
Cumulative Hazard, % 8
Cumulative Hazard, % 8
Pedersen 2005, p2441 Fig 2, col 1 4 4
HR = 0.89 (95% CI, 0.76–1.01) P = .07
HR = 0.87 (95% CI, 0.78–0.98) P = .02 1 2 3 4 5 1 2 3 4 5
Years Since Randomization
Years Since Randomization
Any coronary event – secondary end point
Any CV event – secondary end point 40
Simvastatin
Atorvastatin 40
Simvastatin
Atorvastatin
16% RRR
During treatment, mean LDL-C levels were 104 mg/dL in the simvastatin group and 81 mg/dL in the atorvastatin group. The primary end point of IDEAL (a composite of CHD death, nonfatal MI, and resuscitated cardiac arrest) did not reach statistical significance (HR = 0.89; 95% CI, ; P = 0.07). Atorvastatin treatment was associated with reductions in the secondary end points of major CV events (HR = 0.87; 95% CI, ; P = 0.02), any coronary event (HR = 0.84; 95% CI, ; P < 0.001), and any CV event (HR = 0.84; 95% CI, ; P < 0.001).
Pedersen TR, Faergeman O, Kastelein JJP, et al; for the Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) Study Group. High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction. The IDEAL Study: a randomised controlled trial. JAMA. 2005;294: 30 30
16% RRR
Cumulative Hazard, % 20
Cumulative Hazard, % 20 10 10
HR = 0.84 (95% CI, 0.76–0.91) P < .001
HR = 0.84 (95% CI, 0.78–0.91) P < .001 1 2 3 4 5 1 2 3 4 5
Years Since Randomization
Years Since Randomization
The primary end point of IDEAL (a composite of CHD death, nonfatal MI, and resuscitated cardiac arrest) did not reach statistical significance (HR = 0.89; 95% CI, ; P = 0.07).
Pedersen TR et al. JAMA. 2005;294:

9. Relative Risk Reduction (%)
Effects of Atorvastatin 80 mg/d vs Simvastatin 20 to 40 mg/d on Any CV Event
Tikkanen, p 2356, F2
Subjects With Event
Relative Risk Reduction (%)
P Value
Events
HR (95% CI)*
1st
(0.77 – 0.90) 17
<.0001
2nd
(0.67 – 0.86) 24
<.0001
3rd
(0.67 – 0.99) 19
.035
4th
(0.57 – 1.01) 24
.058
A post hoc analysis of the IDEAL trial examined the effects of atorvastatin 80 mg versus simvastatin 20 to 40 mg on CV events after the first event. Compared with patients taking simvastatin 20 to 40 mg daily, patients receiving atorvastatin 80 mg daily had their relative risk of a first CV event reduced by 17% (P < ), of a second by 24% (P < ), of a third by 19% (p 0.035), of a fourth by 24% (P = 0.058), and of a fifth by 28% (P = 0.117). These findings demonstrate that intensive statin therapy continued to be more effective than standard statin therapy for events beyond the first event and in the long term.
Tikkanen MJ, Szarek M, Fayyad R, et al; Total cardiovascular disease burden: comparing intensive with moderate statin therapy: insights from the IDEAL (Incremental Decrease in End Points Through Aggressive Lipid Lowering) trial. J Am Coll Cardiol. 2009;54;
5th
(0.48 – 1.09) 28
.117
0.50
0.75
1.0
1.25
1.50
Atorvastatin better
Simvastatin better
*Adjusted for sex and age at baseline.
Tikkanen MJ et al. J Am Coll Cardiol. 2009;54:

10. MIRACL (Myocardial Ischemia Reduction With Aggressive Cholesterol Lowering): Study Design
Patient Population
Non-Q-wave MI or unstable angina
Randomized 24–96 hours from admission
Atorvastatin 80 mg
3086 Patients
Primary End Point
Placebo
TNT randomized 10,001 patients to either atorvastatin 10 mg with a goal of an average LDL-C of 100 mg/dL versus atorvastatin 80 mg with an average LDL-C of 80 mg/dL after an 8-week open-label run-in on atorvastatin 10 mg. The primary end point was time to first occurrence of a major CV event (CHD death, nonfatal non–procedure-related MI, resuscitated cardiac arrest, fatal or nonfatal stroke). Patients were followed for 5 years.
During the open-label period, the LDL-C level was reduced by 35% from a mean of 152 mg/dL (3.9 mmol/L) to a mean of 98 mg/dL (2.6 mmol/L). After randomization, mean LDL-C levels during the study were 77 mg/dL (2 mmol/L) among patients receiving atorvastatin 80 mg and 101 mg/dL (2.6 mmol/L) among those receiving atorvastatin 10 mg .
LaRosa JC, Grundy, Waters DD, et al; for the Treating to New Targets (TNT) Investigators. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;352:
Time to ischemic events (CHD death, nonfatal MI, documented angina requiring hospitalization)
16 weeks double-blind
Schwartz GG et al. JAMA. 2001;285:

11. MIRACL: Primary Efficacy Measure— Time to First Event*
17.4%
16%
RRR
Schwartz, p 1715, fig 5, p 1716, table 2
Placebo (n = 1548)
LDL-C 135 mg/dL (3.5 mmol/L) 15
14.8%
Atorvastatin 80 mg (n = 1538)
LDL-C 72 mg/dL (1.9 mmol/L) 10
Cumulative Incidence, % 5
RR = 0.84 P = .048
95% CI, 0.701–0.999
After 16 of weeks follow-up, the primary end point measure (time to first occurrence of death, nonfatal acute MI, resuscitated cardiac arrest, or worsening angina with new objective evidence requiring urgent rehospitalization) occurred in 228 patients in the atorvastatin group (14.8%) and 269 patients in the placebo group (17.4%). Compared with placebo, atorvastatin treatment produced a significant (P = 0.048) 16% reduction in the risk of the primary composite end point (95% CI, ).
LDL-C in the atorvastatin 80 mg arm was 72 mg/dL (1.9 mmol/L), and in the placebo arm it was 135 mg/dL (3.5 mmol/L).
Schwartz GG, Olsson AG, Ezekowitz MD, et al; for the MIRACL Study Investigators. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes. JAMA. 2001;285: 4 8 12 16
Time Since Randomization, weeks
*Death (any cause), nonfatal MI, resuscitated cardiac arrest, worsening angina with new objective evidence and urgent rehospitalization.
Schwartz GG et al. JAMA. 2001;285:

12. MIRACL: Stroke Placebo (n=1548) Atorvastatin (n=1538) Total strokes 2513
Fatal stroke 2 3
Nonfatal stroke 23 10
Type of stroke
Hemorrhagic
Embolic 1
Thrombotic/embolic 19
Indeterminate
Number patients experiencing a stroke (P=0.04) (%)
24 (1.6)
12 (0.8)
2 (0.1)
3 (0.2)
Nonfatal stroke (P=0.02)
22 (1.4)
9 (0.6)
Intensive lipid lowering with atorvastatin 80 mg in the MIRACL trial reduced secondary stroke end points versus placebo. Strokes were adjudicated by a blinded end-point committee using standard clinical and imaging criteria. Of 38 events (in 36 patients) adjudicated as fatal or nonfatal strokes, 3 were classified as hemorrhagic, 1 as embolic, and 29 as thrombotic or embolic; 5 could not be categorized. Nonfatal stroke occurred in 9 patients in the atorvastatin group and 22 in the placebo group (relative risk, 0.40; 95% CI, 0.19 to 0.88; P = 0.02).
Fatal or nonfatal stroke occurred in 12 atorvastatin patients and 24 placebo patients (relative risk, 0.49; 95% CI, 0.24 to 0.98; P = 0.04). All 3 hemorrhagic strokes occurred in the placebo group.
Intensive cholesterol lowering with atorvastatin over 16 weeks in patients with ACS reduced the overall stroke rate by half and did not increase hemorrhagic stroke.
Waters DD, Schwartz GG, Olsson AG, et al; for the MIRACL Study Investigators. Effects of atorvastatin on stroke in patients with unstable angina or non–Q-wave myocardial infarction: a Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) substudy. JAMA. 2001;285:
Water DD et al. Circulation. 2002;106:

13. PROVE IT-TIMI (Pravastatin or Atorvastatin Evaluation and Infection Therapy– Thrombolysis in Myocardial Infarction) 22: Study Design
Patient Population
Hospitalized for an acute coronary syndrome in the preceding 10 days
TC ≤240 mg/dL (6.2 mmol/L) or TC ≤200 mg/dL (5.2 mmol/L) if receiving lipid-lowering therapy
Atorvastatin 80 mg
4162 Patients
Primary End Point
Pravastatin 40 mg
TNT randomized 10,001 patients to either atorvastatin 10 mg with a goal of an average LDL-C of 100 mg/dL versus atorvastatin 80 mg with an average LDL-C of 80 mg/dL after an 8-week open-label run-in on atorvastatin 10 mg. The primary end point was time to first occurrence of a major CV event (CHD death, nonfatal non–procedure-related MI, resuscitated cardiac arrest, fatal or nonfatal stroke). Patients were followed for 5 years.
During the open-label period, the LDL-C level was reduced by 35% from a mean of 152 mg/dL (3.9 mmol/L) to a mean of 98 mg/dL (2.6 mmol/L). After randomization, mean LDL-C levels during the study were 77 mg/dL (2 mmol/L) among patients receiving atorvastatin 80 mg and 101 mg/dL (2.6 mmol/L) among those receiving atorvastatin 10 mg .
LaRosa JC, Grundy, Waters DD, et al; for the Treating to New Targets (TNT) Investigators. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;352:
Time to first occurrence of a major cardiovascular event (death from any cause, MI, unstable angina, revascularization, stroke
Double-blind
925 primary end points
Cannon CP et al. N Engl J Med. 2004;350:

14. Death or Major CV Event, %
PROVE IT: Primary End Point (All-Cause Death or Major CV Events in All Randomized Subjects)
26.3%
Cannon, p 5 col 1, p 6, fig 2 30
Pravastatin 40 mg (n = 1548)
95 mg/dL (2.5 mmol/L)
16% RRR
(P = .005) 25
22.4% 20
Intensive lipid lowering with atorvastatin 80 mg reduced LDL-C to 62 mg/dL (1.6 mmol/L) compared with 95 mg/dL (2.5 mmol/L) in the pravastatin 40 mg group for a 35% reduction in LDL-C. The Kaplan-Meier event rate of primary outcome at 2 years was 26.3% in the standard-dose pravastatin arm versus 22.4% in the high-dose atorvastatin arm, which was associated with a 16% reduction in the HR (95% CI, 5-26%; P = 0.005).
Cannon CP, Braunwald E, McCabe CH, et al; for the PROVE-IT Investigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350: 15
Atorvastatin 80 mg (n = 2099)
62 mg/dL (1.6 mmol/L)
Death or Major CV Event, %
–35% LDL reduction 10 5 3 6 9 12 15 18 21 24 27 30
Months of Follow-up
Major CV event = MI, unstable angina requiring rehospitalization, revascularization, or stroke.
Cannon CP et al. N Engl J Med. 2004;350:

15. PROVE IT-TIMI 22: Intensive Therapy With Statins in Patients With ACS: Early and Long-term Benefits
Ray, p 1408, fig 3, p 1409 fig 5
Month 6 to end of study
RRR = 28% P = .003 6 12 18 24
Months following randomization
Composite triple end point* (%) 2 4 8 10
n = 1752
n= 1812
Randomization to 30 days
Days following randomization
Composite triple end point* (%) 10 5 15 20 30 25 2 1 3
RRR = 28% P = .046
n = 2063
n = 2099 4
An analysis of the PROVE IT trial examined the early effect of intensive lipid therapy with atorvastatin 80 mg versus moderate lipid therapy with pravastatin 40 mg at 30 days after acute coronary syndrome. This analysis used a triple composite end point (death, MI, or rehospitalization for recurrent ACS), which is the end point commonly used in ACS trials for evaluation of early outcomes. The outcome was that at 30 days, atorvastatin 80 mg was associated with a 28% risk reduction (HR = 0.72; 95% CI, ; P = 0.046). The effect of intensive lipid therapy occurred early. When the triple end point was used in an analysis of patients followed from 6 months to the end of the study at 2 years, the risk reduction was consistent (HR=0.72, 95% CI , P = 0.003). Intensive lipid therapy with atorvastatin 80 mg produced benefits over standard therapy early and late in patients with ACS.
Ray KK, Cannon CP, McCabe CH, et al. Early and late benefits of high-dose atorvastatin in patients with acute coronary syndromes. Results from the PROVE IT-TIMI 22 Trial. J Am Coll Cardiol. 2005;46:
Atorvastatin 80 mg
Pravastatin 40 mg
*Death, MI, or rehospitalization with recurrent ACS.
Adapted from Ray KK et al. J Am Coll Cardiol. 2005;46:

16. Safety of Atorvastatin 80 mg in Clinical Trials
Cannon, p 6, col 1
Follow-up
Patients
ALT/AST
>3x ULN*
CK >10x ULN*
Newman et al†
variable
4798
26 (0.6%)
2 (0.06%)
PROVE-IT
2 years
2099
69 (3.3%) NA
TNT
4.9 years
4995
60 (1.2%)
IDEAL
4.8 years
4439
61 (1.38%)
SPARCL
2365
51 (2.2%)
2 (0.08%)
Total
18,696
267 (1.43%)
4 (0.021%)
Newman, p 66, table 2
LaRosa, p 8
Pedersen, p 2442
Amarenco, p 557, table 3
Atorvastatin 80 mg has been studied in >18,000 patients in clinical trials1-5 that documented a low incidence of myopathy and liver enzyme elevation.
Newman C, Tsai J, Szarek M, Luo D, Gibson E. Comparative safety of atorvastatin 80 mg versus 10 mg derived from analysis of 49 completed trials of 14,236 patients. Am J Cardiol. 2006;97:61-67.
Cannon CP, Braunwald E, McCabe CH, et al; for the PROVE-IT Investigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350:
LaRosa JC, Grundy, Waters DD, et al; for the Treating to New Targets (TNT) Investigators. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;352:
Pedersen TR, Faergeman O, Kastelein JJP, et al; for the Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) Study Group. High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction. The IDEAL Study: a randomised controlled trial. JAMA. 2005;294:
The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med. 2006;355:
*Consecutive measurements.
†Newman C et al. Am J Cardiol. 2006;97:61-67; Cannon CP et al. N Engl J Med. 2004;350: ; LaRosa JC, et al. N Engl J Med. 2005;352: ; Pedersen TR et al; for the IDEAL Study Group. JAMA. 2005;294: ; Amarenco P et al. N Engl J Med. 2006;355:

17. Overview of Adverse Events for Atorvastatin 10 mg and 80 mg and Placebo
Parameter
Placebo
(n=2180)
Atorvastatin 10 mg
(n=7258)
Atorvastatin 80 mg
(n=4798)
≥1 AE
All cause
768 (35.2%)
3870 (53.3%)
2285 (47.6%)
Treatment associated
270 (12.4%)
983 (13.5%)
699 (14.6%)
Withdrawals due to AEs
51 (2.3%)
251 (3.5%)
136 (2.8%)
27 (1.2%)
171 (2.4%)
84 (1.8%)
Serious nonfatal AEs
122 (5.6%)
453 (6.2%)
385 (8.0%)
92 (4.2%)
12 (0.2%)
25 (0.5%)
The overall adverse event profiles were similar for the placebo group and both atorvastatin groups.
The rates of withdrawal due to treatment-associated adverse events were:
2.4% in the atorvastatin 10-mg group
1.8% in the atorvastatin 80-mg group
Incidences of all-cause and treatment-associated serious, nonfatal adverse events were comparable between both atorvastatin groups.
Newman C, Tsai J, Szarek M, et al. Comparative safety of atorvastatin 80 mg versus 10 mg derived from analysis of 49 completed trials in 14,236 patients. Am J Cardiol. 2006;97:61-67.
Newman C et al. Am J Cardiol. 2006;97:61-67.

18. TNT: Changes in LDL-C by Treatment Group
LaRosa 2005, p6, Fig 2, p 5 rt col
Baseline
160
140
120
100 80 60 40 20
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
Atorvastatin 10 mg (n = 5006)
Atorvastatin 80 mg (n = 4995)
Mean LDL-C level = 101 mg/dL (2.6 mmol/L)
Mean LDL-C, mg/dL
Mean LDL-C, mmol/L
Mean LDL-C level = 77 mg/dL (2.0 mmol/L)
In TNT, during the open-label period, the LDL cholesterol level was reduced by 35% from a mean of 152 mg/dL (3.9 mmol/L) to a mean of 98 mg/dL (2.6 mmol/L). After randomization, mean LDL-C levels during the study were 77 mg/dL (2 mmol/L) among patients receiving atorvastatin 80 mg and 101 mg/dL (2.6 mmol/L) among those receiving 10 mg atorvastatin.
LaRosa JC, Grundy, Waters DD, et al; for the Treating to New Targets (TNT) investigators. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;352:
P < .001
Screen 3 12 24 36 48 60
Final
Study Visits, months
LaRosa JC et al. N Engl J Med. 2005;352:

19. PROVE IT: Reductions in Major Cardiac End Points
Cannon, p 7, fig 4
2-Year Event Rates
RR Atorva 80 Prava 40
28% 2.2% 3.2%
30% 1.1% 1.4%
13% 6.6% 7.4%
18% 8.3% 10.0%
14% 16.3% 18.8% % 3.8% 5.1%
25% 12.9% 16.7%
All-Cause Mortality
CHD Death MI
Death or MI
Revasc >30 d
In PROVE IT, Intensive lipid lowering with atorvastatin 80 mg reduced secondary end points including death or MI, revascularization at 30 days, unstable angina requiring hospitalization and death/MI, urgent revascularization.
Cannon CP, Braunwald E, McCabe CH, et al; for the PROVE-IT Investigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350:
UA Req Hosp
Death/MI/Urg. Revasc
0.5
0.75
1.0
1.25
1.5
Atorvastatin 80 mg Better
Pravastatin 40 mg Better
Cannon CP et al. N Engl J Med. 2004;350:

20. Effect of Intensive Statin Therapy on Clinical OutcomesAmong Patients Undergoing Percutaneous Coronary Intervention for ACS: PCI-PROVE IT Substudy
Gibson, p 2293, fig 1
Post hoc analysis of 2868 patients who underwent PCI just prior to enrollment
30%
25%
Pravastatin
Pravastatin
25%
20%
20%
15%
Atorvastatin
Primary End Point
15%
Death, MI, RI, UA
Atorvastatin
10%
10%
Hazard ratio 0.78
95% CI, 0.67–0.91
P < .001
Hazard ratio 0.73
95% CI, 0.61–0.87
P < .001
In a post hoc analysis, of 2868 patients in the PROVE IT study who underwent PCI just prior to enrollment, atorvastatin was associated with significant reductions of the primary end point (hazard ratio % CI, P < .001) and of an end point consisting off death/MI, recurrent ischemia/and unstable angina requiring revascularization (hazard ratio % CI, P < .001).
Gibson CM, Pride YB, Hochber CP. Effect of intensive statin therapy on clinical outcomes among patients undergoing percutanous coronary intervention for acute coronary syndrome. PCI PROVE IT: A PROVE IT TIMIE 22 Substudy. J Am Coll Cardiol. 2009;54: 5% 5% 0% 0%
120
240
360
480
600
720
120
240
360
480
600
720
Time, days
Time, days
Gibson CM et al. J Am Coll Cardiol. 2009;54:

21. Long-term Statin Treatment in IDEAL Maintained Benefit Over 5 Years
Cannon, p 6, F 2
Pedersen, p 4, F4
Longest Period of Follow-up of ACS Patients on Statin Therapy
*Composite end point = death, nonfatal MI, hospitalization for UA, or coronary revascularization 20 40 30 10
30 months
5 years
Composite End Point *, % 50 60
Atorvastatin 80 mg
Pravastatin 40 mg
Simvastatin mg
18% RRR
P = 0.04
PROVE IT (MI or UA)
IDEAL (All MI)
16% RRR
P = 0.005
A post hoc analysis of the IDEAL trial examined a subgroup of 999 patients who had a first acute myocardial infarction (MI) <2 months before randomization. The analysis used the same composite end point used in the Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE IT) trial (death, MI, hospitalization for unstable angina, revascularization, and stroke). Rates of the composite end point were 44.7% (n = 226) in the simvastatin group and 37.9% (n = 187) in the atorvastatin group (hazard ratio 0.82, 95% confidence interval 0.67 to 0.99, p = 0.04). Although statistical power was smaller than that of the PROVE IT trial, the relative risk decrease observed at 5 years is consistent with that in the 2-year follow-up in PROVE IT.
Cannon CP, Braunwald E, McCabe CH, et al; for the PROVE-IT Investigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350:
Pedersen TR, Faergeman O, Kastelein JJP, et al; for the Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) Study Group. High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction. The IDEAL Study: a randomized controlled trial. Am J Cardiol. 2010;106:
Cannon CP et al. N Engl J Med. 2004;350: ; Pedersen TR et al. Am J Cardiol. 2010;106:

22. MIRACL: Secondary End Points
No. of Events (%)
Atorvastatin
Placebo
Schwartz, p 1716, fig 4, table 2
Stroke (fatal and nonfatal)
12 (0.8)
24 (1.6)
Revascularization
(CABG or PTCA)
254 (16.5)
250 (16.1)
Worsening angina (without
objective evidence of ischemia)
91 (5.9)
106 (6.8)
In MIRACL, the secondary end point of fatal and nonfatal stroke was significantly reduced (P = 0.045).
Schwartz GG, Olsson AG, Ezekowitz MD, et al; for the MIRACL Study Investigators. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes. JAMA. 2001;285:
Worsening congestive
heart failure
40 (2.6)
43 (2.8)
0.25
0.50
0.75
1.00
1.25
1.50
*P = .045.
Atorvastatin Better
Placebo Better
Relative Risk
Schwartz GG et al. JAMA. 2001;285:

23. Association of Dyslipidemia and myocardial Infarction Risk: INTERHEART
Smk DM
HTN
Lipids
1+2+3
all4 +O
+PS
All RFs 1 2 4 8 16 32 64
128
256
512
OR (99% CI)
3-fold increase in risk of acute MI
Risk of AMI With Multiple Risk Factors
Yusuf et al. p7, fig 2
The INTERHEART study assessed the relationship between various factors and the risk of acute myocardial infarction from study participants in 52 countries around the world, including several countries in Asia. This study showed that abnormal lipid levels lead to a 3-fold increase in the risk of acute myocardial infarction.
AMI, acute myocardial infarction; Smk, smoking; DM, diabetes mellitus; HTN, hypertension; O, obesity; PS, psychosocial; RF, risk factors; OR; odds ratio.
Yusuf S, Hawken S, Ôunpuu S, et al; on behalf of the INTERHEART study investigators. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet. 2004;364:
AMI, acute myocardial infarction; Smk, smoking; DM, diabetes mellitus; HTN, hypertension; O, obesity; PS, psychosocial; RF, risk factors; OR; odds ratio.
Yusuf S et al. Lancet. 2004;364:

24. ASCOT CRP Analysis
Post hoc subgroup (nested case control) analysis of ASCOT data
To assess baseline CRP and risk of CV events: 5.5 years follow-up, 485 patients with major CV events matched with 1367 controls from baseline population (ASCOT BPLA)
To assess the effect of statin treatment on CRP and risk of CV events: 5.5 years follow-up, 235 patients with major CV events matched with 777 controls from statin trial population (ASCOT LLA)
Baseline CRP and risk of CV events
Inclusion of CRP in a Framingham risk model modestly improved the prediction of CV events beyond use of standard CV risk factors by a small amount
On-statin-treatment CRP and risk of CV events
Levels of LDL-C were strongly associated with reductions in CV events
On-statin-treatment CRP levels were not predictive of CV outcomes
Atorvastatin 10 mg reduced median CRP by 27%
The ASCOT trial investigators performed a post hoc subgroup analysis to assess the viability of using CRP levels to independently predict cardiovascular outcomes. The authors concluded that CRP reduction due to statin therapy cannot be used as an independent predictor of cardiovascular outcomes.
Sever PS, Poulter NR, Chang C-L, et al. The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT): testing C-reactive protein at baseline and on-treatment as an independent predictor of cardiovascular outcomes. Presented at: American Heart Association Scientific Sessions; November 13-17, 2010; Chicago, IL. Abstract Accessed March 9, 2011.
Late Breaking Clinical Trials. AHA Scientific Session Abstract downloaded from