statin landmark trials across the spectrum of risk: secondary cv prevention

Statin Landmark Trials Across the Spectrum of Risk:

Secondary CV Prevention

2

TNT: Study Design Treating to New Targets

5 years

10,001 Patients

• Clinically evident CHD

• LDL-C 130250 mg/dL following up to 8-week washout and 8-week open-label run-in with atorvastatin 10 mg

Patient Population

• Time to first occurrence of a major cardiovascular event (CHD death, nonfatal non–procedure-related MI, resuscitated cardiac arrest, fatal or nonfatal stroke)

Primary End Point

Atorvastatin 10 mgLDL-C target: 100 mg/dL

LaRosa JC et al. N Engl J Med. 2005;352:1425-1435.

Atorvastatin 80 mgLDL-C target: 75 mg/dL

3

TNT Primary Efficacy Outcome Measure:Major Cardiovascular Events*

*CHD death, nonfatal non–procedure-related MI, resuscitated cardiac arrest, fatal or nonfatal stroke.


HR = 0.78 (95% CI, 0.69–0.89)P < .001

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Atorvastatin 10 mg (n = 5006)LDL-C 101 mg/dL (2.6 mmol/L)

0.14

0 1 2 3 4 5 6

0.08

0.12

0.04

0.10

0.06

0.02

0

Relative risk reduction = 22%

Time, years


4

TNT: Primary and Secondary Efficacy Outcomes

HR

0.780.800.780.960.75

0.80

0.77

0.970.74

1.01

0.79

0.81

P Value

.001 .09

.004 .89.02

.002

.007

.76 .01

.92

<.001

<.001

Major CV eventCHD deathNonfatal non–procedure-related MIResuscitated cardiac arrestFatal/nonfatal stroke

Major coronary event*

Cerebrovascular event

Peripheral arterial diseaseHospitalization for CHF

All-cause mortality

Any coronary event

Any cardiovascular event

Primary Efficacy Measure

Secondary Efficacy Measures

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;352:1425-1435.

5

TNT: Time to First Fatal or Nonfatal Stroke


0 1 2 3 4 5 6

Time (years)

0

0.01

0.02

0.04

0.03

HR = 0.75 (95% CI 0.59-0.96)P=0.02

Relative RR = 25%

Atorvastatin 10 mg

Atorvastatin 80 mg

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6

TNT: Safety Profile

Persistent = 2 consecutive measurements.


Atorvastatin 80 mg (n=4,995)

Atorvastatin 10 mg (n=5,006)

P<0.001

P =0.72

P<0.001

(n=406) (n=289) (n=241) (n=234) (n=9)(n=60)

8.1

5.84.8 4.7

1.2 0.2

10

8

6

4

2

0

Treatment-RelatedAdverse Events

Treatment-RelatedMyalgia

Elevated Liver Enzymes*

% o

f P

atie

nts

7

IDEAL (Incremental Decrease in EndPoints Through Aggressive Lipid Lowering): Study Design

4.8 yearsOpen label with blinded

end-point evaluation

8888 Patients

• Previous hospitalization with definite acute MI or a history of definite MI

• Eligibility for statin therapy according to respective national guidelines at discharge

Patient Population

• Time to occurrence of a major cardiovascular event (CHD death, nonfatal acute MI, resuscitated cardiac arrest)

Primary End Point

Atorvastatin 80 mg

Pedersen TR et al. JAMA. 2005;294:2437-2445.

Simvastatin 20 mg; titrationto 40 mg for TC >190 mg/dL

8

IDEAL: Primary and Secondary End Points

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, 0.78-1.01; P = 0.07).

Pedersen TR et al. JAMA. 2005;294:2437-2445.

Years Since Randomization

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0 1 2 3 4 50

4

8

12

16

HR = 0.89 (95% CI, 0.76–1.01) P = .07

11%RRR

SimvastatinAtorvastatin


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0 1 2 3 4 50

4

8

12

16

HR = 0.87 (95% CI, 0.78–0.98) P = .02

13%RRR



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0 1 2 3 4 50

10

20

30

40

HR = 0.84 (95% CI, 0.76–0.91) P < .001

16%RRR



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0 1 2 3 4 50

10

20

30

40

HR = 0.84 (95% CI, 0.78–0.91) P < .001

16%RRR


Any coronary event – secondary end point Any CV event – secondary end point

Major CV events – secondary end pointMajor coronary events – primary end point

9

Effects of Atorvastatin 80 mg/d vs Simvastatin 20 to 40 mg/d on Any CV Event

*Adjusted for sex and age at baseline.Tikkanen MJ et al. J Am Coll Cardiol. 2009;54:2353-2357.

1st

2nd

3rd

4th

5th

(0.77 – 0.90)

(0.67 – 0.86)

(0.67 – 0.99)

(0.57 – 1.01)

(0.48 – 1.09)

17

24

19

24

28

<.0001

<.0001

.035

.058

.117

0.50 0.75 1.0 1.25 1.50Atorvastatin

betterSimvastatin

better

Events HR (95% CI)*Relative RiskReduction (%)

P Value

SubjectsWith

Event

2546

1048

416

192

93

10

MIRACL (Myocardial Ischemia Reduction With Aggressive Cholesterol Lowering): Study Design

16 weeks double-blind

3086 Patients

• Non-Q-wave MI orunstable angina

• Randomized 24–96 hoursfrom admission

Patient Population

• Time to ischemic events (CHD death, nonfatal MI, documented angina requiring hospitalization)

Primary End Point

Atorvastatin 80 mg

Schwartz GG et al. JAMA. 2001;285:1711-1718.

Placebo

11

MIRACL: Primary Efficacy Measure—Time to First Event*

*Death (any cause), nonfatal MI, resuscitated cardiac arrest, worsening angina with new objective evidence and urgent rehospitalization.


Time Since Randomization, weeks

RR = 0.84P = .04895% CI, 0.701–0.999


Placebo (n = 1548) LDL-C 135 mg/dL (3.5 mmol/L)

0

5

10

15

0 4 8 12 16

17.4%

14.8%

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16%RRR

12

MIRACL: Stroke

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

Total strokes 25 13

Fatal stroke 2 3

Nonfatal stroke 23 10

Type of stroke

Hemorrhagic 3 0

Embolic 1 0

Thrombotic/embolic 19 10

Indeterminate 2 3

Number patients experiencing a stroke (P=0.04) (%)

24 (1.6) 12 (0.8)

Fatal stroke 2 (0.1) 3 (0.2)

Nonfatal stroke (P=0.02) 22 (1.4) 9 (0.6)

Water DD et al. Circulation. 2002;106:1690-1695.

13

PROVE IT-TIMI (Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction) 22: Study Design

Double-blind925 primary end points

4162 Patients

• 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

Patient Population

• Time to first occurrence of a major cardiovascular event (death from any cause, MI, unstable angina, revascularization, stroke

Primary End Point

Atorvastatin 80 mg

Cannon CP et al. N Engl J Med. 2004;350:1495-1504.

Pravastatin 40 mg

14

Months of Follow-up

0 3 18 21 24 27 306 9 12 15

30

25

20

15

10

5

0

16% RRR

(P = .005)

26.3%

22.4%

Dea

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V E

ven

t, %

–35% LDL reduction

Pravastatin 40 mg (n = 1548) 95 mg/dL (2.5 mmol/L)

Atorvastatin 80 mg (n = 2099) 62 mg/dL (1.6 mmol/L)

Major CV event = MI, unstable angina requiring rehospitalization, revascularization, or stroke.Cannon CP et al. N Engl J Med. 2004;350:1495-1504.

PROVE IT: Primary End Point (All-Cause Death or Major CV Events in All Randomized Subjects)

15Adapted from Ray KK et al. J Am Coll Cardiol. 2005;46:1405-1410.

*Death, MI, or rehospitalization with recurrent ACS.

PROVE IT-TIMI 22: Intensive Therapy With Statins in Patients With ACS: Early and Long-term Benefits

Atorvastatin 80 mg Pravastatin 40 mg

Month 6 to end of study

RRR = 28%

P = .003

6 12 18 24

Months following randomization

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(%

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2

4

6

8

10

12n = 1752

n= 1812

Randomization to 30 days

Days following randomization

Co

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(%

)

100 5 15 20 3025

2

1

0

3

RRR = 28%P = .046

n = 2063

n = 2099

4

5

16

Safety of Atorvastatin 80 mg in Clinical Trials

Follow-up PatientsALT/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%) 0

IDEAL 4.8 years 4439 61 (1.38%) 0

SPARCL 4.9 years 2365 51 (2.2%) 2 (0.08%)

Total variable 18,696 267 (1.43%) 4 (0.021%)

*Consecutive measurements.†Newman C et al. Am J Cardiol. 2006;97:61-67; Cannon CP et al. N Engl J Med. 2004;350:1495-1504; LaRosa JC, et al. N Engl J Med. 2005;352:1425-1435; Pedersen TR et al; for the IDEAL Study Group. JAMA. 2005;294:2437-2445; Amarenco P et al. N Engl J Med. 2006;355:549-559.

17

Overview of Adverse Events forAtorvastatin 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

All cause 51 (2.3%) 251 (3.5%) 136 (2.8%)


Serious nonfatal AEs

All cause 122 (5.6%) 453 (6.2%) 385 (8.0%)


Newman C et al. Am J Cardiol. 2006;97:61-67.

18

TNT: Changes in LDL-C by Treatment Group


P < .001

Baseline

Mean LDL-C level = 101 mg/dL (2.6 mmol/L)

Mean LDL-C level = 77 mg/dL (2.0 mmol/L)

160

140

120

100

80

60

40

20

0

4.0

3.5

3.0

2.5

2.0

1.5

1.0

0.5

0.0

0 3 12 24 36 48 60 FinalScreen

Study Visits, months

Mean

LD

L-C

, mm

ol/LM

ean

LD

L-C

, m

g/d

L

Atorvastatin 10 mg (n = 5006)

Atorvastatin 80 mg (n = 4995)

19

2-Year Event RatesRR 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%

29% 3.8% 5.1%

25% 12.9% 16.7%

0.5 1.0 1.5

All-Cause Mortality

Death or MI

Death/MI/Urg. Revasc

MI

Revasc >30 d

UA Req Hosp

0.75 1.25Atorvastatin 80 mg Better Pravastatin 40 mg Better

CHD Death

PROVE IT: Reductions in Major Cardiac End Points

Cannon CP et al. N Engl J Med. 2004;350:1495-1504.

20

Effect of Intensive Statin Therapy on Clinical OutcomesAmong Patients Undergoing Percutaneous Coronary Intervention for ACS: PCI-PROVE IT Substudy

Gibson CM et al. J Am Coll Cardiol. 2009;54:2290-2295.

Post hoc analysis of 2868 patients who underwent PCI just prior to enrollment

25%

20%

15%

10%

5%

0%

Pri

mar

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nd

Po

int

0 120 240 360 480 600 720

Time, days

30%

Pravastatin

Atorvastatin

Hazard ratio 0.7895% CI, 0.67–0.91

P < .001

20%

15%

10%

5%

0%

Dea

th, M

I, R

I, U

A

0 120 240 360 480 600 720

Time, days

25%

Pravastatin

Atorvastatin

Hazard ratio 0.7395% CI, 0.61–0.87

P < .001

21

Long-term Statin Treatment in IDEAL Maintained Benefit Over 5 Years

Cannon CP et al. N Engl J Med. 2004;350:1495-1504; Pedersen TR et al. Am J Cardiol. 2010;106:354-359.

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

0

10

0 30 months 5 years

Co

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nd

Po

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*, % 50

60

Atorvastatin 80 mgPravastatin 40 mgSimvastatin 20 -40 mg

18% RRRP = 0.04

PROVE IT (MI or UA) IDEAL (All MI)

16% RRRP = 0.005

22

MIRACL: Secondary End Points

Relative Risk

Atorvastatin

12 (0.8)

254 (16.5)

91 (5.9)

40 (2.6)

*P = .045.

Placebo

24 (1.6)

250 (16.1)

106 (6.8)

43 (2.8)

0.25 0.50 0.75 1.00 1.25 1.50

*

Atorvastatin Better Placebo Better

Stroke (fatal and nonfatal)

Revascularization(CABG or PTCA)

Worsening angina (withoutobjective evidence of ischemia)

Worsening congestiveheart failure


No. of Events (%)

23

Association of Dyslipidemia andmyocardial Infarction Risk: INTERHEART

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;364:937-952.

Smk DM HTN Lipids 1+2+3 all4 +O +PS All RFs

2.9 2.4 1.9 3.3 13.0 42.3 68.5 182.9 333.7

1

2

4

8

16

32

64

128

256

512

OR

(99

% C

I)

3-fold increase in

risk of acute MI

Risk of AMI With Multiple Risk Factors

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%

Late Breaking Clinical Trials. AHA Scientific Session 2010. Abstract 21685. downloaded from http://sciencenews.myamericanheart.org/sessions/late_breaking.shtml#ascot

statin landmark trials across the spectrum of risk: secondary cv prevention

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