statin landmark trials across the spectrum of risk: secondary cv prevention
DESCRIPTION
Statin Landmark Trials Across the Spectrum of Risk: Secondary CV Prevention . 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. - PowerPoint PPT PresentationTRANSCRIPT
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.LaRosa JC et al. N Engl J Med. 2005;352:1425-1435.
HR = 0.78 (95% CI, 0.69–0.89)P < .001
Cum
ulat
ive
Inci
denc
e of
Maj
or
Car
diov
ascu
lar E
vent
s, % 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
Atorvastatin 80 mg (n = 4995)LDL-C 77 mg/dL (2.0 mmol/L)
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
LaRosa JC et al. N Engl J Med. 2005;352:1425-1435.
0 1 2 3 4 5 6Time (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 mgAtorvastatin 80 mg
Prop
ortio
n of
pat
ient
s ex
perie
ncin
g ev
ents
6
TNT: Safety Profile
Persistent = 2 consecutive measurements.LaRosa JC et al. N Engl J Med. 2005;352:1425-1435.
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
0Treatment-Related
Adverse EventsTreatment-Related
MyalgiaElevated
Liver Enzymes*
% o
f Pat
ient
s
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
Cum
ulat
ive
Haz
ard,
%
0 1 2 3 4 50
4
8
12
16
HR = 0.89 (95% CI, 0.76–1.01) P = .07
11%RRR
SimvastatinAtorvastatin
Years Since Randomization
Cum
ulat
ive
Haz
ard,
%
0 1 2 3 4 50
4
8
12
16
HR = 0.87 (95% CI, 0.78–0.98) P = .02
13%RRR
SimvastatinAtorvastatin
Years Since Randomization
Cum
ulat
ive
Haz
ard,
%
0 1 2 3 4 50
10
20
30
40
HR = 0.84 (95% CI, 0.76–0.91) P < .001
16%RRR
SimvastatinAtorvastatin
Years Since Randomization
Cum
ulat
ive
Haz
ard,
%
0 1 2 3 4 50
10
20
30
40
HR = 0.84 (95% CI, 0.78–0.91) P < .001
16%RRR
SimvastatinAtorvastatin
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.Schwartz GG et al. JAMA. 2001;285:1711-1718.
Time Since Randomization, weeks
RR = 0.84P = .04895% CI, 0.701–0.999
Atorvastatin 80 mg (n = 1538)LDL-C 72 mg/dL (1.9 mmol/L)
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%
Cum
ulat
ive
Inci
denc
e, %
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-up0 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
th o
r Maj
or C
V Ev
ent,
%
–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 24Months following randomization
Com
posi
te tr
iple
end
poi
nt* (
%)
0
2
4
6
8
10
12n = 1752
n= 1812
Randomization to 30 days
Days following randomization
Com
posi
te tr
iple
end
poi
nt* (
%)
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 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%) 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%)
Treatment associated 27 (1.2%) 171 (2.4%) 84 (1.8%)
Serious nonfatal AEs
All cause 122 (5.6%) 453 (6.2%) 385 (8.0%)
Treatment associated 92 (4.2%) 12 (0.2%) 25 (0.5%)
Newman C et al. Am J Cardiol. 2006;97:61-67.
18
TNT: Changes in LDL-C by Treatment Group
LaRosa JC et al. N Engl J Med. 2005;352:1425-1435.
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
0.00 3 12 24 36 48 60 FinalScreen
Study Visits, months
Mean LD
L-C, m
mol/LM
ean
LDL-
C, m
g/dL
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%
Prim
ary
End
Poin
t
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
Com
posi
te E
nd P
oint
*, % 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
Schwartz GG et al. JAMA. 2001;285:1711-1718.
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%
CI)
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