Dr ranjith mp.statins for primary prevention of coronary heart disease
1. Dr Ranjith MP
Senior Resident
Department of Cardiology
Government Medical college
Kozhikode
2. INTRODUCTION
Primary prevention is treating hypercholesterolemia in
patients who do not have clinical evidence of CAD
What is the rationale for this approach ?
Grundy et al. Recent Clinical
Trials and NCEP ATP III ,
JACC Vol. 44, No. 3, 2004
August 4, 2004:720–32
4. Earlier Clinical Trials
WHO Cooperative Trial (clofibrate ) - 10,577 patients
Lipid Research Clinics Coronary Primary Prevention Trial
(cholestyramine) - 3806 patients
Helsinki Heart Study (gemfibrozil ) - 4081 patients
These trials demonstrated
Significant reductions in coronary events (25, 19 & 34 %
respectively)
No reduction in coronary mortality
Increase in mortality from noncardiovascular causes
5. West of Scotland Coronary
Prevention Study (WOSCOPS)
Designed to determine whether the administration of
pravastatin to men with hypercholesterolemia and no
history of myocardial infarction reduced the combined
incidence of nonfatal myocardial infarction and death
from coronary heart disease
James Shepherd, et al, N Engl J Med 1995;333:1301-7
6. West of Scotland Coronary
Prevention Study Group (WOS)
Randomized, double-blind, placebo controlled
6595 men, 45 to 64 years of age
Average follow-up of 4.9 years (seen at 3 month
intervals)
Pravastatin (40 mg each evening) vs. placebo
James Shepherd, et al, N Engl J Med 1995;333:1301-7
8. WOSCOPS Endpoints
Primary
Non-fatal MI or coronary heart disease death as a first event
Secondary
Non-fatal MI
Coronary heart disease death
Other Endpoints
Cardiovascular mortality
Total mortality
Coronary revascularization procedures
9. WOSCOPS Reduction in Lipids
200
placebo (intention -to-treat)
LDL cholesterol mg/dL
180 placebo (actual treatment)
160 pravastatin (intention-to-treat)
140
pravastatin (actual treatment)
120
100
6 12 18 24 30 36 42 48 54 60
Months
20% reduction in TC 26% reduction in LDL
12% reduction in Trigs 5% increase in HDL
James Shepherd, et al, N Engl J Med 1995;333:1301-7
10. Nonfatal MI or CHD Death
(Primary Endpoint)
12
Pravastatin
10 31%
Placebo Risk
8 Reduction
Percent
with 6 P=0.0001
Events
4
2
0
0 1 2 3 4 5 6
Years in Study
James Shepherd, et al, N Engl J Med 1995;333:1301-7
11. Non-Fatal MI
(Secondary Endpoint)
10
Pravastain Placebo
8
31%
Percent 6 Risk
with Reduction
Events 4
P=0.000
5
2
0
0 1 2 3 4 5 6
Years in Study
James Shepherd, et al, N Engl J Med 1995;333:1301-7
12. CHD Death
(Secondary Endpoint)
2.5
Pravastain Placebo
2 28%
Risk
Percent 1.5 Reduction
with P=0.13
Events 1
0.5
0
0 1 2 3 4 5 6
Years in Study
James Shepherd, et al, N Engl J Med 1995;333:1301-7
13. Cardiovascular Death
3.5
3 Pravastain Placebo
32%
2.5 Risk
Percent 2 Reduction
with
Events 1.5
P=0.03
3
1
0.5
0
0 1 2 3 4 5 6
Years in Study
James Shepherd, et al, N Engl J Med 1995;333:1301-7
14. Total Mortality
6
Pravastain Placebo 22%
5 Risk
Reduction
4
Percent
P=0.051
with 3
Events
2
1
0
0 1 2 3 4 5 6
Years in Study
James Shepherd, et al, N Engl J Med 1995;333:1301-7
15. Coronary Interventions
Intervention Placebo Pravastatin Risk
(n= 3293) (n=3302) Reductions p-value
Coronary
Angiography 128 90 31% 0.007
PTCA / CABG 80 51 37% 0.009
James Shepherd, et al, N Engl J Med 1995;333:1301-7
16. WOSCOPS
Results/Clinical Events
Event % Reduction p value
Nonfatal MI + CHD death 31% < 0.001
Definite nonfatal MI 31% < 0.001
Definite CHD death 28% 0.13 (NS)
Definite and suspected CHD death 33% 0.042
All cardiovascular deaths 32% 0.033
Total mortality 22% 0.051 (NS)
CABG/PTCA 37% 0.029
James Shepherd, et al, N Engl J Med 1995;333:1301-7
17. WOSCOPS Conclusions
Treatment with pravastatin significantly reduced the
incidence of myocardial infarction and death from
cardiovascular causes without adversely affecting the
risk of death from noncardiovascular causes in men
with moderate hypercholesterolemia and no history of
myocardial infarction
Pravastatin had no effect on noncardiovascular-related
hospital admissions
Pravastatin therapy also resulted in a 30 percent
reduction in the risk of developing diabetes
James Shepherd, et al, N Engl J Med 1995;333:1301-7
18. WOS Projected Benefits
Treatment of 1000 hypercholesterolemic middle aged
men with pravastatin for five years will avoid:
14 coronary angiograms
8 revascularization procedures
20 nonfatal MIs
7 CHD deaths
2 additional deaths
James Shepherd, et al, N Engl J Med 1995;333:1301-7
19. Management of Elevated Cholesterol in the
Primary Prevention Group of Adult Japanese
(MEGA) Trial
7,832 ,men age 40-70 years and postmenopausal women up to age 70
with total cholesterol 220-270 mg/dL
Mean BMI 23.8 kg/m2, 21% Diabetics, 20% Current Smokers,
baseline total cholesterol 242.6 mg/dL, LDL 157 mg/dL, HDL 57.5 mg/dL, triglycerides 127 mg/dL
32% Female, Mean Age 58 years, Mean Follow-Up 5.3 years
Prospective. Randomized. Open-label.
Diet Modification Diet Modification + Pravastatin
10-20 mg/day
n=3,966 n=3,866
Primary Endpoints: Composite of coronary heart disease events, defined as cardiac
and sudden death, fatal and nonfatal myocardial infarction (MI), angina and cardiac or
vascular intervention.
Secondary Endpoints: Stroke, CHD composite or cerebral infarction, any
cardiovascular event, total mortality.
Eishu Nango et al, lancet 2006;368:11555-63
20. MEGA Trial: Cholesterol and
Triglyceride Levels
Total LDL HDL Triglycerides
Cholesterol
5.8 • Total cholesterol,
3.2 LDL, Triglyceride
4 1.3 reduction was larger
0 in the pravastatin
group
-4 -2.1
mg/dL
-3.2 -3.1
-8 •HDL increase was
greater in the
-12 pravastatin group
-11.5
-16
-20 -18.0
Pravastatin+diet Diet
Eishu Nango et al, lancet 2006;368:11555-63
21. MEGA Trial: Primary Composite Endpoint
Primary composite endpoint of coronary
heart disease events
p = 0.01
5 5.0
3.3 vs 5.0 per 1000 patient
years, hazard ratio 0.67,
# per 1000 patient years
4 p=0.01
3.3
3
2
1
0
Pravastatin+diet Diet
Eishu Nango et al, lancet 2006;368:11555-63
22. MEGA Trial: Secondary Endpoints
•Total mortality was non-significantly lower in the pravastatin group (2.7 vs 3.8, HR 0.71,
p=0.055)
•MI occurred less often in the pravastatin group (0.9 vs 1.6, p=0.03)
•No significant difference was observed in stroke (2.5 vs 3.0, p=0.33) or cerebral infarction
plus TIA (2.0 vs 2.6, p=0.23)
p=0.055
4 3.8 p=0.33 p=0.23
# per 1000 patient years
3.0
3 2.7 2.6
2.5
p=0.03 2.0
2 1.6
0.9
1
0
Total mortality MI Stroke Cerebral
infarction+TIA
Pravastatin+diet Diet
Eishu Nango et al, lancet 2006;368:11555-63
23. MEGA Trial: Safety Data
Frequency of cancer Frequency of elevated liver function
(per 1000 patient years) abnormalities (%)
6 5.5 5.7 3.0% 2.8% 2.8%
5 2.5%
# per 1000 patient years
4 2.0%
%
3 1.5%
2 1.0%
1 0.5%
0 0.0%
Pravastatin+diet Diet Pravastatin+diet Diet
• There was no difference in the frequency of cancer or elevated liver function
abnormalities and no cases of rhabdomyolysis.
Eishu Nango et al, lancet 2006;368:11555-63
24. MEGA Trial: Summary
Among Japanese patients with hypercholesterolemia,
treatment with pravastatin was associated with a reduction
in the primary composite endpoint of coronary heart disease
The cardiac morbidity and mortality in Japan is much
lower than in the U.S. and other western countries where
statin therapy has been predominantly studied.
The present study demonstrated that even in this lower
risk population, primary prevention with low-dose statin
therapy can be effective in reducing cardiac events, with a
modest reduction in lipid parameters.
Eishu Nango et al, lancet 2006;368:11555-63
25. Antihypertensive and Lipid-Lowering Treatment to
Prevent Heart Attack Trial and ALLHAT–Lipid-
Lowering Trial (ALLHAT)
ALLHAT: N = 42,418: stage 1/2 hypertension + >1 CV risk factor
Chlorthalidone Amlodipine Lisinopril Doxazosin*
12.5–25 mg/d 2.5–10 mg/d 10–40 mg/d 2–8 mg/d
n = 15,255 n = 9048 n = 9054 n = 9061
Step 1: titration
Step 2: open-label atenolol 25–100 mg/d, clonidine 0.1–0.3 mg bid, reserpine 0.05–0.2 mg/d
Step 3: open-label hydralazine 25–100 mg bid
ALLHAT-LLT: N = 10,355; CHD, LDL-C 100 to 129 mg/dL or no CHD, LDL-C 120 to 189 mg/dL
Pravastatin 40 mg/d (n = 5170) Usual care (n = 5185)
ALLHAT Collaborative Research Group.
*Arm discontinued JAMA. 2002;288:2981-2997, 2998-3007.
26. ALLHAT-LLT: Effects of statin
or usual care on outcomes
N = 10,355 with treated hypertension, baseline LDL-C 120–189 mg/dL
(no CHD) or LDL-C 100–129 mg/dL (CHD)
At 4 yrs, LDL-C by 28% (statin) and 11% (usual care)
All-cause mortality CHD death + nonfatal MI
18 18
15 RR = 0.99 15 RR = 0.91
12
(95% CI, 0.89–1.11) 12
(95% CI, 0.79–1.04)
Cumulative
rate 9 9
(%)
6 6
3 3
0 0
0 1 2 3 4 5 6 0 1 2 3 4 5 6
Time to death (years) Time to event (years)
Pravastatin Usual care
27. ALLHAT: Clinical implications
BP-lowering trial
Diuretic, ACEI, CCB equivalent in CHD death and MI
Lipid-lowering trial (ALLHAT-LLT)
Statin, usual care equivalent in all-cause mortality
Modest differential in on-treatment cholesterol levels
may have contributed to result
ALLHAT BP results support importance of BP lowering,
regardless of drug class used
ALLHAT-LLT results are consistent with other statin trials
28. Prospective Study of Pravastatin in the
Elderly at Risk (PROSPER)
5804 patients aged 70–82 years with a history of
vascular disease or with cardiovascular risk factors
Randomized to pravastatin 40 mg/d or placebo
Baseline TC 155–348 mg/dL
Follow-up 3.2 years (mean)
Primary endpoint (composite): coronary death,
nonfatal MI, fatal or nonfatal stroke
Shepherd J et al. Lancet 2002;360:1623–1630
29. Major Endpoints: PROSPER
Pravastatin Placebo Hazard
Endpoint (%) (%) ratio p
Primary endpoint:
CHD death/MI/stroke 14.1 16.2 0.85 0.014
Secondary endpoints:
CHD death/MI 10.1 12.2 0.81 0.006
Fatal or nonfatal stroke 4.7 4.5 1.03 0.81
Other outcomes:
Nonfatal MI 7.7 8.7 0.86 0.10
Nonfatal stroke 4.0 4.1 0.98 0.85
Transient ischemic attack 2.7 3.5 0.75 0.051
All CV events 15.7 18.0 0.85 0.012
Shepherd J et al. Lancet 2002;360:1623–1630
30. Mortality by Cause: PROSPER
Pravastatin Placebo Hazard
Cause of death (%) (%) ratio p
CHD 3.3 4.2 0.76 0.043
Stroke 0.8 0.5 1.57 0.19
Vascular 4.7 5.4 0.85 0.16
Nonvascular 5.6 5.1 1.11 0.38
Cancer 4.0 3.1 1.28 0.082
Trauma/suicide 0.1 0.2 NA NA
All causes 10.3 10.5 0.97 0.74
Shepherd J et al. Lancet 2002;360:1623–1630
31. PROSPER Conclusion
Pravastatin given for 3 years reduced the risk of
coronary disease in elderly individuals
PROSPER therefore extends to elderly individuals the
treatment strategy currently used in middle aged
people
Shepherd J et al. Lancet 2002;360:1623–1630
32. Air Force/Texas Coronary Atherosclerosis
Prevention Study (AFCAPS/TexCAPS)
Randomized, double-blind, placebo-controlled trial
To compare lovastatin with placebo for prevention of
the first acute major coronary event (UA, fatal and non-
fatal MI and sudden cardiac death)
6605 pts without CHD , 5608 men and 997 women
Average follow-up was 5.2 years
Lovastatin (20-40 mg daily) or placebo
Downs JR, et al, JAMA 1998;279:1615-1622
33. AFCAPS/TexCAPS Endpoints
Primary
First Acute Major Coronary Event (UA, Fatal or Non-fatal
MI ,Sudden Cardiac Death)
Secondary
Fatal or Non-Fatal MI
Unstable Angina
Fatal or Non-Fatal Cardiovascular Events
Fatal or Non-Fatal Coronary Events
Tertiary Endpoints
Total Mortality, Non-Cardiovascular Mortality
Fatal and Non-Fatal Cancer
Discontinuation of Medication because of Adverse Effects
Downs JR, et al, JAMA 1998;279:1615-1622
36. Baseline Lipid Levels
Compared with U.S. Reference Population Based
Upon NHANES III
Wilford Hall U.S. NHANES Ref.
Avg + SD Population2
Lipid Level (mg/dL) NHANES Mean + SD
(mg/dL) N=6605 Percentile1 (mg/dL)
Mean TC 221 + 21 51 225 + 45
Mean LDL 150 + 17 60 142 + 37
Mean HDL 50 + 16
Men 36 + 5 25
Women 40 + 5 16
Median TG 158 + 76 63 140 + 120
1 Percentile ranks from US NHANES III reference population for study population averages
2 Men aged 45-73, and women aged 55-73, without cardiovascular disease
Downs JR, et al, JAMA 1998;279:1615-1622
37. AFCAPS Reduction in Lipids-year
Placebo Lovastatin
Mean TC 228.1 + 27.7 183.7 + 23.8
Mean LDL-C 156.4 + 24.5 114.6 + 20.1
Mean HDL-C 37.5 + 7.9 39.3 + 8.0
162.8 + 82.1 142.8 + 72.8
Median TG
Ratios
4.3 1.1
+ 3.0 + 0.8
Mean LDL-C/HDL-C
6.3 2.5
+ 4.8 + 1.0
Mean TC/HDL-C
Downs JR, et al, JAMA 1998;279:1615-1622
38. Percent Change in Lipid Parameters
Baseline to Year 1
30
p-value < 0.001 for all lovastatin treatment groups
20 42% of lovastatin patients achieved LDL-C goal of < 110 mg/dL (placebo 3%)
81% of lovastatin patients achieved LDL-C goal of < 130 mg/dL (placebo 12%)
10 6
0.9 1.5 1.2 1.7 1.6
Percent
0
-2.3
-10
-20 -15
-18.4
-21.8
-30 -25 Placebo
-28
Lovastatin, avg dose 30 mg
-40
TC LDL HDL TG TC/HDL LDL/HDL
Downs JR, et al, JAMA 1998;279:1615-1622
39. Primary Endpoint ~ First Acute Major
Coronary Event*
0.06
*Includes unstable angina,
fatal and non-fatal MI &
0.05 sudden cardiac death
Cumulative Incidence
Placebo 37% Risk Reduction
0.04
(p < 0.001)
0.03
Lovastatin
0.02
0.01
0.00
0 1 2 3 4 5 5+ Years
# At Risk Years of Follow-up
Lovastatin N=3304 N=3270 N=3228 N=3184 N=3134 N=1688
Placebo N=3301 N=3251 N=3211 N=3159 N=3092 N=1644
Downs JR, et al, JAMA 1998;279:1615-1622
40. Primary Endpoint ~ First Acute Major
Coronary Event*
Fatal & Non-fatal MI, Unstable Angina, Sudden Cardiac
Death
250 reduced by 37% (p < 0.0008)
Cumulative Number of Participants
Placebo (n=3301)
200 Lovastatin (n=3304) 183
with Events
150 135
116
100 91
100
66 70
40 46
50
23
0
1 2 3 4 5+ years
Years Since Randomization
Downs JR, et al, JAMA 1998;279:1615-1622
41. Lovastatin Reduced the Risk of
First Acute Major Coronary Events
> Median
Men Women by Age Smokers Hypertension Diabetes
N=5608 N=997 N=3180 N=818 N=1448 N=156
0
-10
Percent Risk Reduction
-20
-30
-31
-40 -37 -38
-42
-50 -46
-60
-58
-70
Downs JR, et al, JAMA 1998;279:1615-1622
42. Lovastatin Reduced the Risk of First Acute Major
Coronary Events in All Baseline LDL Tertiles
0
-10
Percent Change
-20
-30
-40 -34 -36
-41
-50 Relative Risk Reduction
-60
90.4-141.9 142.0-156.8 156.9-235.4
Baseline LDL Tertiles
Downs JR, et al, JAMA 1998;279:1615-1622
43. AFCAPS/TexCAPS
Role of Baseline LDL on Outcomes
90
Placebo 77
80
70 Lovastatin
Number of Events
60 54 52
50 46
40 37
33
30
20
10
0
< 142, n=2210 143-156, n=2195 > 157, n=2199
Baseline LDL Level (mg/dL)
Downs JR, et al, JAMA 1998;279:1615-1622
44. AFCAPS/TexCAPS
Role of Baseline HDL on Outcomes
80
71
68 Placebo
70
Lovastatin
60
Number of Events
50 44
40 41
40 35
30
20
10
0
< 34 35-39 > 40
Baseline HDL Level (mg/dL)
Downs JR, et al, JAMA 1998;279:1615-1622
47. AFCAPS/TexCAPS
Mortality
Placebo Lovastatin
Event n=3301 n=3304 P-value
Total Mortality 77 80 N.S.
Cardiovascular 25 17 too few*
Non-cardiovascular 52 63 N.S.
*Too few for survival analyses
Downs JR, et al, JAMA 1998;279:1615-1622
48. Tertiary Analysis
Fatal and Non-Fatal Cancer*
0.08
*Excludes non-melanoma skin cancer
0.07
P = NS
Placebo
Cumulative Incidence
0.06
0.05
Lovastatin
0.04
0.03
0.02
0.01
0.00
0 1 2 3 4 5 5+ years
Years of Follow-up
# At Risk
Lovastatin N=3304 N=3249 N=3188 N=3117 N=3059 N=1626
Placebo N=3301 N=3234 N=3171 N=3105 N=3043 N=1603
Downs JR, et al, JAMA 1998;279:1615-1622
49. AFCAPS/TexCAPS Summary of Results
Clinical benefit
appeared within the first year of treatment and
continued
was apparent for all LDL-C tertiles
Range 90-235 mg/dl
was consistent for subgroups
Women
Risk Factors - Age, DM, HTN, Smokers
Downs JR, et al, JAMA 1998;279:1615-1622
50. AFCAPS/TexCAPS Conclusions
In conjunction with a prudent diet, regular exercise
and risk factor modification Lovastatin 20-40 mg/day
could be used to lower the risk of the first acute major
coronary event for primary prevention candidates -
Men > 45 years, Women > 55 years
HDL < 50 mg/dl
LDL > 130 mg/dl
Downs JR, et al, JAMA 1998;279:1615-1622
51. The Anglo-Scandinavian Cardiac outcomes Trial
(ASCOT )
Multicenter trial with 2 treatment comparison
A prospective, randomized, open, blinded end point
design comparing 2 antihypertensive regimen
A double blind placebo controlled trial of atorvastatin
10mg/day in the substrate of patients with total
cholesterol ≤250mg/dl
Primary end point: nonfatal MI or CHD death
Planned follow up average of 5yr
58. The Anglo-Scandinavian Cardiac Outcomes
Trial: 11-year mortality follow-up of the
lipid-lowering arm in the UK
• The aim of this study was to determine the outcome
benefits in those originally assigned atorvastatin in
ASCOT Trial—8 years after closure of the lipid-lowering
arm of the trial among the UK population
• Post trial mortality data were collected every 2-
3months
Sever PS et al, Eur Heart J August 28, 2011
59. ASCOT-LLA 11 year mortality study profile
Sever PS et al, Eur Heart J August 28, 2011
67. CARDS: Lipid Levels by Treatment
Total Cholesterol (mg/dL) LDL Cholesterol (mg/dL)
Average difference 26%, Average difference 40%,
54 mg/dL; P<0.0001 46 mg/dL; P<0.0001
240 Placebo 160
Median LDL-C (mg/dL)*
Median TC (mg/dL)*
Placebo
120
160
Atorvastatin 80
80 Atorvastatin
40
0 0
0 1 2 3 4 4.5 0 1 2 3 4 4.5
Years of Study Years of Study
Colhoun HM et al. Lancet 2004;364:685-696.
68. CARDS: Effect of Atorvastatin on the Primary
Endpoint: Major CV Events Including Stroke
Relative Risk Reduction 37% (95% CI, 17–52)
P = 0.001
Cumulative Hazard, (%)
15
Placebo
127 events
10
5
Atorvastatin
83 events
0
0 1 2 3 4 4.75
Years
Placebo 1410 1351 1306 1022 651 305
Atorvastatin 1428 1392 1361 1074 694 328
Colhoun HM et al. Lancet 2004;364:685-696.
69. CARDS: Adverse and Serious Adverse Events
Patients (%) with Event
Placebo Atorvastatin 10 mg
Type of Event (n = 1410) (n = 1428)
Serious adverse event 20 (1.1%) 19 (1.1%)
possibly associated
with study drug
Discontinued for AE 145 (10%) 122 (9%)
Rhabdomyolysis 0 0
Myopathy AE report 1 (0.1%) 1 (0.1%)
CPK 10 ULN 10 (0.7%) 2 (0.1%)
ALT 3 ULN 14 (1%) 17 (1%)
AST 3 ULN 4 (0.3%) 6 (0.4%)
Colhoun HM et al. Lancet 2004;364:685-696.
70. CARDS Implications and Clinical Relevance
In patients with Type 2 DM with lower LDL-C levels, atorvastatin
10 mg daily was safe, well tolerated & significantly efficacious in
reducing the risk of first CHD events
CARDS supports recommendations that made by the ADA that
patients with Type 2 DM should be considered as candidates for
statin treatment—even at lower LDL-C levels
Colhoun HM et al. Lancet 2004;364:685-696.
71. Primary Prevention Trials of Lipid-Altering Therapy
Including Patients with Diabetes
Total N CHD* Risk vs
Diabetic,* in Lipid-Altering Placebo in Diabetic
Trial n Study Drug, mg/d Patients, %
CARDS † 2,838 2,838 Atorvastatin 10 –37 (p=.001)
AFCAPS 155 6,605 Lovastatin 20–40 ‡ –44 (NS)
HPS § 2,912 7,150 Simvastatin 40 –33 (p=.0003)
ASCOT 2,532 10,305 Atorvastatin 10 –16 (NS)
PROSPER 623 5,804 Pravastatin 40 +27 (NS)
HHS 135 4,081 Gemfibrozil 1200 –68 (NS)
* By history
† Prospective trial in diabetic subjects; others are subgroup analyses
‡ Mean 30 mg/d
§ Type 1 or 2 diabetes
Bays H et al. Future Cardiology 2005;1:39-59. | Colhoun HM et al. Lancet 2004;364:685-696. | Downs JR et al. JAMA
1998;279:1615-1622. | HPS Collaborative Group. Lancet 2003;361:2005-2016. | Sever PS et al. Lancet 2003;361:1149-
1158. | Shepherd J et al. Lancet 2002;360:1623-1630. | Koskinen P et al. Diabetes Care 1992;15:820-825.
72. Measuring Effects of Intima-Media Thickness:
An Evaluation of Rosuvastatin
METEOR Trial
Evaluated the effect of rosuvastatin compared with placebo
on carotid intima-media thickness (CIMT) among
asymptomatic patients at low risk for cardiovascular disease
Study period was two-year
Randomized controlled trial
Rosuvastatin 40 mg daily vs placebo
Crouse JR 3rd, et al, JAMA 2007; 297:1344.
73. METEOR Trial: Study Design
984 asymptomatic patients with moderately elevated cholesterol and low risk of CVD
according to the National Cholesterol Education Program Adult Treatment Panel III guidelines criteria (0-1 risk factor
and LDL 120-190mg/dL or > 2 risk factors and LDL 120 to <160mg/dL with a 10-year coronary heart disease risk <
10%); HDL-C <60mg/dL; triglycerides <500mg/dL; evidence of thickening of the walls of the extracranial carotid
arteries as measured by B-mode ultrasound (max CIMT between 1.2 and <3.5mm)
5:2 Randomized. Double-blinded. Placebo-controlled.
Mean age = 57 years. 40% Female.
R
Rosuvastatin (40mg) Placebo
n=702 n=282
6, 12, 18 and 24 mos. follow-up
Primary Endpoint: Annualized rate of change in maximum CIMT
Secondary Endpoint: Annualized rate of change in maximum CIMT derived
from the near and far walls of the right and left common carotid artery; the
right and left carotid bulb; the right and left internal carotid artery; and
annualized rate of change in mean CIMT for the near and far walls of the
right and left common carotid artery.
74. METEOR Trial: Primary Endpoint
Change in maximum CIMT with rosuvastatin vs. placebo
0.015 0.0131 • After two years,
Change in CIMT for 12 Carotid Artery sites
treatment with
rosuvastatin was
0.010 associated with a
p < 0.001 statistically significant
reduction in the rate of
(mm/year)
progression of CIMT
0.005 thickening in overall
carotid segments, while
Rosuvastatin n = 282
the placebo group
0.000 displayed progression
n = 702 Placebo (p<0.001).
-0.0014
-0.005
75. METEOR Trial: Secondary Endpoint
Change in maximum CIMT with rosuvastatin vs. placebo
Change in CIMT for common carotid sites (mm/year)
0.010 • After two years,
0.0084
treatment with
rosuvastatin was
associated with a
0.005 p < 0.001 statistically significant
reduction in the rate of
progression of CIMT
thickening in common
Rosuvastatin n = 282
carotid sites, while the
0.000 placebo group
n = 702 Placebo displayed progression
(p<0.001).
-0.005 -0.0039
76. METEOR Trial: Secondary Endpoint
Change in maximum CIMT with rosuvastatin vs. placebo
0.020 • After two years,
Change in CIMT for carotid bulb sites (mm/year)
0.0172 treatment with
rosuvastatin was
0.015 associated with a
p < 0.001
statistically significant
reduction in the rate of
0.010 progression of CIMT
thickening in carotid
0.005 bulb sites, while the
placebo group
displayed progression
Rosuvastatin n = 282
0.000 (p<0.001).
n = 702 Placebo
-0.005 -0.0040
77. METEOR Trial: Secondary Endpoint
Change in maximum CIMT with rosuvastatin vs. placebo
0.015 0.0145
Change in CIMT for internal carotid artery sites
• After two years,
treatment with
rosuvastatin was
0.010 p = 0.02 associated with a
statistically significant
(mm/year)
lower progression in
CIMT thickening in
internal carotid sites as
0.005 0.0039 compared with the
placebo group (p=0.02)
n = 702 n = 282
0.000
Rosuvastatin Placebo
78. METEOR Trial: Limitations & Summary
Compared with placebo, subjects treated with
rosuvastatin had a marked reduction in LDL-cholesterol
(-49 versus -0.3 percent)
The study was not designed to evaluate clinical events,
It is uncertain how well changes in CIMT predict clinical
events, particularly in this low risk population.
This study does not convincingly support the use of
high dose statins (such as rosuvastatin 40 mg daily) for
primary prevention in patients at low risk for CHD
events
79. Justification for the Use of statins in Primary
prevention: an Intervention Trial Evaluating
Rosuvastatin (JUPITER)
JUPITER is the first large-scale, prospective study to examine
the role of statin therapy in individuals with low to normal LDL-C
levels, but with increased cardiovascular risk identified by
elevated CRP
Nearly half of all cardiovascular events occur in patients who
are apparently healthy and who have low or normal levels of
LDL-C
hsCRP predicts cardiovascular disease independent of LDL-C
levels
Ridker et al, NEJM 2008359:2195-07
80. JUPITER
Rosuvastatin 20 mg (N=8901) MI
No Prior CVD or DM Stroke
Men >50, Women >60 Unstable
LDL <130 mg/dL 4-week Placebo (N=8901) Angina
hsCRP >2 mg/L run-in CVD Death
CABG/PTCA
Baseline LDLC 104 mg/dL
Baseline HDLC 49 mg/dL
Baseline hsCRP 4.2 mg/L
Women 6,800
Non-Caucasian 5,000
Ridker et al, NEJM 2008359:2195-07
82. JUPITER
Grouped Components of the Primary Endpoint
Myocardial Infarction, Stroke, or Arterial Revascularization or
Cardiovascular Death Hospitalization for Unstable Angina
HR 0.53, CI 0.40-0.69 HR 0.53, CI 0.40-0.70
P < 0.00001 P < 0.00001
0.05
0.06
Placebo Placebo
0.05
0.04
0.04
Cumulative Incidence
Cumulative Incidence
0.03
- 47 %
0.03 - 47 %
0.02
0.02
Rosuvastatin
0.01
Rosuvastatin
0.01
0.00
0.00
0 1 2 3 4 0 1 2 3 4
Follow-up (years) Follow-up (years)
Ridker et al, NEJM 2008359:2195-07
83. JUPITER
Individual components of the Primary Endpoint
Endpoint Rosuvastatin Placebo HR 95%CI P
Primary Endpoint* 142 251 0.56 0.46-0.69 <0.00001
Non-fatal MI 22 62 0.35 0.22-0.58 <0.00001
Any MI 31 68 0.46 0.30-0.70 <0.0002
Non-fatal Stroke 30 58 0.52 0.33-0.80 0.003
Any Stroke 33 64 0.52 0.34-0.79 0.002
Revascularization
or Unstable Angina 76 143 0.53 0.40-0.70 <0.00001
MI, Stroke, CV Death 83 157 0.53 0.40-0.69 <0.00001
*Nonfatal MI, nonfatal stroke, revascularization, unstable angina, CV death
Ridker et al, NEJM 2008359:2195-07
84. JUPITER
Primary Endpoint – Subgroup Analysis
N P for Interaction
Men 11,001 0.80
Women 6,801
Age < 65 8,541 0.32
Age > 65 9,261
Smoker 2,820 0.63
Non-Smoker 14,975
Caucasian 12,683 0.57
Non-Caucasian 5,117
USA/Canada 6,041 0.51
Rest of World 11,761
Hypertension 10,208 0.53
No Hypertension 7,586
All Participants 17,802
0.25 0.5 1.0 2.0 4.0
Rosuvastatin Superior Rosuvastatin Inferior
Ridker et al, NEJM 2008359:2195-07
85. JUPITER
Primary Endpoint – Subgroup Analysis
N P for Interaction
Family HX of CHD 2,045 0.07
No Family HX of CHD 15,684
2
BMI < 25 kg/m 4,073 0.70
BMI 25-29.9 kg/m 2 7,009
2
BMI >30 kg/m 6,675
Metabolic Syndrome 7,375 0.14
No Metabolic Syndrome 10,296
Framingham Risk < 10% 8,882 0.99
Framingham Risk > 10% 8,895
hsCRP > 2 mg/L Only 6,375
hsCRP > 2 mg/L Only 6,375
All Participants 17,802
0.25 0.5 1.0 2.0 4.0
Rosuvastatin Superior Rosuvastatin Inferior
Ridker et al, NEJM 2008359:2195-07
86. JUPITER
Adverse Events and Measured Safety Parameters
Event Rosuvastatin Placebo P
Muscle weakness 1,421 (16.0) 1,375 (15.4) 0.34
Myopathy 10 (0.1) 9 (0.1) 0.82
Rhabdomyolysis 1 (0.01)* 0 (0.0) --
Incident Cancer 298 (3.4) 314 (3.5) 0.51
Cancer Deaths 35 (0.4) 58 (0.7) 0.02
Hemorrhagic stroke 6 (0.1) 9 (0.1) 0.44
GFR (ml/min/1.73m2 at 12 mth) 66.8 (59.1-76.5) 66.6 (58.8-76.2) 0.02
ALT > 3xULN 23 (0.3) 17 (0.2) 0.34
Fasting glucose (24 mth) 98 (91-107) 98 (90-106) 0.12
HbA1c (% at 24 mth) 5.9 (5.7-6.1) 5.8 (5.6-6.1) 0.01
Glucosuria (12 mth) 36 (0.5) 32 (0.4) 0.64
Incident Diabetes** 270 (3.0) 216 (2.4) 0.01
*Occurred after trial completion, trauma induced. All values are median (interquartile range) or N (%)
**Physician reported
Ridker et al, NEJM 2008359:2195-07
87. JUPITER
Statins and the Development of Diabetes
HR (95% CI)
WOSCOPS Pravastatin 0.70 (0.50–0.98)
PROSPER Pravastatin 1.34 (1.06–1.68)
HPS Simvastatin 1.20 (0.98–1.35)
ASCOT-LLA Atorvastatin 1.20 (0.91–1.44)
PROVE-IT Atorvastatin 1.11 (0.67–1.83)
VS
Pravastatin
JUPITER Rosuvastatin 1.25 (1.05–1.54)
0.25 0.5 1.0 2 4
Statin Better Statin Worse
Ridker et al, NEJM 2008359:2195-07
89. JUPITER
Conclusions
In this trial of low LDL/high hsCRP individuals who do
not currently qualify for statin therapy, rosuvastatin
significantly reduced
All-cause mortality by 20 percent
Incident myocardial infarction, stroke, and cardiovascular
death by 47 percent
Ridker et al, NEJM 2008359:2195-07
90. CONCLUDE
Statin trials in primary prevention, starting with the
landmark WOSCOPS trial, have found substantial
relative reductions in cardiovascular events without
an increase in noncardiovascular mortality
In view of the evidence, statins should be seriously
considered in people with diabetes at least by age 50
in men and 60 in women
Also, men aged 55 years or above with multiple risk
factors, and women aged 65 years or above, should be
seriously considered for generic statin use.
