Collaborative Atorvastatin Diabetes Study
CARDSHelen Colhoun, John Betteridge, Paul Durrington, Graham
Hitman, Andrew Neil, Shona Livingstone, Margaret Thomason, Michael Mackness, Valentine Menys, John Fuller
on behalf of the CARDS Investigators
CARDSThe Rationale
• Type 2 diabetes is associated with elevated cardiovascular risk
• The role of lipid-lowering particularly with statins for secondary prevention of CHD is clear
• More data on the benefits of lipid-lowering for the primary prevention of CHD and stroke are needed
• The effectiveness and safety of lipid lowering for primary prevention in patients with low levels of LDL-C is unclear
Aim of CARDS
To evaluate the effectiveness and safety of
atorvastatin 10mg daily versus placebo in the
primary prevention of cardiovascular disease
(major coronary events, revascularisation and
stroke) in patients with type 2 diabetes without
raised cholesterol levels
6 week pre-randomisation placebo run in phase then visits at month 1, 3, 6 and 6 monthly
Atorvastatin 10mg
Placebo
2838patients
CARDS Design
Placebo
CARDS Eligibility Criteria
• Type 2 diabetes
• Males or females
• 40-75 years of age
• No clinical history of coronary, cerebrovascular or severe peripheral vascular disease
• LDL-C 4.14 mmol/L (160 mg/dL)
• TG 6.78 mmol/L (600 mg/dL)
• One of :– Hypertension defined as receiving antihypertensive treatment or
SBP 140 mm Hg or DBP 90 mm Hg
– Retinopathy
– Microalbuminuria or macroalbuminuria
– Current smoking
CARDS Endpoints
• Acute CHD death
• Non-fatal MI including silent MI
• Hospitalised unstable angina
• Resuscitated cardiac arrest
• Coronary revascularisation
• Stroke
Major coronary events
Primary Efficacy Parameters
Secondary Efficacy Parameters
• Total mortality
• Any cardiovascular endpoint
• Lipid and lipoproteins
Power 90%
Significance level <0.05
Treatment effect 30%
Assumed placebo event rate 2.35% per annum
Sample size needed 2322
Allowing 20% dropout 2786
Randomised 2838
Expected termination 304 events – mid 2005
Actual termination after 2nd interim analysis 210 events – June 2003
CARDS Sample Size and Statistical Power
CARDS Statistical Methods
• Intention to treat analysis
• Cox proportional hazards model of time to first primary end point (major coronary events and stroke)
• Tested to show no treatment time interaction and the proportional hazard assumption holds
• Main model then adjusted for age, sex, and stratified by centre
• Tests for heterogeneity for subgroup analysis
132 Centres in UK and Ireland
1398 (99.1%) Complete follow up1398 (99.1%) Complete follow up 1421 (99.5%) Complete follow up1421 (99.5%) Complete follow up
Recruitment and Follow Up
1410 Allocated placebo 1410 Allocated placebo
* 1 subject lost after first primary endpoint
4053 Screened4053 Screened
3249 (80%) 3249 (80%) Entered baselineEntered baseline
1428 Allocated atorvastatin 10mg daily1428 Allocated atorvastatin 10mg daily
Lost to follow up for: Lost to follow up for: mortality 4 (0.3%)mortality 4 (0.3%)
morbidity 12 (0.9%)*morbidity 12 (0.9%)*
Lost to follow up for: Lost to follow up for: mortality 1 (0.1%)mortality 1 (0.1%)morbidity 7 (0.5%)morbidity 7 (0.5%)
2838 (70%) 2838 (70%) RandomisedRandomised
Follow up Time for Primary Endpoint
3.97 (1day, 5.51 yrs)3.91 (1 day, 5.56yrs) Median (min, max)
Atorvastatin 10mgPlacebo
CARDS Patient Baseline Characteristics
1350 (94.5%)1326 (94.0%)White ethnicity
28.7 (3.6)28.8 (3.5)BMI Kg/m2 (SD)
515 (36.1%)537 (38.1%)Obese (BMI >30Kg/m2)
456 (31.9%)453 (32.1%)Women
167 (11.7%)173 (12.3%) > 70
703 (49.2%)708 (50.2%) 60-70
558 (39.1%)529 (37.5%) < 60
Mean age (years)
Atorvastatin
N (%)
Placebo
N (%)
61.8 61.5
CARDS Patient Baseline Characteristics
Smoking
498 (34.9%)485 (34.4%)
Current
622 (43.6%)601 (42.7%) Ex-smoker
308 (21.6%)323 (22.9%)
Never
956 (67)940 (67)On BP drug
Blood pressure
83 (8.5)83 (8.4) Diastolic BP (mmHg)
144 (15.9)144 (16.1) Systolic BP (mmHg)
AtorvastatinMean (SD)or N (%)
PlaceboMean (SD)or N (%)
CARDS Diabetes Related Characteristics
214 (15.0%)228 (16.2%) Diet only
932 (65.3%)916 (65.0%) Oral hypoglycaemic only
210 (14.7%)207 (14.7%) Insulin only
72 (5.0%)59 (4.2%) Insulin+oral hypoglycaemic
10.0 (3.3)9.8 (3.2)Plasma glucose mmol/L
7.9 (1.4)7.8 (1.4)HbA1c %
Diabetes treatment
7.9 (6.4)7.8 (6.3)Diabetes duration (years)
AtorvastatinMean (SD) or N (%)
PlaceboMean (SD) or N (%)
Hypertension*
Clinical History* of Microvascular Disease
148 (14.7 %)153 (15.0 %)Microalbuminuria (ACR >2.5mg/mmol)
24 (2.4 %)17 (1.7 %) Macroalbuminuria (ACR >25 mg/mmol)
426 (29.8%)427 (30.3%)History of retinopathy
Atorvastatin N (%)
Placebo N (%)
*SBP≥140 mm Hg or DBP≥90 mm Hg or on BP drug
1193 (83.5 %)1184 (84.0 %)
CARDS Patient Baseline Lipids*
1.3 (1.2-1.6)52 (45-60)
1.4 (1.2-1.6)53 (46-61)
HDL-cholesterol (mmol/L)(mg/dL)
3.1 (2.6-3.6)119 (100-138)
3.1 (2.6-3.6)118 (100-137)
LDL-cholesterol (mmol/L)(mg/dL)
5.4 (4.8-5.9)207 (186-228)
5.4 (4.8-5.9)207 (185-229)
Total cholesterol (mmol/L)(mg/dL)
AtorvastatinMedian (IQR)
PlaceboMedian (IQR)
* Subject to final verification
CARDS Patient Baseline Lipids*
150 (134-169)
116 (101-132)
150 (132-168)
115 (98-131)
Apolipoprotein A1 (mg/dL)
Apolipoprotein B (mg/dL)
4.0 (3.4-4.5)154 (132-174)
3.9 (3.4-4.5)152 (130-174)
Non-HDL-C (mmol/L)(mg/dL)
1.7 (1.2-2.4)150 (106-212)
1.7 (1.2-2.4)150 (106-212)
Triglycerides (mmol/L) (mg/dL)
AtorvastatinMedian (IQR)
PlaceboMedian (IQR)
* Subject to final verificationIQR = Interquartile range
% (n) Taking at least one statin by treatment arm*
87.1
6.9
Year 2
85.7
11.9
Year 3
90.0
2.4
Year 1
78.3Atorvastatin
14.8Placebo
Year 4
*% of those randomised and not known to be dead who have not yet had a primary endpoint at any given time. Assumes non-compliance if no compliance data available
Compliance and Non-Study Statin Use
85.3
9
Average
Adverse and Serious Adverse Events
No of events (% of patients with event)
122 (8.5%)145 (10%)Discontinued for AE
19 (1.1%) 20 (1.1%)Associated SAE
13,238 (97%)13,365 (98%)Any adverse event
835 (29%)920 (31%)Serious AE
599 (23%)609 (25%)Associated AE
Atorvastatin 10mgPlaceboType of Event
Muscle and Liver Related Adverse Events
<1% (2)1% (11)CPK ≥ 10 ULN
1% (17)1% (14)ALT ≥3 ULN
<1% (6)<1% (4)AST ≥3 ULN
0% (0)0% (0) Rhabdomyolysis
0% (0)
<1% (1)
<1% (1)
<1% (1)
CPK ≥ 10 ULN & symptoms
Myopathy AE report
Atorvastatin 10mg
% of patients (n)
Placebo
% of patients (n)Type of Event
Specific Adverse Events
Number of patients (% with event)
41 (2.9%)48 (3.4 %)Non CVD death*
4 (0.3%)3 (0.2%)Accident/suicide/violent death
139 (9.7%)
16 (3.5%)
148 (10.5%)
15 (3.3%)
Cancer or neoplasm
Breast cancer or neoplasm
Atorvastatin 10mgPlaceboType of Event
* Censoring time 3 weeks beyond last follow up date, not June 12th 2003
Lipid Levels by Treatment
Total cholesterol (mmol/L) LDL cholesterol (mmol/L)
0 2 3 41 4.5 2 3 41 4.5
Years of Study Years of Study
00
1
2
3
4
0
2
4
6
Placebo Atorvastatin
Average difference 26%
1.4 mmol/L (54mg/dL) p<0.0001
Average difference 40%
1.2 mmol/L (46mg/dL) p<0.0001
Median Lipid Levels by Treatment
HDL cholesterol (mmol/L) Triglycerides (mmol/L)
0 2 3 41 4.5 2 3 41 4.5
Years of Study Years of Study
00
1
21.4
0
.2
.4
.6
.8
1
1.2
Placebo Atorvastatin
Average difference 1%
0.02 mmol/L, 0.8mg/dL p=0.4
Average difference 21%
0.4 mmol/L, 35mg/dL p=0<0.001
Proportion Below LDL-C Guideline Target Levels (< 2.6 mmol/L or 100mg/dL) by Treatment
0
20
40
60
80
100
(%)
Pre treat 3 mths 12 mths 24 mths 36 mths 48 mths
Placebo Atorvastatin
Cumulative Hazard for Primary Endpoint
Relative Risk Reduction 37% (95% CI: 17-52)
Years
328305
694651
10741022
13611306
13921351
AtorvaPlacebo
14281410
Placebo127 events
Atorvastatin83 events
Cu
mu
lati
ve H
azar
d (
%)
0
5
10
15
0 1 2 3 4 4.75
P=0.001
Composition of Primary Endpointby Treatment Group
Endpoint Category Placebo Atorvastatin 10mg
Fatal MI 20 8
Other acute CHD death 4 10
Non fatal MI 41 25
Unstable angina 9 7
CABG or other surgery 18 12
Fatal stroke 5 1
Non fatal stroke 30 20
Total 127 83 *One atorvastatin group patient had a Non fatal MI followed by Surgery on the same day only the MI is shown
One Placebo group patient had a CABG followed by stroke on the same day only the CABG is shown
Treatment Effect on the Primary Endpoint
21 (1.5%)
24 (1.7%)
51 (3.6%)
83 (5.8%)
Atorva*
48% (11-69)39 (2.8%)Stroke
31% (-16-59)34 (2.4%)Coronary revascularisation
36% (9-55)77 (5.5%)Acute coronary events
37% (17-52)
p=0.001127 (9.0%)Primary endpoint
Hazard Ratio Risk Reduction (CI)Placebo*Event
* N (% randomised)
.2 .4 .6 .8 1 1.2
Favours Atorvastatin Favours Placebo
Consistency of Effect
No evidence of heterogeneity by:
• Age p=0.58
• Sex p=0.59
• Baseline lipids p≥0.4 for all
• Baseline systolic blood pressure p=0.2
• Retinopathy p=0.7
• Albuminuria p=0.34
• Smoking p=0.70
Subgroup* Placebo** Atorva** Hazard Ratio Risk Reduction (CI)
LDL-C ≥ 3.06 (120) 66 (9.5) 44 (6.1) 38% (9-58)
LDL-C < 3.06 (120) 61 (8.5) 39 (5.6) 37% (6-58)
p=0.96
HDL-C ≥ 1.35 (54) 62 (8.4) 36 (5.2) 41% (11-61)
HDL-C < 1.35 (54) 65 (9.6) 47 (6.4) 35% (5-55)
p=0.71
Trig. ≥ 1.7 (150) 67 (9.6) 40 (5.5) 44% (18-62)
Trig. < 1.7 (150) 60 (8.4) 43 (6.1) 29% (-5-52)p=0.40
* units in mmol/L (mg/dL) ** N (% of randomised)
Treatment Effect onthe Primary Endpoint by Subgroup
.2 .4 .6 .8 1 1.2
Favours Atorvastatin Favours Placebo
Absolute Effect of Treatment
PEP incidence rate / 100 person years at risk
Placebo 2.46
Atorvastatin 1.54
Expected events per 1000 patients over four years
Placebo 98.3
Atorvastatin 61.7
Events avoided per 1000 treated for four years 36.7
Absolute risk reduction in four years 3.7%
NNT for four years 27
Cumulative Hazard for Any CVD Endpoint
Relative Risk Reduction= 32% (95% CI 15-45)
p=0.001
Years
306287
663621
1040992
13371275
13721334
AtorvaPlacebo
14281410
Placebo189 events
Atorvastatin134 events
Cu
mu
lati
ve H
azar
d (
%)
0
5
10
15
20
0 1 2 3 4 4.75
Cumulative Hazard for All Cause Mortality
Relative Risk Reduction 27% (95%CI: -1-48) p=0.059
Cu
mu
lati
ve H
azar
d (
%)
Years
AtorvaPlacebo
Placebo82 deaths
Atorvastatin61 deaths
351332
730709
11101094
14011370
14181395
14281410
1 2 3 4 4.750
2
4
6
8
10
0
Cause of Death By Treatment Arm
Atorvastatin
6121 112
25 (1.8 %)
220410
36 (2.5 %)
Placebo
8225372
37 (2.6%)
130311
45 (3.2 %)
Total deathsCoronary Other cardiac CerebrovascularOther cardiovascular
Total cardiovascular deaths
Diabetes related deathCancer deathSuicide accident or violent death Other death
Total non-cardiovascular deaths
Summary
• Trial terminated about 2 years earlier than anticipated, because a highly significant reduction in the PEP was observed at the 2nd interim analysis
• 37% reduction in major CVD events
• 48% reduction in stroke
• 27% reduction in all cause mortality of borderline statistical significance
• Consistent effect regardless of age, sex, lipids and complications (hypertension, smoking, retinopathy or macro/microalbuminuria) at baseline
• Atorvastatin 10mg was well tolerated with no cases of rhabdomyolysis and no differences in muscle and liver adverse effects
Conclusion
• CARDS shows that in patients with type 2 diabetes and with cholesterol levels at the lower end of the distribution, atorvastatin 10mg daily is safe and highly efficacious in reducing the risk of first CVD events, including stroke
• CARDS suggests that there is no justification for having a threshold level of LDL-C as the sole arbiter of which patients with type 2 diabetes should receive statin treatment. The overall cardiovascular risk should be the principle determinant
• The debate about whether all patients with type 2 diabetes warrant statin therapy should now focus on whether there are any patients at sufficiently low risk for this safe and efficacious treatment to be withheld