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

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mu

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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

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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