Collaborative Atorvastatin Diabetes Study CARDS

1
Collaborative Atorvastatin Diabetes Study CARDS
Helen 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
2
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

3
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
4
CARDS Design
Placebo
6 week pre-randomisation placebo run in phase
then visits at month 1, 3, 6 and 6 monthly
5
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

6
CARDS Endpoints
Primary Efficacy Parameters

• Acute CHD death
• Non-fatal MI including silent MI
• Hospitalised unstable angina
• Resuscitated cardiac arrest
• Coronary revascularisation
• Stroke

Major coronary events
Secondary Efficacy Parameters

• Total mortality
• Any cardiovascular endpoint
• Lipid and lipoproteins

7

CARDS Sample Size and Statistical Power

• Power 90
• Significance level lt0.05
• 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

8
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

9
132 Centres in UK and Ireland
10
Recruitment and Follow Up
4053 Screened
3249 (80) Entered baseline
2838 (70) Randomised
1428 Allocated atorvastatin 10mg daily
1410 Allocated placebo
1398 (99.1) Complete follow up
1421 (99.5) Complete follow up
Lost to follow up for mortality 4
(0.3) morbidity 12 (0.9)
Lost to follow up for mortality 1
(0.1) morbidity 7 (0.5)
1 subject lost after first primary endpoint
11
Follow up Time for Primary Endpoint
Atorvastatin 10mg
Placebo
3.97 (1day, 5.51 yrs)
3.91 (1 day, 5.56yrs)
Median (min, max)
12
CARDS Patient Baseline Characteristics
61.8
61.5
13
CARDS Patient Baseline Characteristics
AtorvastatinMean (SD)or N ()
PlaceboMean (SD)or N ()
Blood pressure
144 (15.9)
144 (16.1)
Systolic BP (mmHg)
83 (8.5)
83 (8.4)
Diastolic BP (mmHg)
956 (67)
940 (67)
On BP drug
Smoking
308 (21.6)
323 (22.9)
Current
622 (43.6)
601 (42.7)
Ex-smoker
Never
498 (34.9)
485 (34.4)
14
CARDS Diabetes Related Characteristics
15
Clinical History of Microvascular Disease
Atorvastatin N ()
Placebo N ()
426 (29.8)
427 (30.3)
History of retinopathy
148 (14.7 )
153 (15.0 )
Microalbuminuria (ACR gt2.5mg/mmol)
24 (2.4 )
17 (1.7 )
Macroalbuminuria (ACR gt25 mg/mmol)
Hypertension
1193 (83.5 )
1184 (84.0 )
SBP140 mm Hg or DBP90 mm Hg or on BP drug
16
CARDS Patient Baseline Lipids
AtorvastatinMedian (IQR)
PlaceboMedian (IQR)
5.4 (4.8-5.9)207 (186-228)
5.4 (4.8-5.9)207 (185-229)
Total 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)
1.3 (1.2-1.6)52 (45-60)
1.4 (1.2-1.6)53 (46-61)
HDL-cholesterol (mmol/L) (mg/dL)
Subject to final verification
17
CARDS Patient Baseline Lipids
AtorvastatinMedian (IQR)
PlaceboMedian (IQR)
1.7 (1.2-2.4)150 (106-212)
1.7 (1.2-2.4)150 (106-212)
Triglycerides (mmol/L) (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)
150 (134-169) 116 (101-132)
150 (132-168) 115 (98-131)
Apolipoprotein A1 (mg/dL) Apolipoprotein B
(mg/dL)
Subject to final verificationIQR
Interquartile range
18
Compliance and Non-Study Statin Use
(n) Taking at least one statin by treatment arm
Year 2
Year 3
Year 1
Year 4
Average
9
6.9
11.9
2.4
14.8
Placebo
87.1
85.7
90.0
78.3
Atorvastatin
85.3
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
19
Adverse and Serious Adverse Events
20
Muscle and Liver Related Adverse Events
21
Specific Adverse Events
Atorvastatin 10mg
Placebo
Type of Event
Number of patients ( with event)
41 (2.9)
48 (3.4 )
Non CVD death
139 (9.7) 16 (3.5)
148 (10.5) 15 (3.3)
Cancer or neoplasm Breast cancer or neoplasm
4 (0.3)
3 (0.2)
Accident/suicide/violent death
Censoring time 3 weeks beyond last follow up
date, not June 12th 2003
22
Lipid Levels by Treatment
Total cholesterol (mmol/L)
LDL cholesterol (mmol/L)
Average difference 26 1.4 mmol/L (54mg/dL)
plt0.0001
Average difference 40 1.2 mmol/L (46mg/dL)
plt0.0001
4
6
3
4
2
2
1
0
0
0
2
3
4
1
4.5
2
3
4
1
4.5
0
Years of Study
Years of Study
Placebo
Atorvastatin
23
Median Lipid Levels by Treatment
Triglycerides (mmol/L)
HDL cholesterol (mmol/L)
Average difference 21 0.4 mmol/L, 35mg/dL
p0lt0.001
Average difference 1 0.02 mmol/L, 0.8mg/dL p0.4
2
1.4
1.2
1
.8
1
.6
.4
.2
0
0
0
2
3
4
1
4.5
2
3
4
1
4.5
0
Years of Study
Years of Study
Placebo
Atorvastatin
24
Proportion Below LDL-C Guideline Target Levels (lt
2.6 mmol/L or 100mg/dL) by Treatment
25
Cumulative Hazard for Primary Endpoint
Relative Risk Reduction 37 (95 CI 17-52)
P0.001
Placebo 127 events
Atorvastatin 83 events
Cumulative Hazard ()
Years
305
651
1022
1306
1351
Placebo
1410
328
694
1074
1361
1392
Atorva
1428
26
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
27
Treatment Effect on the Primary Endpoint
.2
.4
.6
.8
1
1.2
Favours Atorvastatin Favours Placebo
N ( randomised)
28
Consistency of Effect

• No evidence of heterogeneity by
• Age p0.58
• Sex p0.59
• Baseline lipids p0.4 for all
• Baseline systolic blood pressure p0.2
• Retinopathy p0.7
• Albuminuria p0.34
• Smoking p0.70

29
Treatment Effect onthe Primary Endpoint by
Subgroup
Subgroup Placebo Atorva Hazard Ratio Risk Reduction (CI) Hazard Ratio Risk Reduction (CI)
LDL-C 3.06 (120) 66 (9.5) 44 (6.1) 38 (9-58)
LDL-C lt 3.06 (120) 61 (8.5) 39 (5.6) 37 (6-58) p0.96
HDL-C 1.35 (54) 62 (8.4) 36 (5.2) 41 (11-61)
HDL-C lt 1.35 (54) 65 (9.6) 47 (6.4) 35 (5-55) p0.71
Trig. 1.7 (150) 67 (9.6) 40 (5.5) 44 (18-62)
Trig. lt 1.7 (150) 60 (8.4) 43 (6.1) 29 (-5-52)p0.40
.2
.4
.6
.8
1
1.2
Favours Atorvastatin Favours Placebo
units in mmol/L (mg/dL) N ( of randomised)
30
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

31
Cumulative Hazard for Any CVD Endpoint
Relative Risk Reduction 32 (95 CI 15-45)
p0.001
Placebo 189 events
Atorvastatin 134 events
Cumulative Hazard ()
Years
621
992
1275
1334
Placebo
1410
287
663
1040
1337
1372
Atorva
1428
306
32
Cumulative Hazard for All Cause Mortality
Relative Risk Reduction 27 (95CI -1-48) p0.059
Placebo 82 deaths
Cumulative Hazard ()
Atorvastatin 61 deaths
Years
Placebo
332
709
1094
1370
1395
1410
Atorva
351
730
1110
1401
1418
1428
33
Cause of Death By Treatment Arm
34
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

35
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