Dr Akhil Kapur London Chest Hospital, Barts and the London NHS Trust, London, UK

On behalf of the CARDia Investigators

2

Revascularisation in Diabetic Patients with Multivessel Disease

• CABG generally considered superior to PCI• 1996 presentation of the BARI diabetic subset (353

patients)• At 5 years angioplasty had double the mortality of

patients receiving surgery • No specific randomised comparison of CABG and PCI

until now• Largest randomised comparison to date• The CARDia Trial compared a strategy of optimal PCI

with up to date CABG

3

CARDia Investigators

• Principal Investigators: Akhil Kapur, Roger Hall, Kevin Beatt

• Sponsored by Hammersmith Hospitals NHS Trust • Study Management Group : Akhil Kapur, Roger Hall,

Marcus Flather• Steering Committee : Roger Hall, Akhil Kapur, Kevin Beatt,

Marcus Flather, Iqbal Malik, Petros Nihoyannopoulos, Keith Oldroyd, Andreas Baumbach, Gianni Angelini, Jon Anderson, Mark de Belder, Adam de Belder

• Critical Event Committee: Iqbal Malik, Prakash Punjabi, Kevin Fox, Simon Corbett, Doug Fraser, Andrew Archbold, Simon Kennon, Tim Gilbert, Iain Simpson, Mark Gunning, Tony Page

4

CARDia InvestigatorsCARDia Investigators

• DSMB : Desmond Julian, Tom Treasure, Adrian Banning• Coordinating Centres and Data management: Clinical Trials

and Evaluation Unit, Royal Brompton Hospital, London –Director Marcus Flather, Fiona Nugara, Claire Foley, Nicola Delahunty, Katie Qureshi, Jean Booth ; HH NHS Trust – Marie Claire Rickard, Claire Sheehy, Marie Leahy, Jeremy Butts

• Statisticians: Michael Roughton, Konrad Jamrozik, Judith Cooper

• Supported by major grants from Eli Lilly, Cordis, BMS/Sanofi, Hammersmith Hospitals special trustees,

• Further support from Boston Scientific, Medtronic, Guidant and Jomed

5

CARDiaParticipating Centres

Centre Local investigator Patients Recruited

Hammersmith Hospital, London Kevin Beatt, Punit Ramrakha 84St Mary’s Hospital, London Iqbal Malik 62London Chest Hospital Martin Rothman, Akhil Kapur 52St James Hospital, Dublin Peter Crean 42Royal Sussex County, Brighton Steve Holmberg, Adam de Belder 34Bristol Royal Infirmary Andreas Baumbach, Gianni

Angelini33

James Cook University Hosp, Middlesboro Mark de Belder 32Western Infirmary, Glasgow Keith Oldroyd 30King’s College Hospital Martyn Thomas 27Manchester Royal infirmary Fath Ordoubadi 19Hairmyres Hospital Keith Oldroyd, Barry Vallance 13St Thomas’ Hospital Simon Redwood, Graham Venn 12

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CARDiaParticipating Centres continued

Centre Local investigator Patients recruited

City Hospital, Birmingham Teri Millane 12Royal Victoria, Blackpool David Roberts 11Beaumont, Dublin David Foley 11St Bartholomew’s Hospital, London Richard Schilling, Akhil Kapur 10Papworth Hospital, Cambridge Peter Schofield 8Royal Brompton Hospital Carlo di Mario 4

North Staffs, Stoke Mark Gunning 4

City Hospital, Nottingham Kamran Baig, Rob Henderson 3

CTC, Liverpool Rod Stables 3

Northern General, Sheffield Ever Grech 2

Harefield Hospital Charles Ilsley 1Mayday, Surrey Kevin Beatt 1

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CARDia Trial Hypothesis

In diabetic patients with multivessel disease amenable to both CABG or PCI

Optimal PCI is not inferior to up-to-date CABG

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CARDia Trial DesignDiabetic patients with multivessel disease

or complex single vessel disease

Suitable for PCI or CABG

Inclusion and exclusioncriteria met

CONSENT

Randomisation

Up to date CABG Optimal PCI stent +abciximab

DES 71% BMS 29%

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Main Exclusion Criteria

• Informed consent could not be obtained• Age >80 years• Previous CABG or PCI• Left main stem disease• Cardiogenic shock• Recent ST elevation myocardial infarction• Contraindications to abciximab, aspirin and clopidogrel

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Trial Design contd

• CABG historically assumed to be superior to PCI (based on BARI

subset)

• Investigator Initiated Trial designed to show non inferiority of PCI

• Sample size of 600 patients based on ARTS and EPI trials • and the hypothesis (test of non-inferiority) to be tested is:

• Ho: pe > 1.3ps (10 EP in PCI group >1.3 times to 10 EP in the CABG group)

• Ha: pe < 1.3 ps (10 EP in PCI group <1.3 times to 10 EP in the CABG group)

• 510 patients recruited from Jan 2002 to May 2007Early termination due to slowing recruitment but follow up extended to 5 years

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Primary endpoint:• Composite event rate at 1 year of death/non-fatal MI/non-

fatal stroke (time to first event)Major secondary: • Further revascularisation at 1 yearSecondary• Severe bleeding complications at 30 days• New requirement for permanent dialysis• Neurological morbidity• Quality of life • Cost difference between treatments• Change in LV function

Endpoints

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Definitions of primary outcomes

• Death: All cause mortality• Non fatal MI :

• First 7 days post revascularisation one or more of following –• CK or CKMB >3x ULN, Tn (T or I ) >1, ECG new q waves

• After first 7 days – at least 2 of following –• raised enzymes (CK/CKMB >x2 ULN or Troponin Tor I

>1), new q waves on ECG, clinical evidence of ischaemicsymptoms

• Non Fatal Stroke :• Neurological signs/symptoms that persist for more than 24

hrs with a neurological imaging study that does not indicate a different aetiology

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CARDia Patient flow Chart

254 patients8=withdrew consent

1=data not yet available

510 Pts randomised

CABG PCI

96% (245) in 1 year follow up 98% (251) in 1 year follow up

229=received CABG1=died

11=cross over to PCI

256 patients2=withdrew consent

2 data not yet available

252=received PCI1=cross over to CABG

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Baseline Clinical Characteristics

4.94.3Other

2.52.1Black

25.918.8South Asian

0.26466.774.8White

%Ethnicity

0.31883.384.8kgWeight

0.386168.6169.4cmHeight

0.38668.769.8Beats/minHeart rate

0.68373.673.2mmhgDiastolic blood pressure

0.766136.7137.3 mmHgSystolic Blood pressure

0.06870.777.8%Male

0.49464.363.7YearsAge256254Number in group

p valuePCICABGUnitsVariable

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Baseline Clinical Characteristics

p valuePCICABGUnitsVariable

63.363.6Non-smoker

%Smoking Status

0.75210.010.3YrsYears with Diabetes

30.669.4

31.468.6

Insulin treatedNon Insulin treated

%Diabetes Status

78.576.3Elective

0.54721.523.7Acute

%Admission Type

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Baseline Clinical Characteristicsp valuePCICABGUnitsVariable

0.60159.160.0%EF

0.84155.458.7Normal or Good

%LV function

0.637104.2106.9Creatinine

0.5997.97.9%Hba1c

0.5211.413.3%Cerebrovascular disease history

0.283.55.6%Chronic lung disease history

0.9319.49.6%Peripheral vascular disease history

0.4375.54.0%Renal failure

0.03292.987.2%Hyperlipidaemia history

0.26376.480.5%Hypertension history

0.13164.858.3%3 vessel disease

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Procedural details

1(1,4)9 (7,16)493median days (interquartile

range)

Time in hospital

37 (13,59)64 (27,110)493median days(interquartile

range)

Time from randomisation to index procedure

PCICABGValid nunits

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PCI procedural detailsUse prior to procedure of:

• aspirin - 100%• clopidogrel - 94%• abciximab - 95%

---------------------------------------------------------------------------------• 3 vessel disease - 65%• 3 vessels treated in these patients - 88%---------------------------------------------------------------------------------• average no. of stents per patient - 3.5• average stent length - 71mm---------------------------------------------------------------------------------• DES patients (cypher) - 71% (180)• BMS patients - 29% (72)

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CABG procedural details

• 3 vessel disease - 58%• 3 vessels treated in these patients - 90%

----------------------------------------------------------------------------

• average no of grafts - 2.8• LIMAs - 89%• % with at least two arterial grafts - 17%• % off pump - 31%

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Results – adjudicated events – intention to treat analysis

5.31(2.00,14.11)

0.0019.9% (25)2.0% (5)Further revascularisation

1.72(1.02,2.87)

0.0417.5%11.0%Composite outcome of death, MI, stroke, repeat revasc at 1 year

1.15(0.65,2.03)

0.6311.6% (29)10.2% (25)Death, MI and stroke at one year –primary outcome

0.16(0.02,1.33)

0.090.4% (1)2.5% (6)Non fatal stroke

1.51(0.75,3.03)

0.258.4% (21)5.7% (14)Non fatal MI

0.98 (0.36,2.64)

0.833.2% (8)3.3 % (8)Death

OR and 95% CI

p valuePCI(251)

CABG(245)

Adjudicated events post randomisation

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Primary composite outcome at 1 year

p =0.63

Death, non fatal MI, non fatal stroke

p =0.63

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1 2 3

Individual 1 year outcomes Individual 1 year outcomes

3.2 %3.2 %(n=8)(n=8)

DeathDeath

p=0.83 p=0.34 p=0.09

Non fatal MINon fatal MI

3.3 %3.3 %(n=8)(n=8)

5.7%5.7%(n=14)(n=14)

8.4%8.4%(n=21)(n=21)

2.5%2.5%(n=6)(n=6)

0.4%0.4%(n=1)(n=1)

Non fatal strokeNon fatal stroke

CABG (n=245)

PCI (n=251)

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Survival at 1 year CABG vs PCI

p=0.83p=0.83

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Death, MI, stroke and repeat revascularisation

p=0.04p=0.04

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Subgroup - CABG vs PCI-DES

0.0137.3%2.0%Further revascularisation at 1 year

0.9810.1%10.2%Composite outcome of death, non fatal MI and non fatal stroke at one year – primary outcome

0.0410%2.5%Non fatal stroke

0.21715.1%11.0%Composite outcome of death, non fatal MI, non fatal stroke and repeat revasc at 1 year

0.8526.2%5.7%Non fatal MI

0.7233.9%3.3%Death

p valueCABG vs DES

PCI (DES)n=179

CABGn=245

Comparison of CABG vs DES in PCI group

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Subgroup - CABG vs PCI-DES Composite endpoint at 1 year

Death, non fatal MI, non fatal stroke

p=0.98

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Study Limitations

• Planned recruitment not achieved 510 patients out of 600 recruited – 85%

• Formal non-inferiority parameters not fulfilled (insufficient power)

• These are preliminary results – a few events are still to be adjudicated

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CARDia: Main Conclusions

• No apparent difference between PCI and CABG at one year in:• Death • Composite of Death, MI and stroke

• More repeat revascularisation in the PCI group

• PCI may now be considered a reasonable strategy in diabetic patients with multivessel disease

• Longer follow up is needed