1. RITA-3 ESC Hotline 2005 Long-Term Outcome: Intervention vs Conservative Therapy in Non-ST Elevation ACS Keith A A Fox on behalf of the Executive Committee and Investigators of RITA-3 British Heart Foundation RITA-3 Trial

2. RITA-3 ESC Hotline 2005 Rationale: The long-term outcome of an interventional strategy in non-ST elevation ACS is unknown. The net benefits of a routine invasive strategy, at one year, may be offset by the impact of ischemia driven revascularization. Conversely, by limiting myocyte injury a routine invasive strategy may avoid adverse remodelling & late cardiac complications.

3. RITA-3 ESC Hotline 2005 RITA 3 Study Design Non-ST ACS Intervention Conservative PCI/CABG Angio/PCI/CABG Medical Rx Follow-up & endpoints 4 months to 5 year5 Aspirin Enoxaparin Angio +ischemia Baselineenzymes,markers N = 895 N = 915 N = 1810 Completeness of follow-up was 99.6% for vital status (8 patients emigrated) 3.3% had incomplete data on MI at 5yrs

4. RITA-3 ESC Hotline 2005 Baseline ECG, Enzymes & Troponin 109CK & troponin normal 78 71 Troponin  17 19 CK  2 fold Marker elevation: 4 3 LBBB 70 74 T  42 40 ST  or  * >0.1mV 92 93 ECG abnormal Conservative Intervention All data given as percentages. *Transient elevation.

5. RITA-3 ESC Hotline 2005 Baseline Characteristics 3635 Angina grade 3/4 prior to index episode 68 Any prior angina 2630Previous MI 131/73132/74Mean BP (mmHg) 35 Hypertension* 3639Female 6263Mean age (years) ConservativeIntervention Percentages unless otherwise stated. *receiving therapy for hypertension. **beta-blocker in 74% of patients.

6. RITA-3 ESC Hotline 2005 Secondary Prevention: Medications On discharge: 70% statins, 72%  blockers, >90% aspirin At median of 5 years: 80% statins, 57%  blockers, 81% aspirin At one year: 75% statins, 61%  blockers, 86% aspirin

7. RITA-3 ESC Hotline 2005 Timing of first arteriogram randomization to 1 year RITA-397%49% 97% (48hrs) 16%

8. RITA-3 ESC Hotline 2005 Timing of first revascularisation randomization to 1 year RITA-357.6%28.3%

9. RITA-3 ESC Hotline 2005 0 10 20 30 40 50 Percentage 0-1m1-4m4m-1y1-2y2-3y3-4y4-5y Period of follow-up 0 10 20 30 40 50 Percentage 0-1m1-4m4m-1y1-2y2-3y3-4y4-5y Period of follow-up InterventionConservative Revascularization: PCI and CABG PCI CABG

10. RITA-3 ESC Hotline 2005 Cumulative risk of death, MI or refractory angina RITA-3 p = 0.001 Risk ratio = 0.66 (95% CI 0.51–0.85) 14.5% 9.6% Lancet 2002, 360, 743-751

11. RITA-3 ESC Hotline 2005 Death, MI or Refractory Angina at One Year 0.58 0.91 (0.67–1.25) 8.37.6Death/MI 0.003 0.72 (0.58–0.90) 18.413.5Death/MI/RA <0.001 0.56 (0.41–0.76) 11.66.5RA 0.29 0.79 (0.51–1.22) 4.83.8MI 0.42 1.16 (0.75–1.80) 3.94.6Death p valueRisk ratio (95% CI) Conservative n=915 (%) Intervention n=895 (%) Outcome Lancet 2002, 360, 743-751

12. RITA-3 ESC Hotline 2005 Death or Non-Fatal MI: median of 5 yrs 0.044 0.78 (0.61–0.99) 178 (20.0)142 (16.6)Death/MI 9062CV Death 0.054 0.76 (0.58–1.00) 132 (15.1)102 (12.1)Death p valueOdds ratio (95% CI) Conservative n=915 (%) Intervention n=895 (%) Outcome Non CV Death4042 CV Death/MI0.030 0.74 (0.56–0.97) 139 (15.9)105 (12.2) 0.68 (0.49–0.95) 0.026 ns

13. RITA-3 ESC Hotline 2005 Conservative Intervention 0 5 10 15 20 25 Cumulative percentage 012345 Follow-up time (years) Primary Outcome: Death or Non-Fatal MI 16.6% 20.0% p = 0.044 odds ratio: 0.78 95% CI 0.61 - 0.99

14. RITA-3 ESC Hotline 2005 Conservative Intervention 0 5 10 15 20 25 Cumulative percentage 012345 Follow-up time (years) Deaths P = 0.054 odds ratio: 0.76 95% CI 0.58 - 1.00 15.1% 12.1%

15. Risk factorOdds ratio95% CIp-value Age2.401.97 to 2.92<0.001 Diabetes1 1.79 - 1.28 to 2.51 0.001 Previous MI1 1.55 - 1.17 to 2.04 0.002 Current smoker1 1.57 - 1.18 to 2.11 0.002 Pulse rate1.071.02 to 1.120.003 ST depression1 1.48 - 1.14 to 1.92 0.004 Severe angina (grade 3/4)1 1.46 - 1.12 to 1.90 0.005 Gender1 1.44 - 1.09 to 1.89 0.010 Left bundle branch block1 1.91 - 1.06 to 3.47 0.032 Randomised treatment1 0.77 - 0.59 to 0.99 0.044

16. RITA-3 ESC Hotline 2005 1 2 3 4a 4b Conservative 0 5 10 15 20 25 30 35 40 45 50 Cumulative percentage 012345 Follow-up time (years) Cumulative risk of death or MI by risk score and treatment group

17. RITA-3 ESC Hotline 2005 1 2 3 4b 4a Intervention Cumulative risk of death or MI by risk score and treatment group

18. RITA-3 ESC Hotline 2005 Cumulative risk of death or MI by risk score and treatment group

19. RITA-3 ESC Hotline 2005 Conclusions Results in fewer deaths/ non-fatal MIs Decreases the incidence of subsequent angina and late revascularization The major part of the benefit is seen in patients at higher baseline risk No benefit is seen in those at very low risk The long term impact of a strategy of intervention in moderate-risk patients:

20. RITA-3 ESC Hotline 2005 Clinical Implications A strategy of routine angiography and intervention is appropriate for all moderate and higher risk patients with non-ST elevation ACS Systematic analysis of baseline risk is required to identify those with the potential for benefit

21. RITA-3 ESC Hotline 2005 Recruiting & Intervention Centres ♥ Edinburgh RIE ♥ St. Peter's, Chertsey ♥ RAE, Wigan ♥ Macclesfield ♥ Rotherham ♥ Pontefract ♥ Stafford General ♥ Lincoln ♥ Eastbourne ♥ Nottingham City ♥ Pinderfields, ♥ Royal Hallamshire ♥ St James's ♥ Ninewells, Dundee ♥ RVI, Newcastle ♥ Wansbeck ♥ Borders Gen ♥ Darlington Memorial ♥ St Richards, ♥ Royal Sussex Brighton ♥ Sunderland Royal ♥ Conquest, Hastings ♥ Luton & Dunstable ♥ Southend ♥ Bromley ♥ St. John's, Livingston ♥ Aberdeen Royal ♥ WGH, Edinburgh ♥ King George Ilford ♥ Friarage, Northallerton ♥ Barnsley ♥ Whiston ♥ Dryburn ♥ Victoria Kirkcaldy ♥ Royal Liverpool ♥ Dr Gray's, Elgin ♥ QEQM, Margate ♥ Countess of Chester ♥ Lister, Stevenage ♥ Blackpool Victoria ♥ Halton General ♥ Guy's/St Thomas's ♥ City Gen Stoke ♥ St. Mary's, London ♥ QMC, Nottingham ♥ London Chest ♥ Northern General, Sheffield ♥ Royal Brompton ♥ Southampton General ♥ Wythenshawe, Manchester ♥ London Chest ♥ Northern General, Sheffield ♥ Royal Brompton ♥ Southampton General ♥ Wythenshawe, Manchester ♥ Cardiothoracic Centre, Liverpool ♥ Freeman, Newcastle ♥ Harefield ♥ James Cook University Hospital ♥ King’s College London ♥ Leeds General Infirmary ♥ Cardiothoracic Centre, Liverpool ♥ Freeman, Newcastle ♥ Harefield ♥ James Cook University Hospital ♥ King’s College London ♥ Leeds General Infirmary Intervention Centres

22. RITA-3 ESC Hotline 2005 Trial Organisation Executive committee KAA Fox Data Monitoring JR Hampton Event Validation S Holmberg Statistical Centre SJ Pocock Quality control D Chamberlain ECG screening M Pryde Study coordinators - Rosemary Knight, Claire Marley Statistical analysis - Tim Clayton, Mark Alston Database manager - Laura VanDyck Computing support - Mike Bennett Research nurse - Heather Rake Randomisation - Nottingham Clinical Research Funding Support: British Heart Foundation Aventis Pharma, NHS Executive