1. RITA-3 ESC 4 th September 2005 The impact of underlying risk and gender on the benefit of early intervention in non-ST elevation acute coronary syndrome patients: findings from the RITA-3 trial TC Clayton, SJ Pocock, RA Henderson, PA Poole-Wilson, TRD Shaw, DJ Wheatley, KAA Fox British Heart Foundation RITA-3 Trial

2. RITA-3 ESC 4 th September 2005 RITA 3 Study Design Unstable angina / non-ST-elevation MI InterventionConservative PCI/CABGAngio/PCI/CABGMedical Rx +ischemia n=1810 n=895n=915 Medical Rx Angiography +72 hours - 48 hours Randomisation Primary endpoints: (i) death / MI / refractory angina at 4 months (ii) death / MI at 12 months

3. RITA-3 ESC 4 th September 2005 Background and objectives OutcomeIntervention (n=895) Conservative (n=915) RR (95% CI) Death/MI/ref angina (4m) Death/MI (12m) 86 (9.6%) 68 (7.6%) 133 (14.5%) 76 (8.3%) 0.66 (0.51- 0.85) 0.91 (0.67-1.25) Results as published:

4. RITA-3 ESC 4 th September 2005 Background and objectives Intervention (n=895) Conservative (n=915) Interaction p-value Men(I=545,C=583) Women(I=350,C=332) 48 (8.8%) 38 (10.9%) 101 (17.3%) 32 (9.6%) 0.004 Death/MI/refractory angina at 4m by gender: Aims: To assess whether the benefits of early intervention are restricted to patients with higher underlying risk To consider possible reasons for any gender differences in the benefits of early intervention

5. RITA-3 ESC 4 th September 2005 Methods Gender differences in patient characteristics were assessed A multivariate logistic regression model was developed for death/MI/refractory angina at 4 months Baseline risk factors were included that were significantly related to the outcome Patients were stratified into quartiles of underlying risk and the impact of treatment assessed Gender differences in outcome within each quartile were tabulated

6. RITA-3 ESC 4 th September 2005 Baseline characteristics Men (n=1128) Women (n=682) P-value Mean age (years)61.863.30.002 Mean BMI (kg/m 2 )27.728.10.14 Current smoker (ex-smoker)35% (48%)29% (39%)<0.001 Angina CCS grade 3/432%42%<0.001 Previous MI31%22%<0.001 Diabetes13%14%0.47 Mean systolic BP (mmHg) Mean diastolic BP (mmHg) 132 75 131 71 0.38 <0.001 Mean pulse rate (beats/min)6870<0.001 Mean cholesterol (mmol/l)5.55.8<0.001

7. RITA-3 ESC 4 th September 2005 Risk factors of outcome Risk factorEvents/Total (219 / 1807) Odds ratio P-value* Severe angina Age (per 10 years) Treatment FemaleCons Inter MalesCons Inter ST elevation Pulse rate (per 10 beats/min) 104 / 647 32 / 332 38 / 350 101 / 583 48 / 545 27 / 139 1.83 1.32 1 1.17 1 0.46 1.88 1.14 <0.001 0.53 <0.001 0.007 0.008 * Gender/treatment interaction, p=0.003

8. RITA-3 ESC 4 th September 2005 Treatment effect by quartile of risk Quartile of risk Intervention (n=893) Conservative (n=914) Odds-ratio (95% CI) First Second Third Fourth Events 18 (7.7%) 19 (8.5%) 25 (11.3%) 24 (11.1%) 14 (6.4%) 25 (11.0%) 35 (15.2%) 59 (24.9%) 1.22 (0.59-2.52) 0.75 (0.40-1.41) 0.71 (0.41-1.24) 0.38 (0.22-0.64) Total*Events86 (9.6%)133 (14.5%)0.63 (0.47-0.83) * Interaction between risk and treatment, p=0.003

9. RITA-3 ESC 4 th September 2005 Cumulative risk by quartile RITA-3 Cumulative percentage 30 25 15 10 5 0 InterventionConservative Time since randomisation (days) 35 20 0306090120180270365

10. RITA-3 ESC 4 th September 2005 Treatment effect by quartile of risk and gender QuartileMenWomen of riskInter (n=545) Cons (n=583) Inter (n=350) Cons (n=332) First Second Third Fourth 3 / 42 (4.8%) 8 / 135 (5.9%) 17 / 162 (10.5%) 21 / 204 (10.3%) 3 / 43 (7.0%) 16 / 140 (11.4%) 27 / 148 (15.2%) 55 / 221 (24.9%) 16 / 191 (8.4%) 11 / 89 (12.4%) 8 / 59 (13.6%) 3 / 11 (27.3%) 11 / 175 (6.3%) 9 / 88 (10.2%) 8 / 53 (15.1%) 4 / 16 (25.0%)

11. RITA-3 ESC 4 th September 2005 Possible reasons for gender differences Chance - caution needed in interpretation of subgroups (low event rate seen in Conservative women) Gender differences seen in several important factors (but did not explain results observed) Women appear to be treated less aggressively (72% men with 3 VD received CABG vs 51% women) Women may experience more complications from invasive treatment

12. RITA-3 ESC 4 th September 2005 Conclusions Most benefit of early intervention seen in higher risk patients Benefit of early intervention seen in men but not in women (similar results seen for death/MI at 12 months) Caution needed in interpretation of results (unlikely that risk from intervention increased in women) Short term outcomes only assessed Further research is required to identify treatments to improve the prognosis of women