1. The Benefit of an Invasive Strategy in Women Versus Men with Non-ST-Elevation ACS: A Collaborative Meta-Analysis of Randomized Trials Michelle O’Donoghue, Marc S. Sabatine, William E. Boden, Eugene Braunwald, Christopher P. Cannon, Tim C. Clayton, Robbert J. de Winter, Keith AA. Fox, Bo Lagerqvist, Peter A. McCullough, Sabina A. Murphy, Rudolf Spacek, Eva Swahn, Lars Wallentin, Fons Windhausen

2. Background FRISC II (12 months) TACTICS-TIMI 18 (6 months) RITA 3 (12 months) CONS INV Death or MI (%) 15.8 10.1 9.4 9.6 7.0 7.6 0 2 4 6 8 10 12 14 16 18 Male CONS INV 10.5 5.1 9.7 12.4 8.6 6.6 Female

3. Aims l l To compare an invasive and conservative strategy in women vs men with non-ST-elevation ACS l l To examine the relative benefit in high-risk subgroups

4. Methods l l Identified randomized trials comparing an invasive vs conservative strategy in NSTE-ACS l l Obtained event rates stratified by gender for each trial l l Random-effects model with weighting based on inverse variance

5. Year Follow-up (months) Female (n) Male (n) TIMI IIIB199412497976 MATE19985272129 VANQWISH19981224895 FRISC II1999606721523 TACTICS - TIMI 18 200167571463 VINO2002125180 RITA 32002606821128 ICTUS200512320880 TOTAL 30 months (weighted mean)30757074

6. Baseline Characteristics Women(n=3075)Men(n=7074) P value Age (weighted mean) 64 y 61 y <0.01 Smoker29%36%<0.01 Diabetes mellitus 19%17% 0.01 0.01 Hypertension52%41%<0.01 Hyperlipidemia47%39%<0.01 Prior MI 25%34%<0.01 ST-segment depression 38%37% 0.20 0.20 T wave inversion 54%43%<0.01 CK-MB or troponin elevation 49%65%<0.01 GP IIb/IIIa inhibitor 28%24%<0.01

7. Coronary Revascularization INVCONSINVCONS Revasc during index hospitalization 55%23%63%26% Revasc by end of f/u 59%42%70%49% i) Percutaneous intervention by end of f/u 42%26%43%28% ii) CABG by end of f/u 21%17%30%24% FEMALE MALE

8. Extent of Coronary Artery Disease None 1 VD 2 VD 3 VD Left Main Restricted to patients in invasive arms, ≥ 50% stenosis FEMALE MALE VD= vessel-disease

9. 8% 24% 0 5 10 15 20 25 30 Absence of Significant CAD All * Restricted to patients in invasive arms, <50% stenosis All 6% 16% ST-segment depression + 6% 14% CK-MB/ Troponin + Prevalence of non-obstructive CAD (%) FEMALE MALE

10. TIMI IIIB MATE VANQWISH FRISC II TACTICS-TIMI 18 RITA 3 VINO ICTUS OVERALL Death, MI or Rehospitalization with ACS 51.00.2 Favors invasive Favors conservative 51.00.2 Favors invasive Favors conservative OR 0.83 (95% CI 0.68-1.01) FEMALE MALE OR 0.75 (95% CI 0.58-0.98) P heterogeneity (gender) = 0.54 n=3075 n=7074 Randomization to end of long-term f/u

11. Female OR (95% CI) Death, MI or Rehospitalization with ACS0.83 (0.68-1.01) Death or Non-Fatal MI0.95 (0.69-1.30) Male Death, MI or Rehospitalization with ACS0.75 (0.58-0.98) Death or Non-Fatal MI0.87 (0.65-1.16) 5.01.00.2 Favors invasive Favors conservative Death0.94 (0.72-1.22) Non-fatal MI0.80 (0.60-1.09) Rehospitalization with ACS0.68 (0.55-0.83) Death1.03 (0.78-1.35) Non-fatal MI0.92 (0.61-1.39) Rehospitalization with ACS0.68 (0.56-0.82) Randomization to end of long-term f/u

12. OR (95% CI) P interaction Initial Hospitalization Women 1.49 (0.72-3.09) Men 1.33 (0.93-1.89) Hospital D/C to End of Follow-up Women 0.79 (0.62-1.02) Men 0.72 (0.56-0.92) 5.01.00.2 Death or Non-Fatal MI Timing of Death or MI 0.78 0.60 Favors invasive Favors conservative

13. Number OR (95% CI) P interaction CK-MB or Troponin +15450.73 (0.57-0.93) CK-MB or Troponin -14870.95 (0.64-1.42) CK-MB or Troponin + 45970.71 (0.52-0.97) CK-MB or Troponin - 23770.77 (0.58-1.02) 5.01.00.2 Death, MI or rehospitalization with ACS High-Risk Subgroups FEMALE MALE Randomization to end of long-term f/u 0.27 0.70 Favors invasive Favors conservative

14. Number OR (95% CI) P interaction CK-MB or Troponin +1545 0.83 (0.54-1.26) CK-MB or Troponin -1487 1.29 (0.78-2.13) CK-MB or Troponin + 4597 0.84 (0.59-1.19) CK-MB or Troponin - 2377 0.92 (0.68-1.24) 5.01.00.2 Death or Non-Fatal MI High-Risk Subgroups FEMALE MALE 0.19 0.70 Randomization to end of long-term f/u Favors invasive Favors conservative

15. Conclusion l l High-risk women and men have a comparable benefit from an invasive strategy in NSTE-ACS l l Biomarkers are useful for identifying women who may benefit most from an invasive strategy l l Women with negative biomarkers do not appear to benefit from an invasive strategy