1. Relationship of Time to Treatment and Door-to-Balloon Time to Mortality in Patients with Acute Myocardial Infarction Treated with Primary Angioplasty Christopher P. Cannon, M.D., C. Michael Gibson, M.D., Costas T. Lambrew, M.D., David A. Shoultz, Ph.D., William J. French, M.D., Joel M. Gore, M.D., W. Douglas Weaver, M.D., William J. Rogers, M.D., Alan J. Tiefenbrunn, M.D., for the NRMI-2 Investigators

2. Cannon CP, et al JAMA: June 2000. Background Increasing time to treatment with thrombolysis has been associated with increased mortality Rapid reperfusion -> improved survival Angiographic trials (e.g., GUSTO -I) have shown link between 90 minute, but not 180 minute, patency and improved survival Small differences in time to reperfusion make clinically important differences in survival

3. Cannon CP, et al JAMA: June 2000. Background In randomized trials of primary angioplasty, mortality was low and superior to thrombolytic therapy –"Door-to-Balloon" times 60-90 mins –Experienced operators In registries, when time delays were greater, mortality higher and not different than thrombolysis –Suggesting that the "door-to-balloon" time may be an important factor in mortality. Prior studies had limited power to evaluate effects of time delays on mortality

4. Cannon CP, et al JAMA: June 2000. Methods NRMI-2 is registry conducted from 6/94 to 3/98 at 1,474 hospitals across the U.S.; 661 perform primary PTCA. Participants in the registry agree to enroll all consecutive MI patients regardless of type, treatment, or outcome. Edit checks on the Case Report Forms are carried out by Data Coordinating Center, and queries sent to the Coordinators for clarification. However, no independent, on-site monitoring of the data is performed.

5. Cannon CP, et al JAMA: June 2000. Statistical Analysis Plan In this pre-specified analysis: –Patients included with primary PTCA as initial reperfusion strategy + ST elevation or new LBBB. Patients were divided into 6 groups by their time -to- treatment and by door-to-balloon time Baseline characteristics compared Univariate and Multivariate analysis was performed Subgroups evaluated (e.g., thrombolytic eligible, cardiogenic shock)

6. Cannon CP, et al JAMA: June 2000. Baseline Characteristics - Time to Treatment 0-2 h >2-3 >3-4>4-6>6-12>12P value No. Pts2,176 6,353 5,7185,8524,6802,301 Age 58.3 60.2 61.7 63.0 62.9 61.3 <0.00001 Male (%)80.1 75.170.366.565.564.5<0.00001 DM (%)11.6 14.117.319.922.723.7<0.00001 Prior MI (%)17.117.518.117.817.415.10.05 Anterior (%)41.939.438.038.340.740.50.003 Shock %4.24.33.83.73.02.2<0.00001 Lytic contra10.914.518.221.218.712.2<0.00001 Transferred 2.15.111.116.522.724.3<0.00001

7. Cannon CP, et al JAMA: June 2000. Baseline Characteristics - Door to Balloon Time 0-6061-9091-120121-150 151-180 >180 Pvalue No Pts2,2305,7326,6144,4592,6255,406 Age 60.1 60.3 61.4 62.3 63.0 62.3 <0.00001 Male (%)76.374.271.168.165.765.5<0.00001 Diabetes (%)13.214.116.919.920.823.2<0.00001 Prior MI (%)15.415.516.918.017.120.8<0.00001 Anterior (%)37.337.938.240.343.140.6<0.00001 Card. Shock 4.13.13.54.14.63.40.006 Tlytic contra 10.011.714.718.423.324.0<0.00001 Transferred 1.72.26.210.817.738.4<0.00001

8. Cannon CP, et al JAMA: June 2000. Multivariate Model of in-hospital Mortality CharacteristicOdds Ratio P value Systolic BP (per 10mmHg)0.81 <0.0001 Age (per 10 years)1.70<0.0001 Killip class IV6.27<0.0001 Heart rate (10 beats/min)1.18<0.0001 Anterior MI1.86<0.0001 Killip class III3.08<0.0001 Killip class II1.95<0.0001 Hypercholesterolemia0.58<0.0001 Diabetes1.56<0.0001 Tlytic contraindication 1.54<0.0001 Door-to-balloon >180 mins1.610.0003 Door-to-balloon 150-180 mins1.620.0007 Hypertension1.180.005 Prior CHF1.320.008 Door-to-balloon 120-150mins1.410.01

9. Cannon CP, et al JAMA: June 2000. N=27,080 P = 0.0001 N=27,080 P = 0.0001 NRMI-2: Primary PCI Time to Treatment vs. Mortality Door-to-Balloon Time (minutes)

10. Cannon CP, et al JAMA: June 2000. P=NS 0.99 1.17 1.13 1.19 1.07 NRMI-2: Primary PCI Time-to-Treatment vs. Mortality N=2,176 6,353 5,718 5,852 4,680 2,301

11. Cannon CP, et al JAMA: June 2000. N=27,080 NRMI-2: Primary PCI Distribution of Door-to-Balloon times Door-to-Balloon Time (minutes)

12. Cannon CP, et al JAMA: June 2000. N=27,080 P < 0.00001 N=27,080 P < 0.00001 NRMI-2: Primary PCI Door-to-Balloon time vs. Mortality Door-to-Balloon Time (minutes)

13. Cannon CP, et al JAMA: June 2000. P=0.01P=0.0007P=0.0003P=NS 1.14 1.15 1.41 1.62 1.61 N=2,230 5,734 6,616 4,461 2,627 5,412 NRMI-2: Primary PCI Door-to-Balloon time vs. Mortality

14. Cannon CP, et al JAMA: June 2000. P=0.02P=0.0005P=0.004P=NS 1.19 1.22 1.44 1.77 1.54 N=22,483 Primary PCI Door-to-Balloon time vs. Mortality Thrombolytic Eligible Patients only

15. Cannon CP, et al JAMA: June 2000. P=0.02P=0.001P=0.005P=NS 1.19 1.22 1.44 1.77 1.54 N=23,484 Primary PCI Door-to-Balloon time vs. Mortality Excluding Patients Transferred-in

16. Cannon CP, et al JAMA: June 2000. Limitations Observational database and Patients not randomized –Caputo showed  D-B time and  mortality No on-site monitoring –But NRMI-2 database validated >95% vs. CCP Most hospitals low-volume centers –Not necessarily indicative of “center of excellence” –Accounting for volume: D-B time assoc. with  mortality –NRMI-2 includes 661 of 1190 (56%) hosp with 1 o PCI

17. Cannon CP, et al JAMA: June 2000. Summary and Conclusions In a cohort over 27,000 Patients at 661 US hospitals, Door to balloon times > 2 hours was –Present in 46 % Patients –Associated with 40-60% increase in adjusted mortality –Association present in pre-specified subgroups MD’s and Healthcare systems should monitor and work to  door-to-balloon time. Door-to-balloon time should be considered when choosing between thrombolysis and Primary PCI

18. Cannon CP, et al JAMA: June 2000. NRMI-2: Hospital Volume of Primary PCI vs. Mortality N=4,740 14,078 8,262 P=0.033 P=0.0001 0.86 0.67