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© CM Gibson 2006 Cross-sections of left ventricle after experimental coronary artery occlusion Cross-sections of left ventricle after experimental coronary artery occlusion Reimer KA, et al. Circulation. 1977;56: Time Dependence of Reperfusion Therapy: “Wavefront” Phenomenon of Necrosis in Dogs Duration of occlusion 3 h Area supplied by occluded artery x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x XXXX Necrosis Ischemic but viableNonischemic 24 h 40 min
© CM Gibson 2006 Time is Muscle: Delays in Symptom to Door Time are Associated with Poorer Flow in the Muscle Independent of Flow in Artery 16% rise in risk of a closed muscle for every hour of delay in STEMI (p=0.0005) Gibson, JACC 2004 Normal Large Capillary Lumen Clinical Picture: Open Artery Closed Muscle Blistering of Capillaries & Endothelium “Blistered” / Swollen Endothelium / wall of the capillary Normal non-infarcted wall without edema Infarcted wall with edema (white areas) Interstitial Edema EHJ (2004) 25, 794–803
© CM Gibson 2006 GUSTO I GUSTO I Median Time (hrs) Between Symptom Onset and Treatment GUSTO III GUSTO III InTIME II InTIME II ASSENT ASSENT ASSENT II ASSENT II GUSTO V GUSTO V Time from Symptom Onset to Study Treatment in Large Scale Thrombolytic Trials Gibson CM, Circulation 2001;104:
© CM Gibson 2006 Adapted from Tiefenbrunn AJ, Sobel BE. Circulation. 1992;85: Time-Dependent Benefit of Reperfusion Therapy
© CM Gibson 2006 Adapted from Timm TC, et al. Circulation. 1991;84(suppl II):II-230. Mortality Rate (%) P=0.05 TIMI 2: 6-Week Mortality
© CM Gibson 2006 Adapted from Lee KL, et al. Circulation. 1995;91: Importance of Time-to-Treatment: Results of GUSTO-I 2 =149 (1 df ) 30-Day Mortality ( %)
© CM Gibson 2006 Rapid Treatment Is Associated With Decreased Mortality Data source: Boersma E, et al. Lancet. 1996;348: Number of lives saved per 1,000 patients treated with fibrinolytics (based on 35-day mortality) Time from symptom onset to thrombolysis 50,246 pt meta-analysis ,246 pt meta-analysis
© CM Gibson 2006 Adapted from Weaver WD, et al. JAMA. 1993;270: P=0.04 P<0.001 Percent MITI: Mortality, Infarct Size, and Time
© CM Gibson 2006 Berger PB, et al. Circulation. 1999;100: P=0.001 Door-to-Balloon Time (minutes) Importance of Door-to-Balloon Time: 30-Day Mortality in the GUSTO-IIb Cohort Mortality (%) > < PTCA not performed
© CM Gibson 2006 Cannon CP, Gibson CM et al, JAMA 2000
© CM Gibson 2006 Patency and Mode of Reperfusion Time (minutes) 90-minute patency 90-minute patency ED arrival ED arrival Drug administration Drug administration Adapted from Gibson CM. Ann Intern Med. 1999;130:
© CM Gibson 2006 Hypothetical Relationship Between Early Reperfusion, Mortality Reduction, and Extent of Myocardial Salvage Gersh BJ, et al. JAMA. 2005;293: Time From Symptom Onset to Reperfusion Therapy (hours) Mortality Reduction, (%) Mortality Reduction (%) Extent of Salvage (% of area at risk) Critical Time-dependent Period Goal: Myocardial Salvage D-B – Harm A-B – No Benefit Shifts in Potential Outcomes A-C – Benefit B-C – Benefit D-C – Harm 0 Time-independent Period Goal: Open Infarct-related Artery 4 D C B A 81620
© CM Gibson 2006 Door to Balloon Time <60 min (44 min ± 12) n= min (75 min ± 9) n= min (103 min ± 8) n=304 >120min (156 min ± 30) n=403 p-value Onset-to-Door (mins)197 ± ± ± ± 124< Onset-to-Balloon (mins) 235 ± ± ± ± 126< Death 30-days0.6%0.7%4.7%2.5% MACE 30-days1.6%2.4%7.6%5.5% Infarct Size (% LV) 14.2 ± ± ± ± Does a 90-Minute Door-to-Balloon Time Matter? Observations From Four Current Reperfusion Trials EMERALD, COOL MI, AMIHOT, ICE-IT O’Neill, et al. JACC,2005:Suppl A:45:225A.
© CM Gibson 2006 Time from Symptom Onset to Treatment Predicts 1-year Mortality after Primary PCI De Luca et al, Circulation 2004 The relative risk of 1-year mortality increases by 7.5% for each 30-minute delay n=1791
© CM Gibson 2006 Time from Symptom Onset to Treatment Predicts One-year Mortality p = <2 hrs 2-4 hrs 4-6 hrs p = 0.02 De Luca at al, JACC 2003 >6 hrs All Patients Low-Risk p = NS High-Risk
© CM Gibson 2006 Time from Symptom Onset to Treatment Predicts One-year Mortality Among Patients with Occluded Epicardial Arteries p = <2 hrs 2-4 hrs 4-6 hrs p = NS De Luca at al, JACC 2003 >6 hrs Pre-PCI TIMI 2/3 Flow Pre-PCI TIMI 0/1 Flow
© CM Gibson 2006 Predictors of Door-to-Balloon Delay in Primary Angioplasty Mean Door-to-balloon time (hours) Time of hospital arrival (24 hour clock) n=40,017 Angeja BG, et al. Am J Cardiol 2002;89: )
© CM Gibson 2006 What is Primary Angioplasty ? Primary Angioplasty: Door to balloon time <1 hour Secondary Angioplasty: Door to balloon time hours Tertiary Angioplasty: Door to balloon time hours Post MI Care: Door to balloon time hours Elective Case: > 4 hours Primary Angioplasty: Door to balloon time <1 hour Secondary Angioplasty: Door to balloon time hours Tertiary Angioplasty: Door to balloon time hours Post MI Care: Door to balloon time hours Elective Case: > 4 hours CM Gibson 2006
© CM Gibson 2006 PCI-Related Time Delay vs Mortality Benefit in 22 Randomized Studies of PCI vs Fibrinolytic Therapy Nallamothu and Bates, AJC RCTs For every 10 min delay to PCI: 1 % reduction in Mortality Difference Between PCI & Lysis N= 7419 p=0.006 DANAMI: on site PCI 90 DB – 50 DN = 40 min delay DANAMI: with transfer 110 DB – 50 DN = 60 min delay “USA AMI” with transfer: 171 DB – 32 DN = 139 min delay DANAMI: on site PCI 90 DB – 50 DN = 40 min delay DANAMI: with transfer 110 DB – 50 DN = 60 min delay “USA AMI” with transfer: 171 DB – 32 DN = 139 min delay
© CM Gibson 2006 NRMI 2,3,4 452,544 Reperfusion Eligible STEMI Patients 1,963 Hospitals Transfer Out Patients n=119,235 Missing Time Intervals n=13,137 Did Not Receive PCI or Fibrinolytic Therapy as Initial Reperfusion n=89,524 Study Population 192,509 Patients 645 Hospitals 230,648 Patients 1,860 Hospitals ≥20 STEMI Patients Treated Treatment of ≥10 patients with Primary PCI and ≥10 patients with Fibrinolytic Therapy Pinto DS … Gibson CM, Circulation 2006
© CM Gibson 2006 Mortality Increases with Increasing PCI Related Delay PCI Related Delay (DB-DN) (min) In Hospital Mortality (%) For every 30 minute delay, mortality increases 10% Pinto DS … Gibson CM, Circulation 2006
© CM Gibson 2006 Odds of Death with Fibrinolysis PCI Related Delay (DB-DN) (min) PCI Better Fibrinolysis Better The Advantage of PCI Compared with Fibrinolyisis Decreases as the PCI Related Delay Increases Pinto DS … Gibson CM, Circulation 2006
Odds of Death with Fibrinolysis PCI Related Delay (DB-DN) (min) PCI Better Fibrinolysis Better Pinto DS … Gibson CM. Circulation. 2006*Betriu A. Am J Cardiol. 2005; 95: Randomized Studies*
© CM Gibson 2006 Prehospital Delay & Timing of Reperfusion Strategy Equivalence Prehospital Delay (min) 19,517 5,296 9,812 41,774 16,119 20,424 10,614 PCI Related Delay (DB-DN) Where PCI and Fibrinolytic Mortality Are Equal (Min) 3,739 Pinto DS … Gibson CM, Circulation 2006
© CM Gibson 2006 Pre- hospital Delay (Min) Age <65 years & Anterior Infarction (n=patients, n=hospitals) Age <65 years & Non-anterior Infarction (n=patients, n=hospitals) Age ≥65 years & Anterior Infarction (n=patients, n=hospitals) Age ≥65 years & Non-anterior Infarction (n=patients, n=hospitals) min Met goal without transfer: 2.6% Met goal with transfer: 3.6% (n=19,517 pts; n=269 hospitals) 56 min Met goal without transfer: 20.2% Met goal with transfer: 17.3% (n=41,774 pts; n=385 hospitals) 109 min Met goal without transfer: 94.1% Met goal with transfer: 92.8% (n=9,812 pts; n=180 hospitals) 154 min Met goal without transfer: 99.8% Met goal with transfer: 100.0% ( n=20,424 pts; n=271 hospitals) min Met goal without transfer: 7.9% Met goal with transfer: 11.9% (n=5,296 pts; n=117 hospitals) 103 min Met goal without transfer: 89.1% Met goal with transfer: 82.2% (n=16,119 pts; n=244 hospitals) 142 min Met goal without transfer: 98.1% Met goal with transfer: 97.1% (n=3,739 pts; n=91 hospitals) 183 min Met goal without transfer: 100.0% Met goal with transfer: 100.0% (n=10,614 pts; n=191 hospitals) Time At Which PCI Looses Superiority In Survival Over Fibrinolysis Varies Depending Upon Patient Risk Pinto DS … Gibson CM, Circulation 2006
© CM Gibson 2006 Time of Onset ED Time Point 1: DOOR ED Time Point 2: DATA ED Time Point 3: DECISION ED Time Point 4: DRUG Time Interval III Decision to drug Time Interval II ECG to decision to treat Time Interval I Door to ECG NHAAP Recommendations. U.S. Department of Health NIH Publication: 1997: The Four Ds
© CM Gibson 2006 Minutes (Median) NRMI 1 NRMI 2 NRMI 3 NRMI 4 NRMI Non-Transfer-In Patients NRMI Transfer-In Patients Door to Balloon Times By Transfer Status, Primary PTCA Patients : DANAMI Transfer 90: DANAMI On Site
© CM Gibson 2006 Percent of Patients NRMI 1 NRMI 2 NRMI 3 NRMI 4 Non-Transfer-In Patients Transfer-In Patients Door to Balloon Times <90 Minutes By Transfer Status, Primary PTCA Patients
© CM Gibson 2006 Percent of Patients NRMI 1 NRMI 2 NRMI 3 NRMI 4 All Patients Door to Balloon Times <90 Minutes 34.5 % 29.4 %
© CM Gibson 2006 National Trends in AMI Management: Door to Drug Time with Thrombolysis NRMI 1 NRMI 2 NRMI 3 (Activase only) (All lytics) (All lytics) NRMI 1: Includes patients where initial ECG was the method of MI diagnosis NRMI 2 and 3: Includes patients with ST on 1st 12-lead ECG results, where 1st 12-lead ECG date/time = 1st 12-lead ECG with ST and/or BBB date/time Non-transfer-in patients 75th percentile, 52 25th percentile, 22
© CM Gibson 2006 National Trends in AMI Management: Door to Balloon Time in PPTCA NRMI 2 NRMI Includes patients with ST on 1st 12-lead ECG results, where 1st 12-lead ECG date/time = 1st 12-lead ECG with ST and/or BBB date/time (non-transfer-in patients)
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Multiplication X 1 1 x 1 = 1 2 x 1 = 2 3 x 1 = 3 4 x 1 = 4 5 x 1 = 5 6 x 1 = 6 7 x 1 = 7 8 x 1 = 8 9 x 1 = 9 10 x 1 = x 1 = x 1 = 12 X 2 1.
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