Keeley and Grines article from Lancet of 23 trials – supports primary PCI over thrombolysis
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A recent publication from the Zwolle group in the Netherlands looked at the relationship between ischemic time and 1-year mortality assessed as a continuous function and plotted with a quadratic regression model. The d otted lines represent 95% CIs of predicted mortality. Circulation . 2004;109:1223-1225 About the study: “ The study population consisted of 1791 patients with STEMI treated by primary angioplasty. The relationship between ischemic time and 1-year mortality was assessed as a continuous function and plotted with a quadratic regression model. The Cox proportional hazards regression model was used to calculate relative risks (for each 30 minutes of delay), adjusted for baseline characteristics related to ischemic time. Variables related to time to treatment were age 70 years ( P - 0.0001), female gender ( P - 0.004), presence of diabetes mellitus ( P - 0.002), and previous revascularization ( P - 0.035). Patients with successful reperfusion had a significantly shorter ischemic time ( P - 0.006). A total of 103 patients (5.8%) had died at 1-year follow-up. After adjustment for age, gender, diabetes, and previous revascularization, each 30 minutes of delay was associated with a relative risk for 1-year mortality of 1.075 (95% CI 1.008 to 1.15; P _ 0.041). Conclusions —These results suggest that every minute of delay in primary angioplasty for STEMI affects 1-year mortality, even after adjustment for baseline characteristics. Therefore, all efforts should be made to shorten the total ischemic time, not only for thrombolytic therapy but also for primary angioplasty”. Actual abstract, pg 1123
Prepared By Paul D. Frederick, Ovation Research Group for Genentech, Inc. Reperfusion eligibile patients are defined as STEMI patients (see definition above) who presented at the first hospital with 12 hours (720 minutes) of symptom onset and are not classified as killip class 4.
Implications of the transfer ami trial for clinical practice
Implications of the TRANSFER AMI Trial for Clinical Practice Tim Henry, MD Director of Research Minneapolis Heart Institute Foundation
Clinical Practice in 2010: Standard of Care?• PCI centers should do PCI (in a timely manner <90 min)• Short Distance Transfer Pts should have PCI (in a timely manner <120?)• Long Distance transfer or Pts with expected delay remains an area of controversy!!
Raising the Bar on Reperfusion Speed for STEMI• Door-to-balloon (D2B) time <90 min (Class I-A)• First Medical contact-to-balloon < 90min (Class I-B)• ACC/AHA 2004 STEMI Guidelines JACC 44:671
Primary PCI: Access• 42.0% PCI hospital is closest facility• 79.0% within 60 minute prehospital timeNallamothu et al. Circulation 2006;113:1189
STEMI – Door to Balloon and Door to Needle Times: Cumulative 12 Month Data 100% 81% 80% 60% 57% 40% High performing institutions are engaged in QI Monitoring 18% 20% 0% DTB <= 90 min - DTB <= 90 min - DTN <= 30 min - All Non-Transfer In Transfer In ACTION Registry-GWTG DATA: January 1 – December 31, 2008 DTB = 1st Door to Balloon for Primary PCI DTN = Door to Needle for Lytics
What is the Optimal ReperfusionStrategy for STEMI Patients with expected delays?
Real Life!• 70 year old Lawyer presents to ED 120 miles from a PCI center with acute onset of 9/10 chest pain at 09:15 pm called 911.• Arrived at the community ED at 9:36 EKG obtained at 9:43
Options for Patients with Prolonged Transfer Times1. Full dose fibrinolytic with elective transfer or for rescue2. Full dose fibrinolytic with routine transfer and rescue as needed3. Facilitated PCI4. Primary PCI (no matter how long it takes)5. All of the above: Depending on the time of day and which cardiologist is on call!
Primary PCI vs Lysis for STEMI – Meta-analysis of 23 trials Short Term Events P<0.0001 16 14 14 12 P=0.0003 10 P<0.0001 8 7 PTCA 8 7 p=0.0004 Thrombolytic 6 5 P<0.0001 4 3 1 2 2 1 0.05 0 Death Re MI Total ICH Death + CVA Re-MI + CVAKeeley, Lancet Jan 2003
Cumulative Mortality During the First Year Stenestrand, U. et al. JAMA 2006;296:1749-1756.
Transfer for PCI is better than LYSIS! (In a timely manner)
Relative Risks of Transfer for Primary PCI vs Fibrinolysis
REACT: 6 month Primary composite (Death, MI, CVA, or severe heart failure) •The primary composite endpoint of death, MI, CVA or severe heart failure at 6 months 35 p<0.001 p=0.002 31.0 was significantly lower in the 29.8 rescue PCI group compared 30 with either the repeat 25 thrombolysis group or the conservative management 20 group 15.3% 15 10 5 0 Repeat Rescue PCI Conservative Thrombolysis Management Presented at AHA 2004
Immediate PCI is better thanLYSIS +/- Delayed PCI!
Limitations of ASSENT-4• Full dose Lytic: Focus on bleeding not patency• Inadequate antiplatelet (No IIb/IIIa / delayed clopidogrel)• Inadequate antithrombin (bolus only)• Lower patency than expected• 15% of deaths were CVA• 45% in PCI hospital• < 5% US• Limited transfer delays (excluded long delays)
FINESSE: Study Design Acute ST-elevation MI (or new LBBB) within 6h pain onsetPresenting at Hub or Spoke with estimated time to PCI between 1 and 4 hours Randomize 1:1:1 N=3000 *Only 5U if ≥ 75 Placebo Placebo Reteplase (5U+5U)* Placebo Abciximab Abciximab Transfer To Cath Lab ASA, unfractionated heparin 40U/kg (max 3000 U) or enoxaparin (0.5 mg/kg IV + 0.3 mg/kg SC) – substudy only Abciximab Placebo Placebo Primary PCI with Abciximab Infusion (12 h) Primary endpoint at 90 days: All- cause mortality, resuscitated VF occurring > 48h, cardiogenic shock, or readmission/ED visit for CHF
TIMI Flow in IRA Pre-PCI % Subjects with TIMI 2/3 (Patency) Pre-PCI 120% p<0.0001 100% 80% p<0.0001 61% Percentage 60% TIMI 2 25% 40% 25% 26% 20% 12% 11% 36% TIMI 3 13% 15% 0% Primary PCI (in lab Abciximab Facilitated Reteplase/Abciximab Abciximab) (n=790) PCI (n=809) Facilitated PCI (n=815) Ave Time from First Abciximab Bolus to Angiogram In Facilitated Groups: 74min 76minModified ITT Population with Index PCI: ITT, PCI and any dose of study drug (active or placebo); Investigator assessment
FINESSE• Best trial available• Slow enrollment, therefore underpowered• 40% spoke hospitals with D-B 155 min• Increase bleeding (are all regimens =?)• Signals in Ant MI, High Risk, < 3 hrs
Pharmacoinvasive (Facilitated) PCIis better than Lytic + Rescue PCI
CARESS: Treatment summary ASA 300-500 mg iv ASA 300-500 mg iv 2 xx5 U bolus (30’) Reteplase 2 5 U bolus (30’) Reteplase UFH (40 U/kg (max 3000); 7 U/kg/h) UFH (40 U/kg (max 3000); 7 U/kg/h) Abciximab 0.25 mg/kg bolus Abciximab 0.25 mg/kg bolus 0.125 µg/kg/min xx12 h 0.125 µg/kg/min 12 hFACILITATED PCI MEDICAL TREATMENT/ RESCUE40 U/kg Heparin Bolus (max. 3,000 40 U/kg Heparin Bolus (max. 3,000 40 U/kg Heparin Bolus (max. 3,000 40 U/kg Heparin Bolus (max. 3,000U) + 7 U/Kg/h during transfer U) + 7 U/Kg/h during transfer U) + 7 U/Kg/h for 24 hours U) + 7 U/Kg/h for 24 hoursPCI ACT adjusted to 200-250” and PCI ACT adjusted to 200-250” and In case of Rescue PCI ACT In case of Rescue PCI ACTheparin stopped after procedure heparin stopped after procedure adjusted to 200-250” and heparin adjusted to 200-250” and heparin stopped after procedure stopped after procedureClopidogrel Started in the Cath Lab and Maintained for 1-12Clopidogrel Started in the Cath Lab and Maintained for 1-12 months only after Stenting up to Nov 2005 (514 Pts, 82%) months only after Stenting up to Nov 2005 (514 Pts, 82%)
Primary Outcome at 30 days Death, re-MI, refractory ischaemia 11.1% OR 0.34 (95%CI 0.17-0.68) P=0.001 4.1%
‘High Risk’ ST Elevation MI within 12 hours of symptom onset TNK + ASA + Heparin / Enoxaparin + Clopidogrel Community Hospital “Pharmacoinvasive “Standard Treatment” Strategy” Emergency Urgent Transfer to PCI Centre Assess chest pain, ST↑ resolution Department at 60-90 minutes after randomization Failed Reperfusion* Successful Reperfusion Cath / PCI within 6 Cath and Rescue Elective Cath hrs regardless of PCI ± GP IIb/IIIa ± PCI PCI Centre reperfusion status Inhibitor > 24 hrs later Cath Lab Repatriation of stable patients within 24 hrs of PCIST segment resolution < 50% & persistent chest pain, or hemodynamic instabilityRandomization stratified by age (≤75 vs. > 75) and by enrolling site
Problems with a Rescue Strategy• How do you decide when to go?• Who decides when to go?• Guaranteed delays!!!• And cath lab unhappiness• CARESS and TRANSFER AMI !!!!!
Problems with PCI no matter how long it takes!• Time may be less critical with PCI but TIME STILL MATTERS!• Delays still occur especially with Transfer Pts (<15% treated <2hours)• When your mother (or your lawyer Pt) has a large Anterior STEMI do you want them waiting 3 hours for Reperfusion?
Options for Patients with Prolonged Transfer Times• Full dose fibrinolytic with elective transfer or for rescue• Full dose fibrinolytic with routine transfer and rescue as needed• Primary PCI (no matter how long it takes)• Pharmacoinvasive PCI• All of the above: Depending on the time of day and which cardiologist is on call!
What conclusions can we make!• PCI centers should do PCI (in a timely manner <90 min)• Short Distance Transfer Pts should have PCI (in a timely manner <120?)• Pharmcoinvasive PCI is an excellent choice for Pts with expected delay!!• The ideal regimen and timing of PCI remain unclear!
Facilitated PCI• ACC/AHA guidelines include facilitated PCI as a IIa recommendation• Reduced dose fibrinolytic followed by PCI results in earlier reperfusion• Pharmacoinvasive PCI maybe a better reperfusion strategy to primary PCI when transfer delays are expected
Time from Symptom Onset to Treatment Predicts 1-year Mortality after Primary PCI n=1791The relative risk of 1-year mortality increases by 7.5% for each 30-minute delay De Luca et al, Circulation 2004;109:1223-1225
Door-to-Balloon Time< 90 Minutes by Transfer Status 41% 45 Non-transferPercent of Patients 40 33.1% 35 30 25 20 15 Transfer 10 5 3.9% 5.4% 0 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004R Brindis Year of Discharge Nallamothu et alACC 2005 Circ 111: 761:2005
There Still is a Role for Facilitated PCI!We just need to change the NAME!• Pharmacoinvasive strategy• FAST PCI• ROUTINE RESCUE PCI
“Humanity’s greatest advances are not in its discoveries – but in how those discoveries are applied ...” Bill Gates, June 7, 2007 Harvard Commencement Address
Limitations of Keeley Meta-analysis• 17 trials with tremendous variation: – 9: IIb/IIIa only – 6: lytic only – 2: ½ dose + IIb/IIIa• No trials in Pts with transfer delay• 50% of Lytic data from Assent 4• Relatively low risk pts in PCI hospitals or with short transfer distances
FINESSE Enrollment (2002-2006): Projection vs Actual N=2452 Enrollment Terminated Dec 30, 2006
ST Segment Resolution (>70%) at 60-90 Min: Core Lab % Evaluable Subjects with ST Segment Resolution 100% p=0.003 p=0.010 p=NS 80% p=0.013 p=0.011 64%Percentage 57% 60% 51% 44% 36% 40% 31% 33% 23% 24% 20% 0% All (n=745) Prior to Balloon After Balloon Inflation (n=525) Inflation (n=154) Primary PCI with in lab Abciximab (n=242) Abciximab Facililated PCI (n=257) Reteplase/Abciximab Facilitated PCI (n=246)*Half of subjects randomly selected for Core Lab over-read
Major Secondary EndpointsAll Cause Mortality Complications of MI 8.9% 7.5% 5.5% 7.4% 5.2% 4.5%
Michael Simons, MD, Nathaniel W. Niles, MDTimothy D. Henry, MD,David M. Larson, MD Holger Thiele, MD Gerhard Schuler, MD AMICO: Alliance for Myocardial Infarction Care OptimizationAli. E. Denktas, MD, Haris Athar, MD, Stefano Sdringola, MD,H. Vernon Anderson, MD, Richard W. Smalling, MD, PhD Chul Ahn, PhD Raymond G. McKay, MD
AMICO Registry 30-Day Outcomes FAST-PCI PPCI p = <0.000110.0% 8.90%9.0% p = 0.0028.0%7.0% 6.30%6.0% 5%5.0%4.0% 3.60% p = NS p = 0.00063.0% 1.90%2.0% 1.40% 1.10% 0.80%1.0%0.0% Death Stroke Re-MI Any Event
CAPITAL AMI Trial Primary Composite 30-Day 30-Day Recurrent Reinfarction Unstable Ischemia Endpoint at 30 days p=0.034 25% 20% 17 .9 % 21.4% 15% 11.9 % 10% 20% 4 .7 % 7.0 % 5% 0% 15% TNK TNK TNK TNK +PCI +PCI% 10% 9.3% • Composite event rate remained lower in the TNK+PCI arm at 30 days, again driven by reductions in 5% reinfarction and recurrent unstable ischemia, with no difference in 0% mortality (2.3% vs. 3.6%). • Length of hospital stay shorter in TNK TNK+PCI the TNK+PCI arm (5 vs. 6 days, p=0.009).Presented at ACC Scientific Sessions 2004
What Happened in Real Life• MHI Level 1 MI protocol activated• ASA, Clopidogrel 600mg, IV heparin, IV metoprolol• ½ dose lytic at 10:03 (door to needle time 27 minutes)• Repeat EKG while waiting for helicopter
The Number of Randomized Trials in Patients with Prolonged Transfer Times 0
All Facilitated PCIregimens are not created = !!!!