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					Impact of Treatment Delays on Outcomes
     After Primary PCI for AMI:
        Implications for Patient Triage

              Bruce R Brodie, MD
   LeBauer Cardiovascular Research Foundation
     Moses Cone Heart and Vascular Center
                Greensboro, NC

       Dartmouth-Hitchcock Medical Center
                 Lebanon, NH
                 April 29, 2004
The New York Times, November 16, 1988
The New York Times April 17, 2002
    Short-term Clinical Outcomes:
Primary PCI vs Thrombolytic Therapy
     Summary of 23 Randomized Trials
                   (n=7739)

          PCI                        p<0.0001
                                     OR=0.57
          Lytic
      p=0.0003    p<0.0001



                              p=0.0004




                                                Keeley Lancet 2003
Traditional Paradigm for the Mechanism of
 Benefit of Reperfusion Therapy for AMI:

 Ÿ Early restoration of normal blood flow to
   the myocardium will result in myocardial
   salvage and better short and long-term
   survival
Time to Treatment and Mortality with tPA
                                                                     NRMI-2
  Adjusted Odds Ratio of In-hospital Death

                                             2


                                                            (n=71,253)




                                             1




                                                 <1   1-2      2-3       3-4   4-5   5-6     6-8     8-12
                                                              Time to Treatment (hrs)
                                                                                        Goldberg RJ AJC 1998;82:259
Time to Reperfusion and 30 Day Mortality
                       Moses Cone Primary PCI Registry
                                                    9.3%         9.5%
                                         9.0%
  30 Day Mortality %




                                                                            (n=1,352)
                            4.3%




                             <2          2-4         4-6          >6
                           (n=164)     (n=581)     (n=332)      (n=275)
                                     Time to Reperfusion (hr)
                                                                          Brodie JACC 1998
Time to Reperfusion and Late Cardiac Survival
                  Moses Cone Primary PCI Registry
      Cardiac Survival %




                                               £2 hrs
                                               >2-4 hrs
                                               >6 hrs
                                               >4-6 hrs




                               Years
                                                Brodie JACC 1998
Time to Reperfusion and Late Cardiac Mortality
      Moses Cone Primary PCI Registry
 Adjusted Hazard Ratio
                         Late Cardiac Mortality




                                                                          1.80
                                                              1.49                        1.53




                                                  <2       2-4          4-6            >6

                                                       Time to Reperfusion (hrs)
                                                                                   Brodie JACC 1998 (updated)
                       Time to Reperfusion and One Year
                                  Mortality
                             CADILLAC Trial (n=2002)                            4.8
                                                                      4.4
                                                         4.2
                                 p=0.04
One Year Mortality %




                           (<3 hrs vs >3 hrs)

                            2.6              2.6




                            <2               2-3         3-4          4-6       6-12
                          (n=121)          (n=438)     (n=455)    (n=475)      (n=513)

                                          Time to Reperfusion (hrs)
                                                                            Brodie JAAC 2003
Time to Reperfusion and One Year Survival
                CADILLAC Trial

                                  (n=2,002)




         p=0.14 (overall)
         p=0.04 (<3 vs. >3 hrs)




                                          Brodie JACC 2003
Door-to-Balloon Time and In-Hospital Mortality
                                           NRMI-2 Registry
                        2.2
                         2
  Adjusted Odds Ratio




                                                                                (n=27,080)
                        1.8
                        1.6                                     1.62     1.61

                        1.4                             1.41
                        1.2                      1.15
                                         1.14
                         1
                        0.8
                        0.6
                              <1.0   1.0-1.5 1.5-2.0 2.0-2.5 2.5-3.0   >3.0
                                     Door-to-Balloon Time (hrs)
                                                                   Cannon JAMA 2000;283:2941
Door-to-Balloon Time and Late Cardiac Survival
                      Moses Cone Primary PCI Registry
 Cardiac Survival %




                                             p<0.0001

                                                        <1.5 hrs
                                                        >1.5-2.0 hrs
                                                        >2.0-3.0 hrs
                                                        >3.0 hrs
                        (n=1959)




                                   Years
                                                        Brodie ACC 2004
Door-to-Balloon Time and Late Cardiac Mortality
                                Moses Cone Primary PCI Registry

                          2.5
                                                                     (n=1959)
 Late Cardiac Mortality
 Adjusted Hazard Ratio




                           2

                          1.5                                                   1.51
                                                              1.41
                                                 1.17
                           1

                          0.5

                           0
                                   <1.5      1.5-2.0     >2.0-3.0          >3.0
                                          Door-to-Balloon Time (hrs)
                                                                            Brodie ACC 2004
Door-to-Balloon Time and Late Mortality
 In Patients with Early Presentation (< 2 hrs)
      Moses Cone Primary PCI Registry




                                       Brodie ACC 2004
Door-to-Balloon Time and Late Cardiac Mortality
                    In Patients with Early Presentation (< 2 hrs)
                        Moses Cone Primary PCI Registry
Late Cardiac Mortality
Adjusted Hazard Ratio




                                                       1.58       1.65

                                           1.29




                            <1.5      1.5-2         >2-3        >3
                                   Door-to-Balloon Time (hrs)
                                                                Brodie ACC 2004
Door-to-Balloon Time and Late Mortality
  In Patients with Late Presentation (> 2 hrs)
       Moses Cone Primary PCI Registry




                                        Brodie ACC 2004
Door-to-Balloon Time and Late Cardiac Mortality
                         In Patients with Late Presentation (> 2 hrs)
                             Moses Cone Primary PCI Registry
Late Cardiac Mortality
Adjusted Hazard Ratio




                                                                      1.28
                                                1.03        1.09




                                 <1.5       1.5-2       >2-3         >3

                                        Door-to-Balloon Time (hrs)
                                                                     Brodie ACC 2004
Door-to-Balloon Time and One Year Mortality
      Stratified by Time to Presentation
                         CADILLAC Trial

                                5.1%           p=NS
     p=0.12
                                        4.8%

                  3.9%
                                               DB Time < 1.5 hrs
                                               DB Time > 1.5 hrs
        1.9%




              <2 hrs              >2 hrs
                 Time To Presentation
                                                      Brodie ACC 2003
Importance of Time to Reperfusion:

        High Risk Patients
               vs.
        Low Risk Patients
Time to Reperfusion and 6 Month Mortality
      In Low and High Risk Patients
               Florence, Italy Group
                               12.9%
                                            11.5%
                                                    High Risk

                   7.9%
                    High Risk:
                       Age > 70 yrs
        4.8%           Anterior MI
                       HR > 100 bpm
         1.6%        1.3%       1.3%
                                             0%     Low Risk

         <2          2-4        4-6          >6
                Time to Reperfusion (hrs)
                                            Antoniucci AJC 2002;89:1248
Time to Reperfusion and In-hospital Mortality
      In Shock and Non-shock Patients
       Moses Cone Primary PCI Registry

                                         62%

                          50%            Shock (n=138)


            31%


                                   Non-shock (n=1705)
            5.8%            4.6%          4.8%

             <3            3-<6           >6

                   Time to Reperfusion
                                               Brodie AHJ 2003;145:708
Time to Reperfusion and One Year Mortality
       in Low and High Risk Patients
                               CADILLAC Trial
                                                                        p=0.09
                                                              7.0%
                       Reperfusion Time < 3 hrs
One Year Mortality %




                       Reperfusion Time > 3 hrs
                               High Risk:
                                     Age > 70 yrs
                                                       4.1%
                                     Killip Class 2 - 3
                           p=0.77    Anterior MI

                                1.7%
                        1.1%



                          Low Risk                     High Risk
                                                                     Brodie ACC 2003
Importance of Time to Reperfusion

     Ÿ Reinfarction
     Ÿ Microvascular Reperfusion
     Ÿ Myocardial Salvage
                      Time to Reperfusion and Re-infarction
                            CADILLAC                            Stent PAMI
                            (One Year)                          (6 Months)

                                                                     4.2%
                                                                                   p=0.03
                                        3.3%
    Re-infarction %




                                                                            3.0%
                                 2.6%          p=0.003


                          1.5%                                1.4%


                                                         0%
                           <3     3-6   >6               <2    2-4   4-6    >6
                                    Time to Reperfusion (hrs)

Brodie AJC 2001;88:1085                                                     Brodie ACC 2003
          Time to Reperfusion and
Myocardial Blush and ST-Segment Resolution
                      CADILLAC Trial
                 Grade 2-3               Complete (>70%)
               Myocardial Blush        ST-Segment Resolution
                                             68%
                                       64%            p=0.0002
 Frequency %




                             p=0.007
                55%
                      53%

                                                   47%
                             44%




                 <3    3-6    >6       <3    3-6   >6
                                                   Brodie ACC 2004
                                 Myocardial Salvage by
                         Time to Reperfusion with Primary PCI
    Myocardial Salvage Index %




                                        Time to Reperfusion
O’keefe J Nucl Cardiol 1995;2:35
                         Recovery of LV Function by Time to
                           Reperfusion with Primary PCI
                             Moses Cone Primary PCI Registry
                            59.5%
                                                                (n=606)
LV Ejection Fraction %




                             6.9             55.7%    55.8%
                                    54.8%
                                     2.5      3.7         3.9



                            52.6    52.3     52.0     51.8




                             <2      2-4      4-6     >6
                              Time to Reperfusion (hrs)
                                                                  Brodie JACC 1998;32:1312
Improvement in LV Ejection Fraction
      by Time to Reperfusion
                               CADILLAC Trial
                             4.8%
Improvement LVEF % (7 mos)




                                                                p=0.03

                                              2.5%




                                                                -0.2%



                             <3                3-6                >6
                                    Time to Reperfusion (hrs)
                                                                         Brodie ACC 2003
Why is the Impact of Time to
 Treatment Different with
  Primary PCI than with
 Thrombolytic Therapy?
  Effect of Time to Treatment on Reperfusion
       Rates with Thrombolytic Therapy
           TIMI Flow (2-3 or 3 %)




                                                  63%                         62%
                                                     54%
                                                       50% 47%
                                     45%
                                                                                   40%
                                                              35%
                                        27%
                                           17%


                                     2-4 4-6 >6hrs <2 2-4 4-6hrs £6 >6hrs      £6 >6hrs
                                        SK          tPA      tPA               rPA
                                      TIMI 1      GUSTO-1 RAPID-2            RAPID-2
                                    (TIMI 2-3)    (TIMI 3) (TIMI 3)          (TIMI 3)
Chesebro JH Circulation 1987;76:142              Genetech GUSTO Database    Bode C Circulation 1996;94:891
   Effect of Time to Treatment on
Reperfusion Rates with Primary PTCA
                                                   96 95 96
                   90 93 92 92      91 92 89 92
   TIMI 3 Flow %




                   <2 2-4 4-6 >6   <2 2-4 4-6 >6   <3 3-6 >6
                   Moses Cone      STENT PAMI CADILLAC
Time to Treatment with Fibrinolytic Therapy
   and Risk of Cardiac Rupture (GISSI)
      Mortality from Cardiac Rupture %
                                                                         2.0%



                                                         1.3%
                                                  1.2%

                                         0.7%




                                         0-3      3-6       6-9           9-12
                                                Time to Treatment
                                                                    Mauri F G lta Cardiol 1987;17:37
Expanded Paradigm for the Mechanism of Benefit of
     Reperfusion Therapy with Primary PCI:

 Ÿ Early reperfusion (< 2-3 hrs) will improve survival
   by enhancing myocardial salvage. This is a very
   time dependent process.

 Ÿ Later reperfusion (> 2-3 hrs) improves survival
   through the benefits of an open infarct artery (by
   preventing remodeling and promoting electrical
   stability) rather than myocardial salvage. This
   process is not very time dependent.
What are the clinical implications for
triage of patients for Primary PCI?
Moses Cone Heart and Vascular Center
Greensboro, NC
                           Eden
                           Morehead Hospital

                      34 miles          Reidsville
                                     Annie Penn Hospital

                                  23 miles
              Greensboro                      Burlington
                                             Alamance Hospital
                Moses Cone            18 miles
                Hospital         Wesley Long
                                  Hospital


                             30 miles
                                         Asheboro
                                          Randolph Hospital
Treatment Delays in Transferred vs Non-transferred Patients
           Moses Cone Primary PCI Registry

                  Symptoms to ED Door-to-Balloon   Reperfusion Time

                       1.8             1.9
Non-Transferred
(n=1161)                                             3.7 hrs



                       1.6               2.8
Transferred
(n=680)                                                      4.4 hrs


          Additional Treatment Delay
                                             54 minutes
            in Transferred Patients
                                                          Brodie AJC 2002
Outcomes in Transferred vs Non-Transferred Patients
          Moses Cone Primary PCI Registry




                                            Brodie AJC 2002
  Multivariate Predictors of 30 Day Mortality
                Moses Cone Primary PCI Registry

Cardiogenic Shock                                                  13.9
                                             7.3
TIMI Flow £ 2
                                2.7
Age > 70 yrs
                            2.1
Diabetes
                           1.9
Anterior MI
                          1.7
3 Vessel CAD
                     1.3
Women
                     1.2                Transferred vs Non-transferred
Prior CABG
                    0.9                 OR = 0.90 95% CI 0.59 – 1.36
Prior MI
                    0.9
Transferred

                           Adjusted Odds Ratio 30 Day Mortality
                                       (95% CI)
                                                               Brodie AJC 2002
Late Survival in Transferred vs Non-transferred Patients
           Moses Cone Primary PCI Registry

                                           Non-transferred
                                              (n=1,161)
      Cardiac Survival %




                                   Transferred
                                    (n=680)



                                                  p=0.47




  Late clinical follow-up in 98%
  Mean follow-up time 6.1 yrs      Years
                                                             Brodie AJC 2002
             Denmark




DANAMI - 2




                  Anderson NEJM 2003
DANAMI-2: Median Treatment Times (min)

tPA
(Local)             108                60       168 minutes
                Pre-hospital    Door-needle




 PCI
(Transported)      103            50           34       42    229 minutes
                Pre-hospital    In-door             Door-Balloon
                                Out-door
                                            Transport

                               61 minute treatment delay
              DANAMI-2: 30 Day Outcomes
Local tPA vs Transport for Primary PCI
                                     (n=1129)


                 tPA                                       14.2
                                                                    p=0.002
                 PCI (55 minute treatment delay)
Incidence %




                 8.5                                              8.5
                       6.5     6.2     p<0.001



                                     1.9         2.0 1.6


                 Death       Re-infarction        CVA      MACE

                                                            Anderson NEJM 2003
PRAGUE-2
Time intervals from pain onset to reperfusion


                                  185 minutes




                                  277 minutes




                        92 minute treatment delay
        Outcomes in AMI Treated with
Local Lytic Therapy vs Transfer for Primary PCI
                                   PRAGUE 2
                                                             15.2%

                      p=0.12                                           p=0.003
  30 Day Events




                  10.0%
                                                                   8.4%
                      6.8%
                                    p=0.15

                                                 p=0.03
                                 3.1%
                                               2.0%
                                     1.4%
                                                   0.2%

                   Death       Re-infarction    Stroke       Composite
                                                      Widimsky Eur Heart J 2003;24:94
Mortality Benefit of Primary PCI vs
 Lytics by Time to Presentation
                          PRAGUE 2
 30 Day Mortality




                                       15.3%




                    7.4% 7.3%
                                                 6.0%




                     <3 hrs               3-12 hrs
                        Time to Presentation
                                               Widimsky Eur Heart J 2003;24:94
              Facilitated PCI


Ÿ Pharmacologic therapy (low dose thrombolytic
  therapy plus GP IIb/IIIa platelet inhibitors)
  given ASAP after the dx of AMI

Ÿ Emergent transfer to interventional facilities for
  coronary intervention (facilitated PCI)
   Benefit of an Open Artery on Arrival
              at the Cath Lab
                     Closed Artery  Open Artery    p value
                     TIMI 0-1       TIMI 2-3
                     (n=1,214)      (n=272)
_________________________________________________________
Procedural Outcomes
  Procedural Success 94%            97%              .02
  Adverse Events     13.1%          5.0%             <.001
Hospital Outcomes
  30 Day Mortality   8.9%           4.8%             .02
  Peak CK(U/L)       2,790          1,328            <.001
LV Function
  Acute EF           51.6%          54.3%            .05
  6 Month EF         54.9%          59.2%            .004
                                            Brodie AJC 2000; 25:13
       Late Survival in Patients with
Open vs Closed Artery on Arrival to Cath Lab


                                TIMI 2-3
 Survival %




                        TIMI 0-1


              p=0.009




                        Years
                                           Brodie AJC 2000;25:13
TIMI-3 Flow Before Mechanical Reperfusion
     Therapy for AMI Is an Independent
         Determinant of Survival
              PAMI Trials




                       Gregg W. Stone Circulation 2001;104:636
Risk of Bleeding with Combination Therapy

GUSTO V        rPA    ½ rPA + Ab    p value
ICH
     <75 yrs   0.5%     0.4%        NS
     >75 yrs   1.1%     2.1%        0.07
Major Bleed    0.5%     1.1%       <0.001


ASSENT-3    TNK ½ TNK+ Ab TNK+LMWH p value
ICH          0.9%   0.9%      0.9%    NS
Major Bleed 2.2%    4.3%     3.0%   0.0005
 Facilitated INtervention
with Enhanced Reperfusion
   Speed to Stop Events
       Cleveland Clinic
             Lilly
          Centocor


                     The FINESSE Trial
        CAPTIM Protocol
                STEMI <6 hrs
                 STE >2mm
             Thrombolytic Eligible
               (No Shock, CABG)
                         Randomize (n=840)


      UFH + ASA             Lytic Therapy           Home
       Transfer              UFH + ASA                or
                              Transfer             Workplace
             Ambulance Transfer


     Primary PCI            Facilitated PCI
                             (if indicated)

Primary Endpoint: Death, MI, Stroke at 30 days
                                     Steg Circulation 2003;108:2851
Mortality with Pre-hospital Lysis vs Primary PCI
     According to Time to Randomization
                      CAPTIM Trial

                        30 Day Mortality (Randomized <2 hrs):
    Mortality %




                           Pre-hospital Lysis   Randomized
                                                  2.2%
                           Primary PCI            5.7%
                                                   <2 hrs
                                        p=0.053


                        30 Day Mortality (Randomized >2 hrs):
    Mortality %




                            Shock
Development of CardiogenicPre-hospital Lysis         5.9%
in patients randomized <2 hrs:
                                                 Randomized
                           Primary PCI               3.7%
   Pre-hospital Lysis                                 >2 hrs
                           1.3% Significant interaction between
                                         p=0.34
   Primary PCI             5.3% delay and treatment effect
              p=0.032                        p=0.045
                         Days              Steg Circulation 2003;108:2851
 Moses Cone Heart and Vascular Center
Guidelines for Treatment of Patients with
 AMI Presenting at Outlying Hospitals
Ÿ All patients receive mechanical reperfusion
  as part of the reperfusion strategy
Ÿ All patients receive ASA, UFH (70 u/kg),
  and clopidogrel 300 mg
Ÿ In patients presenting early (<2 hrs) if the
  bleeding risk is not high, give ½ dose lytic
  and IIb/IIIa and transfer for facilitated PCI
Ÿ In patients presenting later (>2 hrs), give
  IIb/IIIa and transfer for primary PCI

				
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