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Time Is Myocardium and the Wavefront of Necrosis

Time Is Myocardium and the Wavefront of Necrosis. CM Gibson 2002. The DANAMI-2 Trial. Danish Trial in Acute Myocardial Infarction-2 Presented at the American College of Cardiology 51st Annual Scientific Session Atlanta, GA Dr. Henning Rud Andersen for the DANAMI-2 investigators.

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Time Is Myocardium and the Wavefront of Necrosis

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  1. Time Is Myocardium and the Wavefront of Necrosis CM Gibson 2002

  2. The DANAMI-2 Trial Danish Trial in Acute Myocardial Infarction-2 Presented at theAmerican College of Cardiology 51st Annual Scientific Session Atlanta, GA Dr. Henning Rud Andersen for the DANAMI-2 investigators

  3. DANAMI-2: Study Design High-risk ST elevation MI patients (>4 mm elevation), Sx < 12 hrs 5 PCI centers (n=443) and 22 referring hospitals (n=1,129), transfer in < 3 hrs Primary PCI without transfer (n=223) Primary PCI with transfer (n=567) Lytic therapy Front-loaded tPA 100 mg (n=782) Death / MI / Stroke at 30 Days Stopped early by safety and efficacy committee

  4. DANAMI-2: Centers

  5. DANAMI-2: Primary Results Non-Transfer Sites Transfer Sites Combined P=0.048 P=0.0003 P=0.002 RRR 40% RRR 45% RRR 45% Death / MI / Stroke (%) Lytic Primary PCI Lytic Primary PCI Primary PCI Lytic

  6. Trials Comparing Primary PTCA With Fibrinolytic Therapy: GUSTO-IIb Cohort Composite Outcome (%) P=0.033 P=NS GUSTO-IIb Angioplasty Substudy Investigators. N Engl J Med. 1997;336:1621-1628.

  7. DANAMI-2: Results Stroke Death Recurrent MI P=0.15 P<0.0001 P=0.35 Lytic Primary PCI Lytic Primary PCI Primary PCI Lytic

  8. DANAMI-2: Commentary on Low Rate of Rescue/Adjunctive PCI • The benefit in the primary composite endpoint result is driven predominantly by a lower rate of recurrent MI among patients treated with fibrinolysis compared with primary PCI • Rescue PTCA for failed fibrinolysis was carried out infrequently in DANAMI 2, in only 2.5% of cases. • The trial confirms what has been observed in the past: fibrinolytic monotherapy when administered with unfractionated heparin is associated with a significant rate of recurrent myocardial infarction if not accompanied by either rescue, facilitated or delayed PCI. • It could be speculated that the incidence of recurrent MI may be reduced with a more aggressive strategy of performing rescue or adjunctive PCI soon after fibrinolytic administration. Gibson CM, 2002

  9. DANAMI-2: Commentary on Biases Inherent in the Assessment of the Recurrent MI Endpoint Among patients treated with fibrinolysis: Recurrent MI may be secondary to reocclusion of a patent infarct vessel following thrombolysis or may occur following delayed PCI after thrombolytic administration Among patients treated with primary PCI: Recurrent MI may be secondary to stent thrombosis or late vessel occlusion several days following the procedure Because of the inability to detect recurrent MI during the index primary PCI (unlike during the performance of a later delayed PCI), this limits the number of post PCI CK MIs detected in this strategy Gibson CM, 2002

  10. DANAMI-2: Commentary on Low Rate of Rescue/Adjunctive PCI • Thus, the detection of post PCI CK elevations may be limited to only those patients enrolled in the fibrinolytic arm of the study • Determination of the timing of the recurrent MI is critical: did the recurrent MI occur before or after the PCI • Lower rates of GP 2b3a inhibitor use may be associated with higher rates of post PCI CK elevations, and it is critical to understand the proportion of patients treated with adjunctive GP 2b3a inhibition during elective or late PCI Gibson CM, 2002

  11. Thrombus Remains Following Thrombolysis Van Belle et al. Circulation. 1998;97:26-33.

  12. Clinical Impact of Reocclusion: Data from the TAMI trials: • 810 patients, cath 90 min & 7 days later: • 12.4% reocclude • 58% symptomatic • In-hospital mortality 11.0% vs 4.5% (P=0.01). Ohman et al. Circulation. 1990;82:781-791.

  13. Recent Efforts to Reduce Reocclusion / Reinfarction • In order to reduce the risk of reocclusion, several strategies have been employed in recent thrombolytic trials • Mechanical • Adjunctive / Rescue / and delayed PCI • Pharmacologic • GP 2b3a inhibition • Treatment with the antithrombotic agent enoxaparin CM Gibson 2002

  14. 1.00 0.75 0.50 0.25 0.00 0 .5 1 1.5 2 2 Year Survival Following Rescue PCI Rescue PCI Survival was Improved in patients with 90 minute TIMI Grade 0/1 Flow after TNK who underwent rescue PCI in the TIMI 10B trial Log rank p=0.006 No PCI Survival Years CM Gibson, AHA 2001

  15. DANAMI 2: Commentary on Low Rate of Rescue / Adjunctive PCI Use • In recent large scale thrombolytic trials in which rescue / adjunctive PCI has been performed more aggressively, lower rates of recurrent MI have been observed • In the setting of ST segment elevation MI treated with thrombolytic monotherapy, the administration of enoxaparin has been associated with a reduced rate of reinfarction when compared to unfractionated heparin. • Would the use of Rescue / Adjunctive PCI and enoxaparin have been associated with a lower rate of reinfarction in the DANAMI 2 study? Gibson CM, 2002

  16. Rate of Rescue / Adjunctive PCI Use in DANAMI 2 Compared with Other Recent Trials % Recurrent MI tPA + Hep rPA + Hep TNK + Hep TNK + Abx TNK + Enox rPA + Abx TNK + Enox 11.9% 9.1% 5.6% 2.5% 8.6% 14.4% Urgent PCI 44.4%* Non-Urgent PCI 17.4% 19.4% 16.5% CM Gibson 2002 * Urgent & non-urgent combined

  17. ENTIRE TIMI 23: 30 Day Death/MI 11.3 P=0.01 4.9 FULL Dose TNK HALF Dose TNK + Abx P=0.002 15.9 P=0.005 159 324 % Pts 6.5 5.5 4.4 MI P=0.003 Death N = 82 160 77 164

  18. ENTIRE TIMI 23: Recurrent MI In Patients NOT Undergoing PCI (N=259) FULL Dose TNK HALF Dose TNK + Abx 180 79 % Pts 38 77 N= 103 41

  19. DANAMI-2 Commentary on Door to Balloon Times • In DANAMI 2, door-to-balloon times were approximately 114 minutes for those patients transferred to another facility • Based upon the data presented by Cannon et al, a door-to-balloon time of 114 minutes was not associated with a significant increase in mortality in the NRMI 2 database when compared to a door-to-balloon time of < one hour • If transfer for primary PCI is elected, then door to balloon times should be similar to those observed in DANAMI 2 • In NRMI 4, the current median door to balloon time among patients transferred to another facility in the US for primary PCI is much longer at 198 minutes Gibson CM, 2002

  20. DANAMI 2: Door to Balloon Times Community Hospital Thrombolysis (n=782) PCI, non-transported patients (n=223) PCI, transported patients (n=567)

  21. Cannon CP et al, JAMA 2000

  22. NRMI-2: Primary PCI Door-to-Balloon time vs. Mortality N=27,080 P < 0.00001 Door-to-Balloon Time (minutes)

  23. Door to Balloon Times Among Patients Transferred in NRMI 4 Data to Cath Lab Arrival: 50th: 137 Min. 25th: 87 Min. 75th: 220 Min. Cath Lab to Balloon: 50th: 39 Min. 25th: 29 Min 75th: 53 Min. Door to Data: 50th: 8 Min. 25th: 4 Min. 75th: 16 Min. 8 137 39 Total Door to Balloon Time: 198 minutes (25th: 137; 75th: 281) Percent of Patients with Door to Balloon Time < 90 Min.: 4.8% Sample Size: 1,292; Time Period: October 2000 – September 2001 NRMI 4 Transfer-In Annual Data Report 2002 Gibson CM, 2002

  24. Importance of Operator Experience and Volume in Primary PCI Outcomes • A significant proportion of the DANAMI operators had little prior experience with primary PCI. • Is operator and hospital volume associated with PCI outcomes in larger series? Gibson CM, 2002

  25. NRMI 2-3: Primary PCI vs. Thrombolysis: 1996-2000N=62,000 Patients In-hospital Mortality Volume % Hosp Tlysis Prim PCI P value < 16 /yr 25% 5.9 6.2 NS 17-48/yr 50% 5.9 4.5 <0.001 >48/yr 25% 5.4 3.4 <0.001 Non-fatal stroke 1.1 0.4 <0.001 Magid et al. JAMA 2000

  26. NRMI-2: Primary PCI Institutional Volume vs. Mortality N=27,080 P < 0.00001 Institutional Monthly Volume of Primary Angioplasty Cases

  27. Primary PCI: Door-to-Balloon time vs. Mortality Stratified by Institutional Volume <1 / month N=4,740 P = 0.0008 1-3 / month N=14,078 P < 0.0001 >3 / month N=14,078 P < 0.0001 Door-to-Balloon Time (minutes)

  28. Hospital Volume of Primary PTCA vs. Mortality 0.87 0.83 0.72 P value for trend < 0.001 N: Pt = 2,825 5,245 9,303 19,162 Hosp =113 112 113 112 Canto. NEJM 2000

  29. Randomized Trial Results Versus Community-Setting Results: NRMI-2 Cohort n=2,958, lytic eligible, no shock at presentation Percent P=NS P=NS Tiefenbrunn AJ, et al. J Am Coll Cardiol. 1998;31:1240-1245.

  30. Trials Comparing Primary PTCA With Fibrinolytic Therapy: MITI Cohort Thrombolytic therapy Primary angioplasty P=0.80 Time After Discharge (years) Every NR, et al. N Engl J Med.1996;335:1253-1260.

  31. DANAMI-2 Commentary: Facilitated PCI Not Evaluated • This trial tested the efficacy of thrombolytic therapy with very little use of rescue/adjunctive PCI (2.5%) versus “primary PCI” without significant pharmacologic therapy before the PCI • The trial provides no data regarding the efficacy of “facilitated PCI” in which a thrombolytic agent or GP 2b3a inhibitor would be administered prior to rescue or adjunctive PCI. • The concept of “facilitated PCI” will be tested in upcoming trials. Gibson CM, 2002

  32. Relative Speed and Magnitude of Patency Lytic + 2b3a: 94% by 60 min. Pre Hospital Lytic + 2b3a Lytic 2 hour Door to Balloon  ED arrival  Drug administration  Pre Hospital Drug administration Time (minutes) Adapted from Gibson CM. Am Interm Med. 1999;130:841-847.

  33. Fibrinolytic Therapy Pre-PCI PRAGUE* PACT * Patients transferred for PCI % TIMI 2/3 flow pre PCI % TIMI 2/3 flow pre PCI SK Placebo tPA Placebo Adapted from Ross AM, et al. J Am Coll Cardiol. 1999;34:1954-1962. Adapted from Widimsky P, et al. J Eur Heart J. 2000;21:823-831.

  34. Convalescent LV Function by Patency Group: Global Ejection Fraction P=0.004 % Convalescent LVEF Adapted from Ross AM, et al. J Am Coll Cardiol. 1999;34:1954-1962.

  35. Relationship of TIMI 3 Flow Before PCI to 6 Month Survival Stone et al. Circ 2001; 104: 636-641

  36. Preliminary Designs of Upcoming Facilitated PCI Trials CM Gibson 2002

  37. DANAMI 2 Conclusions • Among patients transferred for primary PCI with a median door to balloon time of 114 minutes, the incidence of the composite endpoint of death, recurrent MI, and stroke is reduced compared with the administration of tPA and heparin when used in conjunction with a rescue / adjunctive PCI rate of 2.5%. CM Gibson 2002

  38. DANAMI 2 Conclusions • The median US door to balloon time for transfer patients is 198 minutes, and is not as rapid as in DANAMI 2 (114 minutes) • The composite endpoint was driven primarily by a lower rate of recurrent MI among PCI patients • Current strategies that employ higher rates of rescue and adjunctive PCI after fibrinolysis and higher rates of enoxaparin use have been associated with lower rates of recurrent MI than that reported in DANAMI 2 CM Gibson 2002

  39. DANAMI 2 Conclusions • As an endpoint, recurrent MI may more often be detected among patients treated with fibrinolysis who undergo delayed or late PCI because post PCI CK release may not be detected during primary PCI • DANAMI 2 trial was performed in a dedicated network of centers. Larger hospital / and operator volumes are associated with improved outcomes and the ability to implement this strategy in smaller volume hospital systems with less experienced operators is not yet tested • To this end, US community hospital registry experience suggests no benefit of primary PCI over fibrinolysis CM Gibson 2002

  40. DANAMI 2 Conclusions • DANAMI 2 did not assess the effectiveness of “facilitated PCI” in which pharmacologic and mechanical strategies are combined. • Upcoming trials will test the effectiveness of “facilitated PCI” CM Gibson 2002

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