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The DANAMI-2 Trial

The DANAMI-2 Trial. A Comparison of Coronary Angioplasty with Fibrinolytic Therapy in Acute Myocardial Infarction Henning Rud Andersen et al for the DANAMI-2 investigators N Engl J Med 2003; 349: 733-42. DANAMI-2: Study Design.

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The DANAMI-2 Trial

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  1. The DANAMI-2 Trial A Comparison of Coronary Angioplasty with Fibrinolytic Therapy in Acute Myocardial Infarction Henning Rud Andersen et al for the DANAMI-2 investigators N Engl J Med 2003; 349: 733-42

  2. 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 N Engl J Med 2003; 349: 733-42

  3. DANAMI-2: Primary Results Non-Transfer Sites Transfer Sites Combined P=0.05 P<0.001 P=0.002 30 Day Death / MI / Stroke (%) N=63 N=107 N=15 N=80 N=48 N=27 Lytic Primary PCI Lytic Primary PCI Primary PCI Lytic N Engl J Med 2003; 349: 733-42

  4. DANAMI-2: Results Stroke Death Recurrent MI P=0.15 P<0.001 P=0.35 Lytic Primary PCI Lytic Primary PCI Primary PCI Lytic N Engl J Med 2003; 349: 733-42

  5. DANAMI-2: Risk of Recurrent MI Largely Drives Results of the Composite Endpoint The DANAMI 2 Investigators state that: “Although the rates of death, clinical reinfarction, and stroke were all reduced with angioplasty, the better overall outcome after angioplasty was driven primarily by the reduction in the rate of reinfarction. Our finding of a higher 30-day mortality rate among patients with reinfarction accords with recent results by Gibson et al. and indicates that clinical reinfarction in our trial was a severe event.”

  6. Recurrent MI During Index Hospitalization is Associated with Higher Mortality at 2 Years Kaplan - Meier survival estimates, by early reinfarction 1 No early reinfarction 10.1%, n=19,265 Early reinfarction 19.6%, n=836 0.75 Log - rank p<0.0001 0.5 0 0.5 1 1.5 2 Years Gibson CM et al, J Am Coll Cardiol 2003;42:7–16.

  7. Similar to DANAMI 2, A Lower Rate of Recurrent MI Following PCI Drives the Benefit Observed in Many of the Recent Primary PCI vs Fibrinolytic Trials *Pre-hospital administration. P<0.05: ReMI;death (PCAT only); stroke (PCAT only). Grines C, et al. Am Heart J. 2003;145:47-57. CM Gibson 2003

  8. If Recurrent MI Drives The Results of DANAMI 2 and Other Recent Trials, Can We Reduce The Risk of Recurrent MI Following Fibrinolytic Administration? • Yes. • Performance of early rescue PCI (early PCI of a closed artery), adjunctive PCI (early PCI of an open artery) , and delayed PCI are collectively associated with a reduction in recurrent MI after fibrinolytic administration. Gibson CM et al, J Am Coll Cardiol 2003;42:7–16.

  9. Risk of Early Recurrent MI Following Thrombolysis in 20,101 Patients P< 0.001 % Recurrent MI Gibson CM et al, J Am Coll Cardiol 2003;42:7–16.

  10. Is Performance of Rescue / Adjunctive / Delayed PCI After Fibrinolytic Administration Associated With Improved Mortality at 2 Years? • Yes. • Performance of early rescue PCI (early PCI of a closed artery), adjunctive PCI (early PCI of an open artery) , and delayed PCI are collectively associated with a reduction in mortality. Gibson CM et al, J Am Coll Cardiol 2003;42:7–16.

  11. 2 Year Survival Following Rescue PCI Rescue PCI Log rank p=0.03 Survival No Rescue PCI Survival was Improved in patients with 90 minute TIMI Grade 0/1 Flow who underwent rescue PCI Years Gibson et al, Circulation 2002, 105:1909-1913

  12. 2 Year Survival Associated with Adjunctive PCI in Patients with an Open Artery Following Thrombolytic Administration Immediate Adjunctive PCI Delayed PCI No PCI p=0.11; after adjusting for stent use p=0.07 for adjunctive PCI Survival tended to be improved in patients with an open artery at 90 minutes who underwent immediate adjunctive or delayed PCI Years Gibson et al, Circulation 2002, 105:1909-1913

  13. Performance of Early PCI After Fibrinolysis is Associated with Improved Survival at 2 Years in 20,101 Patients 1 PCI 0.9 No PCI Survival Log rank p<0.0001 0.8 0.7 0 0.5 1 1.5 2 Years Gibson CM et al, J Am Coll Cardiol 2003;42:7–16.

  14. Are The Benefits of PCI After Fibrinolysis True for Both Low Risk and High Risk Patients? • Yes. • Similar relative risk reductions in survival following PCI have been observed among low, intermediate and high risk patients. Gibson CM et al, J Am Coll Cardiol 2003;42:7–16.

  15. Mortality to 2 Years by In-Hospital PCI, Stratified by TIMI Risk Score in 20,101 Patients p<0.001 p<0.001 p<0.001 Mortality (%) PCI PCI No PCI No PCI PCI No PCI High Risk TRS >5 Intermediate Risk TRS 3-4 Low Risk TRS 0-2 Gibson CM et al, J Am Coll Cardiol 2003;42:7–16.

  16. Are the There Recent Randomized Trials to Support PCI Following Fibrinolytic Administration? • Yes. • In August of 2003, the SIAM 3 and ALKK study were published contemporaneously with the DANAMI 2 Trial. CM Gibson 2003

  17. SIAM III Trial Randomized trial of thrombolysis (rPA) with transfer for early PCI (within 6 hours; n=82) or thrombolysis with delayed angiography at 2 weeks (n=81) in patients with acute MI presenting at community hospitals Death/reMI/ischemic events/TLR at 6 months p=0.001 EF at 6 months p=0.018 rPA + Delayed PCI rPA + Delayed PCI rPA + Early PCI rPA + Early PCI J Am Coll Cardiol 2003;42:634-41

  18. ALKK Trial Randomized trial of angioplasty (n=149) or medical therapy (n=151) in stable patients 8-42 days post acute MI Survival at Long-term (mean 56 months) follow-up p=0.02 Event-free* Survival at 1 Year p=0.06 Medical Therapy Medical Therapy PTCA PTCA * Survival free of reinfarction, ischemia-driven (re) PTCA, CABG, or rehospitalization for severe angina Circulation. 2003;108:1324-1328

  19. If PCI After Fibrinolysis is Associated with Benefit, was PCI Frequently Performed After Fibrinolysis in DANAMI 2? No. As stated by the authors: “The frequency of rescue angioplasty was low.” Rescue angioplasty was performed infrequently (15 cases, 1.9% of patients)

  20. If PCI After Fibrinolysis is Associated with Benefit, Could the Results in the Fibrinolytic Arm Have Been Improved in DANAMI 2? Observational and randomized trial data from other trials presented above suggest that outcomes may have been improved if PCI had been performed more frequently after fibrinolysis, but this cannot be ascertained from the data at hand in DANAMI 2. CM Gibson 2003

  21. Are Prolonged Door to Balloon Times Associated With Higher Mortality? • Yes. • Door to balloon delays beyond 90 minutes are associated with a rise in mortality.

  22. NRMI-2: Primary PCI Door-to-Balloon time vs. Mortality N=27,080 P < 0.00001 Door-to-Balloon Time (minutes) JAMA 2000; 283:2941-7.

  23. Primary PCI for STEMITime to Reperfusion and 30-Day Mortality CADILLAC Zwolle 6 12 n=2,002 n=1,7911994-2001 9.6 5 10 P=0.04 ( 3h v  3h) P<0.001 4 8 5.6 Mortality (%) 3 6 2.3 2.2 2 4 3.1 2.5 0.9 1 2 0 0 <3 3-6 >6 <2 2-4 4-6 >6 Time to Reperfusion (h) Time to Reperfusion (h) Brodie BR, et al. J Am Coll Cardiol. 2003;41(suppl A):368A. De Luca G, et al. J Am Coll Cardiol. 2003;41(suppl A):368A.

  24. Was the Door to Balloon Delay in Performing PCI 3 Hours in DANAMI 2? • No. • It was actually much quicker at 90 to 110 minutes. • Are door to balloon times among transfer patients this quick in the United States? • No. • Currently, the median delay in the US is 185 minutes, only 4.8% of arteries are opened in under 90 minutes as suggested by the ACC/AHA guidelines. CM Gibson 2003

  25. DANAMI vs US AMI: Are We As Quick in the US? 225 200 185 175 150 125 110 Median Time (min) 90 100 75 50 25 0 DANAMI On-Site Primary PCI DANAMI Transfer Primary PCI US AMI Transfer Primary PCI Pinto D, et al. Cardiovascular Reviews and Report. 2003;24:267-276.

  26. Is There A Time Dependence of the Potential Advantage of PCI Over Fibrinolysis? • Yes. • Delays in door to balloon times of over 60 minutes beyond that of a center’s door to needle time may nullify the benefits of primary PCI.

  27. Benefits of PCI vs Lysis: The Importance of Timing Kent DM et al Eff Clin Pract 4: 214, 2001

  28. Are There Potential Benefits of Even Quicker Fibrinolytic Administration Such as Pre Hospital Fibrinolytic Therapy? • Yes. • A recent meta analysis of 6 trials suggests a relative risk reduction in mortality of 16% • The CAPTIM trial suggests that pre hospital therapy administered to those patients with a short duration of symptoms (< 2 hours) may be associated with improved clinical outcomes over primary PCI.

  29. Results of Randomized Trials of Pre-hospital Thrombolysis on Hospital Mortality All Trials Favors Favors No. of Quality Pre-hospital In-hospitalStudy Patients Score OR (95% CI) Thrombolysis Thrombolysis MITI, 1993 360 0.91 0.69 (0.30-1.57) EMIP, 1993 5469 0.85 0.86 (0.72-1.03) GREAT, 1991 311 0.78 0.56 (0.25-1.23) Roth et al, 1990 116 0.65 0.80 (0.17-3.77) Schofer et al, 1990 78 0.63 0.46 (0.04-5.31) Castaigne et al, 1989 100 0.48 0.74 (0.14-3.56) Overall 6434 0.83 (0.70-0.98) Morrison LE, et al. JAMA. 2000;283:2686-2691.

  30. CAPTIM 1-Year Results Sx  2 h Sx  2 h 7.5 10.0 Death Death Death P=0.057 P=0.47 5.7 7.5 5.0 5.9 Percent 5.0 3.7 2.2 2.5 2.5 0.0 0.0 Pre-hospital Lysis Primary PCI Pre-hospital Lysis Primary PCI Touboul P. Presented at: The 18th International Symposium on Thrombolysis and Interventional Therapy in Acute Myocardial Infarction - George Washington University Symposium; November 16, 2002; Chicago, Ill.

  31. CAPTIM 1-Year Results Sx  2 h Sx  2 h 7.5 7.5 Death Shock Randomization to DC Shock Randomization to Adm P=0.032 P=0.0007 5.3 5.0 5.0 3.6 Percent 2.5 2.5 1.3 0.0 0.0 0.0 Pre-hospital Lysis Primary PCI Pre-hospital Lysis Primary PCI Touboul P. Presented at: The 18th International Symposium on Thrombolysis and Interventional Therapy in Acute Myocardial Infarction - George Washington University Symposium; November 16, 2002; Chicago, Ill.

  32. Is Restoration of Epicardial Blood Flow Before PCI Associated with Improved Clinical Outcomes in STEMI? • Yes

  33. 100 0.5% 98 2.8% 96 4.4% Survival (%) 94 TIMI 3 (n=375) Log-rank Pfor trendP=0.009 TIMI 2 (n=295) 92 TIMI 0/1 (1,657) 90 0 1 2 3 4 5 6 Months Facilitated PCI in STEMI: Pre-PCI Angiographic Findings and Mortality 1.0 0.9 Survival 0.8 TFG 2 3- way log-rankP=0.0013 TFG 3 TFG 0/1 0.7 0 0.5 1.0 1.5 2.0 1.0 Stone GW, et al. Circulation. 2001;104:636-641. 0.9 • In both primary PCI and adjunctive/rescue PCI, TIMI flow grade before PCI is associated with long-term mortality • In adjunctive/rescue PCI, TIMI myocardial perfusion before PCI is associated with long-term mortality Survival 0.8 TMPG 2/3 Log-rankP=0.03 TMPG 0/1 0.7 0 0.5 1.0 1.5 2.0 Gibson CM, et al. Circulation. 2002;105:1909-1913.

  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. PACT Substudy: Time to Reperfusion and LV Function in MI Probability of Regional LV Dysfunction (Abnormal Chords) Increases as Time to Achieve Reperfusion Increases 0.95 Time Delay(min) 0.90 30 0.85 60 0.80 Probability 0.75 90 0.70 120 0.65 0.60 2 4 6 8 10 0 1 2 3 4 Time (h) Odds Ratio Lundergan CF, et al. Am J Heart. 2002;144:456-462.

  36. Door-to-Thrombolysis in Myocardial Infarction (TIMI) Time and Mortality 8 P<0.05 6.7 7 After linear logistic regression, only age, gender, and door-to-TIMI grade 3 time (OR 1.27/ 15 min) were independently correlated with in-hospital mortality Similar to the OR of 1.6/ 25 min in GUSTO IIb trial (Berger PB et al, Circulation 1999;100:14-20) 6 5 Mortality (%) 4 3 1.8 2 1 n=394 n=105 0  1 h > 1 h Juliard J-M, et al. Am J Cardiol. 2003;91:1401-1405.

  37. Can Glycoprotein IIbIIIa Inhibition Be Administered Safely Following Fibrinolysis in the Cath Lab? • Yes. • Non-randomized trial data suggests that this is not only safe but tends to be associated with reduced mortality.

  38. GP IIb/IIIa Inhibitor Use With Early PCI After Full-Dose Fibrinolytic Therapy: Clinical Outcomes and Bleeding Complications P=0.06 Odds Ratio represents odds of the event for patients receiving GP IIb/IIIa inhibitors. Bleeding reported by GUSTO scale categories. Adapted with permission from Roe MT, et al. Safety of adjunctive glycoprotein IIb/IIIa blockade during rescue/early percutaneous coronary intervention following full-dose fibrinolytic therapy for acute myocardial infarction. Poster presented at the American College of Cardiology 52nd Annual Scientific Session; March 30-April 2, 2003; Chicago, Il. CM Gibson 2003

  39. GP 2b3a Inhibition After Full Dose Lysis Assess risk of ICH: High Risk: elderly female, low body weight, elevated blood pressure, elevated Cr, inferior MI Low Risk: young male, large, normotensive, normal Cr, anterior MI Assess Fibrinogen Depletion: Stat fibrinogen on pt. arrival, ? above 100 TNK does not deplete fibrinogen, drug of choice for combination with PCI tPA drops near 100 for 18-24 hrs rPA often dips below 100 for 18-24 hrs CM Gibson 2003

  40. Conclusions • Time is muscle irrespective of the reperfusion strategy (drug or device) • Benefits of PCI over fibrinolytic therapy are explained at least in part by a reduction in recurrent MI among patients treated with PCI • In the modern era of interventional cardiology (stents, thienopyridines, GP 2b3a inhibition), the performance of PCI after fibrinolytic administration may reduce the risk of recurrent MI and may be associated with reduced long term mortality compared to fibrinolysis alone CM Gibson 2003

  41. Conclusions • Safety and efficacy of full dose fibrinolytic monotherapy is well characterized while half dose fibrinolytic monotherapy is not well characterized • Half dose fibrinolysis with simultaneous full dose GP 2b3a inhibition (“combination therapy”) is equal in clinical efficacy to fibrinolytic monotherapy but is associated with more major bleeding (GUSTO V, ASSENT 3) • This is in contrast to full dose fibrinolytic monotherapy followed by full dose GP2b3a inhibition in the cardiac catheterization laboratory (hours later) which in non-randomized data tends to be associated with lower mortality (4.6% vs 6.6%, p=0.06) yet with a slight rise in moderate (7.1% vs 6.5%) and severe (2.2% vs 1.7%) bleeding CM Gibson 2003

  42. Conclusions • Future prospective randomized trials will assess the efficacy of a variety of fibrinolytic and other pharmacologic agents before PCI and the concept of “facilitated PCI” CM Gibson 2003

  43. Designs of Upcoming Facilitated PCI Trials CM Gibson 2003

  44. Full Dose Fibrinolytic Monotherapy Door to balloon (D-B) > 90 min Lack of access to skilled PCI center (D-B) – (D-N) > 1 h < 1 h from symptom onset Invasive Strategy Cardiogenic shock (age < 75) Bleeding risk Diagnosis in doubt (pericarditis/aneurysm) Door to balloon < 90 min Skilled PCI center available, defined by: Operator experience > 75 cases/yr Team experience > 36 primary PCI/yr Age > 75 Symptoms > 2-3 h Selection of the Optimal Reperfusion Options for the STEMI Patient: 2003 CM Gibson 2003

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