DANAMI II Danish Myocardial Infarction Study

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 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 Lytic therapy Primary PCI Primary PCI Front-loaded tPA 100 mg (n=782) with transfer (n=567) without transfer (n=223) Death / MI / Stroke at 30 Days Stopped early by safety and efficacy committee DANAMI-2: Centers DANAMI-2: Primary Results Combined P=0.0003 Transfer Sites P=0.002 Non-Transfer Sites P=0.048 16% 14% Death / MI / Stroke (%) RRR 45% 16% 14% RRR 40% 16% 12% 12% 9% RRR 45% 12% 12% 8% 8% 8% 8% 7% 4% 4% 4% 0% Lytic Primary PCI 0% Lytic Primary PCI 0% Lytic Primary PCI Trials Comparing Primary PTCA With Fibrinolytic Therapy: GUSTO-IIb Cohort 18 16 14 12 10 8 6 4 2 0 16.1 13.7 9.6 14.1 Composite Outcome (%) PTCA t-PA 30 days P=0.033 6 months P=NS GUSTO-IIb Angioplasty Substudy Investigators. N Engl J Med. 1997;336:1621-1628. DANAMI-2: Results Death P=0.35 8% 7.6% 6.6% 6% Recurrent MI P<0.0001 8% 6.3% 6% 6% 8% Stroke P=0.15 4% 4% 4% 2% 2% 1.6% 2.0% 2% 1.1% 0% 0% 0% Lytic Primary PCI Lytic Primary PCI Lytic Primary PCI 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 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 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 Thrombus Remains Following Thrombolysis Van Belle et al. Circulation. 1998;97:26-33. 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. 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 2 Year Survival Following Rescue PCI 1.00 Rescue PCI 0.75 Survival Log rank p=0.006 No PCI 0.50 0.25 0.00 0 .5 1 Years Survival was Improved in patients with 90 minute TIMI Grade 0/1 Flow after TNK who underwent rescue PCI in the TIMI 10B trial 2 1.5 CM Gibson, AHA 2001 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 Rate of Rescue / Adjunctive PCI Use in DANAMI 2 Compared with Other Recent Trials 7% 6% 6.3% % Recurrent MI 5% 4% 3% 2% 1% 0% DANAMI tPA + Hep 4.2% 3.5% 2.3% 2.7% 2.2% 1.8% ASSENT 3 TNK + Hep GUSTO V rPA + Hep GUSTO V rPA + Abx ASSENT 3 TNK + Abx ASSENT 3 TNK + Enox ENTIRE TNK + Enox Urgent PCI 2.5% 14.4% 16.5% 8.6% 5.6% 9.1% 11.9% Non-Urgent PCI 44.4%* 19.4% CM Gibson 2002 17.4% * Urgent & non-urgent combined ENTIRE TIMI 23: 30 Day Death/MI 12 8 11.3 P=0.01 20 15 % Pts 8.2 4.9 P=0.002 1.8 3.1 FULL Dose TNK 15.9 HALF Dose TNK + Abx 4 3.1 P=0.005 0 UFH ENOX 159 324 10 5 12.2 6.5 4.4 P=0.003 5.5 1.8 3.7 0 UFH N= 82 1.9 2.5 3.9 2.6 MI Death 3.7 ENOX 160 77 UFH 164 ENOX ENTIRE TIMI 23: Recurrent MI In Patients NOT Undergoing PCI (N=259) FULL Dose TNK 9.8 HALF Dose TNK + Abx 10 8 6 4 2 7.6 10 8 1.1 UFH ENOX 0 79 180 % Pts 6 4 2 0 UFH N= 41 1.9 5.3 0.0 ENOX 103 UFH 38 ENOX 77 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 doorto-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 DANAMI 2: Door to Balloon Times Community Hospital Thrombolysis (n=782) PCI, non-transported patients (n=223) PCI, transported patients (n=567) M V Adjusted Odds of Death 2 1.8 1.6 1.4 1.2 1 0.8 0.6 N=27,080 P=0.01 P=NS P=NS P=0.0007 P=0.0003 1.62 1.61 1.41 1.14 1.15 1 2,230 5,734 6,616 4,461 2,627 5,412 0-60 61-90 91-120 121-150 Door-to-Balloon Time (mins) Cannon CP et al, JAMA 2000 151-180 >180 NRMI-2: Primary PCI Door-to-Balloon time vs. Mortality 10 8 N=27,080 P < 0.00001 8.5 6.7 5.1 7.9 Mortality (%) 6 4.2 4 2 0 0-60 4.6 61-90 91-120 121-150 151-180 >180 Door-to-Balloon Time (minutes) Door to Balloon Times Among Patients Transferred in NRMI 4 Door to Data to Cath Lab to Data: 50th: 8 Min. 25th: 4 Min. 75th: 16 Min. Cath Lab Arrival: 50th: 137 Min. 25th: 87 Min. 75th: 220 Min. Balloon: 50th: 39 Min. 25th: 29 Min 75th: 53 Min. 8 137 39 (25th: 137; 75th: 281) Total Door to Balloon Time: 198 minutes Percent of Patients with Door to Balloon Time < 90 Min.: 4.8% Sample Size: 1,292; Time Period: October 2000 – September 2001 Gibson CM, 2002 NRMI 4 Transfer-In Annual Data Report 2002 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 NRMI 2-3: Primary PCI vs. Thrombolysis: 1996-2000 N=62,000 Patients In-hospital Mortality Volume < 16 /yr 17-48/yr >48/yr % Hosp 25% 50% 25% Tlysis 5.9 5.9 5.4 Prim PCI 6.2 4.5 3.4 P value NS <0.001 <0.001 Non-fatal stroke 1.1 0.4 <0.001 Magid et al. JAMA 2000 NRMI-2: Primary PCI Institutional Volume vs. Mortality 10 8.0 8 N=27,080 P < 0.00001 Mortality (%) 6.2 6 4 2 0 4.7 <1 1-3 >3 Institutional Monthly Volume of Primary Angioplasty Cases 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) Hospital Volume of Primary PTCA vs. Mortality MV Adjusted Odds of Death 1.2 1 0.8 0.6 0.4 0.2 0 N: Pt = 2,825 Hosp =113 0.87 0.83 0.72 P value for trend < 0.001 5,245 112 9,303 113 19,162 112 5 to 11 12 to 20 21 to 33 >33 Hospital Volume of Primary Angioplasty per Year Canto. NEJM 2000 Randomized Trial Results Versus Community-Setting Results: NRMI-2 Cohort n=2,958, lytic eligible, no shock at presentation 8 Percent PTCA 5.2 5.4 t-PA 5.6 6.2 6 4 2 0 In-hospital mortality P=NS In-hospital mortality or nonfatal stroke P=NS Tiefenbrunn AJ, et al. J Am Coll Cardiol. 1998;31:1240-1245. Trials Comparing Primary PTCA With Fibrinolytic Therapy: MITI Cohort 100 95 Survival (%) 90 85 80 75 70 0 0.5 1 1.5 2 Thrombolytic therapy Primary angioplasty P=0.80 2.5 3 3.5 4 Time After Discharge (years) Every NR, et al. N Engl J Med. 1996;335:1253-1260. 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 Relative Speed and Magnitude of Patency Pre Hospital Lytic + 2b3a Lytic + 2b3a: 94% by 60 min. 100 80 Lytic 60 40 20 0 2 hour Door to Balloon 0  Pre Hospital Drug administration 30 45 60 75 90 120 150   ED Drug arrival administration Time (minutes) Adapted from Gibson CM. Am Interm Med. 1999;130:841-847. Fibrinolytic Therapy Pre-PCI PACT 70 60 50 40 30 20 10 0 28 TIMI 3 TIMI 2 PRAGUE* * Patients transferred for PCI 50 40 30 20 10 0 12 15 Placebo 30 TIMI 3 TIMI 2 19 33 15 Placebo tPA 17 SK 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. Convalescent LV Function by Patency Group: Global Ejection Fraction TIMI 3 on cath lab arrival TIMI 3 after leaving cath lab Never had TIMI 3 80 62.4 P=0.004 % Convalescent LVEF 60 57.9 54.7 40 20 0 Adapted from Ross AM, et al. J Am Coll Cardiol. 1999;34:1954-1962. Relationship of TIMI 3 Flow Before PCI to 6 Month Survival Stone et al. Circ 2001; 104: 636-641 Preliminary Designs of Upcoming Facilitated PCI Trials ASSENT 4 ADVANCE TIGER TITAN FINESSE TNK TNK + Integrilin TNK Integrilin in ER rPA Heparin / ASA Integrilin TNK + Integrilin Integrilin in Cath Lab rPA + abciximab in ER vs CCL CM Gibson 2002 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 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 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 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