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A Prospective Randomized Trial of Triage Angiography in Suspected Acute Myocardial Infarction Patients who are Considere

A Prospective Randomized Trial of Triage Angiography in Suspected Acute Myocardial Infarction Patients who are Considered Ineligible for Reperfusion Therapy.

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A Prospective Randomized Trial of Triage Angiography in Suspected Acute Myocardial Infarction Patients who are Considere

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  1. A Prospective Randomized Trial of Triage Angiography in Suspected Acute Myocardial Infarction Patients who are Considered Ineligible for Reperfusion Therapy Peter A. McCullough, MD, MPH, William W. O’Neill, MD, Mariann Graham, BSN, Shukri David, MD, Robert Stomel, DO, Felix Rogers DO, Cindy L. Grines, MD William Beaumont Hospital, Royal Oak, MI Providence Hospital, Southfield, MI Botsford Hospital, Farmington Hills, MI Riverside Hospital, Trenton, MI McCullough PA, O’Neill WW, Graham M, David S, Stomel R, Rogers F, Grines CL. A Prospective Randomized Trial of Triage Angiography in Suspected Acute Myocardial Infarction Patients Who are Considered Ineligible for Reperfusion Therapy. Circulation 1996;94:I-570 [oral].

  2. MATE Medicine vs Angiography in Thrombolytic (Reperfusion) Exclusion Patients

  3. Background • Only 15-20% of Acute MI (AMI) patients are considered eligible for reperfusion therapy by conventional criteria • Previous studies have shown high cardiac event rates (recurrent ischemic events and death) for those patients with AMI who are ineligible for reperfusion therapy* *Cragg, D.R., Friedman, H.Z., Bonema, J.D., Jaiyesimi, I.A., Ramos, R.G., Timmis, G.C., O'Neill, W.W., and Schreiber, T.L. Outcome of patients with acute myocardial infarction who are ineligible for thrombolytic therapy. Ann.Intern.Med. 115:173-177, 1991.

  4. Purpose To prospectively test the hypothesis that triage angiography and subsequent revascularization, if indicated, is superior to conservative therapy in those patients who have suspected AMI but do not meet eligibility criteria for reperfusion therapy.

  5. Methods • Randomized, prospective, multicenter trial • Subjects: those patients ages 18 and up who had suspected AMI (< 24 hours of pain) and were considered ineligible for reperfusion therapy due to excessive bleeding risks or uncertain benefit • Randomized 201 subjects to conservative care (ASA, beta-blockers, heparin, and nitrates), observation and non-invasive evaluation vs initial triage angiography upon admission with subsequent therapy guided by the angiogram • Major endpoint: composite of recurrent ischemic events and in-hospital death

  6. Southeast Michigan Participating Centers • William Beaumont Hospital, Royal Oak, Drs. Peter McCullough and Cindy Grines • Botsford Hospital, Farmington Hills, Dr. Robert Stomel • Providence Hospital, Southfield, Dr. Shukri David • Riverside Hospital, Trenton, Dr. Felix Rogers

  7. Analysis • Interim analysis performed at 200 patients • Randomization tested for control of confounders • Major endpoint assessed as the percent risk reduction of recurrent ischemia and death • LOS and true hospital costs calculated

  8. Baseline Characteristics Conservative Triage Angiogram Characteristic P-value Mean Age 61 57 ns Female:Male 38:49 34:79 ns Hx Angina 27 (31%) 30 (27%) ns Hx MI 18 (21%) 25 (22%) ns Hx CABG 8 (9%) 11 (10%) ns Hx PTCA 15 (17%) 14 (12%) ns Diabetes 24 (28%) 12 (11%) .002 HTN 57 (66%) 59 (53%) ns Dyslipidemia 41 (47%) 41 (37%) ns Tobacco Use 47 (54%) 52 (46%) ns Fhx of CAD 29 (33%) 39 (35%) ns

  9. Duration of Sx 8.6 hrs 9.2 hrs ns ECG ST Elevation 23 (26%) 37 (33%) ns ST Depression 22 (25%) 25 (22%) ns T-wave Changes 37 (43%) 49 (43%) ns Q-waves 21 (24%) 27 (24%) ns LBBB 5 (6%) 4 (4%) ns RBBB 4 (5%) 5 (4%) ns Normal 18 (21%) 22 (20%) ns Presentation Conservative Triage Angiogram P-value Feature

  10. Conservative Triage Angiogram Reason P-value Non-dx ECG 71 (83%) 87 (77%) ns Past 6 hours 38 (44%) 55 (49%) ns Bleeding risks 10 (12%) 15 (13%) ns Too elderly 7 (8%) 7 (6%) ns Hx of Stroke 6 (7%) 7 (6%) ns ns Pain free 7 (8%) 17 (15%) Miscellaneous 13 (15%) 15 (13%) ns Reasons for Reperfusion Ineligibility

  11. Mean Peak CPK 461 562 - ns Ruled in for MI 49 (56%) 66 (58%) - ns Chest Pain with ECG or 10 (12%) 4 (4%) 42% (16%-60%) .03 Hemodynamic changes Chest Pain without ECG 21 (24%) 9 (8%) 45% (25%-59%) .002 changes Reinfarction 0 (0%) 2 (2%) - ns Death 2 (2%) 1 (1%) 35% (-46%-71%) ns Aggregate Recurrent 30 (34%) 15 (13%) 45% (26%-59%) 0.0004 Ischemic Events or Death Results Conservative Triage Percent Risk Angiogram Reduction with Outcome P-value Triage Angiogram (95% CI)

  12. Peak CPK 728 887 - ns Chest Pain with ECG or 8 (16%) 3 (5%) 46% (16%-65%) 0.05 Hemodynamic changes Chest Pain without ECG 14 (29%) 2 (13%) 60% (44%-71%) 0.0001 changes Reinfarction 0 (0%) 1 (2%) - ns Death 1 (2%) 0 (0%) - ns Aggregate Recurrent 21 (43%) 6 (9%) 59% (41%-72%) 0.00003 Ischemic Events or Death Infarction Subgroup Conservative Triage Angiogram Percent Risk P-value (n=49) Reduction with Outcome Triage Angiogram (n=66) (95% CI)

  13. Mean Peak CPK 490 847 - ns Ruled in for MI 19 (68%) 32 (80%) - ns Chest Pain with ECG or 5 (18%) 2 (5%) 47% (7%-70%) ns Hemodynamic Changes Chest Pain without ECG 12 (45%) 5 (15%) 56% (26%-73%) 0.004 Changes Reinfarction 0 (0%) 2 (5%) - ns Death 1 (4%) 0 (0%) - ns Aggregate Recurrent 15 (54%) 9 (23%) 53% (18%-73%) 0.009 Ischemic Events or Death ST Elevation or LBBB Subgroup Conservative Triage Angiogram Percent Risk Reduction with P-value Outcome (n=28) Triage Angiogram (n=40) (95% CI)

  14. ST Depression or T-wave Inversion Subgroup Triage Angiogram Percent Risk Conservative P-value Outcome Reduction with (n=28) Triage Angiogram (n=40) (95% CI) Mean Peak CPK 546 505 - ns Ruled in for MI 20 (54%) 27 (56%) - ns Chest Pain with ECG or 3 (8%) 1 (2%) 44 (-4%-70%) ns Hemodynamic Changes Chest Pain without ECG 4 (11%) 3 (6%) 26% (-48%-63%) ns Changes Reinfarction 0 (0%) 0 (0%) - ns Death 1 (3%) 1 (2%) 13% (-254%-79%) ns Aggregate Recurrent 8 (22%) 4 (8%) 60 (3%-63%) ns Ischemic Events or Death

  15. Mean Peak CPK 403 456 - ns Ruled in for MI 21 (55%) 19 (56%) - ns Chest Pain with ECG or Hemodynamic Changes 3 (8%) 1 (3%) 31% (-26%-63%) ns Chest Pain without ECG Changes 13 (34%) 3 (9%) 45% (20%-62%) 0.01 Reinfarction 0 (0%) 0 (0%) - ns Death 0 (0%) 1 (2.9%) - ns Aggregate Recurrent Ischemic Events or Death 16 (42%) 4 (12%) 47% (22%-64%) 0.004 Female Subgroup Triage Angiogram Percent Risk Conservative P-value Reduction with Triage Angiogram (95% CI) Outcome (n=38) (n=34)

  16. Death or Recurrent Ischemia Conservative care better Triage Angiography better ST Elevation or LBBB RR = 0.47 ST Depression or TWI RR = 0.40 <------- -------> Definite MI RR = 0.41 RR = 0.55 Entire Group null = 1

  17. Early Discharge p=0.00007 p=0.03 Triage Angiogram Conservative Care LOS < 2 days LOS < 5 days

  18. Hospital Costs True hospital costs after adjustment for outliers p=0.04

  19. Adverse Event Conservative Triage Angiogram P-value Stroke 2 (2%) 2 (2%) ns Transient Azotemia 3 (3%) 2 (1.8%) ns Transfusion 4 (5%) 11 (10%) ns Vascular 0 (0%) 1 (1%) ns Complications Safety of Triage Angiography

  20. ConclusionsEarly Triage Angiography in those patients with suspected AMI who are reperfusion ineligible: • Can be done safely • Leads to more efficient referral for revascularization with overall increased cost • Reduces in-hospital combined recurrent ischemic events and death (45% risk reduction) • Provides for more effective early discharge to home

  21. Importance of Recurrent Ischemia • PAMI-1: recurrent ischemia occurred in 19% and led to re-infarction in 4% and death in 3% (Stone,JACC,1996) • TIMI-3 Registry: recurrent ischemia occurred in 48% and led to MI, death, or stroke in 4% at 10 days (Kleiman,AJC,1996) • TAMI-1+TAMI-3: recurrent ischemia occurred in 17% and led to MI in 4%, and death in 3% (Ellis,Circulation,1989)

  22. Late Outcomes in the Medicine vs. Angiography for Thrombolytic Exclusion Study Peter A. McCullough, MD, MPH*, William W. O’Neill, MD, Mariann Graham, BSN, Shukri David, MD, Robert Stomel, DO, Felix Rogers, DO, Ali Farhat, MD, Rasa Kazlauskaite, MD, Cindy L. Grines, MD William Beaumont Hospital, Royal Oak, Michigan *Current Institution: Henry Ford Heart and Vascular Institute, Detroit, Michigan McCullough PA, O’Neill WW, Graham M, David S, Stomel R, Rogers F, Farhat A, Kazlauskaite R, Grines CL. Late Outcomes in the Medicine vs. Angiography for Thrombolytic Exclusion (MATE) Study. Circulation, 1997;96:I-595-596 [oral].

  23. Background • The majority of patients with acute ischemic syndromes are not considered candidates for thrombolysis* • The Medicine vs. Angiography for Thrombolytic Exclusion (MATE) Study was a randomized, prospective, multicenter trial of triage angiography performed in the first 24 hours of admission vs. conventional medical care in 201 patients with acute ischemic syndromes considered ineligible for thrombolysis *Cragg, D.R., Friedman, H.Z., Bonema, J.D., Jaiyesimi, I.A., Ramos, R.G., Timmis, G.C., O'Neill, W.W., Schreiber, T.L. Outcome of patients with acute myocardial infarction who are ineligible for thrombolytic therapy. Ann.Intern.Med. 115:173-177, 1991.

  24. M.A.T.E.Southeast Michigan Participating Centers William Beaumont Hospital, n=168 Botsford Hospital, n=15 Riverside Hospital, n=10 Providence Hospital, n=8

  25. Baseline Characteristics Triage AngiographyConservative Care Mean age 57 61 Females:Males 34:77 38:52 Prior AMI 23 (21%) 20 (22%) Prior CABG 10 (9%) 9 (10%) ST  36 (22%) 25 (28%) ST  24 (22%) 23 (26%) T wave  49 (44%) 37 (41%) ECG ineligible 85 (77%) 74 (83%) Sx > 6 hours 55 (50%) 38 (43%)

  26. Treatment Triage AngiographyConservative Care Sx onset to ED 9 ± 6 hrs 9 ± 7 hrs Sx onset to angio 16 ± 14 hrs (n=109) 84 ± 92 hrs (n=54)* Aspirin 109 (98%) 88 (98%) Heparin IV 106 (96%) 89 (99%) Beta Blockers IV/PO 63 (57%) 63 (70%) NTG IV 106 (96%) 86 (96%) PTCA performed 48 (43%) 27 (30%) CABG 18 (16%) 7 (8%) *non-protocol angiography  p=.05  p=.07

  27. In-Hospital Clinical Endpoints Triage AngiographyConservative Care P-value Confirmed AMI 57 (51%) 49 (54%) 0.81 CP + ECG/HD ’s 3 (3%) 12 (13%) 0.004 CP - ECG/HD ’s 9 (8%) 21 (23%) 0.003 Reinfarction 2 (2%) 0 (0%) 0.5 In-hospital death 1 (1%) 3 (3%) 0.3 Composite 14 (13%) 31 (34%) 0.0002 (All recurrent ischemic events or death)

  28. Clinical Benefit of Triage AngiographyReduction of Recurrent Ischemic Events and Death Definite AMI by CK P<0.001 ST  or LBBB P=0.002 ST  or TWI P=0.03 All Patients P<0.001 RR=0.55 (95% CI .41-.63) Number needed to treat (NNT) = 5 RR=1

  29. Translation of Benefit • Does a reduction of in-hospital recurrent ischemic events by early angiography and revascularization, when indicated, translate into a benefit after discharge with respect to rates of re-hospitalization, later angiography and revascularization, and recurrent AMI, development of CHF, or death?

  30. Follow-up Protocol • Subjects underwent a structured phone interview at a median time of 22 months after the index event • Interviewers were blinded to the randomization arm • Endpoints were confirmed by medical record abstraction and personal physician contact • 12 subjects, unable to be tracked, were submitted to the National Death Registry which confirmed vital status for complete follow-up on all 201 subjects

  31. Late Results Triage AngiographyConservative CareP-value Hospitalization 25 (23%) 20 (22.2%) 0.87 Recurrent AMI 2 (2%) 2 (2%) 0.86 Developed CHF 9 (8%) 5 (6%) 0.45 Late Angiography 14 (13%) 18 (20%) 0.20 Late PTCA 13 (12%) 9 (10%) 0.66 Late CABG 2 (2%) 3 (3%) 0.51 Death 11 (10%) 6 (7%) 0.44 Composite Endpoint* 32 (29%) 20 (22%) 0.29 *AMI, CHF, PTCA, CABG or death

  32. Conservatively Treated Subgroup N = 38, 36 from the conservative arm and 2 from the invasive arm who ultimately did not undergo angiography during the hospitalization 38 cases 4 (11%) late deaths median 12 mo.. 2 MI’s 3 CHF 12 (32%) Caths 23 (60%) managed on meds median 26 mo.. F/U 6 PTCA’s 1 CABG

  33. Freedom from Hospitalization Conservative Care Triage Angiography P>0.05 by log rank

  34. Freedom from Late PTCA Conservative Care Triage Angiography P>0.05 by log rank

  35. Composite Endpoint AMI, CHF, Late Revascularization, or Death Conservative Care Triage Angiography P>0.05 by log rank

  36. Long-term Survival Conservative Care Triage Angiography P>0.05 by log rank

  37. Power and Sample Size • This follow-up study had a 80% power to detect a 100% effect size in the crude composite endpoint between the two groups (=.05, two-tailed) • A future study would need ~1100 patients in each group to detect an effect size of 20% (ß=.20, =.05) in the composite endpoint • Similarly, ~7700 patients in each arm would be needed to detect a 20% effect size in mortality between the two strategies

  38. ConclusionsIn Patients with Acute Ischemic Syndromes Ineligible for Thrombolysis • A strategy of triage angiography reduces in-hospital recurrent ischemic events • Follow-up revealed equivalent event rates in each randomization arm • The choice of early angiography and revascularization versus conservative medical therapy presents a trade-off resulting in similar long-term outcomes • Large randomized trials are needed to formally test for a mortality difference between these two strategies

  39. Pre-empting Ischemic Events Stabilize Medically Manage 90% 30% Index Event Recurrent Ischemia Persistent Ischemia Troponin Elevation Reinfarction by CPK 10% Late death or MI

  40. Timing of Intervention

  41. MATE Resources McCullough PA, O’Neill WW, Graham M, David S, Stomel R, Rogers F, Grines CL. A Prospective Randomized Trial of Triage Angiography in Suspected Acute Myocardial Infarction Patients Who are Considered Ineligible for Reperfusion Therapy. Circulation 1996;94:I-570 [oral]. McCullough PA, O’Neill WW, Graham M, David S, Stomel R, Rogers F, Farhat A, Kazlauskaite R, Grines CL. Late Outcomes in the Medicine vs. Angiography for Thrombolytic Exclusion (MATE) Study. Circulation, 1997;96:I-595-596 [oral]. McCullough PA, Al-Zagoum M, Graham M, David S, Stomel R, Rogers F, Farhat A, Kazlauskaite R, Grines CL, O’Neill WW. A Time to Treatment Analysis in the Medicine vs. Angiography for Thrombolytic Exclusion Trial. Cathet Cardiovasc Diag 1998;44:105 [oral]. McCullough PA, Al-Zagoum M, O’Neill WW, Graham M, David S, Stomel R, Rogers F, Farhat A, Kazlauskaite R, Grines CL. A Program of Triage Angiography in Acute Coronary Syndromes Ineligible for Thrombolysis: An Efficacy Analysis. Cathet Cardiovasc Diag 1998;44:105[poster]. McCullough PA, O’Neill WW, Graham M, Stomel RJ, Rogers F, David S, Farhat A, Kazlauskaite R, Al-Zagoum M, Grines CL. A Prospective Randomized Trial of Triage Angiography in Acute Coronary Syndromes Ineligible for Thrombolytic Therapy: Results of the Medicine versus Angiography in Thrombolytic Exclusion (MATE) Trial. J Am Coll Cardiol 1998;32:596-605. NLM CIT. ID: 98412530. McCullough PA, O'Neill WW. Unstable Angina: Early Use of Coronary Angiography and Intervention.Cardiol Clin 1999;17(2):373-386. NLM CIT. ID: 10384833. McCullough PA, O’Neill WW, Graham M, Stomel RJ, Rogers F, David S, Farhat A, Kazlauskaite R, Al-Zagoum M, Grines CL. Impaired Culprit Vessel Flow in Acute Coronary Syndromes Ineligible for Thrombolysis. J Thromb Thrombolysis 2000;00:000-000 McCullough PA, O’Neill WW, Graham M, Stomel RJ, Rogers F, David S, Farhat A, Kazlauskaite R, Al-Zagoum M, Grines CL. A Time to Treatment Analysis in the Medicine versus Angiography in Thrombolytic Exclusion (MATE) Trial. J Inv Card 2000;00:000-000.

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