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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].
MATE
Medicine vs Angiography in Thrombolytic (Reperfusion) Exclusion Patients
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.
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.
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
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
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
Baseline CharacteristicsCharacteristic Conservative Triage Angiogram 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
Presentation
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
FeatureConservative Triage Angiogram
P-value
Reasons for Reperfusion IneligibilityReason Conservative Triage Angiogram
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
Pain free 7 (8%) 17 (15%) ns
Miscellaneous 13 (15%) 15 (13%) ns
Results
OutcomeConservative Triage
AngiogramPercent Risk
Reduction withTriage Angiogram
(95% CI)
P-value
Mean Peak CPK 461 562 - ns
Ruled in for MI 49 (56%) 66 (58%) - ns
Chest Pain with ECG or
Hemodynamic changes
10 (12%) 4 (4%) 42% (16%-60%) .03
Chest Pain without ECGchanges
21 (24%) 9 (8%) 45% (25%-59%) .002
Reinfarction 0 (0%) 2 (2%) - ns
Death 2 (2%) 1 (1%) 35% (-46%-71%) ns
Aggregate Recurrent
Ischemic Events or Death
30 (34%) 15 (13%) 45% (26%-59%) 0.0004
Infarction Subgroup
OutcomeConservative
(n=49)Triage
Angiogram(n=66)
Percent RiskReduction withTriage Angiogram
(95% CI)
P-value
Peak CPK 728 887 - ns
Ischemic Events or Death
Chest Pain with ECG orHemodynamic changes
8 (16%) 3 (5%) 46% (16%-65%) 0.05
Chest Pain without ECGchanges
14 (29%) 2 (13%) 60% (44%-71%) 0.0001
Reinfarction 0 (0%) 1 (2%) - ns
Death 1 (2%) 0 (0%) - ns
Aggregate Recurrent 21 (43%) 6 (9%) 59% (41%-72%) 0.00003
ST Elevation or LBBB Subgroup
Outcome
Conservative
(n=28)
Triage Angiogram
(n=40)
Percent Risk
Reduction with
Triage Angiogram
(95% CI)
P-value
Mean Peak CPK 490 847 - ns
Ruled in for MI 19 (68%) 32 (80%) - ns
Chest Pain with ECG orHemodynamic Changes
5 (18%) 2 (5%) 47% (7%-70%) ns
Chest Pain without ECGChanges
12 (45%) 5 (15%) 56% (26%-73%) 0.004
Reinfarction 0 (0%) 2 (5%) - ns
Death 1 (4%) 0 (0%) - ns
Aggregate RecurrentIschemic Events or Death
15 (54%) 9 (23%) 53% (18%-73%) 0.009
ST Depression or T-wave Inversion Subgroup
OutcomeConservative
(n=28)
Triage Angiogram
(n=40)
Percent RiskReduction with
Triage Angiogram
(95% CI)
P-value
Mean Peak CPK 546 505 - ns
Ruled in for MI 20 (54%) 27 (56%) - ns
Chest Pain with ECG orHemodynamic Changes
3 (8%) 1 (2%) 44 (-4%-70%) ns
Chest Pain without ECGChanges
4 (11%) 3 (6%) 26% (-48%-63%) ns
Reinfarction 0 (0%) 0 (0%) - ns
Death 1 (3%) 1 (2%) 13% (-254%-79%) ns
Aggregate RecurrentIschemic Events or Death
8 (22%) 4 (8%) 60 (3%-63%) ns
Female Subgroup
Outcome
Conservative
(n=38)
Triage Angiogram
(n=34)
Percent RiskReduction with
Triage Angiogram (95% CI)
P-value
Mean Peak CPK 403 456 - nsRuled in for MI 21 (55%) 19 (56%) - nsChest 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%) 0.01Reinfarction 0 (0%) 0 (0%) - nsDeath 0 (0%) 1 (2.9%) - ns
Aggregate Recurrent Ischemic Events or Death
16 (42%) 4 (12%) 47% (22%-64%) 0.004
Death or Recurrent Ischemia
null = 1
ST Elevation or LBBB
Definite MI
Entire Group
RR = 0.47
RR = 0.41
RR = 0.55
RR = 0.40ST Depression or TWI
Conservativecare better
Triage Angiography better
-------><-------
Early Discharge
18%
45%
62%65%
0%
10%
20%
30%
40%
50%
60%
70%
MI (-) MI (+)
LOS < 2 days LOS < 5 days
p=0.00007 p=0.03
TriageAngiogram
ConservativeCare
Hospital Costs
Control,n=70
TriageAngio,n=93
$7,335
$11,239
$0
$2,000
$4,000
$6,000
$8,000
$10,000
$12,000
Control,n=70
TriageAngio,n=93
p=0.04
True hospital costs after adjustment for outliers
Safety of Triage Angiography
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
Complications
0 (0%) 1 (1%) ns
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
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)
Late Outcomes in the Medicine vs. Angiography for Thrombolytic
Exclusion StudyPeter 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].
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.
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
WBH84%
BOTS7%
RVS5%
PROV4%
Baseline Characteristics Triage AngiographyTriage Angiography Conservative CareConservative Care Mean age 57 61Mean age 57 61Females:Males 34:77 38:52Females:Males 34:77 38:52Prior AMI 23 (21%) 20 (22%)Prior AMI 23 (21%) 20 (22%)Prior CABG 10 (9%) 9 (10%)Prior CABG 10 (9%) 9 (10%)
ST ST 36 (22%) 25 (28%) 36 (22%) 25 (28%)ST ST 24 (22%) 23 (26%) 24 (22%) 23 (26%)T wave T wave 49 (44%) 37 (41%) 49 (44%) 37 (41%)
ECG ineligible 85 (77%) 74 (83%)ECG ineligible 85 (77%) 74 (83%)Sx > 6 hours 55 (50%) 38 (43%)Sx > 6 hours 55 (50%) 38 (43%)
Treatment Triage AngiographyTriage Angiography Conservative CareConservative CareSx onset to ED 9 ± 6 hrs 9 ± 7 hrsSx onset to ED 9 ± 6 hrs 9 ± 7 hrsSx onset to angio 16 ± 14 hrs (n=109) 84 ± 92 hrs (n=54)*Sx onset to angio 16 ± 14 hrs (n=109) 84 ± 92 hrs (n=54)*
Aspirin 109 (98%) 88 (98%)Aspirin 109 (98%) 88 (98%)Heparin IV 106 (96%) 89 (99%)Heparin IV 106 (96%) 89 (99%)Beta Blockers IV/PO 63 (57%) 63 (70%)Beta Blockers IV/PO 63 (57%) 63 (70%)NTG IV 106 (96%) 86 (96%)NTG IV 106 (96%) 86 (96%)
PTCA performed 48 (43%) 27 (30%)PTCA performed 48 (43%) 27 (30%) CABG 18 (16%) 7 (8%)CABG 18 (16%) 7 (8%)
*non-protocol angiography *non-protocol angiography p=.05 p=.05 p=.07 p=.07
In-Hospital Clinical Endpoints
Triage AngiographyTriage Angiography Conservative Care Conservative Care P-valueP-value
Confirmed AMI 57 (51%) 49 (54%) 0.81Confirmed AMI 57 (51%) 49 (54%) 0.81CP + ECG/HD CP + ECG/HD ’s 3 (3%) 12 (13%) 0.004’s 3 (3%) 12 (13%) 0.004CP - ECG/HD CP - ECG/HD ’s 9 (8%) 21 (23%) 0.003’s 9 (8%) 21 (23%) 0.003Reinfarction 2 (2%) 0 (0%) 0.5Reinfarction 2 (2%) 0 (0%) 0.5In-hospital death 1 (1%) 3 (3%) 0.3In-hospital death 1 (1%) 3 (3%) 0.3
Composite 14 (13%) 31 (34%) 0.0002Composite 14 (13%) 31 (34%) 0.0002(All recurrent ischemic events or death) (All recurrent ischemic events or death)
Clinical Benefit of Triage AngiographyReduction of Recurrent Ischemic Events and Death
RR=1RR=1
P<0.001P<0.001
P<0.001P<0.001
P=0.002P=0.002
P=0.03P=0.03
Definite AMI by CKDefinite AMI by CK
ST ST or LBBB or LBBB
ST ST or TWI or TWI
All PatientsAll Patients
RR=0.55 (95% CI .41-.63)RR=0.55 (95% CI .41-.63)
Number needed to treat (NNT) = 5Number needed to treat (NNT) = 5
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?
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
Late Results Triage AngiographyTriage Angiography Conservative CareConservative Care P-valueP-value
Hospitalization 25 (23%) 20 (22.2%) 0.87Hospitalization 25 (23%) 20 (22.2%) 0.87Recurrent AMI 2 (2%) 2 (2%) 0.86Recurrent AMI 2 (2%) 2 (2%) 0.86Developed CHF 9 (8%) 5 (6%) 0.45Developed CHF 9 (8%) 5 (6%) 0.45Late Angiography 14 (13%) 18 (20%) 0.20Late Angiography 14 (13%) 18 (20%) 0.20Late PTCA 13 (12%) 9 (10%) 0.66Late PTCA 13 (12%) 9 (10%) 0.66Late CABG 2 (2%) 3 (3%) 0.51Late CABG 2 (2%) 3 (3%) 0.51Death 11 (10%) 6 (7%) 0.44Death 11 (10%) 6 (7%) 0.44
Composite Endpoint* 32 (29%) 20 (22%) 0.29Composite Endpoint* 32 (29%) 20 (22%) 0.29
*AMI, CHF, PTCA, CABG or death*AMI, CHF, PTCA, CABG or death
Conservatively Treated Subgroup
N = 38, 36 from the conservative arm and 2 from the invasive armN = 38, 36 from the conservative arm and 2 from the invasive armwho ultimately did not undergo angiography during the hospitalizationwho ultimately did not undergo angiography during the hospitalization
38 cases38 cases
23 (60%) managed23 (60%) managed on medson meds
median 26 mo.. F/Umedian 26 mo.. F/U
4 (11%) late deaths4 (11%) late deathsmedian 12 mo..median 12 mo..
12 (32%) Caths12 (32%) Caths
6 PTCA’s6 PTCA’s 1 CABG1 CABG
2 MI’s2 MI’s 3 CHF3 CHF
Freedom from HospitalizationRehospitalization
Months Since Index Event
363024181260
Cu
mu
lativ
e S
urv
iva
l
1.0
.9
.8
.7
.6 P>0.05 by log rankP>0.05 by log rank
Conservative CareConservative Care
Triage AngiographyTriage Angiography
Freedom from Late PTCALate PTCA after Discharge
Time to Late PTCA in Months
363024181260
Cu
mu
lativ
e S
urv
iva
l
1.0
.9
.8
.7 P>0.05 by log rankP>0.05 by log rank
Conservative CareConservative Care
Triage AngiographyTriage Angiography
Composite EndpointComposite Endpoint
Months after Index Event
363024181260
Cu
mu
lativ
e S
urv
iva
l
1.0
.9
.8
.7
.6
AMI, CHF, Late Revascularization, or Death
Triage AngiographyTriage Angiography
Conservative CareConservative Care
P>0.05 by log rankP>0.05 by log rank
Long-term SurvivalLong-term Survival
Months after Index Event
363024181260
Cu
mu
lativ
e S
urv
iva
l
1.0
.9
.8
.7
Triage AngiographyTriage Angiography
Conservative CareConservative Care
P>0.05 by log rankP>0.05 by log rank
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
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
Pre-empting Ischemic Events
IndexEvent
Stabilize
PersistentIschemia
Medically Manage
RecurrentIschemia
TroponinElevation
Reinfarctionby CPK
Late death or MI
90%
10%
30%
Timing of Intervention
Study AMI% Timing PTCA%
CABG LatePTCA
LateCABG
LateDeath
MATE 52% 16 43% 16% 10% 3% 10%/7%
TIMI3b
32% 36 38% 25% 21% 11%
VANQWISH
100% 72-168 26% 30% - - -
MATE Resources
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.
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].
