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

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. ONeill,
  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, ONeill 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 199694I-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. 115173-177, 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 (lt 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
FemaleMale
3849
3479
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
Presentation
Conservative
Triage Angiogram
P-value
Feature
10
Reasons for Reperfusion Ineligibility
11
Results
Conservative
Triage
Percent Risk
Angiogram
Reduction with
Outcome
P-value
Triage Angiogram
(95 CI)
12
Infarction Subgroup
Conservative
Triage Angiogram
Percent Risk
P-value
(n49)
Reduction with
Outcome
Triage Angiogram
(n66)
(95 CI)
13
ST Elevation or LBBB Subgroup
Conservative
Triage Angiogram
Percent Risk
Reduction with
P-value
Outcome
(n28)
Triage Angiogram
(n40)
(95 CI)
14
ST Depression or T-wave Inversion Subgroup
Triage Angiogram
Percent Risk
Conservative
P-value
Outcome
Reduction with
(n28)
Triage Angiogram
(n40)
(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
Female Subgroup
Triage Angiogram
Percent Risk
Conservative
P-value
Reduction with
Triage Angiogram (95 CI)
Outcome
(n38)
(n34)
16
Death or Recurrent Ischemia
Conservative care better
Triage Angiography better
ST Elevation or LBBB
RR 0.47
RR 0.40
ST Depression or TWI
-------gt
lt-------
Definite MI
RR 0.41
RR 0.55
Entire Group
null 1
17
Early Discharge
p0.00007
p0.03
Triage Angiogram
Conservative Care
LOS lt 2 days
LOS lt 5 days
18
Hospital Costs
True hospital costs after adjustment for outliers
p0.04
19
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-1TAMI-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.
  ONeill, 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, ONeill 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, 199796I-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. 115173-177, 1991.
24
M.A.T.E.Southeast Michigan Participating Centers

• William Beaumont Hospital, n168
• Botsford Hospital, n15
• Riverside Hospital, n10
• Providence Hospital, n8

25
Baseline Characteristics
Triage Angiography
Conservative Care Mean age
57
61 FemalesMales 3477
3852 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 gt 6 hours
55 (50) 38 (43)
26
Treatment
Triage
Angiography Conservative Care Sx onset to ED
9 6 hrs
9 7 hrs Sx onset to angio 16
14 hrs (n109) 84 92 hrs
(n54) 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 Angiography
Conservative 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
Plt0.001
P0.002
ST ? or LBBB
P0.03
ST ? or TWI
All Patients
Plt0.001
RR0.55 (95 CI .41-.63)
Number needed to treat (NNT) 5
RR1
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
Angiography Conservative Care
P-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 MIs
3 CHF
12 (32) Caths
23 (60) managed on meds median 26 mo.. F/U
6 PTCAs
1 CABG
33
Freedom from Hospitalization
Conservative Care
Triage Angiography
Pgt0.05 by log rank
34
Freedom from Late PTCA
Conservative Care
Triage Angiography
Pgt0.05 by log rank
35
Composite Endpoint
AMI, CHF, Late Revascularization, or Death
Conservative Care
Triage Angiography
Pgt0.05 by log rank
36
Long-term Survival
Conservative Care
Triage Angiography
Pgt0.05 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, ONeill 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 199694I-570 oral.
McCullough PA, ONeill 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, 199796I-595-596 oral.
McCullough PA, Al-Zagoum M, Graham M, David S,
Stomel R, Rogers F, Farhat A, Kazlauskaite R,
Grines CL, ONeill WW. A Time to Treatment
Analysis in the Medicine vs. Angiography for
Thrombolytic Exclusion Trial. Cathet Cardiovasc
Diag 199844105 oral.
McCullough PA, Al-Zagoum M, ONeill 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
199844105poster.
McCullough PA, ONeill 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 199832596-605. NLM CIT. ID 98412530.
McCullough PA, O'Neill WW. Unstable Angina
Early Use of Coronary Angiography and
Intervention. Cardiol Clin 199917(2)373-386.
NLM CIT. ID 10384833.
McCullough PA, ONeill 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
200000000-000
McCullough PA, ONeill 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
200000000-000.