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From Good Samaritan Hospital, Los Angeles, Calif (R.A.K., T.S., K.P.);
the University of Southern California, Los Angeles (R.A.K., K.P.); Brigham and
Womens Hospital and Harvard Medical School, Boston, Mass (E.M.A., C.P.C.,
C.H.M., E.B.); and Covance Inc, Princeton, NJ (K.Y.).
Correspondence to Robert A. Kloner, MD, PhD, Heart Institute, Good Samaritan Hospital, 1225 Wilshire Blvd, Los Angeles, CA 90017.
Methods and Results—We prospectively determined the importance of
the time of onset of preinfarction angina in relation to 30-day
outcomes in the TIMI-9B study from standardized forms. Of the 3002
patients entered into the study, 425 reported angina before their
myocardial infarction. Patients with angina onset within 24 hours of
infarction had a lower 30-day cardiac event rate (mortality, recurrent
myocardial infarction, heart failure, or shock) at 4% than those with
onset of angina >24 hours (17%; P=.030). A history of
any angina alone was not associated with reduced event rate. Peak
creatine kinase levels tended to be lower in the group with angina
within 24 hours. These benefits were not due to higher rates of use of
antianginal medicines or aspirin and were not a consequence of
differences in baseline characteristics or disease states
(hypertension, hypercholesterolemia) among
subgroups.
Conclusions—These temporal observations are consistent
with the concept of preconditioning by preinfarction angina but do not
rule out other mechanisms.
The following cumulative major cardiac events within 30 days of
admission for hospitalization were noted: death, recurrent MI,
new-onset (>4 hours after randomization) severe congestive heart
failure (rales over more than half the lung fields and
pulmonary congestion on chest radiograph), or new-onset (>4
hours after randomization) cardiogenic shock (end-organ hypoperfusion,
systolic pressure <90 mm Hg without inotropic or
intra-aortic balloon support or >90 mm Hg requiring inotropic or
intra-aortic balloon support in the setting of adequate volume
expansion). The definition of recurrent MI was based on ECG and enzyme
criteria.7 Creatine kinase (CK) levels were
obtained at baseline, every 8 hours x2 on the first day, and then
daily. Peak CK units were also recorded. Event rate and CK release
were compared among patients with time between onset of angina and MI
Table 1
Table 2
Table 3
For example, preinfarction angina may initiate the development of new
collateral vessels, which could be protective. Although previous
studies found no difference in the presence of large epicardial vessels
in patients with antecedent angina,1 2 3 4 the
contribution of small intramural or microvascular collaterals not
detected by coronary angiography cannot be excluded. However,
in the present study, it is unlikely that the beneficial effects of
preinfarction angina occurring within 24 hours before infarction are
due to new collateral growth because new collaterals require >24
hours to develop. Another potential explanation is that angina
This study is, in some respects, similar to previous ones investigating
the effect of preinfarction angina on outcome. Like others,
preinfarction angina was beneficial1 2 3 4 5 6 12 in
that it was associated with lower CK values and better outcomes.
However, in this study, our goal was to assess the importance of timing
of onset of angina. In our study, preinfarction angina was only
beneficial for event rate when the time between onset of angina and MI
was within 24 hours; a history of any angina alone was not associated
with a lower event rate. Why this benefit was observed only when angina
occurred within 24 hours while other studies have suggested that any
preinfarction angina is protective is not clear. Certainly the timing
suggests a preconditioning mechanism. The fact that any angina was
associated with a lower peak CK but not event rate suggests that a
preconditioning effect on event rate may be related to more than just
extent of necrosis and could involve effects on factors such as left
ventricular function and vascular stability. Also, one
recent preliminary report13 suggested that only
prodromal angina within 24 hours of the infarction was associated with
improved long-term prognosis. There are other important differences
between this and previous reports. First and most notably, this is one
of the few prospective studies that has investigated preinfarction
angina in a large multicenter trial looking at separate time periods
before infarction. Second, the percentage of patients with
preinfarction angina in the present study was lower than that
reported in our own previous analysis of the TIMI-4
study.1 The reasons for this difference in TIMI-9
compared with TIMI-4 is not known but may represent differences
in the populations studied. Finally, in TIMI-4, any preinfarction
angina appeared to confer protection, while in this study angina within
24 hours was most protective compared with angina before 24 hours. We
did not, however, perform a detailed time between onset of angina and
MI analysis in the TIMI-4 study. Thus the novel observation of
the present prospective temporal analysis is that onset of
angina within 24 hours of MI is associated with a lower 30-day cardiac
event rate and trend toward lower peak CK compared with angina before
24 hours.
One limitation of this type of study is that it is not possible to
obtain controlled data regarding how much silent ischemia might
have occurred before infarction. None of the patients were or could
have been fitted with ambulatory ECG monitors before their MI. It is
certainly conceivable that silent ischemia might have had a
potential additive effect on preconditioning. A recent study by Sandhu
et al14 performed in a rabbit MI model showed
that three cycles of ischemic preconditioning were more
effective than one cycle in reducing infarct size. It is possible that
some patients in our study had silent ischemia, which could
have further preconditioned the myocardium. However, it is
likely that those patients with some angina were more likely to also
have silent ischemia.
Why patients who had onset of preinfarction angina within 24 hours also
had more hypertension and a trend toward more
hypercholesterolemia is unknown. However, it is
interesting that despite a higher incidence of these risk factors, the
patients still had better early outcomes than patients without
preinfarction angina. There was a trend, although not statistically
significant, for patients with angina >24 hours to have more prior MI.
Although we cannot rule out the possibly that this contributed to a
worse outcome, in the TIMI-4 study patients with previous MI were more
likely to have prior angina, which was associated with a better
outcome.1
One potential clinical implication is that if infarctions are smaller
in patients who have angina within 24 hours of infarction, the window
of opportunity for thrombolysis may be wider. That is,
patients with this preinfarction angina may potentially benefit from
thrombolysis even if instituted beyond 12 hours. This
possibility remains to be tested in clinical trials. However, it
probably is worthwhile to question patients regarding the time of onset
of preinfarction angina in order to provide clues as to early
outcomes.
Received June 27, 1997;
revision received November 20, 1997;
accepted November 24, 1997.
2.
Ottani F, Galvani M, Ferrini D, Sorbello F, Limonetti
P, Pantoli D, Rusticali F. Prodromal angina limits infarct size: a role
for ischemic preconditioning. Circulation. 1995;21:291–297.
3.
Anzai T, Yoshikawa T, Asakura Y, Abe S, Meguro T,
Akaishi M, Mitamura H, Handa S, Ogawa S. Effect on short-term prognosis
and left ventricular function of angina pectoris prior to
first Q-wave anterior wall acute myocardial infarction. Am J
Cardiol. 1994;74:755–759.[Medline]
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4.
Anzai T, Yoshikawa T, Asakura Y, Abe S, Akaishi M,
Mitamura H, Handa S, Ogawa S. Preinfarction angina as a major predictor
of left ventricular function and long-term prognosis after
a first Q wave myocardial infarction. J Am Coll
Cardiol. 1995;26:319–327.[Abstract]
5.
Pasceri V, Cianflore D, Finocchiaro ML, Crea F, Maseri
A. Relation between myocardial infarction site and pain location in
Q-wave acute myocardial infarction. Am J Cardiol. 1995;75:224–227.[Medline]
[Order article via Infotrieve]
6.
Kloner RA, Muller J, Davis V. Effects of previous
angina pectoris in patients with first acute myocardial infarction not
receiving thrombolytics. Am J Cardiol. 1995;75:615–617.[Medline]
[Order article via Infotrieve]
7.
Antman EM, for the TIMI 9B Investigators. Hirudin in
acute myocardial infarction: thrombolysis and thrombin
inhibition in myocardial infarction (TIMI) 9B Trial.
Circulation. 1996;94:911–921.
8.
Kloner RA, Yellon D. Does ischemic
preconditioning occur in patients? J Am Coll Cardiol. 1994;24:1133–1142.[Abstract]
9.
Yellon DM. Baxter GF. A "second window of
protection" or delayed preconditioning phenomenon: future horizons
for myocardial protection? J Mol Cell Cardiol. 1995;27:1023–1034.[Medline]
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10.
Andreotti F, Pasceri V, Hackett DR, Davies GJ, Haider
AW, Maseri A. Preinfarction angina as a predictor of more rapid
coronary thrombolysis in patients with acute
myocardial infarction. N Engl J Med. 1996;334:7–12.
11.
Kloner RA, Gibson M, Cannon C, Braunwald E.
Preinfarction angina. N Engl J Med. 1996;335:59–60. Letter.
12.
Hata K, Kloner RA, Przyklenk K. Brief antecedent
ischemia attenuates platelet-mediated thrombosis in damaged
and stenotic canine coronary arteries.
Circulation. 1996;94(suppl I):I-558. Abstract.
13.
Ishihara M, Sato H, Kawagol T, Sakai K. Implication of
prodromal angina pectoris on long-term prognosis after acute myocardial
infarction. Circulation. 1996;94(suppl I):I-611–I-612.
14.
Sandhu R, Diaz R, Mao GD, Wilson GJ. Ischemic
preconditioning: differences in protection and susceptibility to
blockade with single-cycle versus multicycle transient
ischemia. Circulation. 1997;96:984–995.
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports
Prospective Temporal Analysis of the Onset of Preinfarction Angina Versus Outcome
An Ancillary Study in TIMI-9B
Abstract
Top
Abstract
Introduction
Methods
Results
Discussion
References
Background—The timing of onset of
angina before myocardial infarction in relation to outcome is
unknown.
Key Words: angina • myocardial infarction • trials
Introduction
Top
Abstract
Introduction
Methods
Results
Discussion
References
Preinfarction angina
pectoris has been suggested in some studies to have beneficial effects
on myocardial infarction (MI).1 2 3 4 5 6 The exact
mechanism of this protective effect is not known, but it may include
ischemic preconditioning. If preconditioning plays a role, then
anginal episodes closest to the time of infarction should have the most
benefit. However, there are few data available regarding the relation
between the time of onset of angina and outcome in MI. Moreover, many
of the previous analyses of angina and MI have been
retrospective rather than prospective.1 2 6 Thus
our objective was to assess prospectively the relation between the time
of onset of angina before MI and the incidence of primary end points of
the trial (death, recurrent MI, congestive heart failure, or shock)
during the first 30 days after MI in patients enrolled in the TIMI-9B
study. Our primary hypothesis was that patients in whom the time
between onset of angina and MI was within 24 hours would have different
outcomes compared with patients who had onset of angina >24 hours
before infarction.
Methods
Top
Abstract
Introduction
Methods
Results
Discussion
References
The study included 3002 patients with acute MI who were
randomized in the TIMI-9B study, a prospective trial designed to assess
the effect of hirudin versus heparin as adjunctive therapy to
thrombolysis.7 This study was an
ancillary study to TIMI-9B that was designed prospectively. Details
regarding the basic TIMI-9B protocol and inclusion and exclusion
criteria have been published elsewhere.7
Inclusion criteria for MI were ischemic discomfort 
30 minutes
in duration and ST-segment elevation 0.1 mV in two contiguous ECG
leads or new or presumably new left bundle branch block. The presence
or absence and date of onset of angina before MI was noted on
standardized forms. These forms were completed by trained research
coordinators, and independent monitoring of the data was carried out in
all patients. Instructions were provided to all investigators regarding
definition of angina: "Angina pectoris is a discomfort in the chest
with or without radiation to the arms, neck, or back, which is caused
by myocardial ischemia and can be associated with
disturbances in myocardial function, but not necrosis. This is
an important distinction because pain of infarction should not be
classified as angina. In most cases angina is precipitated by exertion
and is generally relieved by rest." In general, angina duration is
<20 to 30 minutes. Ischemic discomfort 30 minutes in
duration was in fact one aspect of eligibility criteria for inclusion
as MI, not angina in this protocol. "Angina is a constellation of
sensations with chest discomfort often described as `constricting,
crushing, heaviness, or squeezing.' It can be a vague numbness or
pressure sensation. In some patients `angina equivalents' are
present such as shortness of breath, fatigue, and belching. When
evaluating a patient's symptoms and daily limitations due to
ischemia, all features described by the patient must be taken
into consideration." 
24 hours, 48 hours, 72 hours, 1 week, 1 month, or >1 month before
infarction, and patients with no preinfarction angina. The data were
further analyzed to compare the outcomes between the patients
with preinfarction angina 24 hours versus those with angina >24
hours. The patient characteristics at baseline were compared between
those with angina 24 hours and those with angina >24 hours. For all
analyses, the 
2 test was applied for
categorical variables and one-way ANOVA for continuous
variables. Effects of potential confounding factors (including
previous disease and use of antianginal medications) were evaluated
with the Cochran-Mantel-Haenszel test and Breslow-Day test. All
statistics were performed by Corning Besselar Covance at
Princeton, NJ.
Results
Top
Abstract
Introduction
Methods
Results
Discussion
References
Of the 3002 patients enrolled in TIMI-9B, 425 reported angina
before their MI and 2577 did not. 
shows the event rates in relation
to the time between onset of reported angina and MI. There was a
difference in the event rate among these multiple categories
(P=.012, by 2). Patients in whom
the time between onset of reported angina and MI was within 24 hours
(24 hours) had lower event rates (4%) versus those in whom this
duration was >24 hours (17%; P=.03).
View this table:
[in a new window]
Table 1. Time of Onset of Angina shows the comparison of maximum
CK values in relation to the duration of reported onset of angina
before MI. Patients with angina 24 hours had a nonsignificant trend
toward lower maximum CK values (mean±SE, 1133±147) compared with
those with angina >24 hours (mean±SE, 1416±55 Units,
P=.09). In addition, patients in whom the time between onset
of angina and MI was within 24 hours had lower maximum CK values
(1133±147) compared with those without angina (1570±21;
P<.01). Patients with any history of angina had lower
maximum total values (1386±52) compared with those without any history
of angina (1570±21; P<.01). The duration between the
angina and the onset of infarction did not correlate with CK values or
outcomes when the duration was treated as a continuous rather than
categorical variable. However, the duration of 24 hours may be a
key point that divides patients into these two
heterogeneous groups.
View this table:
[in a new window]
Table 2. Time of Onset of Angina shows some of the characteristics
of patients in whom the time between onset of angina and MI was within
24 hours, in whom this duration was >24 hours, in whom there was any
history of angina and in whom there was no history of angina. Patients
with a history of hypertension were more likely to have angina 24
hours (P=.04 versus those with angina>24 hours). There was
a nonsignificant trend toward a higher frequency of
hypercholesterolemia (P=.06) among
patients with onset of angina 24 hours versus >24 hours. Patients
with angina >24 hours had a nonsignificant trend toward more aspirin
use than patients with angina 24 hours (P=.06). The
Breslow-Day test was used to examine homogeneity of differences in
event rates across levels of each confounding factor including use of
drugs. None of the drugs used and previous diseases affected the
association between the cardiac event rates and time of onset of
preinfarction angina.
View this table:
[in a new window]
Table 3. Summary of Patient Characteristics
Discussion
Top
Abstract
Introduction
Methods
Results
Discussion
References
The results of this prospective analysis suggest that the
benefit of preinfarction angina on clinical event in the TIMI-9B study
are only manifest when the time between onset of angina and MI are
within 24 hours. This time frame is consistent with (but not
proof of) the concept of cardioprotection by either "classic
preconditioning" and/or "delayed or late
preconditioning."8 9 With classic
preconditioning, the ischemic preconditioning episodes occur
within a few hours of infarction; with delayed or late preconditioning
the onset of ischemic preconditioning occurs 12 to 24 hours
after infarction. Some studies have even suggested that the
myocardium can be protected if the preconditioning occurs
48 to 72 hours before the infarction; although the results of the
present study suggest that in humans, brief ischemia needs
to occur within 24 hours to be protective. However, other potential
mechanisms besides preconditioning may play a role in the findings of
this study. 24
hours before MI is associated with better and earlier
thrombolysis.10 Because
angiography was not a required part of the current protocol, we do not
have systematic angiographic data. However, as part of the TIMI-4
study, we did observe that of 79 patients who had angina within 48
hours of infarction, 46% had TIMI grade 3 flow on 60-minute
angiograms, as compared with 34% of 140 patients with no angina.
Patients with preinfarction angina were less likely to have persistent
occlusion (TIMI grade 0) at 60 minutes (19%) compared with those
without angina (27%).11 In the current study (TIMI-9B) we
did not assess either collateral perfusion or time to angiographic
reperfusion, and these clearly are limitations. However, we have
recently observed that brief antecedent ischemia attenuates
platelet-mediated thrombosis and preserves vessel patency in
damaged and stenotic coronary
arteries.12 Finally, one could argue that the use
of antianginal medicines and aspirin might account for the benefit of
preinfarction angina. However, as indicated in Table 2
, there were no
significant differences in drug use among the cohorts, and the
Breslow-Day test showed that the drugs used did not affect the
association between onset time of angina and cardiac events.
Acknowledgments
We are indebted to Kisook Yoo, PhD, Qi Liu, and Juan T. Torres
of Covance and Corning Besselar for statistical analyses and
Cathy Davisson for preparation of the manuscript.
Footnotes
The complete list of TIMI-9B Investigators is found in the Appendix of reference 7.
References
Top
Abstract
Introduction
Methods
Results
Discussion
References
1.
Kloner RA, Shook T, Przyklenk K, Davis V, Junio L,
Matthews RV, Burstein S, Gibson M, Poole WK, Cannon CP, McCabe CH,
Braunwald E, for TIMI 4 Investigators. Previous angina alters
in-hospital outcome in TIMI 4: a clinical correlate to preconditioning?
Circulation. 1995;91:37–47.
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P. J. Gheeraert, J. P. S. Henriques, M. L. De Buyzere, M. De Pauw, Y. Taeymans, and F. Zijlstra Preinfarction angina protects against out-of-hospital ventricular fibrillation in patients with acute occlusion of the left coronary artery J. Am. Coll. Cardiol., November 1, 2001; 38(5): 1369 - 1374. [Abstract] [Full Text] [PDF]
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M. Ishihara, I. Inoue, T. Kawagoe, Y. Shimatani, S. Kurisu, K. Nishioka, Y. Kouno, T. Umemura, S. Nakamura, and H. Sato Diabetes mellitus prevents ischemic preconditioning in patients with a first acute anterior wall myocardial infarction J. Am. Coll. Cardiol., October 1, 2001; 38(4): 1007 - 1011. [Abstract] [Full Text] [PDF]
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H. Tomoda and N. Aoki Pathophysiology of Early Coronary Angioplasty with Stenting on Non-Q-Wave vs Q-Wave Myocardial Infarction Angiology, October 1, 2001; 52(10): 671 - 679. [Abstract] [PDF]
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G. Heusch Nitroglycerin and Delayed Preconditioning in Humans : Yet Another New Mechanism for an Old Drug? Circulation, June 19, 2001; 103(24): 2876 - 2878. [Full Text] [PDF]
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I. Iglesias-Garriz, F.e. Corral, M. A. Rodriguez, C. Garrote, M. Montes, and E. Sevillano Pre-infarction angina elicits greater myocardial viability on reperfusion after myocardial infarction: a dobutamine stress echocardiographic study J. Am. Coll. Cardiol., June 1, 2001; 37(7): 1846 - 1850. [Abstract] [Full Text] [PDF]
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 D. M. Yellon and A. Dana The Preconditioning Phenomenon : A Tool for the Scientist or a Clinical Reality? Circ. Res., September 29, 2000; 87(7): 543 - 550. [Abstract] [Full Text] [PDF]
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T. Miki, T. Miura, A. Tsuchida, A. Nakano, T. Hasegawa, T. Fukuma, and K. Shimamoto Cardioprotective Mechanism of Ischemic Preconditioning Is Impaired by Postinfarct Ventricular Remodeling Through Angiotensin II Type 1 Receptor Activation Circulation, July 25, 2000; 102(4): 458 - 463. [Abstract] [Full Text] [PDF]
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 W. E. Johnston Preconditioning the Brain and Heart: Implications for Cardiac Surgery Seminars in Cardiothoracic and Vascular Anesthesia, July 1, 2000; 4(2): 70 - 79. [Abstract] [PDF]
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C. Whan Lee, S.-W. Park, G.-Y. Cho, M.-K. Hong, J.-J. Kim, D.-H. Kang, J.-K. Song, H.-J. Lee, and S.-J. Park Pressure-derived fractional collateral blood flow: a primary determinant of left ventricular recovery after reperfused acute myocardial infarction J. Am. Coll. Cardiol., March 15, 2000; 35(4): 949 - 955. [Abstract] [Full Text] [PDF]
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T. Noda, S. Minatoguchi, K. Fujii, M. Hori, T. Ito, K. Kanmatsuse, M. Matsuzaki, T. Miura, H. Nonogi, M. Tada, et al. Evidence for the delayed effect in human ischemic preconditioning: Prospective multicenter study for preconditioning in acute myocardial infarction J. Am. Coll. Cardiol., December 1, 1999; 34(7): 1966 - 1974. [Abstract] [Full Text] [PDF]
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G. Liuzzo, L. M. Biasucci, J. R. Gallimore, G. Caligiuri, A. Buffon, A. G. Rebuzzi, M. B. Pepys, and A. Maseri Enhanced inflammatory response in patients with preinfarction unstable angina J. Am. Coll. Cardiol., November 15, 1999; 34(6): 1696 - 1703. [Abstract] [Full Text] [PDF]
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H.-S. V. Chen, S. C. Body, and S. K. Shernan Myocardial Preconditioning: Characteristics, Mechanisms, and Clinical Applications Seminars in Cardiothoracic and Vascular Anesthesia, July 1, 1999; 3(2): 85 - 97. [Abstract] [PDF]
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