(Circulation. 2000;102:III-339.)
© 2000 American Heart Association, Inc.
Myocardial Protection and Vascular Biology |
Late Results of the Warm Heart Trial
The Influence of Nonfatal Cardiac Events on Late Survival
From the Divisions of Cardiovascular Surgery of Sunnybrook and Women’s College Health Sciences Centre, St Paul’s Hospital, Toronto General Hospital, Toronto, Onatario, Canada, and Institute for Clinical Evaluative Sciences.
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Abstract |
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Background—The Warm Heart Trial randomized 1732 CABG patients to receive warm or cold blood cardioplegia. In the warm cardioplegia patients, nonfatal perioperative cardiac events were significantly decreased and the mortality rate was nonsignificantly decreased (1.4% versus 2.5%, P=0.12). The purpose of the present study was to evaluate the late results of these trial patients.
Methods and Results—Randomization was stratified according to surgeon and urgency of the operation. Seven hundred sixty-two patients recruited from 1 of the centers were followed through the hospital clinic for late events. Late survival (including perioperative deaths) at 72 months was nonsignificantly greater in the warm cardioplegia patients (94.5±1.7%, mean±SEM) than in the cold cardioplegia patients (90.9±2.6%). Independent predictors of mortality by Cox proportional hazards model were redo CABG, diabetes mellitus, renal insufficiency, and increasing age. The influence of nonfatal perioperative events (perioperative myocardial infarction according to computerized ECG readings or low output syndrome as determined by an outcome committee) on late survival was also analyzed. Late survival at 84 months was significantly reduced in the group who experienced nonfatal perioperative outcomes (94.5±1.7% versus 84.9±4.5%, P<0.001) and remained a significant predictor after adjustment for other important variables (risk ratio 6.4, 95% CI 1.87 to 8.73, P<0.0001).
Conclusions—Effective myocardial protection through either cold or warm blood cardioplegia is essential, because late survival is significantly reduced in patients with nonfatal perioperative cardiac outcomes.
Key Words: bypass • cardioplegia • complications • survival • trials
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Introduction |
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In the Warm Heart Trial, 1732 patients who underwent isolated CABG were randomized to receive either normothermic or hypothermic blood cardioplegia.1 The results showed a nonsignificant decrease in mortality rates (1.4% versus 2.5%, relative risk 0.55, 95% CI, 0.28 to 1.11, P=0.12) in favor of the use of warm cardioplegia, similar rates of nonfatal myocardial infarction (MI) according to the computerized ECG readings (10.1% versus 11.1%), and a significant reduction in both low output syndrome (LOS) (6.1% versus 9.3%, relative risk 0.65, 95% CI 0.47 to 0.91, P=0.01) and MI determined with serial creatine kinase (CK)-MB sampling (12.3% versus 17.3%, relative risk 0.72, 95% CI 0.56 to 0.91, P<0.01). The difference in case-fatality rate was due to an increase in both cardiac (16 versus 10 deaths) and noncardiac (6 versus 2 deaths) mortality rates.
A sample size of 750 patients per group was calculated to provide 80%
power to detect a 50% reduction in the combined end point of early
death or nonfatal MI on computerized ECG analysis with the
assumption of a control event rate of 9%. The difference in early
mortality rates had emerged at the time of the planned interim
analysis (750 patients). A sample of 
3000 patients would
have been necessary to achieve statistical significance. Interestingly,
the relative risks for death, LOS, and enzymatic MI were similar,
suggesting that the difference in mortality rates may have been real
and potentially related to myocardial protection rather than due to
chance alone. On the other hand, the rates of Q-wave MI as determined
on computerized ECG analysis were consistent in the 2
groups, suggesting that technical difficulties related to
revascularization were primarily responsible for
this end point rather than differences due to myocardial protection.
(This conclusion was supported by the significant effect due to surgeon
[P=0.02] for the combined end point of death and nonfatal
ECG MI.1 ) We stopped the trial after 1732 patients
were recruited rather than attempt to enroll 3000 patients because the
projected sample size was exceeded, the budget was insufficient to
continue, and the study investigators were experiencing "trial
fatigue."
We postulated that the significantly increased incidence of nonfatal perioperative events in the group randomized to cold cardioplegia, specifically LOS and enzymatic MI, may be associated with increased late mortality rates (ie, leading to improved survival in the warm treatment group late after surgery). In support of this hypothesis is the well described (albeit inconsistent) decrement in the survival of patients after perioperative MI.2 3 The late effect of perioperative LOS or enzymatic (presumably non–Q-wave) MI for hospital survivors is less well described. Late survival is affected, however, in patients undergoing PTCA who have had non–Q-wave MI as determined on the basis of increased periprocedural CK-MB levels.4
The objective of the present study was to evaluate the late results of the Warm Heart Trial with respect to survival. Our underlying hypotheses were that (1) nonfatal perioperative cardiac events are associated with reduced late survival and (2) because nonfatal perioperative cardiac events and mortality rates were decreased in the warm cardioplegia treatment arm, late survival will therefore be enhanced in the warm cardioplegia patients. The Warm Heart Trial was designed to assess perioperative events rather than late survival. For this reason, the current study was completed through an evaluation of the late outcome of trial patients from 1 of the 3 participating centers through its follow-up clinic.
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Methods |
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Protocol
The protocol of the Warm Heart Trial has been presented in detail previously.1 The study was conducted at the 3 adult centers of cardiac surgery at the University of Toronto from November 5, 1990, to December 31, 1992. Patients who underwent isolated CABG were eligible for inclusion in the study. Relative contraindications were hemodynamically significant cerebrovascular disease and renal insufficiency. Patients who proceeded directly from the catheterization laboratory to the operating room were ineligible. Each eligible patient signed a consent form approved by the institutional ethics review board. Randomization was stratified by urgent versus elective surgery and by participating surgeon. Treatment allocation was made with the sealed envelope method, which occurred after the patient’s arrival at the operating room. Of the 1732 patients enrolled into the study, 762 were recruited from the Sunnybrook site (warm cardioplegia n=378, cold cardioplegia n=384) and constitute the patient population for the present study.
The surgical techniques have been described in detail
previously.1 5 Briefly, cardiopulmonary bypass was
established with a single 2-staged right atrial cannula and ascending
aortic perfusion cannula and an ascending aortic cardioplegic
cannula/vent line. Cardiopulmonary bypass management included
membrane oxygenators, arterial line filters, nonpulsatile
flows of 2.4 L · min-1 ·
m-2, mean arterial pressure of 50 to
80 mm Hg, moderate hemodilution with a hematocrit of >20%, and
-stat acid-base balance. In the warm cardioplegia treatment group,
the systemic temperature was 33° to 37°C compared with 25° to
30°C by active cooling in the cold cardioplegia group. The blood
cardioplegia for both groups was prepared by mixing
oxygenated blood with a crystalloid additive (Fremes’
solution)1 in a 4:1 ratio, which was delivered in an
intermittent, antegrade manner.5 In the warm cardioplegia
group, cardioplegia was administered at 37°C, and in the cold
cardioplegia group, it was delivered at 5° to 8°C.
Patients had serial ECGs taken before surgery, 1 day after surgery, and 5 days after surgery; the ECGs were digitized and transferred to the University of Alberta Cardiac Epidemiology Coordinating Research Center for computerized ECG analysis.6 Blood samples for CK-MB analysis were obtained at 0, 4, 8, 12, 20, and 28 hours after the patient’s arrival at the intensive care unit. Records of any patients who received an intra-aortic balloon pump or inotropic support in the intensive care unit were photocopied, stripped of patient identifiers, and reviewed by an adjudicating committee. All patients were contacted at 30 days after surgery by the research personnel.
Warm Heart Trial Outcome Measures
The primary end points of the Warm Heart Trial were 30-day,
all-cause mortality and nonfatal Q-wave MI according to computerized
ECG analysis.1 Patients who were hospitalized for
>30 days but who subsequently died in hospital were counted as
perioperative deaths consistent with the
recommendations of the Society for Thoracic Surgeons.7
Secondary outcomes of the Warm Heart Trial were postoperative
LOS and enzymatic MI according to the CK-MB area of the curve. LOS was
defined as the requirement of inotropes or intra-aortic balloon pump
support, or both, for >60 minutes to maintain the cardiac index at
>2.2 L · min-1 ·
m-2 and the systolic blood pressure at
>90 mm Hg in association with a wedge pressure of 
18
mm Hg. The diagnosis of LOS required a 2-of-3 decision by the LOS
committee, which consisted of 3 intensivists. Enzymatic MI was defined
from serial CK-MB sampling for an area under the curve of >645 IU*h.
This cut point had been validated from previously collected information
regarding technetium pyrophosphate
scans.8
Sunnybrook Site Protocols and Late Follow-Up
Data on >200 demographic, angiographic, operative, and
outcome-related variables were collected prospectively by our
research assistant.
Patients were reviewed in the hospital clinic by the operating surgeon at 3 months after surgery. They were encouraged to return to the clinic for subsequent visits at 1, 3, 5, and 7.5 years after surgery. At each clinic visit, a data form was completed and entered into the computerized database. The patients’ follow-up records were also supplemented from the referring physicians’ correspondence.
Statistical Analysis
The primary outcome measure of the present study was late
death. The primary analysis compares late mortality rates
between the 2 cardioplegia groups for all study patients recruited from
the Sunnybrook site. Late mortality rates are also compared for the
hospital survivors who did or did not experience a nonfatal
perioperative cardiac event.
Data from the Warm Heart Trial concerning treatment assignment and
perioperative outcomes as originally defined were
merged with the data collected from Sunnybrook site concerning clinical
characteristics, angiographic data, operative characteristics, and late
mortality. Continuous data are summarized as mean±SD, categorical data
are given as a frequency or percentage, and late survival data in the
life tables are given as mean±SEM. Baseline between-group comparisons
were performed with unpaired Student’s t tests for
continuous data and 
2 or Fisher’s exact test
for categorical data. Late survival rates were compared between groups
by log-rank methods. Covariant adjustment was performed with
Cox proportional hazards model. Probability values are provided for
each comparison; statistical significance is assumed for
P<0.05. All statistical analyses were performed
with SAS for PC, Version 6.12 (SAS Institute).
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Results |
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Clinical characteristics of the warm and cold cardioplegia patients recruited from the Sunnybrook site are summarized in Table 1
. Apart from an excess of preoperative
hypertension in the warm cardioplegia patients, the baseline
variables were similar. Angiographic data are provided in Table 2. The groups were comparable in terms of
angiographic findings. Operative results are listed in Table 3. There was an excess of
coronary reoperations in the cold cardioplegia group compared
with the warm cardioplegia group, but the incidence was small in both
treatment arms (3.1% versus 0.8%, P=0.03).
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The early results from the Sunnybrook site are presented in
Table 4. The primary outcomes of the Warm
Heart Trial (ie, death and ECG-defined or Q-wave MI) were similar in
the 2 groups. The incidence of LOS was nonsignificantly reduced in the
warm cardioplegia versus the cold cardioplegia patients. An
intra-aortic balloon pump was inserted in 8 of the 8 warm cardioplegia
patients and in 14 of the 18 cold cardioplegia patients with LOS. The
incidence of enzymatic MI was significantly reduced in the warm
cardioplegia treatment arm.
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Actuarial survival rates for the warm and cold cardioplegia patients
are presented in Figure 1.
Survival rates were nonsignificantly increased in the warm cardioplegia
compared with the cold cardioplegia patients at 6 years after surgery
(P=0.56). At 6 years, the survival rate was 94.9±1.6%
versus 91.2±2.9% (P=0.50) when redo patients were excluded
from the analysis. Results of the proportional hazards model
are presented in Table 4
. Redo CABG, diabetes mellitus,
renal insufficiency, and increased age were associated with an
increased risk of late death, whereas the use of the left internal
thoracic artery and female sex were protective. The use of warm
cardioplegia did not significantly influence the late survival rates in
the multivariate analysis after adjustment for
other covariates (risk ratio 0.86, 95% CI 0.40 to 1.84,
P=0.70).
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The predicted survival rate was calculated for each patient according
to the significant risk variables from the proportional hazards
model plus Canadian Cardiovascular Society class, left
ventricular function, cerebrovascular and
peripheral vascular disease, and urgency of operation. The
individual patient results were ranked and then grouped into terciles.
Actuarial survival stratified for estimated risk without adjustment for
cardioplegic assignment is presented in Figure 2. Figure 3
shows the results in the highest risk tercile separately for warm
cardioplegia and cold cardioplegia patients.
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Effect of Perioperative Events on Late
Survival
Late survival rates for hospital survivors are presented
in Table 5. The linearized rate of late
death for patients who had a benign perioperative
course was 1.0%/y. Late survival rates were significantly reduced
after ECG-defined MI and LOS. Figure 4
depicts the actuarial survival rates for patients with and without
perioperative MI or LOS. Late survival rates were
nonsignificantly reduced in patients who had a
perioperative MI according to enzymatic criteria
(89.9±5.8% versus 93.8±1.7%, Table 5, Figure 5). To adjust for differences in baseline
risk profiles, separate individual Cox proportional hazards models were
analyzed including the individual nonfatal
perioperative cardiac events with other risk
variables. The results are summarized in Table 6 and show that Q-wave MI, LOS, or both
adversely affect late survival rates after adjustment for other
important risk variables. Nonfatal enzymatic MI with a threshold
value of 645 IU*h does not significantly influence late survival.
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Discussion |
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"Warm heart surgery" was introduced in the late 1980s9 10 and involved the infusion of blood cardioplegia at normothermic temperatures. It was argued that cardiac arrest was the predominant factor that reduced myocardial oxygen consumption, with minimal additional benefit from hypothermia. The Warm Heart Trial was designed to test for a 50% reduction in the combined end point of death or Q-wave MI. The study investigators expected a positive study result with an unbiased hard clinical end point to be very persuasive evidence for cardiac surgeons to adopt warm blood cardioplegia for CABG. Despite being one of the largest randomized clinical trials ever conducted in cardiac surgery, the Warm Heart Trial has had a smaller-than-expected impact, although enzymatic MI and LOS favored the use of warm cardioplegia, the primary outcomes did not differ between groups.
A systematic overview may also provide important clues regarding the relative benefit of warm versus cold blood cardioplegia. At least 17 trials that compared warm or tepid blood cardioplegia with cold blood or crystalloid cardioplegia have been published in peer-reviewed, English-language journals.1 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 Most of the studies enrolled <100 patients, whereas the Emory trial11 (which was stopped prematurely because of an excess of neurological events in the warm cardioplegia group) and the Toronto study1 each involved >1000 patients. Although the majority of the studies favored warm cardioplegia, smaller studies were generally powered only to detect differences in sensitive surrogate end points. Consistent with the Warm Heart Trial, 5 other studies demonstrated reduced cardiac enzyme release after surgery in the warm or tepid groups.12 14 20 22 26 Estimates of MI and LOS are more limited because of the small sample sizes of most of the studies and the lack of uniformity of definition; crude prevalence estimates by summing across trials were, however, reduced in the warm groups (MI 5.8% [125 of 2142 patients] versus 6.4% [138 of 2155 patients], LOS 9.7% [193 of 2142 patients] versus 12.1% [243 of 2155 patients]). The reporting of perioperative death is presumably more reliable from study to study and less subject to differences in definitions that may occur with nonfatal events. The aggregated data support a protective effect of warm cardioplegia regarding mortality; crude estimates were 1.3% (27 of 2095 patients) versus 1.9% (40 of 2074 patients). We recognized, however, that there are important limitations of overviews and that a single large study is generally stronger evidence.
The present study was conducted to determine whether any differences in late survival existed between the 2 groups, because a statistically significant improvement in late survival rates would also be very compelling evidence to support a particular method of myocardial protection. We postulated that patients who experienced a significant nonfatal perioperative cardiac event could be at an increased risk of subsequent death beyond the perioperative interval, especially if the perioperative event was associated with clinically important myocardial necrosis or ongoing congestive heart failure. Because all early fatal or nonfatal cardiac events favored the warm treatment arm (significantly or nonsignificantly), the warm cardioplegia group would therefore be expected to have a greater likelihood of late survival.
Perioperative Myocardial Infarction
Perioperative myocardial injury after cardiac
surgery has been detected with ECG criteria,2 3 various
serum markers,27 28 29 30 31 32 infarct avid scans,33
and wall motion studies.34 ECG changes with or without
CK-MB elevations are most commonly used. There are limitations of the
diagnostic accuracy (both sensitivity and specificity) of
each of these methods. The use of a combination of techniques may
improve the specificity and identify the clinically more relevant
infarctions. Chaitman et al2 and Schaff et
al3 both published the early and late effects of
perioperative MI from the Coronary Artery
Surgery Study (CASS) Registry. On the basis of new Q waves, Chaitman et
al reported that perioperative MI from data collected
during a single year of the study (incidence 4.6%) was associated with
a significant increase in early death but little subsequent decrement
in survival thereafter. Conversely, Schaff et al used ECG and
enzyme criteria (presumably both Q-wave and non–Q-wave MI, incidence
5.7%) and documented both an early and a late adverse effect on
survival. More recently, the EAST study investigators concluded that
perioperative Q waves, especially inferior
Q waves, were of minimal prognostic significance.35
Svedjeholm et al30 reported that early outcome was more
dependent on the levels of serum markers than Q waves alone, whereas
the worst results were observed in patients who had both elevated serum
markers and new Q waves. The use of a combination of serum markers and
ECG findings may underrepresent the true incidence of
perioperative MI but presumably identifies the infarcts
that are prognostically more important by reducing the number of
false-positive results.
Late survival rates at our institution were influenced to a greater
degree by Q-wave MI rather than by MI determined with CK-MB area under
the curve measurements. It is probable that the CK-MB threshold was
overly sensitive. Although useful for the computation of relative
differences for studies of myocardial protection, both clinically
significant and nonsignificant infarcts were captured with a cut point
of 645 IU*h. The incidence of perioperative MI is
routinely monitored in our institution according to the appearance of
new Q waves or left bundle-branch block in association with a CK-MB of
50 IU/L, which represents 7% of the total CK. The rates of
MI according to ECG plus enzyme criteria were 2.1% and 2.6% in the
warm and cold cardioplegia patients, respectively, which were much
lower than the estimates in these same patients according to ECG or
enzyme criteria alone. Late survival rates after hospitalization were
significantly decreased in patients with or without a clinically
defined MI (83.6±10.8% versus 93.6±1.6% at 72 months), and
perioperative MI remained a significant risk
variable after adjustment for other covariates (risk ratio 3.80,
95% CI 2.83 to 14.45, P=0.04). These point estimates for
late survival are remarkably similar to values for patients discharged
alive from the CASS Registry (85% versus 92% at 5
years).3 It is also noteworthy that the clinically
defined infarcts were prognostically more relevant than the
trial-defined MIs, although they were potentially more biased (Tables 5 and 6).
LOS as Predictor
LOS is a strong predictor of perioperative
death.36 Less is known concerning the late consequences of
perioperative LOS. For patients who had been treated
with an intra-aortic balloon pump, Golding et al37 noted
that 2-year survival rates were excellent in hospital survivors (96%)
on the basis of data collected in the 1970s. Both Naunheim et
al38 and Arafa et al39 presented
results for patients operated on in the 1980s. The 1-year mortality
rate was very high in both groups; for patients surviving 1 year, the
5-year mortality rate was still 20%, compatible with the findings
in our study.
The incidence of LOS is prospectively monitored in our institution with
criteria similar to those of the Warm Heart Trial. This diagnosis of
LOS is not vetted by an adjudication committee, only by chart review.
The incidence of LOS was 13.2% and 12.5% in the warm and cold
cardioplegia patients, respectively. It is important to recognize not
only that these estimates are much higher than those numbers determined
by the LOS committee (Table 4) but also that these estimates are
mainly composed of patients who received inotropic support alone, not
an intra-aortic balloon pump. Late survival rates after hospitalization
were reduced in patients with and without clinically defined LOS
(84.8±4.9% versus 94.6±1.7% at 72 months), and clinically defined
LOS remained an important predictor of late death after the adjustment
of other risk variables (risk ratio 4.5, 95% CI 2.15 to 9.42,
P<0.0001).
Study Limitations
There are several potential reasons why a significant late
survival advantage was not identified for patients randomized to
receive warm cardioplegia, despite confirmation of the first hypothesis
(ie, that late mortality is dependent on nonfatal
perioperative outcomes). The primary limitation of the
current study is that follow-up information was obtained from only 1 of
the participating sites rather than all 3 centers, strictly for
logistical reasons. The Warm Heart Trial was designed and budgeted to
study perioperative events, and therefore research
personnel did not collect subsequent follow-up data. The Sunnybrook
site maintains a comprehensive clinical data base that includes
follow-up information that was not available from the other 2 centers.
Complete follow-up of all 1732 patients would increase the power to
detect a survival advantage, should one exist. In addition, there were
important interinstitutional differences in the prevalence of the
primary and secondary end points of the Warm Heart Trial.1
Operative mortality rates were less in the cold cardioplegia
patients from the Sunnybrook site (0.5% versus 2.5% overall), and
nonfatal cardiac events were reduced in every instance. Such
differences in event rates would minimize the probability of detecting
a separation in survival curves from this single site; conversely, the
chances of observing important differences in survival with data from
all sites would be amplified. Finally, there was a difference in the
prevalence of previous CABG between the warm and cold cardioplegia
patients. Exclusion of these patients did not affect the warm
cardioplegia–cold cardioplegia comparisons. In the entire study,
baseline characteristics were well balanced in the 2 treatment
arms.1
Conclusions
Surveillance for perioperative myocardial injury
is important for quality assurance, postoperative management, and
prognostication. The use of cardiospecific serum markers such as
troponin I30 31 32 may improve the diagnostic
accuracy for the detection of perioperative MI, but
additional follow-up of such patients is essential to identify
appropriate threshold values to differentiate between clinically
important and clinically insignificant necrosis in the surgical
setting. In addition, future clinical trials of myocardial protection
should consider extending the time horizon from 30 days to 12 to 24
months postoperatively, which would increase the numbers of events and
potentially decrease the sample size.
We conclude that perioperative myocardial protection
with warm or cold blood cardioplegia is essential as late mortality is
increased, even in patients with nonfatal perioperative
cardiac events. Furthermore, late survival should be assessed for the
Warm Heart Trial patients from all 3 study sites. Power calculations
have been performed for control event rates that vary between 0.08 to
0.12 (ie, compatible with the late mortality rates observed in the cold
cardioplegia group from this center). The total study population would
provide 80% power for a similar relative difference in late
survival as observed from this single center.
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Acknowledgments |
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This work is supported in part from grants from the Medical Research Council of Canada and the Heart and Stroke Foundation of Ontario. The authors extend their gratitude to Tarja Antila and Jean Waters for secretarial assistance in the preparation of the manuscript.
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Footnotes |
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Reprint requests to Stephen E. Fremes, MD, FRCSC, Sunnybrook and Women’s College Health Sciences Centre, H405-2075 Bayview Ave, Toronto, Ontario, Canada M4N 3M5.
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