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Boersma E, Poldermans D, Bax JJ, et al. Predictors of Cardiac Events After Major Vascular Surgery: Role of Clinical Characteristics, Dobutamine Echocardiography, and β-Blocker Therapy. JAMA. 2001;285(14):1865–1873. doi:10.1001/jama.285.14.1865
Author Affiliations: University Hospital Rotterdam, Rotterdam (Drs Boersma, Poldermans, Steyerberg, van de Ven, van Urk, and Roelandt), the University Hospital Leiden, Leiden (Dr Bax), and University Hospital Utrecht, Utrecht (Dr Banga), the Netherlands; and University of Manitoba, Winnipeg (Dr Thomson).
Context Patients who undergo major vascular surgery are at increased risk of
perioperative cardiac complications. High-risk patients can be identified
by clinical factors and noninvasive cardiac testing, such as dobutamine stress
echocardiography (DSE); however, such noninvasive imaging techniques carry
significant disadvantages. A recent study found that perioperative β-blocker
therapy reduces complication rates in high-risk individuals.
Objective To examine the relationship of clinical characteristics, DSE results, β-blocker
therapy, and cardiac events in patients undergoing major vascular surgery.
Design and Setting Cohort study conducted in 1996-1999 in the following 8 centers: Erasmus
Medical Centre and Sint Clara Ziekenhuis, Rotterdam, Twee Steden Ziekenhuis,
Tilburg, Academisch Ziekenhuis Utrecht, Utrecht, and Medisch Centrum Alkmaar,
Alkmaar, the Netherlands; Ziekenhuis Middelheim, Antwerp, Belgium; and San
Gerardo Hospital, Monza, Istituto di Ricovero e Cura a Carattere Scientifico,
San Giovanni Rotondo, Italy.
Patients A total of 1351 consecutive patients scheduled for major vascular surgery;
DSE was performed in 1097 patients (81%), and 360 (27%) received β-blocker
Main Outcome Measure Cardiac death or nonfatal myocardial infarction within 30 days after
surgery, compared by clinical characteristics, DSE results, and β-blocker
Results Forty-five patients (3.3%) had perioperative cardiac death or nonfatal
myocardial infarction. In multivariable analysis, important clinical determinants
of adverse outcome were age 70 years or older; current or prior angina pectoris;
and prior myocardial infarction, heart failure, or cerebrovascular accident.
Eighty-three percent of patients had less than 3 clinical risk factors. Among
this subgroup, patients receiving β-blockers had a lower risk of cardiac
complications (0.8% [2/263]) than those not receiving β-blockers (2.3%
[20/855]), and DSE had minimal additional prognostic value. In patients with
3 or more risk factors (17%), DSE provided additional prognostic information,
for patients without stress-induced ischemia had much lower risk of events
than those with stress-induced ischemia (among those receiving β-blockers,
2.0% [1/50] vs 10.6% [5/47]). Moreover, patients with limited stress-induced
ischemia (1-4 segments) experienced fewer cardiac events (2.8% [1/36]) than
those with more extensive ischemia (≥5 segments, 36% [4/11]).
Conclusion The additional predictive value of DSE is limited in clinically low-risk
patients receiving β-blockers. In clinical practice, DSE may be avoided
in a large number of patients who can proceed safely for surgery without delay.
In clinically intermediate- and high-risk patients receiving β-blockers,
DSE may help identify those in whom surgery can still be performed and those
in whom cardiac revascularization should be considered.
Patients with severe peripheral vascular disease frequently have underlying
coronary artery disease. Hence, patients undergoing major vascular surgery
are at increased risk for cardiac complications during or shortly after surgery.
Appropriate patient management then includes assessment of the perioperative
cardiac risk, as well as strategies to reduce this risk. Several investigations
demonstrated the utility of dobutamine stress echocardiography (DSE) for preoperative
cardiac risk assessment.1-5
Patients with stress-induced new wall-motion abnormalities (NWMAs), a hallmark
of myocardial ischemia, are at an 8% to 38% risk of cardiac death or myocardial
infarction (MI) within 30 days after surgery.2,4,6,7
In contrast, patients without NWMAs have much lower complication rates: in
the range of 0% to 5%. There are, however, significant disadvantages associated
with the routine use of DSE (or other noninvasive imaging techniques) in all
vascular surgery candidates. These include the substantial costs of the test,
and, more importantly, the risk of delaying surgery in patients with large
aortic aneurysms or critical limb ischemia. The recent Dutch Echocardiographic
Cardiac Risk Evaluation Applying Stress Echocardiography (DECREASE) study
demonstrated that perioperative β-adrenergic blockade with bisoprolol
reduces the risk of 30-day complications in patients with NWMAs to a risk
level as observed in patients without NWMAs.8,9
This finding raises the question of whether DSE is indicated in all patients
scheduled for vascular surgery. Does simple perioperative administration of β-blockers
reduce or eliminate the need for noninvasive preoperative cardiac testing?10 On the other hand, in some patients the cardioprotective
effect of β-blockers may be insufficient to effectively reduce perioperative
cardiac events. These patients may benefit from additional coronary revascularization.
To address these issues we studied the relationship between clinical characteristics,
DSE results, β-blockers, and adverse cardiac outcome in a large series
of consecutive patients scheduled to undergo major vascular surgery.
The study population consisted of 1351 consecutive patients scheduled
for elective major vascular surgery who were screened for eligibility for
the DECREASE study at 8 of the following participating centers: Erasmus Medical
Centre and Sint Clara Ziekenhuis, Rotterdam, Twee Steden Ziekenhuis, Tilburg,
Academisch Ziekenhuis Utrecht, Utrecht, and Medisch Centrum Alkmaar, Alkmaar,
the Netherlands; Ziekenhuis Middelheim, Antwerp, Belgium; and San Gerardo
Hospital, Monza, Istituto di Ricovero e Cura a Carattere Scientifico, San
Giovanni Rotondo, Italy.8 Per protocol, 846
patients with at least 1 of the following risk factors underwent DSE: age
70 years or older, angina, prior MI, congestive heart failure, treatment for
ventricular arrhythmias, treatment for diabetes mellitus, or limited exercise
capacity. Two hundred forty-five additional patients underwent DSE at the
discretion of the treating physician, based on other risk factors (eg, hyperlipidemia
and smoking). Thus, in total 1091 patients (81%) underwent DSE. Perioperative β-blockers
were administered to 360 patients (27%): 301 (22%) of the 1351 patients were
treated long-term with β-blockers, and 59 (5%) were randomized to receive β-blockers
within the framework of the DECREASE study. Eight patients who had extensive
resting and/or stress-induced ischemia were excluded from the DECREASE study.
Four of these underwent coronary artery bypass graft surgery, and 2 of them
died during this operation. The 2 surviving patients subsequently underwent
uneventful vascular surgery with perioperative β-blocker administration
for cardiac protection. The other 4 patients underwent vascular surgery without
prior myocardial revascularization and received β-blockers for cardiac
protection. None of the other non-DECREASE patients received β-blockers
for cardiac protection.
Dobutamine stress echocardiography was performed according to a standard
protocol.11 The left ventricle was divided
into 16 segments and wall motion was scored on a 5-point ordinal scale (1,
normal wall motion; 2, mild hypokinesis; 3, severe hypokinesis; 4, akinesis;
and 5, dyskinesis). The results of DSE were considered positive if new wall-motion
abnormalities (NWMAs) occurred (ie, if wall motion in any segment worsened
by ≥1 more grades during the test, with the exception of akinesis becoming
dyskinesis). The extent and location of ischemia were evaluated and a wall-motion
index was calculated, both at rest and during peak stress.
The study end point was a composite of cardiac death or nonfatal MI
(MI) occurring during the period from screening until 30 days after surgery.
An adverse events committee adjudicated all end points. Deaths were considered
to be cardiac related unless there was explicit evidence for a noncardiac
cause. Myocardial infarction was defined by either a serum creatine kinase
level of more than 110 U/L with a myoglobin isoenzyme fraction of more than
10%, or by new Q waves faster than 30 milliseconds in duration on the 12-lead
Univariable and multivariable logistic regression analyses were applied
to evaluate the relations between a limited number of baseline clinical characteristics,
DSE results, β-blocker therapy, and the composite end points as outlined
above. All variables that reached a P value <.50
in univariable analysis entered the multivariable stage. Multivariable models
were constructed by backward deletion of the least significant characteristics,
applying the Akaike optimal information criterion.12,13
Special attention was paid to the extent to which DSE results and β-blocker
therapy contributed to the prognostic information obtained from clinical characteristics
alone. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs)
Despite the fact that the population consisted of patients undergoing
high-risk surgery, the number of outcome events appeared to be limited. Therefore,
there was a serious concern that model overfitting would occur. To overcome
this, we limited the number of candidate clinical variables to be included
in the model, whereby, particularly, the results of prior risk modeling analyses
in surgical patients were considered.14-17
Furthermore, we applied a clinical risk model that was developed elsewhere
to our data set, and collapsed the clinical risk assessment into 1 index variable.
Subsequently, the prognostic value of this risk index and the additional and
additive prognostic value of DSE results and β-blocker therapy were analyzed
by logistic regression analyses. We chose the risk index that was recently
developed by Lee and colleagues17 in a data
set of 4315 patients undergoing major noncardiac surgery, including 898 patients
undergoing vascular surgery. To compose the Lee risk index, 1 point is assigned
to each of the following characteristics: high-risk type of surgery, known
ischemic heart disease, a history of congestive heart failure, a history of
cerebrovascular disease, diabetes mellitus, and renal failure.
The performance of the risk models was determined by the cardiac index,
which indicates how well a model rank-orders patients with respect to their
outcomes; the cardiac index ranges from 0.5 (not predictive at all) to 1.0
(optimal performance).18 In addition, the Hosmer-Lemeshow
statistic for goodness of fit is presented. The predictive accuracy of the
models was further evaluated by bootstrapping techniques.19
One hundred bootstrap samples were drawn from the original data set (with
replacement) and the full modeling process, including the stepwise selection,
was redone in every bootstrap sample. The models developed in the bootstrap
samples were subsequently tested in the original data set. This process provides
a factor to correct for a possible overoptimism of the cardiac index.20
Based on the results obtained by the described modeling strategies,
a risk score was developed to estimate an individual patient's risk of perioperative
cardiac death or MI. Furthermore, a simple decision-tree is constructed to
help the physician decide in which patients to refer for noninvasive perioperative
The primary patient characteristics are described in Table 1. Obviously, patients receiving β-blockers during surgery
had a risk profile that was worse than that of patients not taking such medication
because they had higher rate of hypertension, ventricular arrhythmias, and
history of coronary disease. Furthermore, patients receiving β-blockers
more frequently used other cardiac medications than those who were not receiving β-blockers.
There were 45 perioperative cardiac complications (3.3%): 31 patients had
cardiac death and another 14 nonfatal MI.
In univariable analysis, a history of heart failure was the most significant
determinant of adverse cardiac outcome among the clinical variables examined
(Table 2). The subgroup of patients
with a history of heart failure (5% of the population) had a more than 5-fold
increase in the risk of perioperative cardiac death or MI compared with those
without such a history. Other important univariable determinants of perioperative
cardiac complications were a history of MI, prior cerebrovascular accident
(CVA), current or prior angina pectoris, and age 70 years and older. Patients
taking cardiac medications had higher event rates than patients not taking
such medication; statistical significance was observed for nitrates and angiotensin-converting
enzyme (ACE) inhibitors. There was no relationship between the type of surgery
and the composite end point.
Patients who did not undergo DSE (ie, patients without clinical cardiac
risk factors) and those without NWMAs during DSE had a significantly lower
cardiac death or MI rate than patients with NWMAs during DSE (0.4% and 1.6%
vs 13.5%, respectively (P<.001; Table 3). Thus, NWMAs were strongly predictive of adverse perioperative
cardiac outcome. Moreover, the extent of stress-induced ischemia also provided
important prognostic information, as the event rates ranged from 10.8% in
those with NWMAs in 1 to 4 segments to 23.9% in patients with NWMAs in 5 or
more segments. The echocardiogram at rest also provided prognostic information.
Patients with 5 or more abnormal segments had a 4- to 6-fold increased risk
of cardiac complications compared with those with a normal or slightly aberrant
(1-4 abnormal segments) wall motion at rest.
Despite their overall risk profile being worse (Table 1), patients receiving β-blockers during surgery had
a significantly reduced risk of cardiac death or MI compared with those not
taking such medication. Among the 254 patients who did not undergo DSE, no
perioperative cardiac complications were observed in the 8.7% of patients
receiving β-blockers, whereas there was 1 event (0.4%) in the remaining
patients. In the 875 patients without stress-induced NWMAs, 22% were receiving β-blockers.
One cardiac complication (0.5%) occurred in this group, and there were 13
(1.9%) in those not receiving β-blockers. Finally, in the 222 patients
with NWMAs, 67% of those receiving β-blockers with 4.7% having a perioperative
cardiac event vs 31.5% among those not receiving β-blockers. There was
no evidence of a differential effect of β-blocker therapy in these patient
categories (homogeneity test for ORs, P = .69), so
that the crude OR is best estimated by the method of Mantel-Haenszel test
(0.1; 95% CI, 0.1-0.3).
Many of the univariably significant clinical determinants of cardiac
outcome remained important in the multivariable analysis (Table 4). After correcting for other determinants, prior CVA showed
the strongest relationship with perioperative cardiac complications. A history
of heart failure and prior MI were the next strongest clinical predictors.
Angina and age 70 years or more were also important. After correcting for
differences in clinical characteristics, patients receiving β-blockers
were still at significantly lower risk for the composite end point than those
who were not (adjusted OR, 0.3; 95% CI, 0.1-0.7).
When clinical data were combined with DSE results, advanced age, angina
pectoris, prior MI, and prior heart failure lost most of their predictive
power with respect to the composite end point. In fact, DSE results (especially
the presence or absence of NWMAs) were the most important determinants of
perioperative cardiac outcome. In connection with both clinical data and DSE
results, β-blocker therapy was again associated with a significantly
reduced risk of the composite end point. The protective effect of β-blocker
therapy was observed in long-term users (OR, 0.1; 95% CI, 0.0-0.3) as well
as in patients who received bisoprolol as part of the DECREASE study (OR,
0.1; 95% CI, 0.0-0.4).
In all, 611 patients (45%) had a Lee risk index of 1, 509 (38%) had
an index of 2, and 231 (17%) had an index of 3 or more points (note that all
patients underwent high-risk surgery, and thus had a risk index ≥1 points).
The incidence of the composite end point in these patients was 1.3%, 3.1%,
and 9.1% (P<.001). Regression analysis revealed
a crude OR of 2.3 for the composite end point associated with a 1-point increase
in the risk index (95% CI, 1.8-3.1). Multivariable analyses again demonstrated
the additional and additive prognostic value of DSE results and β-blocker
therapy (Table 5).
The cardiac index for the composite end point model based on clinical
characteristics only was 0.78, reflecting good ability to discriminate between
patients who did and did not have a life-threatening cardiac complication.
The associated goodness of fit of the χ27 statistic
was 2.1 (P = .95). After correction for overoptimism
the cardiac index was 0.72, still reflecting satisfactory performance. The
multivariable model that combined clinical data with DSE results had considerably
better discriminating power with a cardiac index of 0.87 (goodness of fit χ26 = 7.6, P = .27; optimism-corrected
cardiac index, 0.82). The cardiac index connected with the Lee risk-index-alone
model was 0.71 (goodness of fit χ26, 7.0; P = .32) and improved to 0.87 by adding DSE results and
information regarding β-blocker therapy.
Based on the results described above, a simple scheme was developed
to estimate a patient's risk of perioperative cardiac complications (Figure 1). A clinical risk score can be determined
on the basis of the patient's age and clinical history. If this risk score
is in the range of 0 to 2 points (83% of the patients belonged to this category)
and the β-blockers are administered perioperatively, the estimated cardiac
complication rate is relatively low (<2%), irrespective of the DSE result.
The estimated risk of cardiac complications is also low in patients with a
risk score of 3 or more points without NWMAs, provided β-blockers will
be applied. Patients with a risk score of 3 or more and NWMAs were at a considerable
cardiac risk (>6%), despite β-blocker therapy.
Consistent with other studies,14-17
our analysis of 1351 patients undergoing high-risk noncardiac vascular surgery
demonstrated that advanced age, current or prior angina, and a history of
cardiac or cerebral events are the most important clinical determinants of
perioperative cardiac death or MI. Apart from clinical data, DSE results were
highly predictive of adverse cardiac outcome, which also confirms other investigations.1 Patients receiving β-blockers had significantly
lower risk than those not receiving them. It should be emphasized that patients
receiving β-blockers had a considerably worse overall risk profile than
those not receiving them, which makes this result even more convincing. The
additional and additive prognostic value of DSE results and β-blocker
therapy was confirmed in the analysis that applied the previously developed
Lee risk index. On the basis of a risk score composed of a weighted sum of
the prognostic clinical characteristics, a large group (83%) of low-risk patients
with a score of less than 3 could be defined. In this group, the estimated
risk of cardiac complications is less than 1%, regardless of DSE results,
as long as patients are receiving β-blockers. In the remaining patients,
those without stress-induced ischemia also had a low estimated cardiac risk
in the presence of perioperative β-blocker therapy.
Univariable analyses showed that patients with diabetes mellitus, pulmonary
disease, prior ventricular arrhythmias, or aortic valvular stenosis are at
increased risk of surgical complications. However, in contrast to earlier
studies,16,21 these factors were
not independent predictors in our multivariable analyses. This finding can
be reflect a changing patient population or improved perioperative management
although it may also be a matter of (lack of) power. Additionally, it should
be emphasized that cardiac death or MI during complex surgery is most likely
to occur in patients with stress-inducible cardiac ischemia. Indeed, the occurrence
of NWMAs during DSE was a major determinant of adverse outcome. Because a
stress-induced ischemia was not more common in patients with diabetes mellitus,
pulmonary disease, prior ventricular arrhythmias, or aortic stenosis (78 NWMAs
of 352 cases [22%]) than in patients without such characteristic (144 NWMAs
of 745 cases [19%]; P = .28), these characteristics
are likely not strong determinants of a predisposition to ischemia. In contrast,
patients with prior MI, prior heart failure, or prior CVA were more likely
to have stress-induced ischemia than other patients (150 NWMAs of 545 cases
[28%] vs 72 NWMAs of 552 cases [13%]; P<.001).
Still, factors such as diabetes mellitus, may be predictive of long-term complications.
Diabetes mellitus (and renal failure) were therefore still incorporated in
the clinical risk index (Figure 1).
Figure 2 may help to understand
how results can be translated into clinical practice. The perioperative cardiac
event rate was low (≥1%) in patients with a clinical risk score of less
than 3 points and who were receiving β-blockers. It seems therefore appropriate
to omit DSE (and other noninvasive cardiac testing) in this large (>80%) group
of patients and to proceed expeditiously with surgery under protection by β-blocker
therapy. Dobutamine stress echocardiography is useful to further risk-stratify
patients with a clinical risk score of 3 or more points. If protected by perioperative β-blockade,
patients without stress-induced ischemia still had a low complication rate
(2%) and are also candidates for prompt surgery. Patients with a risk score
of 3 or more points and NWMAs (approximately 6% of the population) had a considerable
complication rate despite the β-blocker therapy. Our data suggest that
the proposed treatment policy in these patients may depend on the extent of
stress-induced ischemia. Although the numbers of patients and events are relatively
small in the specific subgroups, patients with NWMAs in 1 to 4 segments were
properly protected by β-blockers. In patients with more extensive ischemia,
however, β-blockers failed to reduce the rate of perioperative cardiac
complications. Cardiac catheterization and subsequent myocardial revascularization
should be considered in these patients.
The prescription of β-blockers may delay surgery; so far, no study
has indicated what the optimal run-in period of this drug is in this setting.
Therefore, it can be questioned whether such therapy is really necessary in
patients at very low risk. In the group of patients with a risk score of 0
points, 1.2% perioperative complications were observed in those without β-blocker
therapy (Figure 2). This complication
rate seems sufficiently low to refrain from administering medication indeed
and opt for surgery without delay. Another issue is that β-blocker therapy
may be contraindicated, especially in patients with reactive airway diseases,
such as severe asthma or chronic obstructive pulmonary disease with a reactive
component. It should be noticed that these patients are rare: there were no
such cases in our data set. Still, if β-blocker therapy is contraindicated,
the use of calcium antagonists with a negative chronotropic effect may be
considered. The recent Incomplete Infarction Trial of European Research Collaborators
Evaluating Prognosis post-Thrombolysis (INTERCEPT) study of post-MI patients
reported fewer cardiac events in patients randomized to such a drug compared
Because of its retrospective nature, our analysis has limitations, which
should be considered when interpreting the results. The risk-stratification
and modification scheme using a clinical risk score, DSE, and β-blocker
therapy was developed after events had occurred. Furthermore, only some patients
(those participating in the DECREASE study) were randomized to receive either
perioperative β-blockers or standard care. Patient characteristics may
have played an important role in the decision to administer β-blockers
to patients who did not participate in the DECREASE study and could potentially
bias the results. Importantly, we found no difference in the cardioprotective
effect of β-blockers between patients who were randomized within the
framework of the DECREASE study and those whose receipt of β-blockers
was chronic. This suggests that the utility of perioperative β-adrenergic
blockade extends beyond the small subset of high-risk patients who participated
in the DECREASE study. Finally, the observed event rates were relatively low
compared with previous investigations. It should be appreciated that our results
were obtained in selected, high-volume hospitals (3 of the participating hospitals
were university hospitals) and that cardiac event rates might differ in other
Dobutamine stress echocardiography effectively identifies patients at
risk for perioperative cardiac events. Besides, our data showed that the additional
predictive value of DSE is limited in clinically low-risk patients receiving β-blockers.
This observation may have important clinical implications: in a majority of
patients, additional testing by DSE can be avoided and patients can proceed
safely for surgery without delay. In a smaller group of clinically intermediate-
and high-risk patients, DSE may help to identify patients in whom surgery
can still be performed while receiving β-blockers and those in whom cardiac
revascularization should be considered.