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New aspects in the treatment of acute coronary syndromes without ST-elevation: ICTUS and ISAR-COOL in perspective
Franz-Josef Neumann1,*,
Adnan Kastrati2 and
Guido Schwarzer3
1 Herz-Zentrum Bad Krozingen, Südring 15, 79189 Bad Krozingen, Germany
2 Deutsches Herzzentrum München, Technische Universität, München, Germany
3 Institut für Medizinische Biometrie und Medizinische Informatik, Albert-Ludwigs-Universität, Freiburg, Germany
* Corresponding author. Tel: +49 7633 402 8200; fax: +49 7633 402 8204. E-mail address: franz-josef.neumann{at}herzzentrum.de
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Abstract
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For treatment of patients with high-risk acute coronary syndromes,
current guidelines recommend early coronary angiography and
coronary revascularization, when feasible, irrespective of the
primary success of medical treatment. Moreover, the results
of a randomized trial (ISAR-COOL) suggested performing revascularization
as early as possible. The concept of systematic coronary angiography
and revascularization in high-risk acute coronary syndromes
has been challenged recently by another randomized study (ICTUS)
demonstrating an excess of myocardial infarction during 1-year
follow-up with a routine-invasive strategy when compared with
a selectively invasive strategy. This review intends to put
the new trial results in perspective with evidence from previous
studies.
Key Words: Acute coronary syndromes • Percutaneous catheter intervention • Guidelines • Treatment strategies • Timing • Meta-analysis
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Introduction
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The optimal treatment strategies in patients with acute coronary
syndromes without ST-elevation has been debated since the mid-1980s
of the last century. In principle, there are two competing concepts.
The conservative strategy intends to stabilize the patient by
medical therapy, including intense antithrombotic and antianginal
treatment, and reserves coronary revascularization to those
patients who continue to have spontaneous or inducible myocardial
ischaemia despite maximal medical therapy. The alternative invasive
strategy pursues early coronary angiography and coronary revascularization,
when feasible, irrespective of the primary success of medical
treatment. Current ESC guidelines recommend (class 1A) the invasive
strategies for patients with non-ST-elevation myocardial infarction
and acute coronary syndromes with high-risk features including
dynamic ST-segment changes, refractory angina, haemodynamic
or rhythmic instability, and diabetes mellitus.
1,2 This widely
accepted recommendation has recently been challenged by the
ICTUS trial, suggesting that a more selective invasive approach
could be more efficacious than the previously accepted invasive
strategy.
3 This review intends to put the new data in perspective
with previous evidence.
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Evidence supporting an early invasive strategy
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In 2005, Mehta
et al.4 published a meta-analysis of seven
major studies comparing the conservative strategy with the invasive
strategy in non-ST-elevation acute coronary syndromes. This
meta-analysis including a total of 1212 patients demonstrated
a significant (
P < 0.01) benefit of the invasive strategy
with respect to the composite of death and myocardial infarction
during the entire study follow-up [odds ratio (OR), 0.82; 95%
confidence interval (CI), 0.72–0.93]. The benefit from
the invasive strategy was driven by reduction in non-fatal myocardial
infarction (OR, 0.75; CI, 0.65–0.88;
P < 0.01), whereas
there was no significant benefit with respect to survival (OR
for death 0.92, CI, 0.77–1.09;
P = 0.34). During hospitalization,
the incidence of death and myocardial infarction was higher
with the invasive strategy than with the conservative strategy
(OR, 1.36; CI, 1.12–1.66;
P = 0.02), which was attributed
to the early hazard of the invasive procedures. This early hazard,
however, was more than compensated by a reduction in death and
myocardial infarction during long-term follow-up after hospital
discharge (OR, 0.64; CI, 0.55–0.75;
P < 0.01). In this
meta-analysis, the mean follow-up, weighted according to the
sample size of each trial, was 17.3 months. A 5-year follow-up
analysis of the long-term outcome in RITA-3 revealed that the
benefit of the invasive strategy with respect to death and myocardial
infarction continued to increase when compared with the conservative
strategy during the follow-up period.
5 At 5 years after intervention,
the incidence of death and myocardial infarction was 20.0% in
the conservative arm but 16.6% in the interventional arm (
P = 0.04). Moreover, there was an increased survival benefit of
the invasive strategy when compared with the conservative strategy
during the 5-year follow-up (88 vs. 85%), which almost reached
statistical significance (
P = 0.054). The recently reported
5-year follow-up of FRISC-II also demonstrated a significant
reduction in the long-term incidence of death and myocardial
infarction by the invasive strategy when compared with the conservative
strategy (5-year incidence 19.9 vs. 24.5%,
P = 0.009).
6 Subgroup
analyses of the major contemporary trials (including FRISC-2,
7 TACTICS-TIMI18,
8 and RITA-3
9) revealed that the benefit from
the invasive strategy was confined to high-risk patients including
those with refractory angina, elevated cardiac troponin levels,
dynamic ST-segment changes, and diabetes mellitus.
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Optimal timing of catheter intervention
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The meta-analysis of Mehta
et al.4 demonstrated that the
early hazard of the intervention reduces the net benefit of
the invasive strategy. Since the early days of interventional
treatment of acute coronary syndromes, it has been suggested
that the risk of catheter intervention in this situation could
be reduced by an intense antithrombotic pre-treatment, so called
‘cooling-off’. Since there had been no data from
randomized studies supporting this concept, the ISAR-COOL trial
addressed this question. ISAR-COOL investigated whether the
risk of catheter intervention in high-risk acute coronary syndromes
could be reduced by intense antithrombotic pre-treatment with
triple antiplatelet therapy (aspirin, clopidogrel, and tirofiban)
in combination with heparin.
10 Inclusion criteria were typical
unstable angina plus ST-segment depression and/or an elevated
troponin-T
0.03 µg/L. Exclusion criteria were ST-elevation
myocardial infarction with CK-MB > 18 U/L, haemodynamic
instability, and contraindications to study medication. Four-hundred
and ten patients were randomly assigned to either early intervention
within 6 h or intense antithrombotic pre-treatment for
3–5 days. In the early intervention group, catheterization
was performed after a median of 2.4 h, whereas pre-treatment
lasted for a median of 86 h in the cooling-off group. Of
the patients assigned to early intervention, 72% underwent revascularization
and 78% of the patients with prolonged antithrombotic pre-treatment
(90% catheter-based revascularization) (
Table 1).
The incidence of death and myocardial infarction during 30-days
follow-up after catheter intervention was identical between
the two treatment groups. During the pre-treatment phase, only
one event occurred in the early intervention group, whereas
in the cooling-off group, 13 patients (6.2%) incurred a myocardial
infarction or died before catheterization. The incidence of
death and myocardial infarction during the cooling-off phase
did not increase linearly; most of the events occurred during
the first 24 h after randomization (
Figure 1). Owing
to the substantial difference in the event rate during the pre-catheter
phase, ISAR-COOL demonstrated a significant benefit from early
intervention when compared with cooling-off (primary endpoint,
death, and myocardial infarction, 11.6 vs. 5.9%,
P = 0.04).
This difference in outcome was largely driven by a difference
in non-fatal myocardial infarctions (10.1 vs. 5.9%,
P = 0.12),
one-third of which were Q-wave myocardial infarctions. ISAR-COOL
demonstrated that extensive antithrombotic pre-treatment does
not reduce the risk of revascularization procedures. Moreover,
it demonstrated that the risk of infarction during conservative
treatment is highest during the first 24 h after admission.
Therefore, ISAR-COOL suggested that in high-risk acute coronary
syndromes, invasive procedures should be performed as early
as possible to obtain the maximum benefit.
This inference is consistent with non-randomized observations.
In both TACTICS-TIMI18
11 and PURSUIT,
12 event rates were lower
the earlier patients underwent catheterization. Moreover, in
the CRUSADE registry, very early intervention was associated
with a trend towards a survival benefit.
13
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Challenging the concept of routine-invasive strategy: ICTUS
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ICTUS asked the question whether with optimized modern medical
treatment including powerful antithrombotics and vigorous risk
factor modification, a more selective invasive strategy would
be superior to a routine-invasive strategy.
3 The study included
patients with typical unstable angina within 24 h before
study entry plus an elevated troponin (> 0.03 µg/L)
plus ST-segment changes or a history of coronary disease. Exclusion
criteria were ST-elevation, age > 80 years, heart failure,
and contraindications to antithrombotic therapy. In patients
randomized to the early invasive strategy, angiography had to
be performed within 24–48 h and revascularization
was performed on the basis of the coronary anatomy. In the selectively
invasive arm, angiography and revascularization was performed,
only if haemodynamic or rhythmic instability, angina despite
optimal medical treatment, or positive exercise test could be
documented. The antithrombotic regimen consisted of aspirin,
clopidogrel, enoxaparin, and abciximab for PCI. All patients
received clopidogrel after stent placement, and some of the
patients (after 2002) also received a loading dose of clopidogrel
before the intervention. Among the patients included in ICTUS,
604 were randomly assigned to the early invasive arm and 596
to the selectively invasive arm. Compared with ISAR-COOL, the
ICTUS trial comprised more patients who had a positive troponin,
fewer patients with ST-depression, and fewer patients with diabetes
or previous revascularization therapies (
Table 1).
Within 1 year, 79% of the patients in the invasive arm and 54% of the patients in the conservative arm underwent revascularization in ICTUS. In the invasive arm, PCI was timed at 23 h after inclusion in the study vs. 12 days in the selective invasive arm. The primary endpoint, the composite of death, infarction, and re-hospitalization for angina were not significantly different (P = 0.33) between the early invasive arm (22.7%) and the selectively invasive arm (21.2%). The incidence of death was 2.5% in both treatment arms. Re-hospitalization for angina was significantly lower in the early invasive arm when compared with the selectively invasive arm (7.4 vs. 10.9%, P = 0.04). There was, however, a highly significant difference in the incidence of myocardial infarction favouring the selectively invasive strategy (15 vs. 10%, P = 0.005). Despite the fact that this result was obtained from a secondary analysis of a negative study with respect to the primary endpoint, the findings are statistically and clinically meaningful given the large difference with a high P-value.The excess incidence of myocardial infarction was largely due to the early hazard which was not compensated during 1-year follow-up.
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ICTUS in perspective
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As per selection criteria, all patients included in ICTUS had
elevated cardiac troponins which are accepted as the most robust
indicator for an elevated risk in patients with non-ST-elevation
acute coronary syndromes.
3 In comparison with ISAR-COOL and
other studies in the field, however, some of the other variables
were less indicative of a high risk (
Table 1).
10 For example,
the proportion of diabetic patients was lower than in the usual
cohorts of patients hospitalized for coronary artery disease
(CAD). Compared with ISAR-COOL, the patients in ICTUS were younger,
fewer patients had ST-segment depression, and fewer patients
had previous revascularization procedures. Of note, as a play
of chance, the proportion of patients with previous coronary
revascularization was even significantly lower in the selectively
invasive arm of ICTUS than in the invasive arm of ICTUS. It
was commented that the appearance of the European guidelines
endorsing the routine-invasive strategy during the time of the
study might have biased investigators to select the lower risk
spectrum of patients with elevated troponins. Unfortunately,
the proportion of the eligible patients who were not included
is unknown.
In comparison with the three other landmark trials, FRISC-2, TACTICS-TIMI18, and RITA-3,7–9 it is noteworthy that as per design, ICTUS3 had the highest proportion of revascularization in the non-routine-invasive arm (Figure 2). In fact, the use of revascularization procedures in the selectively invasive arm of ICTUS was similar to the routine-invasive arm of RITA-3.9 The high use of revascularization in the selectively invasive arm of ICTUS would have minimized the potential benefit from differences in the extent of revascularization between the two study arms when compared with the previous studies. Nevertheless, the question arises why there was no apparent benefit from the earlier timing of the intervention in the routine-invasive arm when compared with the selectively invasive arm. To this end, it is noteworthy that according to the results of the ISAR-COOL trial, a large proportion of infarction, which the earlier timing of the revascularization intends to prevent, would have already occurred within the 23 h of delay for PCI in ICTUS.
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Figure 2 Log-OR for death and myocardial infarction during 6–12 months of follow-up vs. percentage of patients in the conservative arm of four major trials comparing conservative vs. invasive strategy in acute coronary syndromes.
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These considerations could explain why the benefit from routine-invasive
strategy in ICTUS was smaller than expected on the basis of
the previous studies. Nevertheless, they cannot fully explain
why there was a significant disadvantage of the routine-invasive
strategy when compared with the selectively invasive strategy.
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Earlier and current ACS studies
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We identified nine studies
3,7–9,14–18 that compared
the two treatment strategies in acute coronary syndromes. With
respect to their respective primary endpoint, only two of the
10 studies showed a non-significant difference in favour of
the conservative strategy. In the other seven studies, the respective
primary endpoint demonstrated a benefit of the invasive strategy,
which was statistically significant in five (
Figure 3).
Moreover, the incidence of unplanned PCI or readmissions for
acute coronary syndromes was reduced in any trial that addressed
this endpoint, thus yielding on almost 40% reduction of this
outcome measure with the invasive strategy when compared with
the conservative strategy (
Figure 4). An analysis with
respect to death and myocardial infarction during 6–12
months of follow-up demonstrated an almost significant benefit
with a fixed effects model (
Figure 5). Because we found
significant heterogeneity between the trials, a random effects
model is more appropriate. This approach, however, does not
reveal any significant difference between the two strategies.
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Figure 3 Primary endpoints of studies comparing invasive strategy with conservative strategy in acute coronary syndromes. P-values are shown above the columns. Open columns, conservative strategy; closed columns, invasive strategy. The primary endpoint was death, myocardial infarction, and failure of initial therapy during 42 days in TIMI-IIIB,14 death and myocardial infarction during a mean follow-up of 23 months in VANQWISH,15 death and recurrent ischaemic event during follow-up of > 1 year in MATE,16 death and myocardial infarction during 6 months in FRISC-2,7 death and myocardial infarction during 12 months in TRUCS,17 death and myocardial infarction and re-hospitalization for recurrent angina during 6 months in TACTICS-TIMI18,8 death and myocardial infarction in VINO,18 death and myocardial infarction and refractory angina during 4-month follow-up in RITA-3,9 and death and myocardial infarction and re-hospitalization during 1-year follow-up in ICTUS.3
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Figure 5 OR for death and myocardial infarction during 6–12 months of follow-up in various trials comparing conservative vs. invasive strategy in acute coronary syndromes. OR and 95% confidence intervals are shown.
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When analysing the clinical settings in which the trials were
performed (
Table 2), it is conspicuous that the first three
trials, TIMI-IIIB, VANQWISH, and MATE,
14–16 had no or
negligible stent use, no clopidogrel before or after PCI, and
no GP IIb/IIIa receptor antagonists. In this respect, they differ
from the modern trials with substantial stent use and modern
antiplatelet therapy. If the trials of the modern era are analysed
(
Figure 6), the fixed effects model demonstrates a significant
benefit with respect to death and myocardial infarction at 6–12
months of the invasive strategy when compared with the conservative
strategy. Nevertheless, there is still substantial heterogeneity,
which can be largely attributed to ICTUS. In the random effects
model, the point estimate for the OR for death and myocardial
infarction at 6–12 months is more in favour of the invasive
strategy. Nevertheless, the confidence limits become wider and
statistical significance by conventional limits is just lost.
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Figure 6 OR for death and myocardial infarction during 6–12 months of follow-up in the seven trials of the modern era (stents, clopidogrel, GP IIb/IIIa-antagonists) comparing conservative vs. invasive strategy in acute coronary syndromes. OR and 95% confidence intervals are shown.
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As suggested recently,
19 we also performed a Bayesian analysis.
By the Bayesian approach, observations are interpreted in the
context of relevant background information and, thus, allow
the explicit integration of previous knowledge with new empirical
data. The results of the Bayesian analysis are summarized in
Figure 7. In essence, the message of this analysis is not
different from the message derived from conventional statistical
approaches to the meta-analysis of various trials. The Bayesian
analysis reveals a benefit of the invasive strategy with respect
to the conservative strategy that marginally misses statistical
significance by conventional limits. It demonstrates that it
is unlikely that the invasive strategy causes harm with respect
to death and myocardial infarction and that there is probably
a benefit of around 5% relative reduction in the chance of death
and myocardial infarction.
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Figure 7 The Bayesian analysis of various trials comparing conservative vs. invasive strategy in acute coronary syndromes with respect to death and myocardial infarction during 6–12 months of follow-up. The curves show the probability of a benefit by the invasive strategy of the extent specified on the basis of sequential analysis of the trials in chronological order. The dotted horizontal line represents the boundary for conventional statistical significance.
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Practical consequences
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For the treatment of acute coronary syndromes, previous studies
demonstrated a benefit from the invasive strategy when compared
with the conservative strategy. The same studies, however, also
showed that this benefit was confined to those patient cohorts
who had high-risk characteristics. This knowledge is incorporated
in our current guidelines. Among the markers of risk, troponin-T
is considered the most robust.
20,21 The ICTUS trial tells us,
however, that apparently not all patients with elevated troponins
benefit from revascularization. There appear to be some groups
in which the initial hazard is not remunerated by a long-term
benefit. There are two potential consequences from this inference.
First, any effort should be made to reduce the early hazard
of the intervention. One possibility to achieve this goal would
be a systematic pre-treatment with clopidogrel, which was performed
only in part of the patients of ICTUS. Previous studies have
shown that even in the patients subsequently treated with GP
IIb/IIIa antagonists, clopidogrel reduces the early (30-day)
risk of myocardial infarction by 3.5% absolute and improves
long-term outcome.
22 The second consequence would be to delineate
criteria that identify patients who may not benefit from revascularization
in acute coronary syndromes. Until these criteria are validated
in appropriately sized clinical studies, it appears prudent
to pursue the invasive strategy in most patients with high-risk
acute myocardial infarction, given the evidence form of all
previous trials. In addition, the results of the ISAR-COOL trial
suggest that when pursuing the invasive strategy, intervention
should be performed as early as possible because most cardiac
complications occur within the first day after hospital admission.
Conflict of interest: A.K. has received lecture fees from Sanofi-Synthelabo, Lilly and Bristol-Myers Squibb.
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Abstract
Introduction
