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Lindmark E, Diderholm E, Wallentin L, Siegbahn A. Relationship Between Interleukin 6 and Mortality in Patients With Unstable Coronary Artery DiseaseEffects of an Early Invasive or Noninvasive Strategy. JAMA. 2001;286(17):2107–2113. doi:10.1001/jama.286.17.2107
Context Inflammatory activity is associated with high rates of long-term mortality
in unstable coronary artery disease (CAD). Interleukin 6 (IL-6) induces C-reactive
protein and fibrinogen, systemic markers of inflammation.
Objectives To determine whether plasma levels of IL-6 are predictive of mortality
and to evaluate the interaction of IL-6 levels with the effects of invasive
vs noninvasive treatment strategies in unstable CAD patients.
Design, Setting, and Patients The prospective, randomized Fragmin and Fast Revascularisation During
Instability in Coronary Artery Disease II trial, conducted among 3489 patients,
3269 of whom had plasma samples analyzed for IL-6 levels, with diagnosed unstable
CAD (67% male; median age, 67 years) at 58 Scandinavian hospitals between
June 1996 and August 1998.
Interventions Patients were randomly assigned to receive either an early invasive
(n = 1222) or a noninvasive treatment strategy (n = 1235). The latter group,
as well as 666 patients with contraindications to invasive therapy, were further
randomized to 90-day treatment with low-molecular-weight heparin (dalteparin,
5000-7500 IU twice per day; n = 1140) or placebo (n = 1127).
Main Outcome Measure Mortality at 6 and 12 months in the medically and interventionally randomized
cohorts, respectively, in relation to IL-6 levels, measured at randomization.
Results Plasma levels of IL-6 that were at least 5 ng/L compared with levels
lower than 5 ng/L were associated with greatly increased mortality in the
noninvasive group (7.9% vs 2.3%; relative risk [RR], 3.47; 95% confidence
interval [CI], 1.94-6.21) and in the placebo-treated group (7.9% vs 2.5%;
RR, 3.19; 95% CI, 1.77-5.74). The association remained significant after adjustment
for most established risk indicators. An early invasive treatment strategy
strongly reduced 12-month mortality among those with elevated IL-6 levels
(5.1% absolute reduction; P = .004) whereas mortality
was not reduced among patients without elevated IL-6 concentrations. Those
taking dalteparin with elevated IL-6 levels experienced lower 6-month mortality
than those who did not take dalteparin (3.5% absolute reduction; P = .08).
Conclusions Circulating IL-6 is a strong independent marker of increased mortality
in unstable CAD and identifies patients who benefit most from a strategy of
early invasive management.
Atherosclerosis is characterized by inflammation in the vessel wall.1 On the site of the atherosclerotic plaque, the intima
is infiltrated with activated macrophages and T lymphocytes, which both produce
and secrete cytokines to drive the inflammatory process on. In unstable coronary
artery disease (CAD), increased levels of systemic markers of inflammation,
such as the acute phase reactants C-reactive protein and fibrinogen, are common.2-4 Also, increased plasma
levels of proinflammatory cytokines, such as interleukin (IL) 1 β, IL-6,
and IL-8, have been reported.4-6
Large cohort studies have shown an association between elevated levels of
circulating C-reactive protein or fibrinogen and increased risk for cardiac
events or death, both in patients who have experienced an episode of unstable
CAD2,7,8 as well
as in apparently healthy individuals.9-13
Interleukin 6 is a cytokine with both proinflammatory and anti-inflammatory
effects on many cell types, affecting both B-cell immunoglobulin production
and T-cell cytotoxic activity.14 Interleukin
6 also affects platelet production and reactivity as well as endothelial function.
It is the only substance known to induce synthesis of all of the acute phase
proteins by the liver. Large prospective studies of healthy populations have
shown that IL-6 plasma levels in the upper quartile of the considered normal
range are independently predictive of an increased risk of premature death
or future myocardial infarction (MI), even after accounting for C-reactive
protein level.13,15 This indicates
a possible role for IL-6 in the progression of CAD.
We have previously shown a strong relationship between increased levels
of C-reactive protein, fibrinogen or troponin T and increased risk for long-term
mortality in patients with unstable CAD.8 Since
IL-6 induces both C-reactive protein and fibrinogen, we sought to determine
its predictive value for long-term risk of death or MI in patients included
in the Fragmin and Fast Revascularisation During Instability in Coronary Artery
Disease II (FRISC II) trial. We also investigated the effects of an invasive
vs a noninvasive treatment strategy and prolonged treatment with low-molecular-weight
heparin (dalteparin) in relation to IL-6 levels at admission.
In all, 3489 patients were recruited at 58 Scandinavian hospitals between
June 1996 and August 1998.16,17
Patients were eligible for study inclusion if they had symptoms of ischemia
that were increasing or occurring at rest or that warranted the suspicion
of acute MI, with the last episode within 48 hours before initiating dalteparin
or heparin treatment. Myocardial ischemia had to be verified by electrocardiography
(ST-segment depression ≥0.1 mV or T-wave inversion ≥0.1 mV) or by raised
biochemical markers (creatine kinase (CK)-MB >6 µg/L, troponin T >0.10
µg/L, positive qualitative troponin-T test, or catalytic activity of
CK, CK-B, or CK-MB higher than the diagnostic limit for MI). Exclusion criteria
were increased risk for bleeding episodes, anemia, indication for treatment
in the past 24 hours with thrombolysis, angioplasty in the previous 6 months,
being on a waiting list for a coronary revascularization procedure, other
acute or severe cardiac disease, renal or hepatic insufficiency, known clinically
relevant osteoporosis, other severe illness, hypersensitivity to randomized
drugs, anticipated difficulties with cooperation, or previous participation
in this or another clinical trial. Patients with previous open heart surgery,
advanced age (>75 years), or other disorders that made randomization to early
revascularization inappropriate were excluded from randomized intervention
strategies but were still assigned to receive dalteparin or placebo.
The FRISC II study was a prospective, randomized, multicenter trial
with parallel groups. The details of the FRISC II medical and interventional
studies have been described previously.16,17
A simplified overview of the study design and the subgroups evaluated in this
article are shown in Figure 1.
All patients were initially treated with subcutaneous dalteparin or
standard heparin by intravenous infusion. Randomization into the different
treatment strategies was completed within 72 hours of start of open-label
dalteparin or standard heparin. All patients received dalteparin subcutaneously
(120 IU/kg every 12 hours) for at least 5 days until they underwent an exercise
test or revascularization. Thereafter, they entered the double-blind treatment
with twice-daily subcutaneous injections of dalteparin (5000 IU per dose for
men weighing <70 kg and women <80 kg; 7500 IU per dose for those who
exceeded these weight limits) or placebo until 90 days after entry. The direct
invasive strategy required coronary angiography within a few days of enrollment,
aiming for revascularization within 7 days of the start of open-label treatment.
Revascularization was recommended in all patients with an obstruction of at
least 70% of the diameter of any artery supplying a substantial proportion
of the myocardium. Percutaneous coronary intervention was recommended if there
were 1 or 2 target lesions, and coronary artery bypass surgery was preferred
in patients with 3-vessel or left main artery disease.
In the noninvasive strategy, coronary angiography and, if appropriate,
revascularization were recommended in patients with refractory or recurrent
symptoms despite maximum medical treatment or severe ischemia on an exercise
electrocardiography test before discharge. During follow-up, invasive procedures
were considered, irrespective of randomized strategy, for all patients with
incapacitating symptoms, recurrence of instability, or MI.
Aspirin was given to all patients on admission (initial dose, 300-600
mg; maintenance dose, 75-320 mg once daily), and β-blockers were given
unless contraindicated. Statins for lowering cholesterol, angiotensin-converting
enzyme inhibitors, and aggressive antidiabetic treatment were given at the
discretion of the treating physicians.
The end points investigated in this study were all-cause death and the
composite of death or nonfatal MI, which was the primary end point of the
FRISC II trial. The medical study had a follow-up for 6 months. Concerning
the interventional trial, longer follow-up was preplanned and, hence, information
on death or MI was also available at 12 months. Follow-up was unavailable
for 14 patients in the dalteparin group and for 18 patients in the placebo
group. In the interventional study, vital status was not available for 1 patient
who requested withdrawal from the study. Definitions of the various predefined
end points in FRISC II have been previously described.16,17
The study complied with the Declaration of Helsinki, and all local ethics
committees approved the protocol. Informed consent was obtained from all included
Venous blood samples in tubes containing EDTA (Vacutainer, Becton-Dickinson,
Plymouth, England) were taken from all patients at randomization. The plasma
was separated by centrifugation (2000 g for 20 minutes) within 30 minutes
of blood sampling, aliquoted, and stored at −70°C until analysis.
Troponin T levels were measured with a third-generation assay kit on an Elecsys
2010 instrument (Roche-Boehringer Mannheim, Mannheim, Germany). Concentrations
of C-reactive protein were analyzed using the Immulite Automated Analyzer
and assay kit (DPC, Diagnostic Products Corp, Los Angeles, Calif). The IL-6
antigen levels were measured in plasma from 3269 patients by a sequential
immunometric assay, also using the Immulite analyzer and kit. The lower detection
limit of this system is 5 ng/L, which was therefore used as the cutoff for
the statistical analyses. Levels higher than the cutoff are reported herein
as higher than 5 ng/L, high, raised, or elevated.
The levels of IL-6, below or above the cutoff level were used to test
the association between IL-6 and outcome events. All statistical comparisons
between randomized treatments were performed according to the intention-to-treat
principle. In the medical part of the study, events were recorded from the
initiation of the open-label dalteparin treatment until the 6-month follow-up.
In the interventional study, recording of events terminated at the 12-month
follow-up. The efficacy analyses of the 6-month and 12-month follow-ups were
point estimates including only patients with an adjudicated event or with
recorded absence of the specific event until at least 170 days and 335 days
of the respective follow-up period. Pearson χ2 analysis was
used to test significance of the overall degree of association. Graphs of
the Kaplan-Meier estimate of the survival function were used without statistical
tests. Forward stepwise logistic regression analysis was used to adjust for
established risk indicators regarding mortality and for evaluating factors
that could contribute to elevated IL-6 levels. All P
values are 2-tailed, and values lower than .05 were considered statistically
significant. Relative risks (RRs) and odds ratios (ORs) are expressed with
(95% confidence intervals [CIs]). Data processing and statistical analyses
were performed using SPSS version 10.0 software (SPSS, Chicago, Ill).
As shown in Figure 1, 2267
patients were included in the medical part of the FRISC II trial while 2457
were enrolled in the interventional trial. Within 7 days, 96% of patients
in the invasive group and only 7% of the patients in the noninvasive group
underwent coronary angiography. Within the first 10 days, 71% in the invasive
group and 9% in the noninvasive group underwent revascularization procedures.
Within 12 months, 78% in the invasive and 43% of the patients in the noninvasive
groups had undergone revascularization. The details of treatments, follow-up,
and outcome on these materials have previously been reported.16-18
The 3269 analyzed plasma samples were taken at a median of 39 hours
after onset of the last episode of chest pain (interquartile range, 27-55
hours). Plasma IL-6 levels were distributed equally between the randomized
patient groups (data not shown). There were no significant differences in
other baseline characteristics between the groups.16,17
Baseline characteristics according to IL-6 levels are summarized in Table 1. Of note, patients with increased
IL-6 levels also were more likely to have increased troponin T and C-reactive
protein levels but were only slightly more likely to have ST-segment depression.
Because there was no influence of long-term dalteparin in the comparisons
between the invasive and noninvasive groups, analyses of these cohorts were
performed disregarding medical assignment (Figure 1).
For patients randomized to a noninvasive strategy, IL-6 levels 5 ng/L
or higher at inclusion were associated with a 3.5-fold increase in probability
of death at 12 months; 7.9% compared with 2.3% in patients with IL-6 levels
less than 5 ng/L (P<.001; Table 2). In patients with high IL-6 levels, an early invasive strategy
led to a 5.1% absolute or 65% relative reduction in 12-month mortality (Table 2, Figure 2). At lower IL-6 levels, there was no significant difference
in 12-month mortality between treatment strategies.
For the composite end point of death or MI, elevated plasma IL-6 levels
were not associated with any significantly larger event proportion in the
noninvasive group (Table 2). Accordingly,
an invasive strategy improved the end point outcome irrespective of IL-6 levels.
In the noninvasive placebo-treated group, patients with IL-6 levels
of 5 ng/L or higher had a 6-month mortality rate of 7.9% vs 2.5% in patients
with levels lower than 5 ng/L (P = .001, Table 2). At elevated IL-6 levels, assignment
to dalteparin tended to reduce the risk to 4.4% (P
= .08; Table 2). In patients with
IL-6 lower than 5 ng/L, dalteparin treatment did not influence 6-month mortality.
As for the combined end point, high plasma IL-6 levels were not significantly
associated with risk (RR, 1.16; 95% CI, 0.83-1.62 in the placebo group; Table 2). Assignment to dalteparin treatment
did not reduce the composite of mortality or occurrence of MI at 6 months
regardless of IL-6 levels. However, it significantly lowered the incidence
of these events during the first 60 days of treatment in patients with elevated
plasma IL-6 (P = .01-.04 at 30, 45, and 60 days),
but not in those with lower levels (Figure
The independence of IL-6 levels as a predictor of mortality was assessed
by forward stepwise logistic regression analysis, for which established risk
indicators as well as randomized treatments and interaction terms were evaluated.
Only 7 covariates remained in the interventional part of the trial and 5 covariates
in the medical part as independent predictors (Table 3). Plasma IL-6 levels remained significantly associated with
increased mortality in both the interventional study (adjusted odds ratio
[OR], 2.08; 95% CI, 1.24-3.49; P = .006) and the
medical trial (adjusted OR, 2.09; 95% CI, 1.31-3.33; P
In this study, we found that plasma IL-6 level is an independent marker
for identifying patients with unstable CAD with increased risk of death over
6 to 12 months. Interleukin 6 was ‘predictive' independent of other
risk indicators, including the biochemical markers troponin T and C-reactive
Two studies of healthy adults have shown an association between elevated
IL-6 levels and total and cardiovascular mortality13
and future MI.15 In a study much smaller than
ours, Biasucci et al5 observed that, in patients
with CAD, increased levels of IL-6 were predictive of short-term coronary
events. Based on these observations, as well as the documented prognostic
values of C-reactive protein and fibrinogen,2,7-13
IL-6 seems to settle well as a predictor of long-term mortality of CAD patients
having experienced 1 or more episodes of instability.
The FRISC II interventional trial was the first study to show that an
early invasive treatment strategy reduced mortality and occurrence of MI in
patients with unstable CAD. The greatest beneficial effect was seen in patients
presenting with indicators of higher risk at entry, such as elevated troponin
T levels or ST-segment depression on electrocardiography.17,18
To predict which patients may benefit from an early invasive strategy, additional
markers are needed that provide greater specificity. We now demonstrate that
elevated IL-6 levels, independently of other well-known risk indicators, identify
patients whose risk of death can be considerably reduced by an early invasive
approach. It thus seems that an invasive strategy is of choice despite the
increased inflammatory activity in these patients.
Assignment to prolonged treatment with subcutaneous dalteparin also
tended to reduce the risk of death for patients with IL-6 levels of 5 ng/L
or higher, thus identifying those who would benefit from this kind of treatment.
This is noteworthy since not all patients at high risk are eligible for invasive
treatment, so medical alternatives such as long-term anticoagulant therapy
might be considered.
Elevated plasma IL-6 levels did not correlate with any increased risk
of the composite end point of death or MI at 6 to 12 months. In the medical
study, however, it identified patients for whom assignment to receive dalteparin
had a beneficial effect during the first 60 days. This pattern was also seen
in the main FRISC II medical study for patients with troponin T levels higher
than 0.1 µg/L.16 Therefore, an elevated
IL-6 level might be useful for identification of a high-risk subgroup of patients
who are protected by low-molecular-weight heparin treatment while waiting
for invasive treatment.
The fact that increased IL-6 levels were not predictive for the combined
end point of death or MI is worthy of comment. Considering that the majority
of deaths within a year from a severe unstable episode are likely due to cardiac
causes, it seems that increased IL-6 levels indicate an inflammatory condition
that may result in a higher risk of death from the index MI as well as from
a subsequent MI. We found that patients presenting with elevated IL-6 levels
were older and were characterized by a short angina history, no statin treatment
on admission, low cholesterol levels at admission, myocardial damage as indicated
by increased troponin T levels, and inflammatory activity reflected by elevated
levels of C-reactive protein. These observations suggest that IL-6, which
is present in the atheroma19 and secreted by
endothelial cells, smooth muscle cells, macrophages, and T cells,14,19 may reflect a greater atherosclerotic
burden as well as increased inflammatory activity in the plaques. These would
subsequently be more vulnerable and prone to deeper fissuring, causing more
severe thrombotic episodes and myocardial damage. The ischemic or necrotic
myocardium could also be a source of cytokines.20-22
We saw a moderate but significant correlation between levels of troponin T
and IL-6 (Spearman r correlation coefficient = 0.38, P<.001), which may be explained by this reasoning. However,
IL-6 levels as a predictor of death was additive to but independent of troponin
T. Thus, our results further the understanding that unstable CAD is an inflammatory
One may also regard the issue from the opposite point of view: IL-6
reflects an ongoing low-grade inflammation other than the atherosclerotic
disease and from there contributes to the progression of CAD. In 2 recent
review articles, collected evidence and indices for a central role of IL-6
in the development of coronary heart disease are presented, taking into account
the pleiotropicity of this cytokine and its wide range of actions, including
effects on platelets, endothelium, factors of metabolism, and coagulation.23,24
The method of analysis that we used to measure plasma levels of IL-6
can be considered as rather insensitive. ELISA-based methods can detect levels
of as little as 0.1 ng/L of IL-6, whereas we had a limit of detection already
at 5 ng/L. Possibly, a more sensitive IL-6 assay method would have revealed
more detailed prognostic information.
We also relied on a single blood sample per patient, taken at varying
times after the last episode of chest pain. This could act as a confounder
given the relatively short half-life of IL-6 in plasma (4 hours). Still, our
results very clearly showed a pronounced difference in mortality using 5 ng/L
as a cutoff level and the effect of sample time in predicting high IL-6 levels
was moderate (data not shown). Only the latest sample time quartile had a
slightly lower frequency of elevated levels.
In conclusion, we showed that circulating IL-6 is a strong independent
marker of increased risk for mortality in patients with unstable CAD and that
while patients with high plasma levels of IL-6 have the highest mortality
rates, they also benefit most from a strategy of early revascularization.
Prolonged treatment with subcutaneous dalteparin reduces the risk of death
or MI during the first 60 days of treatment in patients with elevated levels
of IL-6 and could be used while these patients await invasive treatment. Thus,
circulating IL-6 provides important additional information when added to established
indicators for risk stratification in patients with unstable CAD.