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Early invasive strategy in the diabetic patient with non-ST-segment elevation acute coronary syndromes
Marco Roffi*
Division of Cardiology, University Hospital, Zurich, Switzerland
* Corresponding author. Tel: +41 1 255 8573; fax: +41 1 255 4401. E-mail address: marco.roffi{at}usz.ch
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Abstract
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Diabetic patients with non-ST-segment elevation acute coronary
syndromes are at high risk for subsequent cardiovascular events.
At the same time, however, they derive greater benefit than
non-diabetic counterparts from an aggressive acute-phase management
based on platelet glycoprotein IIb/IIIa receptor antagonists
and an early invasive strategy. Despite the benefit, these treatment
modalities remain underutilized among patients with diabetes
mellitus. The widespread use of drug-eluting stents will further
improve outcomes in patients with diabetes undergoing early
percutaneous revascularization. In this patient population,
the sirolimus-eluting stent appears to be superior to the paclitaxel-coated
one.
Key Words: Diabetes mellitus • Acute coronary syndromes • Early invasive strategy • Glycoprotein IIb/IIIa receptor inhibitors • Drug-eluting stents
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Early invasive vs. conservative strategy
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Diabetes mellitus has been identified as an independent predictor
of long-term mortality in the setting of non-ST-segment elevation
acute coronary syndromes (NSTE-ACSs).
1 Several biological and
metabolic abnormalities may enhance the vulnerability of individuals
with diabetes for cardiovascular events in the presence of ACS
and potentially influence outcomes following revascularization.
2 Of particular interest in this setting are the pro-inflammatory
and pro-thrombotic states described in diabetes.
3 Since no study
has specifically addressed the value of an early invasive strategy
in diabetic patients with ACS, we are left with subgroup analyses
of large-scale clinical trials, namely, the FRISC II (Fragmin
and Fast Revascularization During Instability in Coronary Artery
Disease) study
4 and the TACTICS TIMI 18 (Treat Angina with Aggrastat
and Determine Cost of Therapy with Invasive or Conservative
Strategy—Thrombolysis In Myocardial Infarction 18) trial.
5 FRISC II randomized 2457 patients to either an invasive or conservative
strategy and demonstrated a benefit, and even a reduction in
mortality, associated with an early invasive management.
4 The
benefit in terms of 1-year death or myocardial infarction (MI)
was dramatic among patients with diabetes (
n=299), both in terms
of relative risk reduction (RRR, 39%) and absolute risk reduction
(ARR, 9.3%) (
Figure 1A);
6 among individuals without diabetes,
the efficacy was less pronounced (RRR, 28%; ARR, 3.1%). Owing
to differences in sample size, the benefit observed did not
reach statistical significance in patients with diabetes (
P=0.07),
while it was significant among individuals without diabetes
(
P=0.02). In the TACTICS TIMI 18 trial (
n=2220), an early invasive
strategy was associated with a significant reduction in death,
MI, or rehospitalization for ACS at 6 months, compared with
an early conservative strategy.
5 In contrast to FRISC II, in
TACTICS TIMI 18, all patients received platelet glycoprotein
(GP) IIb/IIIa receptor inhibitors. Again, patients with diabetes
derived a greater benefit than those without diabetes from the
early invasive strategy, in terms of both RRR (27 and 13%, respectively)
and ARR (7.6 and 1.8%, respectively) (
Figure 1B). The benefit
reached statistical significance in diabetes (
n=613), but not
in non-diabetics (
n=1607).
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Figure 1 Event rates according to diabetes status and management strategy in the FRISC II trial4 (A) and in the TACTICS TIMI 18 trial5 (B). (Reproduced with permission from FRISC II Investigators4 and Cannon et al.5)
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Therefore, an early invasive assessment and, if appropriate,
revascularization should be considered the strategy of choice
in diabetic patients with ACS. According to the 2002 European
Society of Cardiology (ESC) guidelines, every diabetic patient
with ACS qualifies for an early invasive strategy.
7 Unfortunately,
data from a recent large-scale registry revealed that patients
with diabetes underwent early coronary angiography less frequently
than those without diabetes in the setting of ACS.
8 With respect
to whether percutaneous coronary intervention (PCI) or coronary
artery bypass grafting (CABG) should be chosen in this setting,
the only randomized data available are derived from the AWSOME
(Percutaneous Coronary Intervention Versus Coronary Artery Bypass
Graft Surgery for Patients with Medically Refractory Myocardial
Ischemia and Risk Factors for Adverse Outcomes with Bypass)
trial.
9 This study compared the two revascularization strategies
in patients with medically refractory unstable angina who were
at high risk for CABG. Among 2431 patients identified, 454 were
considered acceptable for both PCI and CABG; 1650 patients were
deemed not to be candidates for either therapy and entered a
physician-directed registry; and 327 who were considered candidates
for both treatments but refused randomization entered a patient-choice
registry. The respective CABG and PCI 3-year survival rates
for patients with diabetes were 72 and 81% for randomized patients
(
n=144), 85 and 89% for those who entered the patient-choice
registry (
n=89), and 73 and 71% for the physician-directed registry
patients (
n=525).
9 None of the differences between patient groups
was statistically significant. These results have to be interpreted
with caution, as from both a surgical (left internal mammary
artery used as arterial conduit in 70% of cases) and an interventional
perspective (stents used in 54% of cases, GP IIb/IIIa antagonists
administered in 11% of patients), the way patients were revascularized
may not comply with current standards. Nevertheless, CABG and
PCI appear to be comparable options for diabetic patients with
ACS, and the choice of revascularization should be made on an
individual basis according to coronary anatomy, ventricular
function, age, and co-morbidities.
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GP IIb/IIIa receptor antagonists
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Intravenous GP IIb/IIIa receptor inhibitors and intracoronary
stents have produced markedly improved outcomes in patients
with diabetes undergoing PCI. A pooled analysis of the early
abciximab trials demonstrated a survival benefit at 1 year among
patients with diabetes receiving the GP IIb/IIIa inhibitor when
compared with those receiving placebo (mortality 4.5 vs. 2.5%;
P=0.031).
10 Although the overall impact of GP IIb/IIIa receptor
inhibitors in the medical management of NSTE-ACS has been modest,
11 a mortality benefit has been detected among patients with diabetes.
Accordingly, a meta-analysis of the diabetic populations (
n=6458)
enrolled in the six large-scale GP IIb/IIIa inhibitor trials,
which investigated the use of these agents in the medical management
of ACS, detected a 26% mortality reduction (from 6.2 to 4.6%;
P=0.007) associated with these potent platelet inhibitors at
30 days when compared with placebo (
Figure 2A).
12 These
findings were reinforced by a statistically significant interaction
between treatment and diabetic status. Even more striking was
the benefit among patients with diabetes undergoing PCI, corresponding
to a 70% 30-day mortality reduction (from 4.0 to 1.2%;
P=0.002)
(
Figure 2B). With respect to the mechanisms underlying
the preferential benefit derived by patients with diabetes from
these agents, a recent study has suggested that a covalent modification
of the GP IIb/IIIa receptor induced by non-enzymatic glycation
may be responsible for the enhanced platelet inhibitory effect
mediated by these agents, which has been observed among diabetic
individuals.
13 The 2002 ESC guidelines recommend the use of
GP IIb/IIIa blockers in all diabetic patients with ACS.
7 However,
as seen with the early invasive strategy, patients with diabetes
currently receive GP IIb/IIIa inhibitors less frequently than
their non-diabetic counterparts.
14
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Figure 2 Odds ratio with 95% confidence intervals (CI) and corresponding P-values for treatment effect on 30-day mortality in the overall diabetic population with ACSs (A) and in the subgroup of patients who underwent in-hospital PCI (B). Values to the left of 1.0 indicate a survival benefit of platelet GP IIb/IIIa inhibition (IIb/IIIa). (Reproduced with permission from Roffi et al.12)
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With respect to whether one GP IIb/IIIa receptor inhibitor may
be preferable in patients with diabetes over another, subgroup
analysis of the only head-to-head comparison did not identify
differences between the small-molecule tirofiban and the antibody
fragment abciximab in the setting of PCI.
15 Although the value
of GP IIb/IIIa receptor inhibitors in patients pre-treated with
high-dose clopidogrel has been recently questioned,
16 no data
are available in ACS. Importantly, the preferential benefit
of GP IIb/IIIa receptor inhibitors observed among diabetic patients
with ACS
12 could not be replicated with clopidogrel in the CURE
(Clopidogrel in Unstable Angina to Prevent Recurrent Events)
trial, despite the large number of diabetic patients enrolled
(
n=2840).
17 Accordingly, the risk of death from cardiovascular
cause, non-fatal MI, or stroke at 12 months was 16.7% among
diabetic patients receiving aspirin and 14.2% in the group receiving
aspirin and clopidogrel (
P=NS).
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Drug-eluting stents
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The impact of drug-eluting stents on restenosis has been dramatic.
The broad use of these devices is expected to markedly improve
the outcomes of diabetic patients with ACS undergoing early
invasive strategy. Recent data suggest that the sirolimus-eluting
stent (Cypher
®, Cordis, Miami, FL, USA) is superior to the
paclitaxel-eluting stent (Taxus
®, Boston Scientific, Natick,
MA, USA) among individuals with diabetes. Accordingly, a pre-specified
subgroup analysis of the diabetic population (
n=201) of the
Swiss randomized SIRTAX (Sirolimus Versus Taxus) trial showed
a significant decrease in the incidence of death, MI, or ischaemia-driven
target lesion revascularization at 9 months in the sirolimus
stent group (hazard ratio, 0.31, 95% confidence interval, 0.12
to 0.78).
18 Similarly, a single-centre German study, which randomized
250 patients with diabetes documented a restenosis rate of 6.9%
for the sirolimus-eluting stent and 16.5% for the paclitaxel-coated
stent (
P=0.03) (results presented by A. Kastrati at the ACC
Annual Scientific Session, Orlando, FL, USA, March 2005).
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Conclusions
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Diabetic patients with ACS are at high risk for subsequent cardiovascular
events but, at the same time, derive greater benefit than non-diabetic
counterparts from aggressive therapy such as GP IIb/IIIa receptor
inhibition and an early invasive strategy. Unfortunately, these
efficacious treatments remain underutilized in ACS patients
with diabetes. Outcomes of patients with diabetes undergoing
PCI will be further improved by the broad use of drug-eluting
stents. In this setting, the sirolimus-eluting stent appears
to be superior to the paclitaxel-coated one.
Conflict of interest: Dr Roffi has received speaker fees and a research grant from Merck & Co.
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References
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