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Wien Med Wochenschr (2010) 160/12: 3038

DOI 10.1007/s10354-010-0747-8

Springer-Verlag 2010
Printed in Austria

Antithrombotic therapy in patients with coronary

artery disease and with type 2 diabetes mellitus
Serdar Farhan1, Thomas Hchtl1, Alexandra Kautzky-Willer2, Johann Wojta3 and Kurt Huber1
1

Third Department of Cardiology and Emergency Medicine, Wilhelminen Hospital, Vienna, Austria
Third Department of Endocrinology and Metabolism, University of Medicine, Vienna, Austria
3
Second Department of Cardiology, University of Medicine, Vienna, Austria
2

Received December 15, 2009; accepted December 16, 2009

Antithrombotische Therapie bei Patienten mit
koronarer Herzkrankheit und Typ2 Diabetes
mellitus
Zusammenfassung. Die koronare Herzerkrankung (KHK) ist
die fhrende Mortalittsursache bei Patienten mit Diabetes mellitus (DM). Die Langzeitprognose des Diabetikers ohne Myokardinfarkt-Anamnese ist vergleichbar mit der eines Patienten, der
einen Myokardinfarkt (MI) bereits durchgemacht hat, aber keinen DM hat. Der Antiplttchen-Therapie bei Patienten mit einer
KHK und DM kommt eine zentrale Rolle zu, wobei dem ADPRezeptorblocker Prasugrel eine grere Efzienz zugeschrieben
wird im Vergleich zu Clopidogrel und Ticlopidin. Patienten mit
DM und akuten Koronarsyndrom (ACS), die einer interventionellen Therapie unterzogen werden, protieren mehr von eine
additiven Therapie mit Glycoprotein IIb/IIIa-Inhibitoren als Patienten ohne DM. Weiters kommen verschiedene, direkte und
indirekte Antithrombine in der Therapie des ST-Hebungs-Infarktes (STEMI) und nicht ST-Hebungs-Infarktes (NSTEMI) zur
Anwendung. Unter diesen Medikamenten haben sich sowohl das
niedermoleklare Heparin Enoxaparin als auch der direkte
Thrombin-Inhibitor Bivalirudin als sicher und efzient bei Diabetikern im Vergleich zu unfraktionierten Heparin erwiesen.
Schlsselwrter:
Koronare
Herzerkrankung,
Koronarsyndrom, Diabetes mellitus

akutes

Summary. Diabetes mellitus (DM) is a life-threatening disease. Patients with DM have a 2- to 4-fold higher risk of developing cardiovascular disease compared to their non-diabetic
counterparts. Several drugs are available for the treatment of
stable coronary artery disease (CAD) and acute coronary syndrome (ACS). Among oral antiplatelet agents (acetylsalicylic acid,
ticlopidine, clopidogrel, and prasugrel), prasugrel has shown the
highest efcacy in patients with DM and ACS. The use of glycoprotein IIbIIIa receptor inhibitors in diabetic subjects with ACS

Correspondence: Serdar Farhan, M.D., Third Department of

Medicine, Cardiology and Emergency Medicine, Wilhelminenspital,
Montleatstrasse 37, 1160 Vienna, Austria.
Fax: 43-1-49150 2309, E-mail: serdar.farhan@wienkav.at

30

undergoing percutaneous coronary intervention (PCI) reduces

adverse clinical events in a greater extent than in non-diabetics.
Several direct and indirect antithrombins are recommended for
the treatment of ACS such as unfractionated heparin (UFH),
enoxaparin, fondaparinux, and bivalirudin. Enoxaparin and
bivalirudin have been shown to be superior to UFH among
patients with ST-elevation MI (STEMI) and non-ST elevation MI
(NSTEMI) also in diabetic subgroup analyses.
Key words: Coronary artery disease, acute coronary syndrome, diabetes mellitus

Introduction
Type 2 diabetes mellitus (DM) is a disease with an
increasing prevalence worldwide. Individuals with DM
have a 2- to 4-fold higher risk to develop cardiovascular
disease (CVD) compared with non-diabetics [1]. The
mortality of a patient with DM without history of myocardial infarction (MI) is as high as that of an individual
with prior MI but without DM [2]. When diabetics
develop myocardial infarction hospital course is more
complicated and the incidence of recurrent cardiovascular events is higher compared to their non-diabetic
counterparts [3, 4]. Moreover, the prognosis for diabetic
patients who undergo coronary revascularization procedure is worse compared to non-diabetic subjects
including higher peri- and post-procedural complications and a reduced infarct-free survival [5, 6]. In
diabetics the increased risk for atherothrombotic cardiovascular events is independent of the existence of
other cardiovascular risk factors such as hypertension,
dyslipidemia, cigarette smoking, obesity, and albuminuria [7, 8]. Accordingly, combined antithrombotic therapeutic strategies are mandatory to reduce this
increased atherothrombotic risk in diabetic patients
and the development of more efcacious but safe

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agents is the permanent aim of ongoing scientic

activities.

Diabetes and the pro-thrombotic milieu

Platelet hyperreactivity in patients with DM
Platelets from diabetic patients show an increased
thromboxan A2 (TXA2) release, reduced production of
nitric oxide (NO) and prostacyclin, a disordered calcium homeostasis, magnesium deciency, and an increased expression of adhesion molecules and
receptors [9, 10]. TXA2 is a potent vasoconstrictor
[11] and tight metabolic control with insulin therapy
has been shown to reduce TXA2 release [10] as also a
therapy with acetylsalicylic acid [10, 12]. Decreased NO
production in patients with DM could be a result of
insulin resistance, which is the hallmark of the metabolic syndrome shifting the balance towards aggregation and vasoconstriction. Increased intracellular
calcium and decreased magnesium concentrations
[13] alter membrane uidity. Supplementation of magnesium can reduce abnormal platelet function in those
individuals [13]. It has been demonstrated that platelets
from diabetics exhibit increased expression of a variety
of adhesion molecules such as CD31, CD36, CD49b,
CD62P, CD63, and P-Selectin [9]. Furthermore glycoprotein (GP) IIb/IIIa receptors, which mediate the
binding of platelets to brinogen, were found to a
higher extent in diabetic compared to non-diabetic
individuals [14].
The coagulation system in patients with DM
DM or insulin resistance is associated with an imbalance between pro-thrombosis and pro-brinolytic
parameters as reected by elevated plasma concentrations of brinogen, von Willebrand factor (vWF)
[1518], and thrombin-antithrombin complex (TATc),
a marker for thrombin generation [1924]. A decreased

brinolytic potential is reected by reduced tissue type

plasminogen activator (t-PA) plasma levels and an
increase in plasminogen activator inhibitor type 1
(PAI-1) [25] even in subjects in pre-diabetic conditions
[26]. In a study performed in healthy subjects, hyperglycemia resulted in stimulation of coagulation
and hyperinsulinemia in decreased brinolytic
activity [19].

Antithrombotic strategies in patients

with diabetes mellitus with coronary
artery disease
Antiplatelet therapy
Acetylsalicylic acid
ASA is an inhibitor of cyclooxygenase type 1 (COX-1),
which is the key enzyme that catalyzes the production
of TXA2 from arachidonic acid (Fig. 1). In higher dosages ASA can also inhibit cyclooxygenase type 2 by
which it impedes the production of prostaglandin
thereby exerting anti-inammatory action. ASA is recommended by the American Diabetes Association in
the primary prevention of CVD in patients with DM
[12]. It confers a 19% reduction for atherothrombotic
disease [27]. A meta-analysis by the antiplatelet trialistsCollaboration found that the benet of ASA is limited to
patients suffering from DM [28]. In this analysis ASA
therapy was associated with a 7% non-signicant reduction in vascular events [28]. In contrast, in a study
carried out in diabetic patients with acute coronary
syndrome (ACS) ASA was not associated with a signicant mortality benet [29]. Similar results were obtained from the primary prevention program [30] as
well as from the POPADAD and JPAD trials [31, 32].
Further randomized clinical trials are on the way to
clarify the denite role of ASA in primary prevention of
cardiovascular mortality in patients with DM.

ADP receptor
blockers
type 2-purinergic receptor
ADP

Activation

Collagen, thrombin
and TXA2

Gp IIb-IIIa receptor
COX-1 activation
TXA2
Gp IIb-IIIa inhibitors
ASA

Fig. 1: Mechanism of action of antiplatelet drugs. TXA2 Thromboxan A2; COX-1 cyclooxygenase 1; ADP adenosin diphosphat; Gp IIb-IIIa glycoprotein
Iib-IIIa recpeptor and inhibitor

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Thienopyridines: Ticlopidine, clopidogrel, prasugrel

This class of drugs inhibits the binding of adenosine
diphosphate (ADP) to the platelet type 2-purinergic
receptor (P2Y12). For presently clinically available
ADP-receptor blockers this binding is irreversible. Accordingly the inhibitory effect lasts for the lifetime of the
platelet [9]. Blockade of the ADP receptor prevents
activation of the GPIIb-IIIa receptor and the subsequent binding of brinogen (Fig. 1). Three different
types of thienopyridins are currently availableticlopidine, clopidogrel, and prasugrel.
Ticlopidine, although of comparable efcacy, has
been substituted due to its side effects, i.e., severe
neutropenia, agranulocytosis, or thrombotic thrombocytopenic purpura [9, 33] by clopidogrel.
Clopidogrel is an important accompanying
medication in patients undergoing percutaneous
coronary interventions (PCI), whereby a loading dose
of 300 mg in stable coronary artery disease (at least
624 hours before the intervention) and 600 mg in
patients with ACS (at least 2 hours before PCI),
followed by a maintenance dose of 75 mg once daily,
is at present recommended by international guidelines [34, 35] and has been also proven in a real-world
scenario [36]. Clopidogrel has been shown to be
superior to ASA in patients with stable cardiovascular
disease [37] and exerts in combination with ASA (dual
antiplatelet therapy, DAPT) an about 20% relative risk
reduction in patients with an ACS [38]. Patients with
ACS without DM seem to have a greater benet of
DAPT compared to those with DM [39]. Moreover,
elevation of the maintenance dose of clopidogrel
resulted in a greater inhibition of the platelet function
in the OPTIMUS-trial [40]. The recently presented
CURRENT/OASIS-7 trial (presented at the ESC Annual Meeting, Barcelona 2009) demonstrated a signicant advantage for 600 mg loading dose of clopidogrel
followed by 150 mg daily for 7 days and a further
reduction to 75 mg/day. Moreover, high-dose ASA
(325 mg p.o. QD) in addition to high dose was favorable over low dose in this study.
With respect to the reduced benet of clopidogrel
in diabetic patients prasugrel, the newest thienopyridine on market, might overcome this unfavorable situation. In the TRITON-TIMI-38 study prasugrel (loading
dose: 60 mg; maintenance dose: 10 mg/d) was compared with clopidogrel (LD 600 mg, MD: 75 mg/d) and
exhibited a greater benet in patients with ACS undergoing PCI and coronary stenting [41]. It is suspected
that the faster, greater, and more efcient generation of
the active metabolite of prasugrel, which is based on a
single metabolic step in the liver (in opposite to two
32

metabolic steps for clopidogrel), is responsible for this

benet [42, 43], as ex vivo addition of the active clopidogrel metabolite also led to the maximal inhibition of
aggregation in all patients (comparable with that of the
active prasugrel metabolite). A poor response to clopidogrel is assumed by an ineffective generation of its
active metabolite, rather than from P2Y12 receptor heterogeneity [43].
The more efcient action of prasugrel vs. clopidogrel could be demonstrated early as well as late after
initiation of treatment [44] and led also to a better
reduction of recurrent ischemic endpoints after a rst
atherothrombotic event [45].
In the whole patient cohort and especially in
patients with a history of cerebrovascular events
(stroke and transitoric ischemic attack), in the elderly
(>75 years), and in underweighted patients (<60 kg)
prasugrel was associated with a higher incidence of
bleeding complications [46]. Accordingly, prasugrel is
contraindicated in patients with a history of stroke or
transitory ischemic attack, and should be used in the
maintenance phase in reduced dosage (5 mg/day) in
the elderly and light weighted, if at all as long as
clinical data are not fully available (TRILOGY trial).
The TRILOGY trial is designed to test the hypothesis
that the combination of aspirin and prasugrel is superior to aspirin and clopidogrel in the treatment of
medically managed high-risk patients enrolled within
7 days or 10 days of the qualifying NSTE-ACS index
event.
Of importance is that prasugrel has demonstrated
its benet over clopidogrel without increasing severe
bleeding complications in the predened subgroups of
diabetics [47] (Tab. 1) and STEMI patients [48].

Ticagrelor
Recently, the new reversible ADP receptor antagonist
ticagrelor, which does not belong to the group of thienopyridines, has been shown to be superior over clopidogrel in patients with ACS with respect to hard
clinical endpoints (MI, cardiovascular and non-cardiovascular death). Due to its reversible action and
relatively short half-life compared to clopidogrel the
peri-operative bleeding rate in patients referred for
acute and subacute coronary bypass surgery was reduced. Total severe bleeding hazards, however, were
higher compared with clopidogrel and similar to prasugrel in the TIMI-38 trial. Ticagrelor has still to be
approved by the FDA and EMEA before it will be
available for clinical use. Its role in patients with diabetes is still uncertain [49].

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Tab. 1: Important antithrombotic trials with special outcome data for patients with diabetes mellitus
Study

Patient population

Anithrombotic regimen
comparators

Evidence

TRITON-TIMI 38
[47]

NSTEMI and STEMI with PCI

and stent implantation

Prasugrel vs. Clopidogrel

Prasugrel was superior

to clopidogrel

ISAR-SWEET [53]

Elective PCI

Abciximab (GPI) vs. placebo

Lower incidence of restenosis

Rof et al. [50]

NSTEMI patients with PCI
stent

implantation

GPI vs. placebo

GPI use was superior to non-use

OASIS 5 [77]

NSTE-AMI

Fondaparinux vs. Enoxaparin

Fondaparinux was superior to

enoxaparin in terms of reduced
major bleeding rate and reduced
mortality and stroke rates

REPLACE-2 [71]

UA/NTEMI patients with acute

as well as elective PCI

Bivalirudin vs. UFH plus GPI

Lower risk of bleeding with

similar adverse event rate for
bivalirudin

ACUITY [72]

ACS

Bivalirudin vs. UFH or enoxaparin

plus GPI

Lower risk of bleeding with

similar adverse event rate for
bivalirudin

DM diabetes mellitus; ACS acute coronary syndrome; GPI glycoprotein IIb/IIIa inhibitor; UFH unfractionated heparin; STE-AMI ST
elevation acute myocardial infarction; NSTE-AMI non-ST elevation myocardial infarction; PCI percutaneous coronary intervention.

Tab. 2: European society of cardiology (ECS) guidelines for the antithrombotic therapy in patients with
non-ST-elevation myocardial infarction [60]
Substance

Non-invasive treatment
strategy

Invasive treatment strategy Early invasive treatment

(within 72 hours)
strategy (within 2 hours)

Enoxaparin

IIa-B

IIa-B

IIa-B

Fondaparinux

I-A

I-A

Bivalirudin

I-B

I-B

UFH

I-C

I-C

Tab. 3: European society of cardiology (ECS) guidelines for the antithrombotic therapy in patients with
ST-elevation myocardial infarction [34]
Substances

Treatment strategy
Primary PCI

Fibrinolysis

No-repefusion

Enoxaparin

IA*, IIa-B #

I-B*

Fondaparinux

III-B

IIa-B #

I-B

Bivalirudin

IIa-B

UFH

I-C

I-A*, IIa-C #

I-B*

Alteplase/reteplase/tenecteplase; # Streptokinase; * If fondaparinux is not available.

GP IIb/IIIa inhibitors
GP IIb/IIIa inhibitors (GPIs) are administered intravenously, have a rapid onset of action and a relatively
short half-life. They inhibit the binding of GP IIb/IIIa
receptor to brinogen, which is the nal endpoint in
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platelet activation and key for platelet aggregation [10]

(Fig. 1). GPIs are used as adjunctive therapy on top of
ASA and clopidogrel/prasugrel in high-risk patients
with ACS (troponin-positive NSTEMI patients and STEMI patients) who undergo acute PCI. Three different

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types of GPIs are available for clinical use: Abciximab,

tiroban, and eptibatide, of which abciximab is besttested agent in coronary interventions. Several studies
reported the benecial effect of GPIs in patients with
CAD. Rof et al. pooled the diabetic population enrolled in six large-scale ACS trials evaluating the use of
these agents [50] (Tab. 1). Treatment with GPIs was
associated with a signicant reduction in mortality at 30
days (OR: 0.74, 95% CI: 0.590.92, P 0.001). In older
trials without concomitant use of thienopyridines, diabetics seemed to derive even a greater benet from the
use of GPI compared to non-diabetics [51, 52]. In
contrast, in a study carried out on patients with DM
and stable CAD who underwent elective PCI, abciximab
did not support an additional mortality benet compared to placebo, when patients were pretreated with
600 mg clopidogrel although, in this study the additional use of abciximab resulted in a reduction of restenosis
in DM patients receiving bare metal stents [53]. Accordingly, the use of GPIs in diabetic patients should be
referred to patients with ACS undergoing PCI. Despite
the benet of GPI use vs. non use in diabetics with ACS,
diabetes mellitus is associated with a higher complication rate consisting of distal embolization, impaired
myocardial perfusion, and higher mortality compared
to non-diabetics in patients with acute STEMI referred
for primary PCI [54].

Antithrombins
Several antithrombins are at present commercially available in patients with coronary artery disease
(CAD) such as unfractionated heparin (UFH), the low
molecular weight heparin (LMWH) enoxaparin, the
pentasaccharide fondaparinux, an indirect factor Xa
inhibitor, as well as the direct thrombin inhibitor bivalirudin. Many more agents are in clinical testing as the
direct factor Xa inhibitors apixaban, rivaroxaban, and
otamixaban, and the direct thrombin inhibitor dabigatran. The point of inhibition of each drug within the
coagulation cascade is depicted in Fig. 2.
Unfractionated heparin and low molecular weight
heparins
Although UFH is usually seen as gold standard beyond
antithrombin agents, enoxaparin has been shown to be
superior to UFH in patients with NSTE-ACS [55].
Among the different LMWHs enoxaparin is the best
and widely tested in cardiology and should therefore be
preferred in patients suffering from cardiovascular diseases. Enoxaparin has been compared to UFH in nu34

Indirect inhibiton

Direct inhibition
-

Fondaparinux

Xa

Apixaban

AT III

Rivaroxaban
Otamixaban

Enoxaparin
AT III

Unfract. Heparin
AT III

II

IIa

Bivalirudin
Dabigatran

Fig. 2: Targets of the different antithrombotic drugs. ATIII Antithrombin III;

Xa activated factor X; II Prothrombin; IIa Thrombin

merous huge trials in NSTE-ACS patients [5659].

Based on the data generated, enoxaparin is recommended in the setting of NSTE-ACS [60]. In these trials
the diabetic subgroups, which accounted for 1928% of
the whole study populations, showed no benecial
effect of enoxaparin vs. UFH [58]. Also in diabetic
patients with high-risk NSTE-ACS (age >60 years, elevated cardiac biomarkers and electrocardiographic abnormalities) there was no benet for enoxaparin over
UFH [61].
Especially studies using enoxaparin as an adjunctive antithrombotic therapy in patients with STEMI
referred for pharmacologic reperfusion (thrombolytic
therapy) have demonstrated superiority to UFH
[6268], especially in diabetic patients [69]. However,
little is known at present about the efcacy and safety of
enoxaparin vs. UFH in patients with STEMI undergoing
primary PCI. In a German registry, the use of enoxaparin vs. UFH in patients with STEMI referred for
primary PCI showed a reduced combined endpoint of
in-hospital death and re-infarction without increasing
bleeding complications [70]. Currently the ATOLL trial
is investigating the role of a reduced dose of enoxaparin
(0.5 mg/kg) vs. usual doses of UFH in patients with
acute STEMI referred for primary PCI.

Bivalirudin
Bivalirudin has the advantages of its direct action on
thrombin and of inhibition also of clot bound thrombin
in contrast to heparins. Due to a very short plasma half
time of 25 minutes and a preferred renal elimination of
its inactive metabolites the danger of accumulation in
case of renal failure and consecutively the bleeding risk
is lower compared with heparins.
Bivalirudin has been investigated in two prospective, randomized trials in patients with NSTE-ACS

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(REPLACE-2 und ACUITY). The REPLACE-2 trial [71],

which included patients undergoing acute as well as
elective PCI, found a signicant reduction in the composite net primary endpoint (death, MI, urgent revascularization or major bleeding) at day 30 for bivalirudin
monotherapy compared to UFH plus a GPI [71]. Furthermore a signicant reduced bleeding rate was observed in bivalirudin-treated patients. This favorable
effects were also reported for the diabetic subgroup
[71]. The ACUITY trial was performed to investigate the
efcacy of bivalirudin monotherapy vs. enoxaparin/
UFH plus a GPI or bivalirudin plus a GPI in patients
with NSTE-ACS. Bivalirudin monotherapy showed similar rates of ischemic events with less major bleeding
rates, resulting in a signicant reduction in net adverse
clinical outcomes [7274].
One major trial investigated the impact of bivalirudin vs. UFH plus a GPI (mainly low molecular weight
agents) in patients with STEMI undergoing primary PCI
[75]. In this trial anticoagulation with bivalirudin monotherapy reduced the net clinical endpoint (death, MI,
recurrent revascularization, and major bleedings at
1 year) signicantly compared with UFH plus a GPI
[75]. However the subgroup of diabetics was not specically reported in this trial.
Fondaparinux
Based on the recommendations of the ESC (Tab. 1),
fondaparinux has a class Ia indication when a conservative strategy or PCI is chosen in patients with NSTEACS [60]. This recommendation is mainly based on
the results of the OASIS 5 trial, in which enoxaparin
(2  1 mg/kg/d s.c.) was compared to fondaparinux

(2.5 mg/d s.c.) [76]. In this trial fondaparinux was

non-inferior to enoxaparin in terms of the combined
primary endpoint consisting of death, MI, and recurrent ischemic events. Most importantly, fondaparinux
was associated with a signicant lower risk for severe
bleeding hazards. These results were paralleled in the
diabetic subgroup [77].
The inuence of fondaparinux on the outcome of
STEMI patients was investigated in the OASIS 6 trial
[78]. This trial exhibited an advantage of adjunctive
fondaparinux use over placebo/UFH in patients referred for conservative treatment only (no reperfusion
therapy) and for pharmacologic reperfusion (thrombolytic therapy with brin-specic and un-specic
agents), but was inferior to UFH in STEMI patients
referred for primary PCI [7880]. Again, no specic data
for the diabetic population in this trial were reported.
Accordingly, the denite role of fondaparinux in STEMI
patients with DM is still uncertain.
New antithombins in investigation
Recently new drugs have been investigated in phase II
prospective randomized dose nding studies: rivaroxaban and apixaban, both oral direct anti-Xa inhibitors
have been tested vs. placebo in the ATLAS ACS-TIMI 46
trial [81] and the APPRAISE trial [82] on top usual DAPT
in the secondary prevention phase after ACS. Preliminary results exhibited dose-depending effects not only
on atherothrombotic-ischemic endpoints but also on
increasing bleeding rates. The optimal efcacy/safety
doses are now investigated in phase 3 clinical trials
(APPRAISE-2 and ATLAS-2). In contrast, the intravenous direct factor Xa inhibitor otamixaban has been

Platelet

Platelet

PAR-1
PAR-4

Fibrinogen

GP
IIb/IIIa

P2Y1
P2Y12
TBXA2-R
EPI-R
5HT2A
GP VI
GP la

Anionic
phospholipid
surfaces

Fig. 3: Platelet-thrombin interaction. Xa Activated factor X; Va activated factor V; II Prothrombin

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tested in a phase-2 dose nding trial (SEPIA-ACS)

against UFH plus the GPI integrelin during the acute
phase of ACS [83]. Also here a phase-3 trial is in
discussion.
Thrombin-receptor antagonist (TRA)
At present, SCH 530348, an oral platelet protease-activated thrombin receptor-1 antagonist is a matter of
extensive studies in patients with ACS in the acute
phase (TRACER trial) as well as in the maintenance
phase after ACS (TRAP-2 trial). The agent blocks the
thrombin-receptor-1 on platelets, which is important
for platelet function activation by thrombin (Fig. 3). Its
potential role in patients with DM will be goal of future
investigations [8486].

Conclusions
Patients with DM exhibit a pro-thrombotic milieu, which involves platelet hyperreactivity, increased
coagulation marker, as well as a decreased brinolytic
potential. This environment contributes to the worse
clinical outcome despite the combined use of antiplatelet and antithrombin agents. Only for few antithrombotic drugs benecial effects have been
demonstrated in diabetic ACS patients: for prasugrel
(compared to clopidogrel) in STEMI patients, for the
GPI abciximab (vs. placebo) in high-risk NSTEMI and
STMI patients undergoing PCI, and for bivalirudin (vs.
UFH and or enoxaparin) in NSTEMI patients. For all
other antithombins and antiplatelet agents the antithrombotic/anti-ischemic effects seem to be reduced or
at maximum equal in diabetics compared with nondiabetics or have not been investigated so far. Additional trials designed to evaluate specic therapeutic
regimens, e.g., specic combination and different
dosages of the above-mentioned drugs are needed
to investigate efcacy/safety ratios in diabetic patients
with coronary artery disease.
Based on the fact that in the majority of studies
performed in the past the diagnosis of DM was insufcient (in most instances diagnosis was based on current
therapy and history) patients with pathologic glucose
metabolisms might not have been detected and attributed to the non-diabetic comparison group. This might
have inuenced the results. Accordingly, it is now
recommended that future prospective randomized
trials have to be performed in well-dened diabetic
patients, which should include oral glucose tolerance
testing for a better differentiation between diabetics
and non-diabetics.
36

Conict of interest
The authors declare that there is no conict of
interest.

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