8/7/2019 May be aspirine replaced in the treatment of myocardial
infarction (2)_0001
2/3
Eur Heart J, Vol. 21, issue 6, March 2000
Editorials 431
aspirin in platelet-dependent unstable angina and
prevent reocclusion after PTCA, but are currently
only available for intravenous administration. Several
trials with oral agents have been terminated prema-turely due to
excessive bleeding or lack of superiorityover conventional
antiplatelet treatment[1 1].
The only currently available alternative to aspirin
in the setting of acute myocardial infarction and
secondary prevention of coronary artery disease, are
drugs that act via cyclooxygenase product formation,
such as triflusal[12] and compounds that interfere with
ADP mediated platelet reduction, such as ticlopidine
and clopidogrel[6]. A recent trial comparing aspirin
and clopidogrel[13] in post myocardial infarction
patients found no benefit in efficacy from clopidogrel,
although a modest benefit was seen in the overallgroup of
ischaemic patients.
Triflusal is an antiplatelet agent structurally
related to salicylates, but does not derive from acetyl-
salicylic acid (aspirin). Antiplatelet properties of
triflusal and its active 3-hydroxy-4trifluoro-
methylbenzoic acid (HTB) metabolite are primarilymediated by
specificinhibition of platelet arachinodic
acid metabolism through inhibition of
cyclooxygenase[12]. Therefore the production of
thromboxane A2, a main contributor of platelet
aggregation, is suppressed, as in aspirin. HTB, the
triflusal main metabolite, is a reversible
cyclooxygenase inhibitor with a prolonged elimin-ation half
life. In addition, triflusal and HTB have
properties of phosphodiesterase inhibition. This
blockade increases platelet and endothelial cyclic
adenosine monophosphate (AMPc) concentrations
and limits intracellular calcium mobilisation. Thus,although
triflusal is a weak inhibitor of platelet
cyclooxygenase, the addition effect of its metabolite
may contribute to the efficacy of triflusal. As a result,
platelet aggregation and secretion are impaired,
improving the antithrombotic activity by acting attwo different
levels of the process. Experimental
studies have also shown that triflusal and HTB have
an inhibitory effect on cardiovascular inflammatorymediators at
a dosage similar to an antiplatelet
effect[14]; this may have important clinical implica-
tions. In the last 10 years several clinical trials
have tested the efficacy of triflusal in different
cardiovascular processes (PTCA, unstable angina,
post coronary bypass surgery, peripheral occlusive
arterial disease, cerebrovascular disease). All
thes e stud ies have proven a clinical efficacy greater
than placebo and/orsimilar to aspirin but with fewer
sideeffects, especiallyhaemorrhagic complications[12].
Based on these results, triflusal appeared to be
auseful alternative to aspirin in the management
of acute myocardial infarction, and clinical trials like
the TIM trial were ready to run[7]. This double-
blind randomized sequential, parallel study was
conducted in patients with confirmed acute
myocardial infarction (ST ascent or Q wave)
randomized to 600 mg of triflusal or 300 mg ofaspirin. The
treatment was started within 24 h ofsymptom onset, with a follow-up
of 35 days. The
baseline characteristics and concomitant treatment
were similar in the two arms with over 1000 patients in
each arm from 29 centres inSpain, Italy and Portugal.
The number of patients taking beta-blockers and
ACE inhibitors in this study is lower than in otherEuropean
countries. However,the majority of patients
were treated with antiplatelet drugs (100%) heparin
(88%) and fibrinolytic agents(more than 70%).
The primary end-point was the combined incidence
of death, non-fatal reinfarction or non-fatal cerebro-vascular
events in the first 35 days after myocardial
infarction. The secondary end-points were death,
non-fatal reinfarction, non-fatal cerebrovascular
events and the need for urgent revascularization.
Although patients in the triflusal arm showed a 12%
lower risk of a primary end-point, the difference was
not statistically significant. However, the incidence of
non-fatal cerebrovascular events was lower in the
triflusal (0.48%) than in the aspirin (1.31%) arm. This
63% reduction represents a reduction of nine cer-
ebrovascular events per 1000 patients treated in
absolute terms. This difference was mainly due to a
reduction in non-fatal cerebral haemorrhage (sixpatients in
aspirin group to none in triflusal group).
The difference in non-fatal cerebrovascular events
seems due to a lower incidence of cerebrovascular
events in the triflusal-treated group than to an
increase in cerebrovascular events in the aspirin-
treated group. The incidence of these events in the
aspirin arm was of 1.3%, in the normal range of
cerebrovascular complications according to other
trials of aspirin.
Although aspirin is the standard antiplatelet drug
in the management of acute ischaemic syndromes
in clinical practice the incidence of haemorrhagic
complications especially cerebrovascular bleeding,
remains a concern. The TIM trial[7]
shows that
efficacy of treatment in the 35 days after myocardial
infarction is maintained with triflusal with a
significant reduction in cerebrovascular bleedings and
with a non-significant but clinically relevant trend
towards fewer bleedings from any site. Thus, triflusal
may be an excellent option in the acute phase of
myocardial infarction, especially in patients at
risk of haemorrhage or aspirin resistance,
intolerance, or allergy. Further studies comparing
the efficacy of triflusal with other antiplatelet agents,
such as ticlopidine and clopidrogel in different subsets
of patientswith acute ischaemic syndromes, studying
efficacy,
8/7/2019 May be aspirine replaced in the treatment of myocardial
infarction (2)_0001
3/3
2000 The European Society of Cardiology
432 Editorials
side effects and cost-effectiveness are needed before
triflusal can be considered a candidate for routine
therapy in myocardial infarction. The TIM trial may
offer an alternative to aspirin, a challenge which willcertainly
stimulate further research in this field.
A. BAYEuS DE LUNA
Director, Catalan Institut of Cardiology,
Hospital Sant Pau, Barcelona, Spain
References
[1] Maseri A 1995 Ischemic Heart Disease. New York:
ChurchillLivingstone Inc.
[2] Knight CJ. New insights into the pathophysiology of
acutecoronary occlusion. Eur Heart J 1999; (Suppl F): F3F6.
[3] Falk E, Shah PK, Fuster V. C oronary plaque
disruption.Circulation 1995; 92: 65771.
[4] Cairns JA. Antithrombotic agents in coronary artery
disease.Chest 1998; 114: 611S33S.[5] Trip MD, Cats VM, van Capeller
JFL, Vreeken J. Platelet
hyper-reactivity and prognosis in survivors of
myocardialinfarction. N Engl J Med 1990; 322: 154954.
[6] Schror K. Antiplatelet drugs. A Comparative review.
Drugs
1995; 50: 728.
[7] Cruz-Fernandez JM, Lo pez-Besco s O, Garcia-Dorado D et
al.Randomized comparative trial of triflusal and aspirin follow-ing
acute myocardial infarction. Eur Heart J 2000; 21: 45765.
[8] Randomised trial of intravenous streptokinase, oral
aspirin,both, or neither among 17 187 cases of suspected
acutemyocardial infarction: ISIS-2. Lancet August 1988; 2:
34960.
[9] Kaski JC, Plaza Celemin L, eds. Antiplatelet treatment
inacute coronary syndromes. Eur Heart J 1999; (Suppl F).
[10] Collaborative overview of randomised trials of
antiplatelettherapy I: Prevention of death, myocardial infarction,
andstroke by prolonged antiplatelet therapy in various categoriesof
patients. Br Med J 1994; 308: 81106.
[11] Topol EJ, Byzova TV, Plow EF. Platelet GPIIB-IIIa
blockers.Lancet 1999; 353: 227321.
[12] McNeely W, Goa KL. Triflusal. Drugs 1998; 55: 82333.[13]
CAPRIE Steering Committee. A randomised, blinded, trial of
clopidogrel versus aspirin in patients at risk of
ischaemicevents. Lancet 1996; 348: 132939.
[14] Bayo n Y, Alonso A, Sanchez-Crespo M.
4-trifluoromethylderivatives of salicylate, triflusal and its main
metabolite2-hydroxy-4-trifluoromethylbenzoic acid, are potential
inhibi-tors of nuclear factor kB activation. Br J Pharmacol 1999;
126:135966.
[15] F e r n a n d e z d e A r r i b a A , C a v a l c a n t i F
, M i r a l l e s Ae t a l. Inhibition of cyclooxygenase-2
expression by 4-trifluoromethyl derivative of salicylate, tr
iflusal, andits deacetylated metabolite,
2-hydroxy-4-trifluoromethyl-benzoacid. Mol Pharmacol 1999; 4:
75361.
European Heart Journal (2000) 21, 432433doi:
10.1053/euhj.1999.1968, available online at
http://www.idealibrary.com on
QT dispersion in ischaemic heart disease
See page 446 for the article to which this Editorialrefers
Almost a century after Einthovens invention of the
string galvanometer, the surface electrocardiograph
retains its central place in cardiological diagnosis. In
seeking to extract yet more information from thestandard 12 lead
ECG, much attention has been given
in recent years to the measurement of QT dispersion.
The QT interval reflects the duration of depolariz-
ation and repolarization of the ventricular myocar-
dium. Abnormal prolongation of the QT interval
(congenital or acquired) predisposes to ventriculartachycardia
of torsade de pointes morphology.
Abnormal QT dispersion (measured as the difference
between the longest and the shortest QT duration
in the 12 ECG leads) reflects inhomogeneous re-
polarization of ventricular muscle which may provide
a substrate for serious ventricular arrhythmias. In the
context of ischaemic heart disease, researchers haveexplored the
measurement of QT dispersion as a
potential marker of arrhythmic risk, of myocardial
ischaemia and of myocardial viability. In none of
these applications has the technique so far established
a place in routine clinical practice, though some
progress has been made in our understanding of themeasurement
and significance of QT dispersion.
In population studies, QT dispersion has been
reported to be an independent predictor of long-term
cardiovascular mortality in subjects with known car-diovascular
disease at entry
[1]. In patients with acute
myocardial infarction, measurement of QT dispersion
has shown little promise as a predictor of long-term
mortality risk for individuals[2]
. However, the link
between myocardial ischaemia and increased QTdispersion has been
elegantly demonstrated in angina
patients subjected to atrial pacing[3,4]
.
In this issue, Ikonomidis and colleagues report a
study of the relationship between QT dispersion and
myocardial viability, as detected by dobutamine
stress echocardiography, in patients with past myo-
cardial infarction[5]
. They also looked for associationsbetween these phenomena, the
patency of the infarct-
related artery and the occurrence of ventricular
arrhythmias during dobutamine infusion. A low dose
dobutamine infusion protocol was chosen (maximum
20 gg . kg-1
. min-1
in most patients) to reduce the
likelihood of inducing ischaemia during the test; in
