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(Circulation. 1999;100:1586-1589.)
© 1999 American Heart Association, Inc.
Editorial |
Pursuing Progress in Acute Coronary Syndromes
From the Department of Medicine, University of Alberta, Edmonton, Canada.
Correspondence to Paul W. Armstrong, MD, Department of Medicine, University of Alberta, Edmonton, Alberta, T6G 2H7, Canada. (Circulation. 1999;100:1586-1589.)
Key Words: Editorials • anticoagulation • heparin • unstable angina • acute coronary syndromes
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"The difficulty in life is the choice."
George Moore
The sheer scope of the burden of acute ischemic heart disease, initially evident in Western civilization but now increasingly a global problem, places a high priority on understanding its pathophysiology and identifying individuals at increased risk of morbid and mortal events. So too is there strong impetus for the timely development and introduction of cost-effective therapeutic solutions coupled with concurrent strategies for both primary and secondary prevention.
Patients presenting with ischemic chest pain and
transient electrocardiographic abnormalities as part of an acute
coronary syndrome have an unfavourable prognosis.1
Their risk is augmented if there are abnormalities in cardiac markers
or enzymes and if older age, diabetes, prior myocardial infarction,
left ventricular dysfunction, or other unfavourable
baseline characteristics are present. Recurrent ischemia,
whether clinically evident or silent, further increases the probability
of mortality and subsequent myocardial damage.1 2 A
bewildering array of therapeutic options has emerged to combat this
common and important problem. Accompanying these diverse options over
the past 5 years has been an explosion in our knowledge of the
pathophysiology of acute coronary syndromes.3
Plaque fissuring promoted by inflammation and possibly infection, as
well as a coronary thrombotic process mediated through the
coagulation cascade and activated platelets, all of which
unfold on a unique genetic template, make it unlikely that a single
pharmacological agent will achieve the results we desire for our
patients (Figure
).
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Low Molecular Weight Heparins
The venerability of our traditional therapy with aspirin and
intravenous unfractionated heparin, although a tribute to
its efficacy, has recently been challenged by the emergence of
glycoprotein IIb/IIIa platelet inhibitors
and low molecular weight heparins (LMWH). Unfractionated heparin's new
depolymerized progeny offer several advantages over its
parent.4 5 Because they bind less strongly to both plasma
and tissue proteins and are more bioavailable, they are capable of
producing both a longer and more predictable anticoagulant effect
without the need for laboratory monitoring. Other advantages of LMWH
include enhanced anti-Xa activity, relative resistance to the
neutralizing effect of platelet factor IV (it is also able to
inhibit factor Xa located on platelet surfaces), inhibition of Von
Willebrand factor, and facilitation of tissue factor
inhibitor release. LMWH achieve their lighter status
(approximately 4500 to 6000 d) through enzymatic or chemical
depolymerization. The exact mechanisms for their
efficacy and hemorrhagic effects are unknown but variation in the ratio
of anti-Xa to anti-IIa (between 
2 to 4:1) have led to
speculation that measuring the anti-Xa activity might provide the
potential for meaningful biological monitoring.
Initial studies in patients with venous thromboembolism confirmed stable therapeutic efficacy, avoidance of the need for laboratory monitoring, and acceptance of patient self-administration, thereby improving cost efficacy through reduced length of hospital stay.6 Given the widespread use of heparin, the lower incidence of LMWH-induced thrombocytopenia (presumed secondary to its reduced binding to platelets and platelet factor IV) is a welcome additional advantage.
Because of the initial success with LMWH in venous thromboembolism, application of this therapy to acute coronary syndromes was a logical next step. Unequivocal evidence concerning the dalteparin variety of LMWH as compared to placebo emerged from the FRISC trial, which demonstrated a 3% absolute and 63% relative risk reduction in death or new MI at 6 days. Attenuation of the benefit of q12h dalteparin (120 IU/kg given for 6 days with a once-daily fixed dose regimen of 7500 IU over 35 to 45 days) raised the possibility that a more effective, prolonged treatment regimen might better sustain or even enhance early benefit.7 The FRIC investigators, using a similar dalteparin regimen, found no improvement and possibly less favorable effects compared to unfractionated heparin during the hospital course: no advantage over aspirin was evident after sustained dalteparin therapy for 45 days.8
Two years ago, the ESSENCE investigators first reported on the therapeutic effects of enoxaparin compared with unfractionated heparin in patients with unstable coronary disease.9 The risk of a composite primary end point of death, myocardial infarction, or recurrent angina at 14 days was reduced from 19.8% to 16.6% (odds ratio 0.80; 95% CI 0.67–0.96). Although no benefit was evident at 48 hours, there was persistence of the 14-day benefit, largely driven by recurrent angina, through 30 days. This has recently been found durable at 1-year follow-up.10 An additional mechanism for benefit in these patients may well be the observation of reduced rebound ischemia, previously demonstrated after cessation of unfractionated heparin.10 11
In this issue of Circulation, the TIMI 11B investigators add
to our knowledge concerning the role LMWH in patients with unstable
angina.12 In a companion article, the TIMI 11B and
ESSENCE investigators combine their data in meta-analysis: it
is instructive to scrutinize these 2 trials.12 13 The TIMI
11B trial evolved from an earlier dose-finding study where a higher
dose of enoxaparin, ie, a 30-mg intravenous bolus followed
by a subcutaneous q12 hourly administration of 1.25 mg/kg was
associated with a major hemorrhage rate of 6.5% within 2 weeks
of enrollment. Accordingly, after demonstrating a reduced rate of major
hemorrhage of 1.9% using a lower maintenance
enoxaparin dose of 1.0 mg/kg, this treatment strategy was used in a
randomized and a double-blinded fashion in TIMI 11B. Initially, 1800
patients, required to have at least 5 minutes of ischemic chest
pain at rest, within 24 hours of randomization, coupled with some
evidence of prior coronary disease defined by history, abnormal
coronary angiogram, prior myocardial infarction, ST-segment
shift, or elevated cardiac markers, were enrolled over a 10-month
period in 10 countries. At this juncture, concern about a lower than
expected aggregate event rate prompted modification of the protocol so
that all patients were required to have either ST-segment shift or
positive cardiac markers at entry. Interestingly, approximately one
third of patients in the TIMI 11B trial were receiving
intravenous unfractionated heparin for up to 24 hours
before enrollment. It would be useful to know whether some of these
individuals represented treatment failures of
unfractionated heparin before randomization. Unlike the ESSENCE study,
the TIMI 11B trial used a weight-adjusted regimen of unfractionated
heparin, thereby positioning the control arm in a more advantageous and
conventional light. An important distinctive feature of the TIMI 11B
protocol was the initiation of LMWH with an intravenous
bolus: this may well have contributed to the early evidence of benefit
48 hours after randomization on the triple composite end point of
death, myocardial infarction, or urgent
revascularization. Whereas death and myocardial
infarction provide a reliable end point cluster, this is less clear
when considering episodes of recurrent angina leading to
coronary revascularization either during or
following the index hospitalization: in TIMI 11B these were
characterized as urgent. This would be considered by many a somewhat
liberal usage of the term urgent in comparison to some other studies.
In the ESSENCE study, enoxaparin and unfractionated heparin were given
for an equal duration, ie, 2.6 days. By contrast, in TIMI 11B,
unfractionated heparin was administered for 3.0 versus 4.6 days for the
enoxaparin group. Although this may have disadvantaged the
unfractionated heparin patients, especially if rebound ischemic
events were operative, the primary end point, ie, a composite of death,
myocardial infarction, and urgent
revascularization, at 8 days was achieved with a
marginally significant 14.4% risk reduction (P=0.048): this
would equate to the avoidance of 21 events per 1000 patients treated,
13 of which would be either death or myocardial infarction. Subgroup
analysis indicates a clear advantage to those patients with
definite ECG changes and no benefit for those without. Interestingly,
patients with non–Q-wave myocardial infarctions did not appear to fare
as well with enoxaparin as those with unstable angina, although the
confidence limits of these subgroups overlap substantially.
Perhaps the most important and novel aspect of the TIMI 11B study is the clear demonstration that continued outpatient therapy through 43 days with 12 hourly weight-adjusted enoxaparin does not produce additional benefit for patients with unstable coronary syndromes. Moreover, the associated promulgation of increased major hemorrhage seems to assure preservation of a biologic effect. In a substantial number of cases, the hemorrhagic events were associated with vascular instrumentation. Because 8 hemorrhagic deaths occurred in the TIMI 11B trial and half of these were in the enoxaparin group, opportunity exists to derive additional therapeutic benefit by reducing unnecessary complications through better monitoring and risk appraisal.
Why Did Outpatient LMWH Antithrombin Therapy Fail to Provide
Additional Benefit?
Although it could be argued that events before hospital discharge
would screen out a lower risk population ultimately proceeding to the
outpatient phase of the TIMI 11B trial, the baseline characteristics
and subsequent events within the control group argue that this was not
the case. Perhaps what is required to achieve the desired therapeutic
effect is a more pluripotential approach directed not only towards the
coagulation system but also coupled with strategies to reduce
inflammation and promote plaque healing. The combined analysis
of TIMI 11B and ESSENCE, also published in this issue of
Circulation, was prospectively planned because neither trial
demonstrated a reduction, nor was adequately powered to test the
effects, on death and myocardial infarction alone.13
It should be noted that the least robust component of the triple
composite end point differed between the 2 studies, ie, it was
recurrent angina in ESSENCE and urgent
revascularization in TIMI 11B. Using this combined
approach, the authors found an 20% reduction in death and
myocardial infarction with enoxaparin, which achieved statistical
significance at day 8 and persisted through days 14 and 43. The
meta-analysis of hemorrhage underestimates its actual
incidence, given that the results are truncated to the acute phase of
treatment unlike the data for efficacy. On balance, it appears that the
risks of major hemorrhage are approximately the same as with
unfractionated heparin, but minor hemorrhage is clearly
increased with enoxaparin. Given the anticipated frequency of vascular
instrumentation and interventional procedures in this patient
population, this is a nontrivial issue, especially because the duration
of effect of enoxaparin is protracted and specific antidotes to its
anticoagulant effect do not exist.
Should This Meta-Analysis Have Incorporated the Results of
Other LMWH?
The authors argue that it is inappropriate to do so because of
some differences in trial design and agent(s) properties; however, this
is debatable because similar issues have not precluded insightful
overviews embracing both fibrinolytic and glycoprotein
IIb/IIIa inhibitor agents of differing properties among
patient populations with acute coronary syndromes. In this
regard, nadroparin, the LMWH used in the FRAXIS trial, has a similar
molecular weight and anti-Xa:anti-IIa ratio as enoxaparin, yet in a
study of 3468 patients randomized to BID nadroparin (Fraxiparin) and
compared to unfractionated heparin, no difference in the primary end
point of death, myocardial infarction or refractory angina was evident
at 6 days.14 Patients treated for 14 days actually fared
worse in the Fraxiparin group when reevaluated at 3 months. These data
and that emerging from the FRISC trial that compared dalteparin with
unfractionated heparin emphasize that we still have much to learn from
future research on these compounds. Head-to-head comparisons of
differing LMWH, the use of LMWH in association with fibrinolytic
therapy, and glycoprotein IIb/IIIa inhibitors
all provide fertile soil for much needed future research. A better
understanding of which patients derive maximum benefit and which are at
increased risk to hemorrhage (possibly coupled with sensitive
and appropriate laboratory monitoring) would be welcome and has been
further developed in TIMI 11B.15
How Do We Interpret This Data as It Relates to Clinical
Implications and Practice?
It would seem that the lessons of TIMI 11B and the
meta-analysis–incorporating ESSENCE provide evidence that LMWH
used early, commencing with an intravenous bolus followed
by a 12 hourly subcutaneous injection of weight-adjusted enoxaparin,
will not only reduce death and myocardial infarction but also reduce
repeat hospitalization and the need for
revascularization in suitable selected patients.
These benefits are maintained at 1 year and cannot be augmented by
out-of-hospital sustained therapy. The shorter course of enoxaparin
therapy (2.6 days) used in ESSENCE seems likely to minimize the risk of
hemorrhagic complications without compromising long-term benefits. The
simplicity of administration, avoidance of the need for laboratory
monitoring, and favorable cost-benefit profile now demonstrated in both
the United States and Canada are all positive aspects supporting the
introduction of LMWH in acute coronary
syndromes.16 17 Care, however, should be taken when using
LMWH in circumstances where coronary interventions are either
planned or anticipated, given its long half-life and absence of
specific antidote. In such circumstances, unfractionated heparin used
before and during such procedures may retain its traditional
desirability.
George Moore, the Irish playwright, opined that life provided difficult
choices. This is surely true for physicians managing patients with
acute coronary syndromes. The continuing morbidity and
mortality of such patients should provide substantial incentive to
patients, physicians, granting agencies, and sponsors to support the
necessary research required to integrate and derive a coherent
therapeutic strategy (Figure
) so that intelligent choices can be made
amidst an exciting array of options.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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References |
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TopReferences |
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