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Br HeartJ 1985; 53: 173-9
Prostacyclin infusion in patients with acute
myocardialinfarction
P HENRIKSSON,* 0 EDHAG,* A WENNMALMtFrom the Deparmes
of*Medicine and tClinical Physiology, Karolinska Institute,
Huddinge University Hospital,Huddinge, Sweden
SUMMARY To investigate whether prostacyclin protects ischaemic
myocardium in humans the effectof prostacyclin or placebo was
studied in two groups of patients with acute myocardial
infarctionwho presented within six and 16 hours of the onset of
symptoms. Intravenous infusion of prostacyc-lin or placebo was
started immediately after admission at a rate corresponding to 4-5
ng/kg/minute.The infusion was maintained for 72 hours. Clinical
status, electrocardiograms, plasma enzymeactivity, infarct
extension during the infusion, and reinfarction after the infusion
were studied.Prostacyclin was well tolerated by most patients:
neither systemic blood pressure nor heart ratediffered between the
two groups. In the 11 patients who received treatment within six
hours of theonset of symptoms prostacyclin significantly lowered
the maximum plasma activities of creatinekinase MB and lactate
dehydrogenase. In the 19 patients who received treatment 6-16 hours
afterthe onset of symptoms prostacyclin had no such effect. None of
the patients receiving prostacyclinhad an extension of the
infarction during the infusion, whereas four patients receiving
placebo did;this difference was significant.These data are the
first to provide evidence that prostacyclin might limit myocardial
injury in
patients with acute myocardial infarction.
Prostacyclin is a metabolite of arachidonic acid that isformed
in vascular endothelium throughout thebody.I-3 Prostacyclin has
vasodilative and plateletantiaggregatory properties, and in view of
theseactions the compound may prevent platelet aggrega-tion and
thrombosis in healthy vessels. Vascular for-mation of prostacyclin
is reduced in athero-sclerosis,46 and this has been proposed as a
factorresponsible for the increased incidence of thrombosisin this
state.The actions mentioned above have also prompted
the proposal of prostacyclin as a suitable agent for
thetreatment of acute myocardial infarction. Thefindings concerning
endothelial production of pros-tacyclin in healthy and
atherosclerotic vessels sug-gested that such treatment might
restore lost pros-tacyclin activity in the cardiovascular system,
espe-cially in the coronary circulation. In fact, prostacyclin
Requests for reprints to Dr P Henriksson, Department of
Medicine,Karolinska Institute, Huddinge University Hospital,,S-141
86 Hud-dinge, Sweden.
Accepted for publication 9 October 1984
reduces the size of experimental infarction in variousanimal
models.7-'0 On the other hand, the administ-ration of prostacyclin
to humans with various signs ofischaemic heart disease has yielded
inconclusiveresults. 11-13To evaluate the effect of prostacyclin in
patients
with acute myocardial infarction, we performed adouble blind
investigation in 30 patients.
Patients and methods
The study was performed during 1983-84 at this hos-pital.
Patients admitted to the hospital coronary careunit and meeting the
selection criteria of the studywere invited to participate.
Informed consent wasobtained from all patients. The study protocol
wasapproved by the local human investigations commit-tee.
SELECTION OF PATIENTSPatients admitted with chest pain typical
of acuteinfarction (>30 min duration) and with
confirmativeelectrocardiogram or plasma enzyme activity or bothwere
included provided that treatment could be
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174
started within 16 hours of the onset of symptoms. Theage limits
were 18-75 years; female patients wereincluded only if
postmenopausal. Either (a) new orpresumably new Q waves of at least
0-04 s durationand amplitude amounting to >25% of the following
Rwave in either (i) leads II, III, and aVF, (ii) leads Iand aVL, or
(iii) two or more precordial leads, or (b)ST segment elevation of
>2 mV in two leads were theconfirmative electrocardiographic
criteria used. A risein plasma activity to at least twice the upper
normallimit of the hospital laboratory's reference value fortwo of
the enzymes-creatine kinase, aspartateaminotransferase, and lactate
dehydrogenase-orappreciably increased myocardial specific
creatinekinase MB activity was accepted as evidence of
acutemyocardial infarction.
Patients with an earlier acute myocardial infarctionwithin the
past two months, as well as those withpsychiatric, endocrinological
or infectious or malig-nant diseases, were excluded.
RANDOMISATION AND STRATIFICATIONA randomisation protocol was
prepared before thestudy and was kept by the pharmacist delivering
thedrug to the coronary care unit during the entire inves-tigation.
The randomisation protocol was adapted toyield 15 patients in each
of the prostacyclin andplacebo groups. The investigation protocol
also pre-scribed a separate study to compare the results ofpatients
receiving prostacyclin with those receivingplacebo within six hours
of the onset of symptoms.These patients were, however, not
randomised sepa-rately.
ADMINISTRATION OF PROSTACYCLIN ORPLACEBOProstacyclin
(synthetised by the Upjohn Companyand formulated by the Wellcome
Foundation), storedas a freeze-dried powder, was dissolved in
glycine buf-fer pH 10-5 immediately before infusion. A fresh
solu-tion was prepared every 12 hours during the infusionperiod.
Glycine buffer at pH 10-5 was infused as theplacebo. The infusion
was given into a peripheral armvein using a volume controlled pump
(IMED 922) at arate corresponding to 1 ng/k8/min and
increasedstepwise over one hour to ammum of 5 ng/kg/min.If systolic
blood pressure fell or heart rate increasedby > 10% before
themaum infusion rate had beenreached the infusion was maintained
at the currentrate. The overall infusion time was 72 hours.
Duringthe last four hours the infusion rate was graduallytapered
off in order to avoid rebound phenomena. Inaddition to the infusion
of prostacyclin, the patientsreceived routine clinical and
pharmacological treat-ment for acute myocardial infarction and were
man-
Henriksson, Edhag, Wennmalm
aged by the ordinary staff of the coronary care unit.The
investigators did not influence the routine care.
EVALUATION OF CLINICAL STATUS ANDLABORATORY FINDINGSAll patients
underwent a baseline clinical and labora-tory evaluation before
infusion of the drug was startedcomprising a physical examination,
a standard 12 leadelectrocardiogram, chest x ray examination,
routinechemical blood examination, and measurement ofplasma
activity of creatine kinase MB, creatine kin-ase, aspartate
aminotransferase, and lactate dehy-drogenase. During the infusion
of prostacyclin a 12lead electrocardiogram was recorded daily.
Plasmacreatine kinase MB activity was measured in samplestaken 8,
16, and 24 hours after the start of the infu-sion. Plasma creatine
kinase, aspartate aminotransfer-ase, and lactate dehydrogenase
activities were meas-ured daily until discharge. At the end of the
study (30days after admission) a physical examination, includ-ing
evaluation of the patient's functional status, andan
electrocardiogram were performed. The 12 leadelectrocardiograms
were analysed using a QRS scor-ing system'4 in which each recording
was scored from0 to 29, with a value >2 strongly suggesting
myocar-dial infarction. QRS scoring was performed on
elec-trocardiograms recorded on days 3, 7, and 30 after thestart of
the infusion. ST segment elevation was meas-ured as the sum of the
vertical distances between theisoelectric line and the midpoint of
the ST segment inthe two leads showing the most prominent
elevationson day 1. ST elevation was assessed on days 1, 2, and3
after the start of the infusion. All electrocardio-graphic
evaluations were performed by a trainedinterpreter who was not a
member of the investigatingteam and was unaware of the type' of
treatment thepatients had received.
Results
COMPARABILITY OF THE GROUPSTable 1 shows the result of the
randomisation proce-dure. The number of patients, their sex
distributionand age, as well as the time from the onset of
symp-toms to the start of infusion did not differ between
theprostacyclin and placebo groups. The number ofpatients receiving
infusion within six hours of theonset of symptoms was slightly
greater in the pros-tacyclin group. Some patient characteristics
related toan increased incidence of ischaemic heart disease
wereover-represented in the prostacyclin group, but thedifference
is not significant. Table 2 shows thenumber of patients receiving
beta blocking drugsbefore or during the infusion of prostacyclin
orplacebo. The proportion of patients given beta block-ing drugs
did not differ between the two groups. The
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Prostacyclin infusion in patients with acute myocardial
infarction
Table 1 Group characteristics in patients with acutemyocardial
infarction randomised to receive prostacyclin orplacebo and the
occurrence offactors related to increasedincidence ofmyocardial
infarction in the two groups. Figures arenumbers ofpatients
Prostacyclin Placebo
Group characteristicsNo of patients 15 15Sex distribution (M/F)
10/5 12/3Age (yr)Mean (SEM) 62 (6) 60 (3)Range 53 (71) 40 (73)
Mean (SEM) time from onset ofpain to start of infusion (h) 8-1
(1-2) 9.6 (1-3)
Infarct localisation(anterior/posterior) 8/7 8/7
No of patients receiving infusionwithin six hours of onset
ofsymptoms 7 4
Infarct localisation(anterior/posterior) 2/5 3/1
Related factorsSmoking 12 9Hypertension 8 6Hyperlipidaemia 2
3Earlier angina 6 3'Cardiac failure before infusion 7 3
proportion of patients receiving beta blocking drugswas in fact
slightly higher in the placebo group, andthis tendency was
reinforced during days 2 and 3 ofinfusion. The difference did not,
however, reachstatistical significance.
DRUG.TOLERANCEOf the patients in the prostacyclin group, 12
could begiven the drug at a rate of 5 ng/kg/minute withoutexceeding
the predetermined systolic blood pressurevalue or pulse rate. In
one patient the infusion ratewas never increased above 4
ng/kg/minute because ofa tendency to hypotension, and in two other
patientsthe rate had to be reduced to 4 ng/kg/minute for thesame
reason. Figure 1 shows the values for the systolicand diastolic
blood pressure and heart rate. Therewere no differences in these
variables before, during,or after the infusion. Table 3 shows the
cardiac stressindex (the product of the systolic blood pressure
andthe heart rate) during the infusion in the two groups.Again
there was no difference between the groups.
CLINICAL OBSERVATIONSTable 4 shows the occurrence of congestive
heart fail-ure before and after the study. Two patients
werereceiving treatment for heart failure when theyentered the
study; both were in the prostacyclingroup. Another five patients in
this group had clinicalor radiographic findings or both indicating
heart fail-ure on entering the study. The number of patients inthe
prostacyclin group requiring treatment for heartfailure did not
increase during the course of the infu-sion. In the placebo group
three patients had clinicalor radiographic evidence of heart
failure on enteringthe study. During the course of the infusion,
thisnumber increased to eight (Table 4).
Table 2 Administration ofbeta blocking drugs in the groups
receivingprostacyclin orplacebo. Figures are numbers
ofpatients(mean24 hour dosages in mg given in parentheses)
Drug Time (h)* Preinfarction Day I Day 2 Day 3
Prostacyclin groupMetoprolol 0-16 1 (200) 1 (200) 4 (125) 4
(125)
0-6 1 (200) 1 (200) 2 (175) 2 (175)Pindolol 0-16 1(10) 1(10)
1(10) 1(10)
0-6 0 0 0 0Atenolol 0-16 1(100) 1 (100) 1 (10) 1(10)
0-6 0 0 0 0None 0-16 12 12 9 9
0-6 6 6 5 5
Placebo groupMetoprolol 0-16 1(100) 2 (125) 7 (107) 7 (121)
0-6 0 0 4(75) 3(83)Alprenolol 0-16 2 (400) 2 (400) 2 (400) 2
(400)
0-6 0 0 0 0Timolol 0-16 0 0 0 1(20)
0-6 0 0 0 0Practololt 0-16 0 0 0 0
0-6 0 1(15) 0 0None 0-16 12 10 5 4
0-6 4 3 0 1
*From onset of chest pain to start of infusion.tGiven
intravenously.
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Henriksson, Edhag, Wennmalm
Table 5 Occurrence of infarct extension, reinfarction, anddeaths
in paients wvith acute myocardial infarcion treated
withprostacyclin or placebo. Figures are numbers ofpatients
Prostacyclin Placebo
Extension of infarction (duringthe infusion) 0* 4
Reinfarction (after the infusion) 2 0Deaths 0 1
*Significant difference from the placebo group: (p
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Prostacyclin infusion in patients with acute myocardial
infarction
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64
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Discussion
Patients receiving prostacyclin within six hours of theonset of
symptoms had significantly lower maximumplasma activity of creatine
kinase MB and lactatedehydrogenase than the placebo group. We
regardthese lower values for plasma creatine kinase MB andlactate
dehydrogenase activity in the prostacyclingroup as indicating
smaller infarcts among thesepatients compared with the placebo
group. As evidentfrom Fig. 3 the patients receiving early placebo
infu-sion had higher maximum plasma creatine kinaseMB, creatine
kinase, aspartate aminotransferase, andlactate dehydrogenase
activities than the group as awhole. This is probably because
patients with largerinfarctions-and hence higher maximum
plasmaenzyme values-experience more pronounced symp-toms and
therefore present earlier. The proportion ofpatients with anterior
wall infarctions was greater inthe placebo group; whether or not
this may haveinfluenced the data cannot be judged at present.
Theproportion of patients taking beta blocking drugs wasnot higher
in the prostacyclin group. Thus theobserved difference in plasma
enzyme activity be-tween the groups can hardly be explained by a
moreactive beta blocking regimen in the prostacycingroup. A direct
cardioprotective action ofprostacycinin acute myocardial infarction
therefore seems pos-sible.
In addition to the differences in maximum plasmacreatine kinase
MB and lactate dehydrogenaseactivities, the time courses of the
plasma activity ofthese enzymes are notable. Thus the curve
forcreatine kinase MB activity in the prostacyclin groupwas flatter
than in the placebo group. In addition, thepeak of the plasma
lactate dehydrogenase curve inpatients infused with prostacyclin
within six hourswas lower than in those given placebo.
Interestingly,the plasma lactate dehydrogenase values in the
pros-tacycin group were numerically lower during theentire
infusion, approaching those in the placebogroup after the
infusion.
Another important finding was that patients receiv-ing
prostacycin appeared to be protected againstinfarct extension
during the infusion. This was evi-denced by a significantly lower
incidence of infarctextension in patients receiving prostacyclin
than inthose receiving placebo. The lower incidence ofinfarct
extension seems to accord well with theobserved lower maximum
plasma creatine kinase MBand lactate dehydrogenase activities
discussed above,in as much as they indicate that myocardium at risk
atthe onset of the infusion is protected by the activedrug and,
consequently, that enzyme release and apossible tendency to infarct
extension are depressed.If this hypothesis is correct patients
receiving pros-
Henriksson, Edhag, Wennmalmtacycin should run an increased risk
of reinfarctionafter the infusion. The incidence of
reinfarctiontended to increase in the present group of
patientsreceiving prostacyclin; two developed reinfarctionafter the
infusion compared with none of the patientswho had received
placebo; the difference was, how-ever, not significant.A drug with
vasodilative activity, like prostacyclin,
can be expected to induce a decrease in peripheralvascular
resistance and a reflex increase in cardiacoutput. The latter is
certainly not desirable in acutemyocardial infarction since the
increase in cardiacoutput may require more dynamic work by the
heart.In the present study prostacyclin did not affect
bloodpressure and heart rate more than placebo-that is,with the
infusion rate limits applied in the presentstudy the drug probably
does not interfere appreci-ably with the central haemodynamics.
Bradycardiawas not a general finding in the placebo group,
prob-ably because the patients were not routinely givenbeta
blocking drugs during the acute phase. Further-more, prostacyclin
did not induce cardiac failure oreven aggravate signs of failure.
In fact all patients inthe placebo group with signs of cardiac
failure beforeinfusion also required treatment for this
afterwards;in addition, five more patients in this group
developedevidence of cardiac failure during the infusion.
Incontrast, of the seven patients in the prostacycingroup who had
signs of cardiac failure before the infu-sion, three did not
require treatment afterwards.
Although the present study points to a beneficialeffect of
prostacyclin in patients with acute myocar-dial infarction, the
possible underlying mechanism isunknown. Since a myocardial saving
effect of pros-tacycin is indicated in patients receiving
treatmentwithin six hours of the onset of symptoms some
con-ceptually related postinfusion treatment (that is,treatment
aimed to counteract platelet aggregationand formation of
thromboxane A2) should be giventhat can keep salvaged myocardium in
a metaboliccondition that allows contractile work to be
main,tained. In men with unstable angina aspirin has beenshown to
protect against acute myocardial infarctionand death15; this drug
should be effective also in thepresent situation, in which
myocardium at risk maypersist after the infusion of
prostacycin.
OE was supported by the Swedish National Associa-tion against
Heart and Chest Diseases, andAW by theSwedish Medical Research
Council. Prostacycin waskindly provided by the Upjohn Company.
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