Download A low molecular weight, selective thrombin inhibitor, inogatran, vs

European Heart Journal (1997) 18, 1416-1425
A low molecular weight, selective thrombin inhibitor,
inogatran, vs heparin, in unstable coronary artery
disease in 1209 patients
A double-blind, randomized, dose-finding study
Thrombin Inhibition in Myocardial Ischaemia (TRIM) study group
Background Unstable coronary artery disease, i.e. unstable
angina or non-Q wave myocardial infarction, is caused
by rupture of atheromatous plaques initiating thrombus
formation. Thrombin is thought to be pivotal in platelet
activation and thrombus growth. The aim of the present
study was to compare the effect of three different doses of a
novel, low molecular weight, selective thrombin inhibitor
(inogatran) with that of heparin in unstable coronary artery
disease. The composite primary end-point was death, incidence of myocardial infarction, refractory angina or recurrent angina after 7 days. Secondary end-points were the same
after 3 and 30 days, as were death and myocardial infarction
with or without refractory angina on all three occasions.
Methods Patients (n=1209) admitted with suspected unstable angina, or non-Q wave myocardial infarction, were
randomly assigned to double-blind treatment with inogatran or heparin bolus doses. This was followed by a 3 day
infusion with a low (LDI), medium (MDI), or high (HDI)
dose of inogatran, aiming at plasma concentrations of 0-15,
0-4 or 0-8 umol. 1 ~ ', or heparin initiated at 1200 U . h " '.
inogatran-treated patients (LDI = 39-4%, MDI = 37-6%,
HDI=361%; P=001). The event rate after 7 days with
respect to the primary end-point, however, did not differ
between the groups (heparin=410%, LDI=45-7%,
MDI=45-9%, HDI=45-5%; ns). Death and myocardial
infarction occurred less frequently in the heparin group
(07%) than in the three inogatran groups (LDI = 3-6%,
MDI=20%, HDI=40%; P<005) after 3 days. After
7 days, this difference was attenuated (heparin = 2-6% vs
LDl=40%, MDI=4-3%, HDI = 67%; P=010). After 30
days there were no significant differences in event rates
between the four groups. Major bleeding occurred in 11%
of the patients within 7 days, with no differences between
the groups.
Findings Treatment with inogatran resulted in median
activated partial thromboplastin times after 24 h of 36, 44
and 53 s in the low, medium and high dose inogatran
groups, respectively, as compared to 54 s in the heparin
group (ns).
Conclusions During study drug infusion the event rate
was very low in the heparin group, and none of the
inogatran dosages were better than heparin in preventing
ischaemic events. Furthermore, there was no relationship
between event rate and inogatran dosage. Thus, this study
does not indicate that the efficacy of inogatran would
improve with higher doses, despite a clear dose-effect as
regards the prolongation of activated partial thromboplastin time. After cessation of heparin or inogatran there
was an increase in event rates, suggestive of a rebound
phenomenon.
(Eur Heart J 1997; 18: 1416-1425)
At the end of the infusion, after 3 days, heparin-treated
patients had fewer composite events (29-5%) than
Key Words: Unstable angina, non-Q-wave myocardial
infarction, thrombin inhibition, heparin.
Introduction
pectoris and non-Q wave myocardial infarction. The
natural course of these syndromes involves a short-term
Thrombus formation induced by rupture of coronary (4-6 weeks) risk of myocardial infarction or death in the
atheromatous plaques is considered the underlying cause order of 10-20%[1>2). This is halved by administration
of unstable coronary artery disease, i.e. unstable angina of aspirin'3"5'. Heparin is also effective in the acute
phase'6"81, and might be additive to the effects of
Revision submitted 3 February 1997, and accepted 24 February aspirin'5'91. During heparin treatment the event rate is
1997.
very low, but after cessation of heparin, reactivation of
Correspondence: Lars Grip, MD, PhD, Division of Cardiology, the thrombotic process seems to attenuate the initial
Sahlgrenska Hospital, S-413 45 Goteborg, Sweden.
gains'9-10'.
0195-668X/97/091416+10 S18.00/0
1997 The European Society of Cardiology
The TRIM Study
Thrombin plays a dominant role in coagulation
and platelet activation after plaque rupture1"1. Direct
thrombin inhibitors may be more effective than heparin
in unstable coronary artery disease, since their action is
independent of antithrombin III and since they also
inhibit clot-bound thrombin1121 as well as thrombininduced platelet activation. The leech-derived peptide
desulfato-hirudin has recently been tested in acute coronary syndromes'131. Synthetic low molecular weight
direct thrombin inhibitors may be a further step forward.
lnogatran is a dipeptide with a molecular weight
of 439 Dalton. It reversibly binds to the catalytic site of
the thrombin molecule, thereby in a stoichiometric fashion inhibiting both clot-bound thrombin and thrombin
in the fluid phase1'4151. Its biological half-life in plasma
is about 1 h and it is evenly eliminated in the urine and
bile'161. lnogatran has shown promising antithrombotic
effects in a porcine model of coronary thrombosis'171.
The aim of the present study was to compare the
effect of three different doses of inogatran with that of
heparin on the clinical outcome in unstable coronary
disease.
Patients and methods
From December 1994 until July 1995, consecutive
patients with a suspicion of unstable angina pectoris or
non-Q wave myocardial infarction were screened for
inclusion in this randomized, multicentre, double-blind
study. A total of 1209 patients who fulfilled the entry
criteria, were, after written consent, included at 61
Scandinavian centres. The study was approved by the
local ethical committees and the Medical Products
Agencies of the participating countries.
Protocol
The entry criterion was either a clinical suspicion of
unstable angina pectoris or a non-Q wave myocardial
infarction. Unstable angina was defined as new onset of
ischaemic chest pain or rapid deterioration of a previously stable effort angina. The clinical diagnosis had to
be supported by at least one of the following criteria
indicating presence of coronary artery disease: ECG
changes compatible with myocardial ischaemia, e.g. ST
depression or T-wave inversion ( > 0 1 mV in at least two
contiguous leads) or a history of previous myocardial
infarction, positive coronary angiography, positive
myocardial perfusion scintigraphy, or a positive exercise
test.
Exclusion criteria were: any condition considered
to increase the risk of bleeding, in particular aortic
aneurysm, uncontrolled hypertension, history of stroke,
gastric ulcer within 2 years, previous urogenital bleeding, or major trauma within 3 months; patients who had
been treated with oral anticoagulants, heparin or fibrinolytic drugs within a week prior to screening; patients
1417
with impending myocardial infarction and indications
for thrombolytic therapy; patients with uncompensated
congestive heart failure, significant arrhythmias, and
myocardial ischaemia not primarily due to coronary
disease; patients with percutaneous transluminal coronary angioplasty or who had undergone coronary
artery bypass graft surgery within the past 3 months;
patients with serum creatinine > 150 umol. 1" ', anaemia
(Hb < 100 g . 1 ~' or 6-21 mmol. 1 ~'), known liver disease, intolerance to heparin, drug addiction or alcoholic
abuse; women with childbearing potential.
Treatment
Treatment was initiated within 24 h of the end of the
qualifying episode of chest pain and continued for 72 h.
Patients were randomized to receive one of four treatment regimens, i.e. low-dose inogatran (Astra-Hassle
AB, Molndal, Sweden) (n = 302), medium-dose inogatran (n = 303), high-dose inogatran (n=299), or heparin
(n = 305). Low, medium and high dose patients received
boluses of 1-10, 2-75 or 5-50 mg inogatran, respectively,
followed by a continuous infusion of 2-0, 50 and
10-Omg.h""1 for 72h. These doses aimed at plasma
concentrations of 015, 0-40 and 080 umol. I" 1 ,
respectively. Heparin was given as a bolus of 5000 units
followed by an infusion of 1200 units . h ~ ' for 72 h. The
activated partial thromboplastin time was routinely
checked before and 6, 24 and 48 h after the start of
infusion. If the activated partial thromboplastin time
exceeded the lower local reference level (usually 24—35 s)
by a factor of three, the infusion rate was reduced
according to a graded stepwise procedure related to the
activated partial thromboplastin time levels. No upward
adjustment of the infusion rate was performed. Aspirin
was recommended, while ticlopidine and oral anticoagulants were not permitted during, and discouraged even
after, study treatment. All other medication was to be
given at the discretion of the responsible physician.
Blood samples for the analysis of plasma concentration of inogatran were obtained after 48 h in 207 low
dose, 199 medium dose and 208 high dose patients,
respectively. In a sub-population of 83 low dose, 84
medium dose and 76 high dose patients, plasma concentrations were also analysed from samples drawn within
1 min of the bolus dose, and after 6, 24 and 72 h. At the
end of the infusion period the patient remained in
hospital for at least another 24 h. Patients were followed
up at outpatient clinics 30-40 days after inclusion.
End-points
The composite primary end-point was the occurrence of
death, myocardial infarction (or reinfarction), refractory
angina or recurrence of angina after 7 days. Secondary
end-points were the same after 3 and 30 days as were the
occurrence of death or myocardial infarction, with or
without refractory angina pectoris, after 3, 7 and 30 days.
Eur Heart J, Vol. 18, September 1997
1418 The TRIM Study
Myocardial infarction was defined as a diagnostic series of ECGs or the occurrence of at least two of
the following: (1) typical ischaemic chest pain, (2) a
diagnostic ECG or (3) typical elevation of cardiac
enzymes; i.e. maximal concentration of creatine
kinase-MB (mass)>upper reference level on one occasion, or maximal catalytic activity of creatine kinase,
creatine kinase-B or creatine kinase-MB > twice the
upper reference level on one occasion, or maximal
activity of creatine kinase, creatine kinase-B or creatine
kinase-MB > the upper reference level on two occasions.
In order to differentiate between an index event
(reason for inclusion) and an end-point, an ongoing
myocardial infarction at inclusion (not an event) was
defined as elevations of creatine kinase, creatine
kinase-B, creatine kinase-MB or creatine kinase-MB
(mass), according to the definition given above, and
within 6 h of the start of study treatment. Hence, a new
myocardial infarction (i.e. regarded as an event) was
defined by normal enzyme levels during the first 6 h of
study drug infusion, followed by elevated levels, as
defined above, or by reappearance of the above criteria
for myocardial infarction after normalization if enzyme
levels were elevated initially.
Refractory angina was denned as recurrence of
chest pain lasting > 5 min, despite maximal ongoing
medication, including intravenous nitroglycerine and
oral beta-blockers or calcium antagonists. The condition
should be associated with transient ECG changes indicative of myocardial ischaemia and leading to coronary
angiography.
Recurrent angina was defined as recurrent chest
pain, > 5 min in duration, typical of myocardial ischaemia and responding to sublingual nitroglycerine, but not
fulfilling the criteria for refractory angina. After hospital
discharge, recurrent angina was defined as readmission
to hospital because of anginal chest pain.
All cases of death, myocardial infarction, occurrence of refractory angina and stroke were evaluated by
an end-point committee.
Safety
A major bleed was: intracranial; required blood transfusion; necessitated prolonged hospitalization; led to
persistent disability; was associated with a drop in
haemoglobin of more than 30%, or in connection with
CABG or PTCA, more than normal as judged by
the investigators. All other bleeding was classified as
minor. The study was continuously monitored by an
independent safety committee.
Statistics
Continuous data were descriptively summarized using
either percentiles (10th, 25th, 50th, 75th and 90th), or
mean values ± SDs. Discrete variables were described in
Eur Heart J, Vol. 18, September 1997
terms of frequency and percentages. Study end-points
were depicted graphically as cumulative relative frequencies over time. Comparisons of frequency of events
between treatment groups were performed using Fisher's
exact test. Differences between study drugs were illustrated by odds ratios with accompanying 95% confidence intervals. Treatment comparisons were performed
according to the intention-to-treat principle, using twosided tests. A multiple logistic regression analysis was
performed, including all relevant baseline characteristics
and evaluation of their influence on the end-points of the
study.
A primary comparison was made between the
heparin-treated and the combined inogatran-treated
groups. Secondly, an analysis of differences between
the three inogatran groups was made to detect any
dose-effect relationship.
Results
Altogether, 1209 patients were included, with the final
diagnosis of unstable angina in 736 and non-Q wave
infarctions in 428 patients, respectively. Among the 45
patients with neither of these diagnoses, 18 had Q wave
infarction, seven suspected myocardial ischaemia and 14
other cardiac or non-cardiac diagnoses, and in six cases
the final diagnosis was unknown.
Although there were minor differences in baseline characteristics between the treatment groups (Table
1), these had no impact on the major results, as demonstrated by multiple logistic regression analysis. After
completion of the study drug infusion, at 72 h, 94-6%
of all patients were on aspirin with a mean dose of
101 ± 59 mg. The usage of aspirin did not differ between
the four groups.
Study-drug infusion and levels of
anticoagulation
The study drug was given, in a similar manner to all four
groups, in complete accordance with the protocol, to
88% of the patients. Dose reductions were effected in
1 -3%-4-4% of the inogatran-treated patients, compared
with 41-3% of the heparin-treated patients.
The heparin group had significantly higher activated partial thromboplastin times (Fig. 1) than the
inogatran groups after 6 h. After 24 and 48 h the activated partial thromboplastin times were similar in the
heparin and the high dose inogatran groups, probably
owing to more frequent dose reductions in the heparin
group. There was a clear dose-effect between inogatran
and activated partial thromboplastin time prolongation.
Inogatran plasma concentrations were somewhat
above those anticipated (Fig. 2), (median concentrations at 48 h 0-20 umol. 1 ~' in the low dose group,
0-52 umol. 1 ~~' in the medium dose group and
100 umol. I" 1 in the high dose group, respectively).
The TRIM Study
1419
Table 1 Baseline characteristics, pre-entry medication and inclusion diagnosis
Inogatran dose
Mean age (years)
Gender (males)
Smokers
Current
Past
Previous infarct
Previous angina >4 weeks
Previous PTCA/CABG
Hypertension
Diabetes
ECG changes at inclusion
T-inversions
ST-depressions
Pre-entry medication
Nitrates
Aspirin
Beta-blockers
Calcium antagonists
Diuretics
Chest pain
No pain at rest <48 h
Pain at rest <48 h
Inclusion diagnosis*
Unstable angina
Non-Q wave infarct
Heparin
n = 305
(LDI) low
n = 3O2
(MDI) medium
n = 303
(HDI) high
n = 299
64±9
69-9%
6 4 ± 10
67-3%
6 4 ± 10
67-9%
64±9
71-1%
21-2%
37-1%
45-4%
66-2%
19-2%
33-4%
18-2%
23-1%
32-3%
46-2%
71-6%
16 8%
34-7%
12-9%
23-7%
28-4%
47-5%
64-5%
16-4%
37-8%
16-7%
23-6%
32-8%
390%
65-6%
14-8%
33-4%
11-8%
62-3%
33-8%
56-8%
35-3%
63-5%
36-8%
63-3%
32-5%
58-3%
57-3%
51-3%
29-1%
24-2%
58-4%
52-9%
45-2%
30-4%
25-7%
57-5%
51-8%
47-2%
27-1%
25-1%
53-8%
48-2%
42-3%
25-2%
18-4%
19-2%
80-8%
15-9%
84-1%
18-7%
81-3%
16-4%
83-6%
185
105
181
109
175
114
195
100
CABG = coronary artery bypass graft operation; HDI = high dose inogatran; LDI = low dose inogatran;
MDI = medium dose inogatran; PTCA = percutaneous transluminal coronary angioplasty.
'Definite diagnosis as established by the end-point committee.
100 -
0
6 24 48
0
6 24 48
0
Time (h)
6
24 48
0
6 24 48
Figure 1 Activated partial thromboplastin times (APTT) at various times as
compared to baseline in the three inogatran and the heparin groups. Given are
medians and 10th, 25th, 75th and 90th percentiles.
Eur Heart J, Vol. 18. September 1997
1420 The TRIM Study
LDI
MDI
HDI
1.8
"L 1.6
ouiri;
1.4
atra
c
1.2
00
o
a 1.0
vels
o
0.8
a 0.6
B
Pla
CO
0.4
0.2
0.0 b
I
0
24
I
I
48
0
I
24 48
Time (h)
I
72
0
24
I
I
48
72
Figure 2 Plasma concentrations of inogatran in the three inogatran groups.
Given are medians and 10th, 25th, 75th and 90th percentiles.
The plasma concentrations remained stable over the
period of infusion. The three inogatran groups were well
separated with respect to plasma levels.
Primary and secondary end-points
The incidence of primary composite end-points is presented in Table 2 and Fig. 3. At the end of the infusion,
the number of events was smaller in the heparin group
(29-5%) than in the inogatran-treated patients (37-7%;
Z'<0-01). There were no dose-related differences within
the inogatran groups. After 7 days there were still fewer
events in the heparin group, but the difference from the
event rate in the inogatran group was not statistically
significant at this time, i.e. the predefined time of
primary comparison. After 30 days there were no significant differences between heparin and inogatran in terms
of the composite cardiac events.
Death, myocardial infarction and refractory
angina tended to be less common after treatment with
heparin than with inogatran during the 3 days of infusion (2-6% vs 5-4%; />=006) (Table 2; Fig. 4). This was
caused by a significantly less frequent occurrence of
death and myocardial infarction during heparin than
inogatran infusion (0-7% vs 3-2%; / > =001) (Table 2;
Fig. 5). The number of deaths and myocardial infarctions rose early after drug cessation. This attenuated the
initial difference between the heparin and inogatran
groups. This increase in events after drug cessation
occurred in the medium and high dose inogatran and
the heparin groups, but not in the low dose inogatran
group.
Eur Heart J, Vol. 18. September 1997
Bleedings
The overall incidence of major bleeding within 7 days
was 13 (11%), and 97 patients (8-0%) suffered minor
bleeding, with no differences between the groups. There
were no intracerebral haemorrhages.
Discussion
Specific thrombin inhibition has been considered a
promising tool for improving intermediate and longterm results in unstable coronary artery disease. In the
recently completed GUSTO IIB trial, however, only a
slight benefit of hirudin over heparin was demonstrated1131. The results of the present study showed that
inogatran was not superior to heparin in the realm of
protection against acute coronary ischaemic events. On
the contrary, there were trends in favour of heparin
during the 30-day follow-up period, and during
the period of study-drug infusion, heparin proved
significantly better than inogatran.
Although this was a fairly large dose-finding
study, the baseline characteristics of the groups were
slightly tipped in favour of the heparin group. This
imbalance did not substantially influence the multiple
regression analysis, but the event rate in the heparin
group may have been disproportionately low.
Several explanations might account for the
results. The heparin regimen may induce more effective initial anticoagulation, as indicated by the higher
activated partial thromboplastin time during the first
few hours. Furthermore, heparin may exert a better
le 2 Primary and secondary endpoints at 3, 7 and 30 days
ary end-point 7 days
+ Ml + Ref+Rec
LDI
n = 302
MDI
n = 303
HDI
n = 299
Inogatran combined
n = 904
Heparin
n = 305
Od
(9
138(45-7%)
139(45-9%)
136 (45-5%)
413(45-7%)
125(41-0%)
1-23
ndary end-points 7 days
+ Ml
+ Ml + Ref
12 (4-0%)
25 (8-3%)
13 (4-3%)
27 (8-9%)
20 (6-7%)
31 (10-4%)
45 (5-0%)
83 (9-2%)
8 (2-6%)
25 (8-2%)
1 -99
1 15
ndary end-points 3 days
+ MI
+ MI + Ref
+MI + Ref+Rec
11 (3-6%)
15 (5-0%)
119(39-4%)
6 (2-0%)
14 (4-6%)
114 (37-6%)
12 (4-0%)
20 (6-7%)
108(36 1%)
29 (3-2%)
49 (5-4%)
341 (37-7%)
2 (0-7%)
8 (2-6%)
90 (29-5%)
5-02
2-17
1-48
ndary end-points 30 days
+ MI
+ MI + Ref
+ MI + Ref+Rec
23 (7-6%)
38(12-6%)
156(51-7%)
25 (8-3%)
37(12-2%)
158(52-2%)
27 (9-0%)
39(13-0%)
159(53-2%)
75 (8-3%)
114(12-6%)
473 (52-3%)
18 (5-9%)
36(11-8%)
146(47-9%)
| -44
1-08
1-21
mparison between combined inogatran groups and heparin.
confidence interval; D = death; HDI = high dose inogatrant; LDI = low dose inogatran; MDI=medium dose inogatran; MI = myocardial infarction; Rec = recurrent angina; Re
na.
1422 The TRIM Study
50
,
40 —
3
30
-i
•'"!.
^ ^
"
7/'"
/
i
3
g 20
o
10
F
1
10
1
15
Time (days)
I
1
20
25
30
Figure 3 Composite events of death, myocardial infarction, refractory angina
and recurrent angina until day 30. - • - • - = l o w dose inogatran; • • •=medium
dose inogatran;
=high dose inogatran;
=heparin. Vertical lines indicate
end of study drug infusion after 3 days and time of primary end-point registration
after 7 days.
antithrombotic effect than inogatran thanks to its more
effective inhibition of prothrombin activation and platelet activation'18', and better suppression of tissue factor
activity via release of tissue factor pathway inhibitor by
heparin. Endogenous coagulation inhibitory pathways,
e.g. protein C, may be more suppressed by inogatran.
Finally, it is possible that the anti-inflammatory effects
of heparin[l9] are important.
When planning the present study, the initial
results from three large trials on direct thrombin inhibitor hirudin were demonstrating an unacceptably high
number of bleeding complications, especially when
hirudin was used in combination with thrombolytics'20"221. Data from these studies suggested that excessively prolonged activated partial thromboplastin
times were associated with bleeding complications. The
15
_r
__,—(CTT.
/
./•••••
—' 7
10 -
s:.:~:~.
.y
J
)/ £
3
6
o
5 -
h
'..:TJ
J
!
I
I
i
i
10
15
Time (days)
20
25
30
Figure 4 Death, myocardial infarction or refractory angina until day 30.
Symbols as in Fig. 3.
Eur Heart J, Vol. 18. September 1997
The TRIM Study
1423
a
0)
3
3
o
10
Figure 5
15
Time (days)
20
25
30
Death or myocardial infarction until day 30. Symbols as in Fig. 3.
inogatran doses used in this study were based on experiences from animal and clinical phase I trials, and
assumed that moderately prolonged activated partial
thromboplastin times would be associated with clinical
efficacy without increasing the risk of bleeding. In a
porcine model of coronary thrombosis generated by a
copper coil inserted in the left anterior descending
coronary artery, inogatran dosages resulting in prolongation of activated partial thromboplastin time by as
little as 1-3 x baseline, proved more effective in inhibiting thrombotic occlusion than heparin in dosages resulting in activated partial thromboplastin time prolonged
by 20-5-4 x baseline'171. Furthermore, in vitro studies
evaluating the inhibiting effects of inogatran demonstrated a 50% inhibiting capacity of 0-015 umol. 1 ~ ' for
fluid phase thrombin as compared to 0023 umol. 1 ~'
for fibrin-bound thrombin1231. Dosages in the order of
ten times this, and higher, were used in the present
study. With these considerations in mind, and with the
wish to keep the study blind, it was decided to adapt the
activated partial thromboplastin time guiding regime
used in the present study. Using our cautious dosing
regimen, the prolonged activated partial thromboplastin
times were well separated by a clear dose-effect for the
three different inogatran doses. The contrasting absence
of a dose-effect in the clinical events makes it unlikely
that any dose outside the range covered by the dose
regimens tested would be more than marginally better
than the doses used in the present study. A U-shaped
dose-effect may still exist, as suggested in previous
studies on bivalirudin'241. Concerning 'harder events'
such as myocardial infarction and death, it seems that
the intermediate dose was the one closest to heparin in
efficacy. The present data do not, however, lead one to
expect that any dose would be better than the heparin
regimen used in the present study.
Reactivation of ischaemic manifestations in
unstable coronary artery disease has previously been
demonstrated early after cessation of anticoagulant
treatment both with heparin1101 and the low molecular
weight thrombin inhibitor argatroban[25]. In the present
study an increased rate of death, myocardial infarction
and refractory angina pectoris was seen during the 24 h
following 72 h treatment with heparin, as well as with
the higher inogatran doses. The favourable results concerning these events with heparin and the intermediate
inogatran dose at 72 h were thereby attenuated and no
differences in long-term outcome were seen. Concerning
the more common event recurrent angina pectoris, there
was no sign of reactivation. This probably means that
recurrent angina is elicited by many different causes,
considerably less often related to thrombotic processes
than episodes of refractory angina and myocardial infarction. These observations indicate that the reactivation of serious clinical events is caused by reactivation
of the coagulation activity early after termination of
thrombin inhibition.
Early benefits may be sustained with treatment
of long duration, as has been demonstrated in the
FRISC trial using low-molecular-weight heparin
(dalteparin)[91. However, in that study, reactivation
tendencies were also seen after lowering the dose after
5-8 days and on cessation of therapy after 41-51 days.
Thus, further investigations are warranted to evaluate
the cause and handling of reactivation or rebound
phenomena and the need for long-term anticoagulation
after termination of various types of antithrombotic
treatment in acute coronary syndromes.
We acknowledge the excellent work performed by all physicians
and nurses at the participating centres, and that of the study
monitors. The study was supported by grants from the Swedish
Eur Heart J, Vol. 18, September 1997
1424
The TRIM Study
Heart and Lung Foundation, it was carried out in co-operation
with ASTRA-HASSLE AB, Molndal, Sweden, and we thank the
company's involved staff for their good co-operation.
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[3] Lewis HD, Davis JW, Archibald DG et al. Protective effects
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[4] Cairns JA, Gent M, Singer J et al. Aspirin, sulfinpyrazone, or
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Appendices
Writing Committee: Lars Grip, Lars Frison, Lars
Wallentin. Steering Committee: Mikael Dellborg, Peer
Grande, Lars Grip (Coordinator), Matti Halinen, Peter
Held (Ex officio, ASTRA representative), Eivind Myhre,
Lars Ryden (Co-chairman), Eva Swahn, Karl Swedberg,
Kristian Thygesen, Lars Wallentin (Chairman). Safety
Committee: Peter Sleight, Lars Wilhelmsen. End-point
Committee: Ulf Naslund
(chairman),
Torstein
Gundersen, Jorgen Fischer-Hansen, Seppo Lehto.
Astra: Monica
Barret,
Peter
Held,
Jan-Erik
Nilsson, Ann-Catrine Teger-Nilsson, Mona Thorsen.
Study monitors: Finn Andersen {Denmark). Maritta
Lundstrom {Finland). Arild Hildebrand {Norway).
Christina deFlon-Olsson, Mikael Forsby, Pernilla
Isberg, Christer Larsson {Sweden).
Study centres and local investigators
Denmark (162 patients): Kristian Thygesen, Bjarne
Norgaard {Aarhus), Sten Rasmussen, Jorgen Videbaek,
Kim Klarlund, Andrea
Landorph {Bispebjerg),
Tonny Nielsen {Esbjerg), Erik Agner, Michael Vinter
Hojgaard {Helsingor), Peer Grande, Steffen Helqvist
{Kopenhamri), Soren Lind Rasmussen {Koge), Kenneth
Egstrup, Lone Mygind {Haderslev), Jorgen Fischer
Hansen, Ahmad Sajadieh {Hvidovre), Sabine Gill,
Torben Haghfelt, John Markenvard {Odense C), Anne
Thomassen, Nanna Jensen {Randers), Jan Petersen,
Gabrielle Jensen, Thomas Fischer {Sonderborg).
The TRIM Study
Finland (140 patients): Risto Sipila, Kai Kiilavuori
(Espoo), Liisa Hamalainen, Jarkko Nurminen (Joensuu),
John Melin (Jyvdskyld), Eero Koskela, Hannu Hurme
(Kotka), Matti Halinen, Ikka Vauhonen (Kuopio),
Tuomo Honkanen (Lahti), Seppo Utriainen, Teuvo
Hamalainen (Lappeenranta), Mauno Lilja, Olavi
Ukkola (Oulu), Harri Kivela, Sten Soderstrom (Vaasa),
Sinikka Pohjola-Sintonen, Esko Hussi (Vantaa).
Norway (62 patients): Torstein Gundersen (Arendal),
Anne Larsen, Jan-Erik Falang (Drammeri), Hall
Schartum-Hansen, Anneline Paulsen (Elverum), Tor
Omland (Flekkefjord), Trond Holm, Thor Edvardsen,
Niels Kristian Thybo (Fredrikstad), Jorgen Haerem,
Helge Kapelrud (Hamar), Kjell Waage, Berte Rossebo
(Haugesund), Kurt Hafsoy, Eivind Myhre (Tromso).
Sweden (845 patients): Eskil Hammarstrom, Lennart
Astrom (Bollnds), Erland Hall, Christer Wettervik,
Sven-Ake Forsberg, Hans Tygesen, Bjorn Fredriksson
{Boras), Steen Ekdahl, Krister Kihlstrom, Jan-Olof
Magnusson (Eksjo), Anders Stjerna, Fiuru Maru
(Eskilstuna), Hans Nilsson, Sami Akrawi (Fagersta),
Helge Saetre, Gosta Ahlmark, Greger Ahlberg, Bjorn
Linde, Lars Hagstrom (Falun), Gunnar Gustafsson,
Per-Erik Gustavsson, A-C Larsson (Gdvle), Karl
1425
Swedberg, Mikael Dellborg, Karl Andersen (Ostra
Hospital, Goteborg), Gosta Riiter, Asbjorn Kierkegaard,
Peter Hardhammar (Halmstad), Jan-Erik Karlsson,
Olof Svensson (Jonkoping), Finn Landgren, Bengt
Holmberg, Stefan Ryden (Kalmar), Leif Weiner, Mikael
Danielewicz (Karlskoga), Bo Malmros, Peter Nicol
(Koping), Eva Swahn, Magnus Janzon (Linkoping),
Hans Ohlin, Ole Hansen, Erik Tingberg (Lund), Ingvar
Nyman, Bjorn Fjelstad (Mora), Per Ahlstrom (Motala),
Bo Hedback, Joep Perk (Oskarshamn), Lars Svennberg,
Jan Ellstrom (Sandviken), Kurt Boman, Jan Remmets
(Skellefted), Bo-Erik Kristensson (Skovde), Lars Grip,
Rikard Linder (Karolinska Hospital, Stockholm), Johan
Hulting, Jonas Hoijer (Soder Hospital, Stockholm),
Bengt Hj. Moller, Mona Lycksell (Sundsvall), Magnus
Wahlin, Lennart Sandstedt, Arne Redfors, Jens
Borretzen, Goran Ostberg (Trollhattan), Ulf Naslund,
Bengt Johansson, Stellan Morner (Umea), Lars
Wallentin, Bertil Lindahl, Jonas Oldgren (Uppsala),
Jorgen Jonsson, Karl Nemecze (Varberg), Stefan
Thorsen, Per-Ake Johansson (Vdrnamo), Bjorn
Sinnerstad, Lars-Erik Larsson (Vastervik), Stellan Band
(Vdsteras), Roger Marsell (Ostersund).
Eur Heart J, Vol. 18, September 1997