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Thromb Haemost 2002; 88: 1805 2002 Schattauer GmbH, Stuttgart

Ra mipril Prior to Thrombolysis Atte nua te s the Ea rly Inc re a se
of PAI- 1 in Pa tie nts with Ac ute Myoc a rdia l Infa rc tion
Andreas Wagner
1
, Harald Herkner
1
, Wolfgang Schreiber
1
, Andreas Bur
1
,
Christian Woisetschlger
1
, Gnther Stix
2
, Anton N. Laggner
1
, Michael M. Hirschl
1
1
Department of Emergency Medicine, General Hospital, University of Vienna, Austria
2
Clinic of Internal Medicine II, Department of Cardiology, General Hospital, University of Vienna, Austria
Ke yword s
Ramipril, thrombolysis, myocardial infarction
Summa ry
In a placebo-controlled, double-blinded, randomized study we
evaluated the effect of ramipril prior to thrombolysis on the course of
PAI-1 plasma levels and on the frequency of postinfarct ischemic
events in patients with acute myocardial infarction. Fifty-one out of
99 patients received 2.5 mg ramipril orally prior to thrombolysis and
12 h later. The blood samples for determination of PAI-1 plasma levels
were collected on admission and 2, 4, 8, 12 and 24 h after thrombolysis.
Postinfarct ischemic events were registered until coronary angiography
was performed and defined as recurrent chest pain and/or evidence of
ischemic signs on the ECG (ST-depression or ST-segment elevation of
1 mm in one or more inferior or anterior leads). Coronary angiography
was performed within 7 days after the onset of myocardial infarction.
Patients were classified into two groups: those without reperfusion of
the infarct-related artery (TIMI grade 0 or 1) and those with reperfu-
sion of the infarct-related artery (TIMI grade 2,3). On admission, PAI-1
plasma levels were similiar in both groups (ramipril: 47.1 [4.8] ng/ml;
placebo: 49.1 [4.8] ng/ml). The PAI-1
AUC
was 77.2 [6.7] ng/ml/h in the
ramipril group and 95.4 [6.2] ng/ml/h in the placebo group (p = 0.013).
Significant differences between groups were observed at 4, 8 and
12 h after thrombolysis (4 h: 85.5 (11.3) vs. 116 (12.3) ng/ml, p <0.01;
8 h: 79.1 (11.2) vs. 100.9 (9.3) ng/ml, p <0.01; 12 hrs: 71.3 (9.5) vs.
87.4 (7.7) ng/ml, p <0.05). The relative frequency of postinfarct
ischemic events was significantly lower in the ramipril group (2.5%
versus 7.1%, p = 0.001). Additionally, we observed a significant higher
rate of TIMI grade 2 and 3 of the infarct-related artery in patients
receiving oral ramipril compared to the placebo group (73% versus
54%; p = 0.035).
Our study demonstrates a favorable effect of ramipril on the fibrino-
lytic system after thrombolysis associated with a lower rate of postin-
farct ischemic events within the first days after myocardial infarction.
Therefore, the application of ramipril prior to thrombolysis appears to
be a reasonable concomitant treatment which may reduce early infarct-
related complications.
Introd uc tion
Angiotensin-converting enzyme inhibitors (ACEI) have a favorable
impact on the fibrinolytic system (1). Suppression of the renin-angio-
tensin-aldosterone system (RAAS) results in a reduction of PAI-1 pro-
duction and mRNA expression in cultured endothelial cells (2). Recent
studies have confirmed the relevance of these findings in vitro and
in vivo (3). Moreover, large multicenter trials have demonstrated a
reduction of myocardial ischemic events in patients with a high risk for
myocardial infarction or ischemic stroke, if ACEI are given over long-
term period (4, 5).
Thrombolysis remains the major treatment option in patients with
acute myocardial infarction (6). However, thrombolytic therapy causes
a marked increase of PAI-1 in patients with acute myocardial infarc-
tion. This increase of PAI-1 may contribute to failure of thrombolytic
therapy and/or early reocclusion of the infarct-related artery shortly
after thrombolytic therapy (7). Hirschl et al. demonstrated recently that
application of intravenous enalaprilat attenuated the increase of PAI-1
in patients with acute myocardial infarction undergoing thrombolytic
therapy (8). The observed attenuation of PAI-1 was associated with a
higher rate of patent infarct-related arteries. However, intravenous
enalaprilat has certain limitations concerning its half-life, the way of
application and its possible acute blood pressure lowering in patients
with acute myocardial infarction.
We, therefore, designed a study to evaluate the effect of the oral
ACEI ramipril given prior to thrombolysis on the course of PAI-1
within the first 24 h after thrombolytic treatment in patients with acute
myocardial infarction.
M e thod s
The study was performed in the Emergency Department of the General Hos-
pital in Vienna between January 1999 and February 2001. It was reviewed and
approved by the Ethical Committee of the University of Vienna and all patients
gave written informed consent.
Study Design
The study was a prospective, randomized, placebo-controlled and double-
blinded clinical trial including patients with AMI undergoing thrombolysis.
Acute myocardial infarction was defined according to the WHO criteria: chest
pain lasting for more than 30 min, ST-elevation > 1 mm in one or more inferi-
or leads or in at least two corresponding anterior leads and a typical rise and fall
in CK and CK-MB. Q-wave infarction was confirmed by serial electrocardio-
graphic abnormalities, with development of Q-waves as well as a typical rise
and fall of serum creatine kinase MB.
Correspondence to: Michael M. Hirschl, M.D., Department of Emergency
Medicine, General Hospital, Waehringer Guertel 18-20, A-1090 Vienna, Aus-
tria - Tel.: ++43-1-40400-1964; Fax: ++43-1-40400-2512; E-mail: michael.
hirschl@akh-wien.ac.at
In Focus
181
Hirschl et al.: Ramipril and Fibrinolysis
Exclusion Criteria
Exclusion criteria were 1) chest pain relieved by nitroglycerin or < 30 min
in duration; 2) history of a myocardial infarction; 3) contraindications to throm-
bolytic therapy, including a history of a bleeding disorder or cerebrovascular
accident, gastrointestinal bleeding or genitourinary bleeding within 4 weeks,
major surgery, trauma or cardiopulmonary resuscitation within 14 days, uncon-
trolled hypertension (diastolic blood pressure > 110 mmHg or systolic blood
pressure > 180 mmHg); 4) contraindications to ramipril administration, inclu-
ding renovascular occlusive disease affecting both kidneys or a solitary kidney,
a renal allograft, serum creatinine > 176.8 mmol/L [2.0 mg/dl], a history of
autoimmune disease, multiple drug allergies or a history of leukopenia; 5)
current therapy with cytotoxic drugs; 6) serious advanced illness; 7) hypoten-
sion on admission (systolic blood pressure < 100 mmHg); 8) cardiogenic shock
defined as systolic blood pressure < 85 mmHg unresponsiveness to volume
expansion; 9) treatment with an angiotensin-converting enzyme inhibitor
within the last 2 weeks; 10) pregnancy or ability to become pregnant; 11) lacta-
tion; 12) physical or psychological inability to participate.
Treatment Protocol
In patients meeting the inclusion and exclusion criteria informed consent
was obtained. The patients were randomly assigned to receive either 2.5 mg
ramipril (Tritace; Fa. Aventis) orally or placebo prior to thrombolysis. Patients
received their second study medication (ramipril 2.5 mg or placebo) 12 h after
inclusion to the study protocol. All patients received 100 mg rt-PA according to
the GUSTO-scheme (9). Thrombolysis was preceded by an intravenous bolus
of 5000 IU heparin and 100 mg aspirin orally. At the end of thrombolysis the
heparin dose was adapted to achieve an activated partial thromboplastin time
(aPTT) between 55 and 70 s. Betablockers were given as clinically
appropriate. The randomized phase of the study was finished 24 h after the start
of thrombolysis. After this time interval all patients received ramipril with a
starting dose of 2.5 mg.
Blood Sampling Protocol and Laboratory Assays
Peripheral venous blood was collected for determination of PAI-1. The
samples were collected in evacuated heparin coated tubes, immediately stored
on ice, centrifugated at 3000 rpm at a temperature of 4 C and then frozen
at -70 C until determination. Samples were collected at the following time
points: prior to thrombolytic treatment, 2, 4, 8, 12 and 24 h after the start of
thrombolysis. Cardiac enzymes were assessed every two hours until peak of
creatine-kinase and creatine-kinase MB-fraction was achieved. (the definition
of peak CK was a retrospective procedure: CK was measured every two hours
until the last measured value was lower than the value measured two hours
earlier). The PAI-1 levels were determined in plasma using an enzyme-linked
immunoabsorbent assay (ELISA) kit (Fa. Technoclone, normal values:
10-30 ng/ml).
ECG
A standard 12-lead electrocardiogram was done immediately after admis-
sion of the patient and was used to calculate the initial area of risk according to
the sum of ST-elevations in the inferior and/or anterior leads (10). ST elevation
was measured to the nearest 0.5 mm at the J point and summed for all leads ex-
cept aVR. ST segment deviation was considered significant, if ST elevation
was > 1.0 mm from baseline. Early thrombolytic success was defined as a reso-
lution of ST-segment elevation more than 70% from the initial elevation within
3 h after thrombolysis (11).
Fig. 1 Course of PAI-1 plasma levels in the placebo group (G) and in the ra-
mipril group (I) on admission, 2, 4, 8, 12, and 24 h later. Values are expressed
as mean and standard error of the mean. *) p <0.05; **) p <0.01
Fig. 2 Percentage of TIMI grade 0,1 versus 2,3 in the
placebo group and the ramipril group (p = 0.035)
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Thromb Haemost 2002; 88: 1805
Table 1 Baseline characteristics and hemo-
dynamic parameters in the two groups at ran-
domization
Postinfarct Ischemic Events
Postinfarct ischemic events were registered until coronary angiography was
performed and defined as chest pain after acute myocardial infarction and
evidence of ischemic signs on the ECG (ST-depression or ST-segment eleva-
tion of 1 mm in one or more inferior or anterior leads).
Coronary Angiography
Coronary angiography was performed within 7 days after the onset of
myocardial infarction. The infarct-related artey was identified by assessing the
electrocardiogram, the ventriculographic location of contractile abnormality
and the presence of stenosis or thrombus in the corresponding artery. Flow was
determined during the initial injection of the contrast agent and graded as
described in the Thrombolysis in Myocardial Infarction (TIMI) trial (12).
According to TIMI grading the patients were classified into two groups:
patients without reperfusion of the infarct-related artery (TIMI grade 0 or 1) and
patients with reperfusion of the infarct-related artery (TIMI grade 2, 3).
Statistical Analysis
Continuous data are expressed as mean and standard error of the mean, if not
indicated otherwise. For the comparison of intraindividual values Friedmans
analysis of variance was used, for the comparison of interindivudual values the
Mann-Whitney U-test was applied. In order to compare serial measurements
the area under the curve (AUC) was calculated and divided by the elapsed time
interval. Dichotomous data were compared by means of Fishers exact test.
Re sults
A total of 99 patients were included in the study protocol, 51 of
which were randomized to receive ramipril orally. The groups were
similiar in demographic-, hemodynamic-as well as infarct baseline cha-
racteristics (Table 1). The infarct-related data concerning ST-segment
resolution within 3 h and laboratory parameters (CK and CK-MB
maximum) were similiar in both groups (Table 1). Values of aPTT
183
Hirschl et al.: Ramipril and Fibrinolysis
were similiar in both groups. In the placebo group the aPTT
AUC
was
67 (23) s/h versus 65 (26) s/h in the ramipril group (p = 0.68).
Side-effects
Initial blood pressure was 138 (20) / 77 (15) mm Hg in the placebo
group and 139 (19) / 77 (13) mmHg in the ramipril group and declined
progressively within the first 24 h in both groups (placebo group:
112 (14) / 73 (10) mmHg; ramipril group: 108 (15) / 72 (12) mmHg,
p = 0.24). Hypotensive episodes were significantly more frequent in the
ramipril group compared to the placebo group within the first 24 h (4%
versus 2%; p <0.05), but no patient had to be withdrawn from the stu-
dy due to severe hypotension. Heart rate showed no significant diffe-
rence in both groups on admission (placebo: 79 (17) beats/min; rami-
pril: 80 (20) beats/min; n.s.) and decreased within the first 24 h in both
treatment groups (placebo: 73 (11) beats/min; ramipril: 70 (12)
beats/min; p = 0.36).
Time of Admission
The patients were admitted to the emergency department at the
following hours: 00:00-4:00 a.m.: ramipril: n = 12, placebo: n = 11;
04:00-08:00 a.m.: ramipril: n = 25, placebo: n = 22; 08:00-12:00 a.m.:
ramipril: n = 5, placebo: n = 6; 12:00-04:00 p.m.: ramipril: n = 2,
placebo: n = 3; 04:00-08:00 p.m.: ramipril: n = 2, placebo: n = 3;
08:00-12:00 p.m.: ramipril: n = 5, placebo: n = 3.
Course of PAI-1 Levels
The PAI-1 levels increased significantly in both groups after throm-
bolysis and remained significantly higher compared to baseline after
24 h. The PAI-1
AUC
was 77.2 [6.7] ng/ml/h in the ramipril group and
95.4 [6.2] ng/ml/h in the placebo group [p = 0.013]. Before thromboly-
sis PAI-1 plasma levels were similiar in both groups (47.1 [4.8] ng/ml
in the ramipril group versus 49.1 [4.8] ng/ml in the placebo group).
Four hours after thrombolysis the PAI-1 level was significantly higher
in the placebo group compared to the ramipril group (116 [12.3] ng/ml
versus 85.5 [11.3] ng/ml; p <0.01). This difference between both
groups remained significant until 12 h after thrombolysis (Fig. 1). At
24 h there was no longer a significant difference of PAI-1 levels
between the ramipril and the placebo group (66.1 [7] ng/ml versus 74.9
[9.7] ng/ml). The levels at 24 h remained significantly higher than the
baseline values (p <0.01). The time of admission (00:00-12:00 a.m. vs.
12:00-00:00 p.m.) exhibited no significant influence on the course of
PAI-1 in both groups (PAI-1
AUC
: early time: ramipril: 81 [5.8] ng/ml/h,
placebo: 98.3 [6.3] ng/ml/h; late time: ramipril: 75 [4.6] ng/ml/h,
placebo: 91.6 [5.2] ng/ml/h).
Postischemic Events
As the time interval from thrombolysis to coronary angiography
varied between the patients, the number of postischemic events are
expressed as a relative frequency, i. e. the percentage of episodes per
patient and day. The frequency of postinfarct ischemic events was
significantly lower in the ramipril group compared to placebo (2.5% vs.
7.1%; p = 0.001).
Other Serious Events
Two patients died within the first week after acute myocardial infarc-
tion (ramipril: n = 1, placebo: n = 1). Causes of death were rupture of
the anterior wall of the left ventricle in one patient and cardiogenic
shock in the other one. Congestive heart failure expressed as relative
frequency was 7.6% in the patients receiving ramipril prior to thrombo-
lysis and 7.7% in the patients receiving ramipril 24 h after thrombolytic
therapy.
Coronary Angiography
Coronary angiography was performed in 83 (84%) patients
(placebo-group: n = 39; ramipril group: n = 44) within a mean of 3 days
(range: 1-6; placebo group: 3.4 (2), ramipril group: 3.1 (2.3) days).
In 16 patients no coronary angiography was performed due to the
following reasons: transfer to another hospital (n = 4), no informed
consent of the patient (n = 6), death of the patient (n = 2), unknown
reasons (n = 4). The number of patients with a TIMI grade 2 or 3 of the
infarct-related artery was significantly higher in the ramipril group
compared to the placebo group (Fig. 2).
Disc ussion
Thrombolysis with r-tPA results in a marked increase of PAI-1
shortly after application of the thrombolytic agent (13). Activation of
platelets accompanying thrombolysis are the main source of the increa-
sed PAI-1 activity in these patients (14). The increased PAI-1 levels at
the end of thrombolysis may predispose to reocclusion of the infarct-
related artery after successful thrombolysis (15).
A previously published study provided some evidence that the
RAAS contributes to the PAI-1 regulation in the acute phase of myo-
cardial infarction (8). In this previous study application of intravenous
enalaprilat resulted in a partial suppression of the PAI-1 increase after
thrombolysis indicating an angiotensin-II dependent mechanism (8).
Our data are in line with this study, as the ACE inhibitor ramipril is al-
so associated with a statistically significant attenuation of PAI-1 anti-
gen increase in myocardial infarction patients receiving thrombolytic
therapy. However, intravenous enalaprilat attenuated the PAI-1 increa-
se much more effective than oral ramipril. A reason for the smaller than
expected attenuation of PAI-1 increase may be the oral application of
ramipril. Effective plasma levels of ramipril are observed approximate-
ly 60 min after oral application. Therefore, the initial increase of PAI-1
within the first hour after thrombolysis cannot be influenced by oral ra-
mipril in contrast to intravenous enalaprilat. Another reason for the
smaller attenuation of PAI-1 increase may be the chosen dose of
2.5 mg, which leads to an incomplete suppression of the RAAS. However,
the low dose of ramipril was chosen to avoid severe hypotensive episo-
des, which may increase the ischemic myocardial area. The analysis of
the hemodynamic data revealed that 2.5 mg ramipril is a safe dose with
regard to hypotensive episodes. It remains speculative whether higher
doses of ramipril would enhance the attenuation of PAI-1 increase
without an increase of severe hypotensive episodes in patients with acu-
te myocardial infarction.
Nevertheless, even the application of a low dose of ramipril prior to
thrombolysis has a significant impact on the course of PAI-1 after myo-
cardial infarction. Ramipril attenuated the increase of PAI-1 in patients
with acute myocardial infarction. The effect was apparent 4 h after
thrombolysis and remained significant until 12 h. The mechanism re-
sulting in lower PAI-1 levels after thrombolysis may be the inhibition
of angiotensin-II production and release. This hypothesis is supported
184
Thromb Haemost 2002; 88: 1805
by previous data demonstrating that angiotensin-II produces an acute
and significant increase in plasma PAI-1 levels in normotensive and
hypertensive individuals (3).
Moreover, Vaughan et al. demonstrated that administration of the
ACE inhibitor ramipril leads to a significant reduction of PAI-1 in pa-
tients with acute anterior myocardial infarction (16). In contrast to our
study the PAI-1 levels were determined 14 days after myocardial infar-
ction. At this time PAI-1 levels were significantly lower in the ramipril
group compared to the placebo group (16).
The reduction in plasma PAI-1 observed in this trial has a significant
clinical impact. As demonstrated in this study the risk for the occurren-
ce of a postinfarct ischemic event was significantly lower in the rami-
pril group compared to patients receiving placebo. We assume that the
reduced increase of PAI-1 by ramipril plays a major role in the reduc-
tion of recurrent myocardial ischemic events after thrombolysis. Our
results are in line with a recently published study, which has observed a
reduction of ischemic events in patients receiving the ACE inhibitor
quinalapril after coronary artery bypass grafting (17).
Our data concerning the occurrence of recurrent ischemic events are
confirmed by the angiographic data assessed within the first seven days
after acute myocardial infarction. As demonstrated in this study pa-
tients treated with ramipril exhibited a higher rate of TIMI grade 2 or 3
of the infarct-related artery compared to placebo. We assume that the
attenuation of plasma PAI-1 by ramipril is responsible for the reduction
of the rate of reocclusion in the infarct-related artery. Previous studies
have demonstrated similiar results, as a decrease of PAI-1 levels
resulted in an improved thrombolytic success and a reduced risk for re-
current myocardial infarction (18, 19). Successful coronary reperfusion
itself can curtail the response of PAI-1 activity to myocardial infarc-
tion, most likely by reducing the extent of ischemia and necrosis and
the consequent acute phase reaction (20). In our study early reperfusion
was assessed by electrocardiographic markers (ST-segment resolution
> 70%) and showed no difference between both groups. This extent of
ST-segment resolution is associated with TIMI grade 2 or 3 in most pa-
tients undergoing thrombolytic therapy (11). We, therefore, assume that
the administration of the ACE-inhibitor ramipril prior to thrombolysis,
and not the primary successful reopening of the coronary artery, was
the main contributor to the significant reduction of PAI-1 increase.
Fibrinolytic factors exhibit major circadian fluctuations. The highest
concentrations of plasminogen activator inhibitor-1 are observed in the
early morning (21). This phenomenon may be an important contributor
to the increased rate of myocardial infarction, stroke and sudden cardiac
death during the early morning hours. Analysis of our data with regard
to the time of inclusion into the study demonstrated that most of the
patients were admitted to our department between 04:00 a.m. and
09:00 a.m. In addition, the PAI-1
AUC
did not demonstrate a significant
difference with regard to admission time. Therefore, the results of this
study seem not to be affected by the time of admission.
It has been recently demonstrated that plasma PAI-1 levels within
the first 24 h after the onset of acute myocardial infarction reflect the
infarct size (22). It may be hypothesized that the higher levels of
PAI-1 in the placebo group may be associated with a larger infarct size
in this group. However, analysis of our data demonstrated that the
initial area of risk (expressed as summation of ST segment elevations)
as well as the CK peak (representative of the final infarct size) were
similiar in both groups. We assume that both factors, i.e. initial area of
risk and CK peak, did not contribute to the different course of PAI-1
levels in both groups.
Some limitations of the study have to be emphasized: first, the
characterization of the fibrinolytic balance is incomplete, as no tPA an-
tigen levels were measured in this study. Patients treated with r-tPA
exhibit a large excess of tPA in plasma, which leads to the development
of PAI-1/tPA complexes. It may be hypothesized that the amount of free
and therefore biologically active PAI-1 level is much smaller than the
total amount of PAI-1, which circulates in form of complexes with tPA.
However, ramipril inhibits the release of PAI-1 via inhibition of the
RAAS. Therefore, the amount of available PAI-1 in the plasma is redu-
ced, which leads to an equal reduction of either free PAI-1 or PAI-1 in
form of complexes in the ramipril group.
Second, the chosen dose of ramipril (2.5 mg) was too small to
establish a complete suppression of the RAAS. Therefore, it may be
discussed whether such a small dose exhibits a relevant biological
effect on the course of PAI-1 in these patients. However, the attenuated
course of PAI-1 is associated with a reduced number of ischemic
events. We, therefore, assume that even a small reduction of PAI-1 has
a relevant biological effect in patients with acute myocardial infarction.
Third, the mean time interval between the acute ischemic event and
coronary angiography was approximately 4 days. We are aware that al-
so other mechanisms, i. e. inflammatory response to the myocardial
necrosis, reperfusion injury, free oxygen radicals, may influence the
grade of perfusion in the infarct-related artery. Nevertheless, the pa-
tients of the ramipril group exhibited a significantly higher rate of TIMI
grade 2 and 3 than those receiving placebo.
Overall, ramipril exhibits a favorable impact on the fibrinolytic
system shortly after thrombolysis associated with a reduced risk for
reocclusion of the infarct-related artery and a reduced rate of myocardi-
al ischemic events. This effect seems to be indepent of admission time,
early reperfusion and infarct size. Therefore, the application of ramipril
prior to thrombolysis is a reasonable concomitant treatment to reduce
early infarct-related complications.
Acknowledgements
We are indebted to Dr. Fuchs, G. Sturm and H. Harjung from Aventis
Pharma, Austria, who provided us with the study medication.
References
1. Vaughan DE. Endothelial function, fibrinolysis, and angiotensin-conver-
ting enzyme inhibition. Clin Cardiol 1997; 20 (suppl.12): II34-7.
2. Vaughan DE, Lazos SA, Tong K. Angiotensin II regulates the expression of
plasminogen activator inhibtor in cultured endothelial cells. J Clin Invest
1995; 95: 995-1001.
3. Ridker PM, Gaboury CL, Conlin PR, Seely W, Williams GH, Vaughan DE.
Stimulation of plasminogen activator inhibitor in vivo by infusion of angio-
tensin II. Evidence of a potential interaction between the renin-angiotensin
system and fibrinolytic function. Circulation 1993; 87: 1969-73.
4. The Heart Outcome Prevention Evaluation (HOPE) Study Investigators.
Effect of ramipril on cardiovascular and microvascular outcomes in people
with diabetes mellitus: results of the HOPE study and MICRO-HOPE
substudy. Lancet 2000; 355: 253-9.
5. The Heart Outcome Prevention Evaluation (HOPE) Study Investigators.
Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardio-
vascular events in high-risk patients. N Engl J Med 2000; 342: 145-53.
6. A Report of the American College of Cardiology/American Heart Asso-
ciation Task Force on Practice Guidelines (Committee on Management of
Acute Myocardial Infarction). 1999 Update: ACC AHA guidelines for the
management of patients with acute myocardial infarction. J Am Coll
Cardiol 1999; 34: 890-911.
7. Levi M, Biemond DJ, Zonneveld AJ, ten Cate JW, Pannekoek H. Inhibition
of plasminogen activator inhibitor-1 activity results in promotion of endo-
185
Hirschl et al.: Ramipril and Fibrinolysis
genous thrombolysis and inhibition of thrombus extension in models of
experimental thrombosis. Circulation 1992; 85: 305-12.
8. Hirschl MM, Wagner A, Gwechenberger M, Herkner H, Mllner M,
Woisetschlger C, Laggner AN. Attenuation of thrombolysis-induced
increase of plasminogen activator inhibitor-1 by intravenous enalaprilat.
Thromb Haemost 1998; 79: 140-3.
9. The GUSTO investigators. An international randomized trial comparing
four thrombolytic strategies for acute myocardial infarction. N Engl J Med
1993; 329: 673-82.
10. Gwechenberger M, Schreiber W, Kittler H, Binder M, Hohenberger B,
Laggner AN, Hirschl MM. Prediction of early complications in patients
with acute myocardial infarction by calculation of the ST score. Ann Emerg
Med 1997; 30: 563-9.
11. Krucoff MW, Croll MA, Pope JE, Granger CB, OConnor CM, Sigmon
KN, Wagner BL, Ryan JA, Lee KL, Kereiakes DJ, Samaha JK, Worley SJ,
Ellis SG, Wall TC, Topol EJ, Califf RM, for the TAMI 7 Study Group. Con-
tinuous 12-lead ST-segment recovery analysis in the TAMI-7 Study Group.
Performance of a noninvasive method for real-time detection of failed
mayocardial reperfusion. Circulation 1993; 88: 437-46.
12. The TIMI Study Group. The Thrombolysis in Myocardial Infarction (TIMI)
trial: phase I findings. N Engl J Med 1985; 312: 932-6.
13. Chen LY, Nichols WW, Saldeen TGP, Mehta JL. Recombinant lys-plasmi-
nogen given before, but not after recombinant tissue-type plasminogen ac-
tivator markedly improves coronary thrombolysis in dogs: Relationship of
thrombolytic efficacy with parameters of fibrinolysis. J Cardiovasc Phar-
macol 1996; 27: 283-9.
14. Fujii S, Abendschein DR, Sobel BE. Augmentation of plasminogen activa-
tor inhibitor type 1 activity in plasma by thrombosis and by thrombolysis.
J Am Coll Cardiol 1991; 18: 1547-54.
15. Lucore CL, Fujii S, Sobel BE. Dependence of fibrinolytic activity on the
concentration of free rather than total tissue-type plasminogen activator in
plasma after pharmacologic administration. Circulation 1989; 79: 1204-13.
16. Vaughan DE, Rouleau JL, Ridker PM, Arnold JMO, Menapace FJ, Pfeffer
MA, on behalf of the HEART Study Inestigators. Effects of ramipril on
plasma fibrinolytic balance in patients with acute anterior myocardial
infarction. Circulation 1997; 96: 442-7.
17. Oosterga M, Voors AA, Pinto YM, Buikema H, Grandjean JG, Kingma JH,
Crijns HJGM, van Gilst WH. Effects of quinapril on clinical outcome after
coronary artery bypass grafting (The QUO VADIS Study). Am J Cardiol
2001; 87: 542-6.
18. Fujii S, Sobel BE. Induction of plasminogen activator inhibitor by products
released from platelets. Circulation 1990; 82: 1485-93.
19. Hamsten A, DeFaire U, Walldius G, Dahlen G, Szamosi A, Landou C,
Blombck M, Wiman B. Plasminogen activator inhibitor in plasma: Risk
factors for recurrent myocardial infarction. Lancet 1987; ii: 3-9.
20. Andreooti F, Roncaglioni C, Hackett DR, Khan MI, Regan T, Haider AW,
Davies GJ, Kluft C, Maseri A. Early coronary reperfusion blunts the proco-
agulant response of plasminogen activator inhibitor-1 and von Willebrand
factor in acute myocardial infarction. J Am Coll Cardiol 1990; 16: 1553-60.
21. Andreotti F, Davies GJ, Hackett DR, Khan MI, De Bart ACW, Aber VR,
Maseri A, Kluft C. Major circadian fluctuations in fibrinolytic factors and
possible relevance to time of onset of myocardial infarction, sudden cardiac
death and stroke. Am J Cardiol 1988; 62: 635-7.
22. Soeki T, Tamura Y, Takeichi N, Shinohara H, Yui Y, Fukuda N, Sui O.
Correlation between plasminogen activator inhibitor-1 (PAI-1) and infarct
size in acute myocardial infarction. Respir Circ 1998; 46: 483-7.
Received November 26, 2001 Accepted after revision February 24, 2002