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| DATE | 2020-05-03 |
| FROM | facebook
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| SUBJECT | Re: [Hangout - NYLXS] good thing they are rushing (the vaccines)
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On 5/1/20 7:09 PM, Carolinedliny wrote:
> I'm too lazy to look it up too, but if pt comes in with or develops acute ischemic stroke and we fill out a criteria for TPA, I'm almost certain if pt was started already started on heparin it would then exclude TPA from being ordered because of hemorrhage risk
why do you say that?
https://www.acepnow.com/article/is-the-tpa-for-stroke-debate-over/
https://www.nejm.org/doi/full/10.1056/NEJMoa021274
The use of thrombolytic agents in the treatment of hemodynamically
stable patients with acute submassive pulmonary embolism remains
controversial.
METHODS
We conducted a study of patients with acute pulmonary embolism and
pulmonary hypertension or right ventricular dysfunction but without
arterial hypotension or shock. The patients were randomly assigned in
double-blind fashion to receive heparin plus 100 mg of alteplase or
heparin plus placebo over a period of two hours. The primary end point
was in-hospital death or clinical deterioration requiring an escalation
of treatment, which was defined as catecholamine infusion, secondary
thrombolysis, endotracheal intubation, cardiopulmonary resuscitation, or
emergency surgical embolectomy or thrombus fragmentation by catheter.
RESULTS
Of 256 patients enrolled, 118 were randomly assigned to receive heparin
plus alteplase and 138 to receive heparin plus placebo. The incidence of
the primary end point was significantly higher in the
heparin-plus-placebo group than in the heparin-plus-alteplase group
(P=0.006), and the probability of 30-day event-free survival (according
to Kaplan–Meier analysis) was higher in the heparin-plus-alteplase group
(P=0.005). This difference was due to the higher incidence of treatment
escalation in the heparin-plus-placebo group (24.6 percent vs. 10.2
percent, P=0.004), since mortality was low in both groups (3.4 percent
in the heparin-plus-alteplase group and 2.2 percent in the
heparin-plus-placebo group, P=0.71). Treatment with heparin plus placebo
was associated with almost three times the risk of death or treatment
escalation that was associated with heparin plus alteplase (P=0.006). No
fatal bleeding or cerebral bleeding occurred in patients receiving
heparin plus alteplase.
CONCLUSIONS
When given in conjunction with heparin, alteplase can improve the
clinical course of stable patients who have acute submassive pulmonary
embolism and can prevent clinical deterioration requiring the escalation
of treatment during the hospital stay.
Thrombolysis is an established treatment for patients with acute massive
pulmonary embolism and hemodynamic instability or cardiogenic shock.1 In
contrast, the effect of thrombolytic agents on the outcome of
hemodynamically stable patients who have submassive pulmonary embolism
has been debated for decades.2,3 Several factors have contributed to the
ongoing controversy: the lack of a large, randomized study assessing
clinical end points,4 the risk of serious hemorrhage associated with
thrombolytic therapy,1,5-7 and the fact that patients' hemodynamic
status may gradually improve with heparin therapy alone.8,9
The clinical data currently available underscore the need to identify
patients in whom thrombolysis may have a favorable risk–benefit ratio.
Studies based on two large, multicenter registries reported that
patients with right ventricular dysfunction due to pulmonary embolism
had increased rates of in-hospital death, even in the absence of
arterial hypotension or shock.5,10 These findings are in accord with the
results of early experimental studies on the pathophysiology of venous
thromboembolism.11 Data from one of these registries also suggested that
early thrombolytic therapy might favorably affect the prognosis of these
patients.12 We therefore undertook a randomized, placebo-controlled
trial to compare the effects of treatment with heparin plus alteplase
with the effects of heparin plus placebo on the outcome of patients with
acute submassive pulmonary embolism. We focused on patients with
pulmonary hypertension, right ventricular dysfunction, or both, but we
excluded those with hemodynamic instability.
Methods
STUDY POPULATION
To be included in the trial, patients with acute pulmonary embolism had
to fulfill at least one of the following criteria, which were defined a
priori: echocardiographically detected right ventricular dysfunction,
defined as right ventricular enlargement combined with loss of
inspiratory collapse of the inferior vena cava, without left ventricular
or mitral-valve disease12; echocardiographically detected
pulmonary-artery hypertension,13 defined as a tricuspid regurgitant jet
velocity greater than 2.8 m per second, followed by confirmation of
pulmonary embolism (by ventilation–perfusion lung scanning, spiral
computed tomography [CT], or pulmonary angiography); a diagnosis of
precapillary pulmonary hypertension based on catheterization of the
right side of the heart, defined as a mean pulmonary-artery pressure
above 20 mm Hg and a pulmonary-capillary wedge pressure below 18 mm Hg,
followed by confirmation of pulmonary embolism; or new
electrocardiographic signs of right ventricular strain (defined as
complete or incomplete right bundle-branch block, S waves in lead I
combined with Q waves in lead III, or inverted T waves in precordial
leads V1, V2, and V3), followed by confirmation of pulmonary embolism.
Patients were excluded from the study if they had one or more of the
following characteristics: age over 80 years; hemodynamic instability,
defined as persistent arterial hypotension (i.e., systolic pressure
below 90 mm Hg), with or without signs of cardiogenic shock; onset of
symptoms more than 96 hours before diagnosis; thrombolytic treatment,
major surgery, or biopsy within the preceding 7 days; major trauma
within the preceding 10 days; stroke, transient ischemic attack,
craniocerebral trauma, or neurologic surgery within the preceding 6
months; gastrointestinal bleeding within the preceding 3 months;
uncontrolled hypertension; a known bleeding disorder; known inability to
tolerate alteplase; known diabetic retinopathy; current therapy with an
oral anticoagulant; current pregnancy or lactation; a life expectancy of
less than 6 months because of underlying disease; or planned use of
thrombolytic agents for extensive deep-vein thrombosis.
The study protocol was approved by the local ethics committee at each
institution. Written informed consent was obtained from all the patients.
STUDY DESIGN
The study was designed as a prospective, randomized, double-blind,
placebo-controlled trial and was conducted between September 1997 and
August 2001 at 49 centers in Germany (see the Appendix) by a committee
that included all the authors. Patients believed to have acute
submassive pulmonary embolism, as previously defined,12 received an
intravenous bolus of 5000 U of unfractionated heparin before undergoing
further diagnostic workup. Patients who met the inclusion criteria and
were enrolled in the study were then randomly assigned to receive 100 mg
of alteplase (Actilyse, Boehringer Ingelheim Pharma) as a 10-mg bolus,
followed by a 90-mg intravenous infusion over a period of two hours, or
matching placebo. Randomization was performed on a 1:1 basis with a
fixed block size of six patients at each center, according to a standard
randomization program. In addition to alteplase or placebo, patients in
both groups received an intravenous infusion of unfractionated heparin.
The infusion was started at a rate of 1000 U per hour, and the rate was
subsequently adjusted to maintain the activated partial-thromboplastin
time at 2.0 to 2.5 times the upper limit of normal. Measurements of the
activated partial-thromboplastin time were performed at 6-hour intervals
on day 1 after randomization, and at 12-hour intervals thereafter for at
least four days. Overlapping oral anticoagulant therapy was started on
day 3 after randomization, and the dosage was adjusted to maintain an
international normalized ratio of 2.5 to 3.5. The trial protocol
permitted breaking of the randomization code if additional therapy had
to be provided on an emergency basis to a patient whose condition was
deteriorating.
DEFINITION OF CLINICAL END POINTS
Patients were evaluated at the end of their hospital stay or on day 30
after randomization, whichever occurred first. The primary end point was
in-hospital death or clinical deterioration that required an escalation
of treatment after the infusion of alteplase or placebo was terminated.
Escalation of treatment was defined as the use of at least one of the
following: infusion of a catecholamine because of persistent arterial
hypotension or shock (except for dopamine infused at a rate no more than
5 μg per kilogram of body weight per minute); secondary, or “rescue,”
thrombolysis (for one of the following indications: worsening clinical
symptoms, particularly dyspnea, or worsening respiratory failure due to
pulmonary embolism; arterial hypotension or shock; and persistent or
worsening pulmonary hypertension or right ventricular dysfunction
detected by echocardiography or right heart catheterization);
endotracheal intubation; cardiopulmonary resuscitation; and emergency
surgical embolectomy or thrombus fragmentation by catheter.
The secondary end points of the study were recurrent pulmonary embolism,
major bleeding, and ischemic stroke. Recurrence of pulmonary embolism
was confirmed by ventilation–perfusion lung scanning, spiral CT, or
pulmonary angiography. Major bleeding was defined as fatal bleeding,
hemorrhagic stroke, or a drop in the hemoglobin concentration by at
least 4 g per deciliter, with or without the need for red-cell
transfusion. Hemorrhagic or ischemic stroke was confirmed by CT or
magnetic resonance imaging.
STATISTICAL ANALYSIS
The data were analyzed by an independent clinical research organization
that also monitored the study (Parexel, Berlin, Germany). All the
authors had full access to the data and participated in the data
analysis. The null hypothesis was that there would be no difference
between the two treatment groups with regard to the primary end point —
that is, that the proportion of patients who reached the primary end
point (death or the need for an escalation of therapy) would be the same
in each group. On the basis of the data provided by the Management
Strategies and Prognosis of Pulmonary Embolism Registry,12 it was
calculated that 217 patients would be required in each group to reject
the null hypothesis with a power of 80 percent and at an alpha level of
5 percent, by the detection of a 33 percent relative reduction (or a 13
percent absolute reduction, from 39 to 26 percent) in the incidence of
the primary end point. An interim analysis after the enrollment of the
first 250 patients was prospectively planned to verify these
calculations. The study was terminated after the interim analysis, which
demonstrated a statistically significant difference in favor of
alteplase treatment at that point.
Statistical analysis was performed according to the intention-to-treat
principle. Differences between the treatment groups were examined with
the use of Fisher's exact test (for proportions) and Student's t-test
(for means of continuous variables). The time from randomization to
death or escalation of treatment was analyzed with the use of the
log-rank test, and Kaplan–Meier estimates of the probability of
event-free survival were calculated. To define further the prognostic
importance of treatment and other base-line variables, a
proportional-hazards model was applied to the primary end point. The
results are presented as relative risks and corresponding 95 percent
confidence intervals. All reported P values are two-sided. Plus–minus
values are means ±SD, unless stated otherwise.
Results
CHARACTERISTICS OF THE PATIENTS
Table 1.

Base-Line Characteristics of the Study Patients.
A total of 256 patients underwent randomization. Of these patients, 118
were assigned to the heparin-plus-alteplase group and 138 to the
heparin-plus-placebo group. The two groups were well matched with regard
to major clinical characteristics at base line (Table 1). There were no
significant differences in systolic or diastolic blood pressure, heart
rate, or the severity of dyspnea or arterial hypoxemia. Catheterization
of the right side of the heart was performed in 43 patients, 19 (16.1
percent) in the heparin-plus-alteplase group and 24 (17.4 percent) in
the heparin-plus-placebo group. There were no significant differences
between the two treatment groups with regard to pulmonary-artery
pressures (systolic: 55.2±14.0 mm Hg in the heparin-plus-alteplase group
and 60.42±15.9 mm Hg in the heparin-plus-placebo group; diastolic:
21.9±8.0 and 23.9±8.9 mm Hg, respectively; mean: 34.0±8.5 and 36.1±10.6
mm Hg, respectively).
Echocardiography was performed in 106 of the patients assigned to
receive heparin plus alteplase (89.8 percent), and 129 of those assigned
to receive heparin plus placebo (93.5 percent). The incidence of right
ventricular dysfunction was almost identical in the two groups (Table
1). Doppler echocardiography revealed that the mean tricuspid
regurgitant jet velocity was elevated in both groups (3.23±0.66 m per
second in the heparin-plus-alteplase group, and 3.31±0.78 m per second
in the heparin-plus-placebo group).
CLINICAL OUTCOME DURING THE IN-HOSPITAL PHASE
Table 2.

In-Hospital Clinical Events.
Table 2 summarizes in-hospital clinical events in the two study groups.
The mean duration of the hospital stay was 16.7±8.4 days (range, 2 to
70). The mortality rate was low in both treatment groups. Four patients
in the heparin-plus-alteplase group died, two from pulmonary embolism
and two from underlying disease. Three patients in the
heparin-plus-placebo group died, two from pulmonary embolism and one
from a bleeding complication. Although the mortality rate in the two
groups was similar, the rate of escalation of treatment because of
clinical deterioration was much higher in the heparin-plus-placebo group
than in the heparin-plus-alteplase group. For example, secondary
(rescue) thrombolysis was performed roughly three times as often in the
heparin-plus-placebo group as in the heparin-plus-alteplase group (Table
2). In the heparin-plus-placebo group, the indications for secondary
thrombolysis were cardiogenic shock (in 4 patients), arterial
hypotension requiring catecholamine infusion (in 4), and worsening
symptoms and respiratory failure (in 24 patients, 3 of whom underwent
endotracheal intubation and mechanical ventilation). In the
heparin-plus-alteplase group, nine patients underwent additional
thrombolysis, one because of arterial hypotension and the remaining
eight because of worsening symptoms; one of the latter patients
underwent endotracheal intubation). Overall, the incidence of the
primary end point (death or escalation of treatment) was significantly
greater in the heparin-plus-placebo group than in the
heparin-plus-alteplase group (34 patients [24.6 percent] vs. 13 patients
[11.0 percent], P=0.006).
Figure 1.

Kaplan–Meier Estimates of the Probability of Event-free Survival among
Patients with Acute Submassive Pulmonary Embolism, According to
Treatment with Heparin plus Alteplase or Heparin plus Placebo.
Table 3.

Determinants of the Risk of In-Hospital Death or Escalation of Treatment.
Figure 2.

Mean Activated Partial-Thromboplastin Time in Patients with Acute
Submassive Pulmonary Embolism, According to Treatment with Heparin plus
Alteplase or Heparin plus Placebo.
In accord with these data, the probability of 30-day event-free survival
according to Kaplan–Meier analysis was significantly higher in the group
of patients treated with heparin plus alteplase than in those treated
with heparin plus placebo (P=0.005 by the log-rank test) (Figure 1).
Further analysis with use of the proportional-hazards model confirmed
that treatment with heparin plus placebo predicted an unfavorable
in-hospital outcome: the relative risk of the primary end point with
heparin plus placebo as compared with heparin plus alteplase was 2.63
(P=0.006) (Table 3). As shown in Figure 2, the favorable outcome of the
patients assigned to heparin plus alteplase was not due to greater
effectiveness of heparin anticoagulation in this group than in the other
group, since the activated partial-thromboplastin time reached similar
levels in the two treatment groups between 12 and 48 hours after
randomization. Of the other base-line variables tested in the
proportional-hazards model, age older than 70 years, female sex, and the
presence of arterial hypoxemia were also found to predict an increased
risk of in-hospital death or escalation of treatment (Table 3).
SECONDARY END POINTS, SAFETY, AND TOLERABILITY
The incidence of recurrent pulmonary embolism was low in both treatment
groups (Table 2). However, its incidence may have been underestimated
because of the relatively strict criteria for confirmation of recurrent
thromboembolic events. Bleeding complications were uncommon, and the
incidence of bleeding was not higher in the heparin-plus-alteplase group
than in the heparin-plus-placebo group. In particular, there was only
one fatal bleeding episode (in the heparin-plus-placebo group), and
there were no hemorrhagic strokes. Minor symptoms that may have been
related to the study medication were reported in 72 patients in the
heparin-plus-alteplase group (61.0 percent) and in 78 patients in the
heparin-plus-placebo group (56.5 percent) (P=0.55), but they did not
result in discontinuation of treatment or breaking of the randomization
code.
Discussion
Previous studies have convincingly demonstrated the ability of
thrombolytic agents to dissolve pulmonary emboli and to improve
pulmonary perfusion and right ventricular function.14-21 These
medications are therefore recommended for the treatment of massive
pulmonary embolism. However, the efficacy of thrombolytic agents in the
treatment of submassive pulmonary embolism has remained unclear,1 and
identifying the patient population in which the benefits of thrombolysis
may outweigh the associated risks of bleeding has been the subject of
debate, mostly because of the lack of large-scale clinical trials.4 Our
study was designed to address these issues directly. Our results
indicate that alteplase, given with heparin, improves the clinical
course of hemodynamically stable patients who have acute submassive
pulmonary embolism and that it does so with a low risk of major
hemorrhagic complications.
The clinical course and prognosis of patients with acute pulmonary
embolism vary widely, depending on their clinical and hemodynamic status
at the time of diagnosis.22-25 In particular, right ventricular
dysfunction has been identified as a predictor of adverse
outcome.5,10,26 Thus, in the current trial, we focused on patients who
presented with evidence of pulmonary hypertension, right ventricular
dysfunction, or both of these conditions,27 which were prospectively
defined according to strict echocardiographic and hemodynamic
criteria.9,12 We excluded patients with persistent arterial hypotension
or shock resulting from overt right ventricular failure; the prognosis
of such hemodynamically unstable patients with massive pulmonary
embolism is so poor10 that withholding thrombolytic therapy (or other
aggressive treatment) would be considered unethical, even though there
is a lack of large clinical trials to prove its efficacy in these
patients.28
In the current study, the patients in the two treatment groups were well
matched with regard to base-line characteristics. Kaplan–Meier analysis
showed that the probability of event-free survival during the hospital
stay was significantly lower in the patients assigned to receive heparin
plus placebo than in those assigned to receive heparin plus alteplase.
Although the in-hospital mortality rate was similar in the two groups,
the incidence of clinical deterioration requiring escalation of
treatment was higher in the heparin-plus-placebo group. In particular,
secondary thrombolysis (for predefined clinical and hemodynamic
indications) was needed three times as often in the patients assigned to
heparin plus placebo. Given the strict randomization and blinding used
in the trial, it seems unlikely that the higher incidence of secondary
thrombolysis in the heparin-plus-placebo group was due to bias on the
part of the investigators in favor of thrombolytic therapy. Therefore,
it seems reasonable to assume that delayed resolution (or lack of
resolution)8,9 or recurrence20 of pulmonary embolism with heparin alone
resulted in persistence or deterioration of pulmonary hypertension and
right-sided heart failure.29
In-hospital mortality rates were low in our study, and there were no
significant differences between the two treatment groups. This finding
was unexpected, in view of the results of analysis of the Management
Strategies and Prognosis of Pulmonary Embolism registry, which showed a
mortality rate of 8 percent among hemodynamically stable patients with
right ventricular dysfunction.10 However, patient monitoring is closer
and the degree of alertness on the part of caregivers is generally
higher in randomized therapeutic trials than in registries, and it is
possible that, in the current trial, clinicians' prompt response to
early signs of clinical deterioration averted some in-hospital deaths.
Thrombolysis may be associated with a significant increase in the risk
of fatal or disabling hemorrhagic complications.7,12,30 However, the
rates of bleeding in our patient population were very low, and no
patient had intracranial or fatal hemorrhage after treatment with
alteplase. Our findings, combined with those of another controlled trial
of thrombolysis in pulmonary embolism,20 support the notion that
alteplase is a safe treatment for hemodynamically stable patients with
acute submassive pulmonary embolism, provided that it is not given to
patients with contraindications to thrombolysis and provided that the
patients' clinical condition and coagulation status are closely monitored.
In conclusion, the findings of this randomized, double-blind,
placebo-controlled trial show that treatment with alteplase, given in
conjunction with heparin, may improve the clinical course of patients
with acute submassive pulmonary embolism and, in particular, that such
treatment may prevent further clinical or hemodynamic deterioration
requiring the escalation of treatment during the hospital stay. On the
basis of these data, we believe that the indications for thrombolysis,
which are currently limited to massive pulmonary embolism, can be
extended to include submassive pulmonary embolism (manifested as right
ventricular pressure overload and dysfunction) in hemodynamically stable
patients. Patients thus treated should be carefully monitored to ensure
that they are at low risk for serious bleeding complications.
Supported by Boehringer Ingelheim Pharma (Ingelheim, Germany).
We are indebted to T. Bregenzer (Parexel, Berlin, Germany) for
statistical analysis and to R. Sigmund and E. Bluhmki (Boehringer
Ingelheim Pharma, Biberach, Germany) for statistical advice.
Author Affiliations
From the Department of Cardiology and Pulmonary Medicine,
Georg-August-Universität, Göttingen (S.K.); the Department of Cardiology
and Angiology, Albert-Ludwigs-Universität, Freiburg (A.G.); Boehringer
Ingelheim Pharma, Ingelheim (G.H.); Krankenhaus Bruchsal, Bruchsal
(F.H.); and Department of Internal Medicine, St. Josefs Hospital,
Wiesbaden (W.K.) — all in Germany.
Address reprint requests to Dr. Konstantinides at the Department of
Cardiology and Pulmonary Medicine, Georg-August-Universität Göttingen,
Robert Koch Str. 40, Göttingen, D-37075 Germany, or at
skonstan-at-med.uni-goettingen.de.
The investigators are listed in the Appendix.
Appendix
The following investigators participated in the Management Strategies
and Prognosis of Pulmonary Embolism-3 Trial: Steering Committee: W.
Kasper, S. Konstantinides, A. Geibel, G. Heusel, E. Bluhmki, F.
Heinrich, and K. Rauber; Participating investigators and centers: W.
Kasper, St. Josefs Hospital, Wiesbaden; E. Wolff, Kreiskrankenhaus,
Demmin; G. Lockert, Krankenhaus Stade, Stade; H. Hoetz, Krankenhaus
Ludmillens, Meppen an der Ems; V. Hitz, Ruppiner Kliniken, Neuruppin; W.
Rösch and G.C. Cieslinski, Krankenhaus Nordwest, Frankfurt am Main; M.
Wiersbitzky, Universitätsklinik, Greifswald; M. Bollhorst,
Kreiskrankenhaus, Sinsheim; F. Höltermann, Kreiskrankenhaus, Weinheim;
W. Sehnert, Evangelisches Krankenhaus, Herne; J. Lehmann, Krankenhaus
vom Deutschen Roten Kreuz, Saarlouis; D. Widmann, Städtisches
Krankenhaus, Pfullendorf; E. Kauder, Kreiskrankenhaus, Tuttlingen; K.
Schlotterbeck, Kreiskrankenhaus, Traunstein; C. Wonhas,
Kreiskrankenhaus, München-Pasing; A. Geibel, Universitätsklinik,
Freiburg; H.D. Bundschuh and M. Haag, Caritas Krankenhaus, Bad
Mergentheim; R. Thiele, Universitätsklinik, Jena; C. Kelbel,
Kreiskrankenhaus, Lüdenscheid; H.J. Simon, Krankenhaus Düren, Düren; G.
Krahnstöver, Katharinen Hospital, Willich; U. Fahrenkrog, Klinikum
Remscheid, Remscheid; A. Zeiher, Universitätsklinik, Frankfurt am Main;
J. Cyran, Städtisches Krankenhaus, Heilbronn; F. Forycki, Krankenhuas
Neukölln, Berlin; J. Kohler, Klinikum der Stadt Villingen-Schwenningen,
Villingen-Schwenningen; B. Kohler, Krankenhaus Bruchsal, Bruchsal; R.
Zahn, Klinikum der Stadt Ludwigshafen, Ludwigshafen; M. Weise and J.
Neidermeyer, Universitätsklinik, Dresden; B. Becker, St. Gertrauden
Krankenhaus, Berlin; P. Limbourg, Stadtkrankenhaus, Worms; P.
Schweitzer, Evangelisches Krankenhaus, Bergisch-Gladbach; H. Ditter,
Städtisches Krankenhaus, Gütersloh; K.E. Hauptmann, Krankenhaus der
Barmherzigen Brüder, Trier; D.C. Gulba, Virchow Klinikum, Humboldt
Universität, Berlin; H. Nebelsieck, Kreiskrankenhaus, Böblingen; W.
Dippold, St. Vienzenz und Elisabeth Hospital, Mainz; M. Rejmann,
Kreiskrankenhaus, Oberviechtach; M. Bähr, Krankenhaus Speyererhof,
Heidelberg; W. Voss, Universitätsklinik, Rostock; E. Altmann,
Städtisches Klinikum, Dresden; A. Jöst, Kreiskrankenhaus, Merzig; H.
Mehmel, Städtisches Klinikum, Karlsruhe; M.H. Hust, Kreiskrankenhaus,
Reutlingen; H. Büttner and G. Müller-Est, Kliniken Konstanz, Konstanz;
R. Dissmann, Zentralkrankenhaus Reinkenheide, Bremerhaven; C. Zipp,
Krankenhaus Radolfzell, Radolfzell; D. Gerlach, Krankenhaus Bethesda,
Stuttgart; and B. Hammer and G. Berg, Universitätsklinik, Homburg an der
Saar — all in Germany.
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Citing Articles (624)
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Figures/Media
Table 1.
Base-Line Characteristics of the Study Patients.

Table 2.
In-Hospital Clinical Events.

Figure 1.
Kaplan–Meier Estimates of the Probability of Event-free Survival among
Patients with Acute Submassive Pulmonary Embolism, According to
Treatment with Heparin plus Alteplase or Heparin plus Placebo.

An event was defined as in-hospital death or clinical deterioration
requiring an escalation of treatment after termination of the infusion
of the study drug. Escalation of treatment was defined as at least one
of the following: infusion of a catecholamine because of arterial
hypotension or shock (except for dopamine infused at a rate of no more
than 5 μg per kilogram per minute), secondary thrombolysis, endotracheal
intubation, cardiopulmonary resuscitation, or emergency surgical
embolectomy or thrombus fragmentation by catheter. P=0.005 by the
log-rank test for the overall comparison between the groups.
Table 3.
Determinants of the Risk of In-Hospital Death or Escalation of Treatment.

Figure 2.
Mean Activated Partial-Thromboplastin Time in Patients with Acute
Submassive Pulmonary Embolism, According to Treatment with Heparin plus
Alteplase or Heparin plus Placebo.

The first measurement was performed at the time of randomization, after
the patient had received 5000 U of heparin as a bolus injection. P=0.02
for the difference between the two treatment groups six hours after
randomization. At all other times up to 48 hours, the difference between
the groups was not significant. The I bars represent standard errors.



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October 10, 2002
N Engl J Med 2002; 347:1143-1150
DOI: 10.1056/NEJMoa021274
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