Prophylaxis of Thrombotic and Embolic Events in Acute
Ischemic Stroke With the Low-Molecular-Weight
Heparin Certoparin
Results of the PROTECT Trial
Hans-Christoph Diener, MD; Erich B. Ringelstein, MD; Rüdiger von Kummer, MD;
Helmut Landgraf, MD; Klaus Koppenhagen, MD; Job Harenberg, MD; Ivan Rektor, MD;
Attila Csányi, MD; Dietmar Schneider, MD; Jürgen Klingelhöfer, MD; Joachim Brom, PhD;
Gottfried Weidinger, PhD; for the PROTECT Trial Group
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Background and Purpose—Patients with stroke are at substantial risk of thromboembolic complications and therefore
require antithrombotic prophylaxis. To show the noninferiority of the low-molecular-weight heparin certoparin to
unfractionated heparin (UFH) for the prevention of thromboembolic complications, we performed a randomized,
double-blind, active-controlled multicenter trial in patients with acute ischemic stroke.
Methods—Overall, 545 patients were randomized within 24 hours of stroke onset to treatment with certoparin (3000 U
anti-Xa OD; n⫽272) or UFH (5000 U TID; n⫽273) for 12 to 16 days. Patients with paresis of a leg and an National
Institutes of Health Stroke Scale score of 4 to 30 points were included. The primary end point was a composite outcome
of proximal deep vein thrombosis, pulmonary embolism, or death related to venous thromboembolism during treatment.
Computed tomography was performed at trial entry, after 7 days, and when clinical deterioration occurred.
Results—The per-protocol analysis revealed 17 (7.0%) primary events in the certoparin group compared with 24 (9.7%)
in the UFH group, thereby demonstrating noninferiority (P⫽0.0011), confirmed by intention-to-treat analysis (6.6%
versus 8.8%; P⫽0.008). Major bleeding occurred during treatment in 3 patients allocated to certoparin (1.1%) and 5
patients allocated to UFH (1.8%).
Conclusions—Certoparin (3000 U anti-Xa OD) is at least as effective and safe as UFH (TID) for the prevention of
thromboembolic complications in patients with acute ischemic stroke. (Stroke. 2006;37:000-000.)
Key Words: cerebrovascular accident 䡲 heparin 䡲 venous thrombosis
V
dependency when compared with general ward management.7
Stroke unit care may also reduce DVT frequency.
Prophylaxis of thrombosis is performed with either unfractionated heparin (UFH) or low-molecular-weight heparin
(LMWH). A few trials have compared either UHF or LMWH
with a control group without anticoagulation,8 –11 but only the
trial of Hillbom et al performed a head-to-head comparison of
UFH versus LMWH.12 This trial showed promising results
for the LMWH. In the past, heparins or heparinoids were
given on the assumption that they improved the outcome after
stroke and not primarily for the prevention of thromboembolic complications. However, the concept of improved
outcome after stroke by inhibiting thrombus growth and
preventing early stroke recurrence has been disproved in a
number of studies.5,13–17
enous thromboembolic complications occur frequently
in patients with acute ischemic stroke, in particular in
patients with leg weakness or patients who are confined to
bed. Without prophylaxis, deep vein thrombosis (DVT)
occurs in 20% to 75% of stroke patients, and 2% of the
patients experience pulmonary embolism (PE).1–3 In 1984,
when heparin was used only sporadically, PE was diagnosed
in 52% of the patients on postmortem examination; in 1988,
only 27% of the patients who died after stroke had PE.4 In
recent studies investigating the use of aspirin versus no
aspirin or placebo in the acute phase of stroke, the rate for
symptomatic PE was 0.1% to 0.8%.5,6
Over the last decade, it has been clearly shown that stroke
patients who are managed in an organized stroke unit are less
likely to die, require institutional care, or have long-term
Received March 16, 2005; final revision received August 1, 2005; accepted September 8, 2005.
From the University of Essen, Germany (H.C.D.), University of Münster, Germany (E.B.R.); Technical University of Dresden, Germany (R.v.K.);
Hospital Friedrichshain, Berlin, Germany (H.L.); Benjamin Franklin Hospital, Berlin, Germany (K.K.); University of Mannheim, Germany (J.H.); Faculty
Hospital, Brno, Czech Republic (I.R.); Petz Aladár County Hospital, Györ, Hungary (A.C.); University of Leipzig, Germany (D.S.); Hospital Chemnitz,
Germany (J.K.); and Novartis Pharma, Nürnberg, Germany (J.B., G.W.).
Correspondence to Hans-Christoph Diener, MD, PhD, Neurologische Klinik und Poliklinik, Universitätsklinikum Essen, Hufelandstr. 55, D-45122
Essen, Germany. E-mail [email protected]
© 2005 American Heart Association, Inc.
Stroke is available at http://www.strokeaha.org
DOI: 10.1161/01.STR.0000195182.67656.ee
1
2
Stroke
January 2006
The rationale for using LMWH compared with UFH is the
easier use (one dose per day) and the well-known tendency
for fewer bleeding complications. The primary objective of
the PROphylaxis of Thromboembolic Events by Certoparin
Trial (PROTECT) was to compare the LMWH certoparin
with UFH standard prophylaxis for the prevention of thromboembolic complications in acute ischemic stroke. The dose
of certoparin was chosen on the basis of the safety trial
Therapy of Patients with Acute Stroke (TOPAS).17 TOPAS
suggested that a dose of 3000 U anti-Xa of certoparin was
safe in patients with stroke and effective in preventing venous
thromboembolism (VTE).
Patients and Methods
Study Design
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PROTECT was a randomized, double-blind, active-controlled, parallel group multicenter trial. PROTECT was performed in 37 centers
in the European Union. The study was approved by all local
institutional ethics committees and was undertaken in accordance
with the Declaration of Helsinki. All patients gave written informed
consent. The study was sponsored by Novartis (Nürnberg, Germany). Novartis was responsible for site monitoring, data management, and statistical planning and analysis. The study was supervised
by a steering committee. An independent Safety Committee monitored safety to recognize any unacceptable risks for continuation of
the trial. The members of all committees had full access to the data
and had full control over the right to publish.
Patients and Treatment
PROTECT included men and women 18 to 85 years of age who had
a clinical diagnosis of acute ischemic stroke. The severity of the
underlying stroke was defined by a score on the National Institutes
of Health Stroke Scale (NIHSS) of 4 to 30 with a mild to severe
paresis of a leg. Patients had to be treated within 24 hours of
symptom onset. Exclusion criteria were: indication for thrombolysis,
no availability of computed tomography (CT), CT-documented signs
of intracerebral or subarachnoidal hemorrhage, current bleeding or
thrombosis, history of bleeding or thrombosis within the last 12
months, recurrent gastrointestinal ulcerations, post-thrombotic syndrome, acute or unstable cardiovascular disease, major infection,
currently active, recurrent or metastatic cancer within the last 5
years, platelet count ⬍75 000/␮L at baseline, known hypersensitivity to heparin, known severe diabetic retinopathy, and an estimated
body weight ⬍55 kg. Pregnant or breastfeeding women were not
included.
Eligible patients were randomized to certoparin (3000 U anti-Xa
subcutaneously injected once daily plus 2 injections of placebo) or
UFH (5000 U UFH 3⫻ daily) according to computer-generated lists
provided by Novartis and allocated to the lowest available randomization number. Randomization data were kept strictly confidential,
accessible only to authorized persons until the time of unblinding.
Duration of treatment was 12 to 16 days. A follow-up visit was
performed after 3 months. Administration of ticlopidine, clopidogrel,
or aspirin alone (ⱕ325 mg daily) or in combination with dipyridamole was allowed.
Computed Tomography
CT was performed at baseline before randomization, routinely at
days 7 to 8, and anytime in the case of clinical deterioration or
suspicion of intracranial hemorrhage. An independent neuroradiologist blinded to clinical information, time of stroke onset, and
treatment allocation evaluated all CT scans. Hemorrhagic transformation of brain tissue was classified by radiological criteria according to Pessin et al18 as either hemorrhagic infarction or parenchymal
hemorrhage.
Outcome Measures
The primary end point was a composite outcome consisting of
symptomatic or asymptomatic proximal DVT, symptomatic PE, or
death related to VTE occurring during treatment. Patients were
screened for DVT by duplex and compression ultrasonography at
baseline, at days 3 to 4, at days 7 to 8, and at days 12 to 16, or when
clinical symptoms occurred. Compression sonography was performed for both legs by a certified sonographer according to a
standardized protocol. Documentation of the paretic leg included
cross-sectional views of the respective veins with and without
compression. For the common femoral vein also, a longitudinal view
Trial profile.
Diener et al
including breath-modulated blood flow was documented. Sonography was also performed for the nonparetic leg, but documentation
was only required if thrombosis was found. An independent end
point committee consisting of 2 external experts blinded to treatment
allocation evaluated sonograms of all patients and decided if DVT
had occurred or not. PE had to be diagnosed by ventilation/perfusion
lung scan, pulmonary angiography, spiral CT, or other appropriate
tools. NIHSS ratings were performed by the local investigators at
baseline, at days 7 to 8, at days 12 to 16, and after 3 months.19,20
Bleeding was classified as major if it was intracranial (only if
parenchymal), retroperitoneal or gastrointestinal, resulted in death,
was clinically overt and led to transfusion of ⱖ2 U of packed red
cells/whole blood, or was associated with a fall in hemoglobin level
of ⱖ2 g/dL. Bleedings that did not meet the criteria above were
classified as minor.
Statistical Analysis
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The primary objective was to demonstrate noninferiority of certoparin versus UFH in the rate of thromboembolic events occurring
during treatment. This limit was derived from a pooled analysis of
trials investigating the efficacy of heparin versus placebo.21 All
confirmatory testing was performed using the per-protocol approach;
however, for sensitivity reasons, intention-to-treat results were also
considered. P values and their corresponding CIs were based on the
method of Blackwelder.22
Assignment of patients to the populations analyzed was performed
before data bank lock, unblinding of the treatment code, and start of
data analysis. The safety population (identical to the intention-totreat population) included all randomized patients who received ⱖ1
dose of study medication. The per-protocol population included all
intention-to-treat patients who had a final assessment after doubleblind treatment without major protocol violation or who experienced
a primary end point before a major protocol violation occurred.
Protocol violations were determined in detail by a review committee
before unblinding. The sample size of 500 evaluable patients was
based on expected incidence rates of thromboembolic events of 7.4%
under LMWH and 9.3% under UFH, which would result in a power
of ⬎80% to reject the hypothesis of inferiority of LMWH at a
one-sided significance level of 2.5% with a noninferiority margin
of 5%. Demographic data and NIHSS scores were presented as
mean⫾SD.
Results
Between January 2001 and September 2003, a total of 545
patients were randomized, 272 patients were allocated to
certoparin, and 273 to UFH (Figure). A total of 490 patients
were available for per-protocol analyses: 242 patients in the
certoparin group and 248 patients assigned to UFH.
Baseline characteristics were well balanced between the 2
treatment groups (Table 1). However, with respect to the
medical history, significantly more patients with cardiac
failure were allocated to certoparin compared with UFH
(2P⫽0.013; Fisher exact test). Additionally, there was a
tendency for more patients with myocardial infarction or
severe respiratory disorders within the certoparin group.
Duration of treatment with study medication was 13.6⫾3.2
days. Patients received platelet aggregation inhibitors as
concomitant medication as follows: aspirin, certoparin group
77.2% versus UFH group 78.4%; aspirin in combination with
dipyridamole, 12.1% versus 11.7%; clopidogrel, 16.9% versus 17.6%; and ticlopidine, 2.9% versus 4.4%.
As shown in Table 2, the primary efficacy end point
occurred in 17 patients in the certoparin group (7.0%) and 24
patients in the UFH group (9.7%; per-protocol population).
This result demonstrates the one-sided equivalence of certoparin to UFH for the predefined limit of noninferiority of
Thromboprophylaxis in Acute Ischemic Stroke
TABLE 1.
3
Baseline Characteristics
Certoparin
n⫽272
UFH
n⫽273
Age, y
66.3⫾10.9
Men
149 (54.8%)
67.3⫾10.6
164 (60.1%)
Body weight, kg
77.9⫾14.1
78.4⫾13.3
Body mass index, kg/m2
27.4⫾4.6
27.1⫾3.9
NIHSS
8.7⫾4.0
8.2⫾3.6
Leg paresis†
2.1⫾0.9
2.0⫾0.9
Grade 1
86 (31.6%)
91 (33.3%)
Grade 2
108 (39.7%)
110 (40.3%)
Grade 3
55 (20.2%)
55 (20.1%)
Grade 4
23 (8.5%)
17 (6.2%)
Time-to-treatment, h
15.4⫾7.2
15.4⫾6.2
Infarction in carotid territory
256 (94.1%)
251 (91.9%)
Previous stroke
42 (15.4%)
37 (13.6%)
Previous transient ischemic attack
10 (3.7%)
7 (2.6%)
210 (77.2%)
207 (75.8%)
Previous cardiac failure
21 (7.7%)
8 (2.9%)
Previous myocardial infarction
23 (8.5%)
15 (5.5%)
Diabetes mellitus
81 (29.8%)
71 (26.0%)
Hyperlipidemia
51 (18.8%)
48 (17.6%)
Previous severe respiratory disorders
20 (7.4%)
13 (4.8%)
6 (2.2%)
9 (3.3%)
Hypertension
Previous thrombosis
Mean⫾SD. †Motor leg score of NIHSS: grade 0, no drift; grade 1, leg drifts,
but does not hit bed; grade 2, some effort against gravity; grade 3, no effort
against gravity; grade 4, no movement.
5% (P value⫽0.0011; 97.5% CI, ⫺100.0, 2.2) as well as up
to a limit of noninferiority of 3% (P value⫽0.0117; 97.5%
CI, ⫺100.0, 2.2). The hypothesis of noninferiority was
confirmed by the intent-to-treat analysis: 6.6% of the patients
allocated to certoparin and 8.8% of the patients allocated to
UFH had an efficacy end point (limit of noninferiority of 5%;
P value⫽0.0008; 97.5% CI, ⫺100.0, 2.3; limit of noninferiority of 3%; P value⫽0.0117; 97.5% CI, ⫺100.0, 2.3).
Nonfatal PE did not occur in any group. For 1 patient, the
investigator suspected PE as the most likely cause of death
because increased D-dimers were measured, but no signs for
a cardiac etiology were found. However, an autopsy was not
performed. The end point committee (blinded to treatment
allocation) decided to count this case as an end point because
PE as a cause of death could not be definitely excluded.
There were no differences in the absolute improvement of
NIHSS over time between the treatment groups (mean⫾SD):
certoparin/UFH, 8.7⫾4.0/8.2⫾3.6 at baseline, 6.6⫾4.7/
6.0⫾4.1 at day 7 to 8, 5.5⫾4.7/5.0⫾4.1 at day 12 to 16, and
3.5⫾3.8/3.4⫾3.4 after 3 months. There were also no differences in the NIHSS item “Motor leg,” indicating a similar
recovery of paresis in both treatment groups. Progressive or
recurrent ischemic strokes were diagnosed in 4.8% of patients
in each treatment group during the entire study up to the
3-month visit.
Bleeding complications occurred during treatment in 3.7%
of patients of each treatment group (Table 3). Major bleeding
occurred in 3 patients allocated to certoparin (1.1%); two of
4
Stroke
January 2006
TABLE 2.
No. of Patients With Primary Efficacy End Points
Per-Protocol Population
Intention-to-Treat Population
Certoparin
n⫽242
UFH
n⫽248
Certoparin
n⫽272
UFH
n⫽273
17 (7.0%)
24 (9.7%)
18 (6.6%)
24 (8.8%)
17
23
18
23
Nonfatal pulmonary embolism
0
0
0
0
Death related to VTE
0
1
0
1
Primary efficacy endpoints
Proximal DVT
For delta 5%, P value⫽0.0011 (97.5% CI, ⫺100.0, 2.2) for per-protocol population; for delta 5%,
P value⫽0.0008 (97.5% CI, ⫺100.0, 2.3) for intention-to-treat population.
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these were parenchymal hemorrhages. Another patient experienced hematuria with a drop of hemoglobin of 2 g/dL. For
the UFH group, overall, 5 hemorrhages were classified as
major ones (1.8%): 3 patients with parenchymal hemorrhages
(1 patient’s bleeding was not revealed by routinely performed
CT, but massive intracerebral bleeding was shown by autopsy
2 days later); and 2 patients with gastrointestinal hemorrhages
from duodenal ulcer. Intracranial bleeding was fatal in 1
patient in each treatment group.
Heparin-induced thrombocytopenia was suspected in 1
patient in the certoparin group (0.4%) and 2 patients in the
UFH group (0.7%). However, no measurement of antibodies
was performed in any of the cases. One of the patients
allocated to UFH experienced proximal and distal DVT after
a drop in platelet count to 48 000/␮L. Study medication was
stopped, and the patient was treated with hirudin.
Altogether, 14 patients died during treatment, 7 patients in
each treatment group (2.6%; Table 4). As expected, the most
frequent reason was progression or recurrence of stroke. At 3
months, the mortality rate within the certoparin group was
7.7% compared with a rate of 5.5% in the UFH group.
Discussion
This is the second randomized, double-blind study to compare efficacy and safety of a LMWH with UFH in the
prevention of thromboembolic events in patients with ischemic stroke. It is also the only study performing routine duplex
and compression ultrasonography of the legs at the beginning
and during treatment. In contrast to previous studies, the dose
of certoparin in this trial was selected on the basis of a safety
trial in stroke patients.17 PROTECT shows noninferiority for
certoparin compared with UFH, with a nonsignificant trend
TABLE 3. No. of Patients With Bleeding Complications
During Treatment
Certoparin
n⫽272
Patients with bleeding complications
UFH
n⫽273
10 (3.7%)
10 (3.7%)
Minor bleeding complications
7 (2.6%)
5 (1.8%)
Major bleeding complications
3 (1.1%)
5 (1.8%)
Extracranial bleeding complications
1
2
Intracranial bleeding complications*
2
3†
*Classified as parenchymal hemorrhage by central CT evaluation; †including
1 patient with no confirmation of bleeding by central CT evaluation at day 8 but
massive intracranial hemorrhage 2 days later confirmed by autopsy.
for superiority. Major intracranial or extracranial bleeding
complications as well as thrombocytopenia were slightly less
frequent with certoparin than with UFH. PROTECT had no
placebo group, a decision that was drawn with respect to the
possible severe consequences. We are therefore unable to
draw any conclusions as to whether either of the 2 prophylactic drugs would exert any benefit on the functional outcome
of stroke.
The only other trial, by Hillbom et al, included 212 patients
who were randomized to enoxaparin 40 mg once daily versus
5000 IU of UFH 3⫻ daily.12 The end point was the occurrence of a thromboembolic event confirmed by venography
during treatment. Thromboembolic events occurred in 19.7%
of patients with enoxaparin and in 34.7% of patients treated
with UHF. It is worthwhile to note that the frequency of
thromboembolic events was less in PROTECT compared
with the study by Hillbom et al. However, it may be difficult
to compare the patient populations of PROTECT and of the
study by Hillbom et al, especially regarding the neurological
impairment at baseline. In the study by Hillbom et al, more
disabled patients were included, explaining the higher rates of
thrombosis compared with PROTECT. With respect to bleeding complications, both studies used routine CT scanning
after stopping the study treatment or at days 7 or 8, respectively, to investigate the occurrence of parenchymal bleeding.
TABLE 4.
Mortality and Causes of Death
Treatment period
Certoparin
n⫽272
UFH
n⫽273
7 (2.6%)
7 (2.6%)
Stroke
4
3 (2)
Cardiac events
2
1
Pneumonia
1
0
Intracranial bleeding
0
1 (1)
Pulmonary embolism
0
1
Chronic obstructive pulmonary disease
Follow-up
Stroke
0
1
14 (5.1%)
8 (2.9%)
3
1
Cardiac events
4 (2)
4 (1)
Pneumonia/sepsis
4 (1)
2
Pulmonary embolism
1 (1)
0
Severe bleeding
1
1 (1)
Unknown
1
0
(n) autopsy was performed and confirmed cause of death.
Diener et al
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Hemorrhage rates were similar in both trials. It should be
considered that nearly all patients received aspirin, aspirin
plus dipyridamole, or clopidogrel for secondary prophylaxis.
It is unknown how the concomitant administration of platelet
aggregation inhibitors influences the rate of thrombosis or
bleeding.
There are several ways of documenting silent or clinically
apparent DVT in stroke patients. We decided to use ultrasonography for the diagnosis of proximal DVT, which is
noninvasive, and, in contrast to venography, does not carry
the burden of x-ray films and allows for blinded evaluation by
tape recording. Ultrasound also allows investigating patients
repeatedly. The use of this method is in accordance with
European guidelines.
In the certoparin group, the mortality rate at 3 months, but
not during treatment, was slightly higher compared with the
UFH group. No particular cause of death was ascertained, but
it should be taken into consideration that more patients in the
certoparin group experienced cardiac failure, myocardial
infarction, and severe respiratory disorders in their medical
history than the patients in the UFH group. The overall
mortality rate of 6.6% at 3 months was remarkably low
compared with the rate in the study by Hillbom et al
(23.1%).12 The most likely explanation for the difference in
mortality is the fact that in PROTECT most patients were
treated in a stroke unit, whereas the Hillbom study was
performed between 1992 and 1994, at a time when stroke care
was less sophisticated than today. Furthermore, the patients
of the present study were started with thromboprophylaxis 1
day earlier than in the study of Hillbom et al, the patients
were allowed concomitant drug treatment (ticlopidine, clopidogrel, and aspirin alone or in combination with dipyridamole), and more cases with mild and rapidly disappearing leg
paresis were perhaps included. Other trials investigating
heparins or heparinoids showed mortality rates of 6.6% (Trial
of Org 10172 in Acute Stroke Treatment [TOAST]), 11.8%
(Tinzaparin in acute ischaemic stroke [TAIST]), 17.9% (Heparin in Acute Embolic Stroke Trial [HAEST]), and 26.9%
(Fraxiparine in Ischaemic Stroke Study [FISS] bis).13–16 In
TOPAS, the mortality rate within the treatment arm with
low-dose certoparin (3000 U anti-Xa) was 4.0%.17
In summary, our data show that VTE remains common in
acute stroke patients, even in modern organized stroke
management wards. The LMWH certoparin was at least as
effective as UFH, with a comparable safety profile. Additionally, thromboprophylaxis with certoparin is easier to use
because it is administered only once a day, and dosage is
independent of body weight.
Appendix
Committees
Steering Committee
H.C.D., University of Essen, Germany (principal investigator);
E.B.R., University of Münster, Germany (coprincipal investigator);
J.H., University of Mannheim, Germany; J.B., Novartis, Nürnberg,
Germany.
External Safety Committee
R.v.K., Technical University of Dresden, Germany; J. Michaelis,
University of Mainz, Germany.
Thromboprophylaxis in Acute Ischemic Stroke
5
Endpoint Committee
H.L., Hospital Friedrichshain, Berlin, Germany; K.K., Benjamin
Franklin Hospital, Berlin, Germany.
Central CT Reader
R.v.K., Technical University of Dresden, Germany.
Writing Committee
H.C.D., University of Essen, Germany; E.B.R., University of Münster, Germany; R.v.K., Technical University of Dresden, Germany;
H.L., Hospital Friedrichshain, Berlin, Germany; K.K., Benjamin
Franklin Hospital, Berlin, Germany; J.H., University of Mannheim,
Germany; I.R., Faculty Hospital, Brno, Czech Republic; A.C., Petz
Aladár County Hospital, Györ, Hungary; D.S., University of Leipzig,
Germany; J.K., Hospital Chemnitz, Germany; J.B., G.W., Novartis,
Nürnberg, Germany.
Statistics and Data Management
H. Bachmann, J. Huss, S. Leifer, Novartis, Nürnberg, Germany.
Data Entry
IMEREM, Nürnberg, Germany.
Study Coordination
A. Dorsch, Novartis, Nürnberg, Germany.
Head of Monitoring Group
R. Ross, Novartis, Nürnberg, Germany.
Contract Organization Responsible for Monitoring in the
Czech Republic and in Hungary
Verum.de, Gilching, Germany.
Project Coordination and Logistics
D. Weber, K. Krause, A. Kuchler, E. Koroleva, Novartis, Nürnberg,
Germany.
Study Centers
The following clinical centers participated in PROTECT (main
investigators in italics).
Germany: University of Essen: H.C.D., Ö. Yaldizli, K. Kröger;
University of Leipzig: D.S., L. Küppers-Tiedt, A. Lämmer,
D. Pfeiffer; Hospital Chemnitz: J.K., J.J. Schwarze; Charité Berlin,
Campus Mitte: L. Harms, N. Amberger, F. Lürtzing, H. Jepsen;
Hospital Bad Neustadt/Saale: B. Griewing,(0)2 H. Sodan; Hospital
Friedrichshain, Berlin: M. Klein, D. Berfelde, A. Holle, H.-P.
Dahse; Hospital Altenburg: J. Berrouschot, O. Niederstrasser, H.
Uhlemann; Charité Berlin, Campus Virchow: A. Villringer, S.
Wegener, G. Häusler, J. Rademaker; University of Münster: E.B.R.,
M. Schilling, W. Heindel; Marien-Hospital Düsseldorf: W. Steinke,
T. Bayraktar, U. Syldath, K. Hayduk; University of Mainz: M. Eicke,
S. Hägele, H. Schinzel; Marien-Hospital Papenburg: B. Pollock,
H.-J. Jantke; Paracelsus-Hospital Ostfildern: W. Habscheid, M.
Heinemann; Paracelsus Hospital, Marl: I. Velancsics, B. CasserNordhues; Humaine Hospital Bad Saarow: K. Wohlfahrt, O. Niederstrasser, J. Petersein; Wenckebach-Hospital, Berlin: E. Becker, G.
Schneider, N. Rambo; Hospital Nürnberg-Süd: F. Erbguth, E.
Glaser; Technical University of Dresden: H. Reichmann, U. Becker;
Hospital Lohr am Main: M. Schlenker, J. Hupe, W. Kestel; Hospital
Lüdenscheid: U. Heckmann, W. Selberis, N. Avci, C. Kelbel;
Hospital Fulda: H.-D. Langohr, D. Bahner, T. Bonzel; FriedrichEbert-Hospital Neumünster: H.-C. Hansen, N. Krause-Pape, KP
Bethge; Charité Berlin, Campus Buch: H.-P. Vogel, H. Prokrant, M.
Liwschitz, L. Völker; Hospital Berlin-Spandau: H. Altenkirch, G.
Walter, H. Burbach; Hospital Minden: O. Busse, J. Glahn; Hospital
Aschaffenburg: A. Schneider, J.M. Dorr, T. Wollenweber; University
of Greifswald: C. Kessler, A. Dressel.
Czech Republic: Faculty Hospital, Brno: I.R., M. Dufek, R.
Mikulik; Faculty Hospital, Hradec Kralove: D. Krajickova, A.
Bartkova; Faculty Hospital, Plzen: J. Polivka, P. Sevcik; Faculty
Hospital, Praha: H. Dvorakova, J. Sroubek, J. Hort, M. Bojar;
Faculty Hospital, Olomouc: K. Urbanek, A. Bartkova, I. Vlachova,
D. Sanak, B. Krupka.
6
Stroke
January 2006
Hungary: Petz Aladar County Hospital, Györ: A.C., L. Javor, G.
Rum, S. Lipoth, I. Adam, I. Toth; Kenezy Gyula County Hospital,
Debrecen: B. Clemens, V. Nagy, G. Bedo, S. Erdelyi; B-A-Z County
Hospital, Miskolc: I. Sagi, A. Eros, J. Pogardi, M. Csalto; Pest
County Flor Ferenc Hospital, Kistarcsa: S. Horvath, G. Jambor, L.
Horvath, V. Kovacs; Zala County Hospital, Zalaegerszeg: J. Nikl, L.
Nemeth, J. Horvath.
11.
12.
Acknowledgments
PROTECT was sponsored by Novartis Pharma, Nürnberg, Germany.
We thank Philip Bath for critical comments.
13.
14.
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Prophylaxis of Thrombotic and Embolic Events in Acute Ischemic Stroke With the
Low-Molecular-Weight Heparin Certoparin. Results of the PROTECT Trial
Hans-Christoph Diener, Erich B. Ringelstein, Rüdiger von Kummer, Helmut Landgraf, Klaus
Koppenhagen, Job Harenberg, Ivan Rektor, Attila Csányi, Dietmar Schneider, Jürgen
Klingelhöfer, Joachim Brom and Gottfried Weidinger
for the PROTECT Trial Group
Stroke. published online November 23, 2005;
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