Intravenous Heparin Started Within the First 3 Hours After

Onset of Symptoms as a Treatment for Acute Nonlacunar

Hemispheric Cerebral Infarctions
Massimo Camerlingo, MD; Pietro Salvi, MD; Giorgio Belloni, MD; Tiziano Gamba, MD;
Bruno Mario Cesana, MD; Angelo Mamoli, MD

Background and Purpose—Heparin is widely used for acute stroke to prevent thrombus propagation and/or multiple
emboli generation, although there is, as yet, no demonstrated efficacy. However, all of the available clinical studies
allowed long intervals from stroke to treatment. The purpose of this study was to try an intravenous regimen of
unfractionated heparin the acute cerebral infarction starting treatment within the first 3 hours of the onset of symptoms.
Methods—The study was an outcome evaluator-blind design trial. Patients had to display signs of a nonlacunar
hemispheric infarction. Selected patients were randomly allocated to receive intravenous heparin sodium or saline.
Heparin was infused at a rate to maintain activated partial thromboplastin time ratio 2.0 to 2.5 ⫻ control for 5 days. The
primary end point was recovery of a modified Rankin score zero to 2 at 90 days of stroke at phone interview by a single
physician blind to treatment. Safety end points were death, symptomatic intracranial hemorrhages, and major
extracranial bleedings by 90 days of stroke.
Results—A total of 418 stroke patients were included. In the heparin group, there were more self-independent patients
(38.9% versus 28.6%; P⫽0.025). In addition, in the same group, there were fewer deaths (16.8% versus 21.9%;
P⫽0.189), more symptomatic brain hemorrhages (6.2% versus 1.4%; P⫽0.008), and more major extracerebral
bleedings (2.9% versus 1.4%; P⫽0.491).
Conclusions—Intravenous heparin sodium could be of help in the earliest treatment of acute nonlacunar hemispheric
cerebral infarction, even keeping into account an increased frequency of intracranial symptomatic brain hemorrhages.
(Stroke. 2005;36:2415-2420.)
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Key Words: anticoagulation 䡲 cerebral ischemia 䡲 heparin 䡲 stroke

N o clinical trial has yet proven efficacy of heparin, both

unfractionated and low-molecular-weight, in the treat-
ment of the human stroke.1,2 Nonetheless, heparin is still
frequently prescribed1 in the hope of preventing either throm-
bus propagation or early recurrences of stroke. All the
studies,3–11 however, allowed long intervals from the onset of
stroke to the initiation of treatment. On the contrary, both
experimental12–14 and clinical experiences15,16 demonstrated
that preservation of ischemic but still viable brain tissue is
time-dependent. Thus, no data for the evaluation of heparin in
the earliest treatment of stroke are presently available.2
Previously, we tested safety of anticoagulation with intrave-
nous heparin started within the sixth hour of an acute carotid
stroke17 in a small pilot study. Basing both on that study and
on the need to even speed up the start of treatment,15 we
designed a randomized, controlled trial, and here we report
the results. The study was made possible because at that time,
intravenous thrombolysis was not yet approved in Italy for
stroke.
Methods
The study was designed to test whether an anticoagulant regimen of
intravenous heparin sodium started within the first 3 hours of an
acute nonlacunar hemispheric cerebral infarction could be effective
and safe.
The trial was performed at 1 stroke unit, and was controlled and
randomized.
Randomization was computer-generated. The study was an out-
come evaluator-blind design trial. Informed consent had to be
obtained. Start of the study was January 1, 1996.
The primary end point of the study was the rate of patients
recovering self-sufficiency by 90 days of stroke. That end point was
evaluated by phone by a single physician blind to treatments. Safety
end points were the rates of deaths symptomatic cerebral hemor-
rhages, and major extracranial bleedings by 90 days.

Received June 12, 2005; final revision received July 13, 2005; accepted August 4, 2005.
From the Second Neurological Unit and the Neuroradiological Unit (M.C., G.B., A.M.), Ospedali Riuniti, Bergamo, Italy; the Rehabilitation Unit (P.S.),
Clinica Quarenghi, S. Pellegrino Terme, Bergamo, Italy; general practitioner (T.G.), Bergamo, Italy; and the Epidemiological Laboratory (B.M.C.),
University of Milan, IRCCS Ospedale Maggiore, Milan, Italy.
Massimo Camerlingo is now at the Neurologic Unit and Giorgio Belloni is at the Neuroradiologic Unit, Policlinico San Marco, Zingonia, Bergamo,
Italy; Bruno Mario Cesana is Associate Professor of Medical Statistics, University of Brescia, Brescia, Italy; Angelo Mamoli is retired.
Correspondence to Massimo Camerlingo, MD, Unità Operativa di Neurologia, Policlinico San Marco, Corso Europa 7, I-24040 Osio Sotto (Bergamo),
Italy. E-mail massimo.camerlingo@virgilio.it
© 2005 American Heart Association, Inc.
Stroke is available at http://www.strokeaha.org DOI: 10.1161/01.STR.0000185730.50480.e7

2415
 2416 Stroke November 2005
The protocol was found to be in agreement with the ethical rules
by our Ethical Committee. Finally, the study was not financially
supported by companies or government grants.
Screening Procedure
We considered all alert patients referred to our Stroke Unit within the
first 3 hours of the onset of an acute neurologic deficit suspected for
cerebral infarction. All those patients were immediately given a
neurologic score of severity18 and submitted to a computed tomog-
raphy (CT) of the brain in addition to blood routine examinations,
electrocardiogram (ECG), and duplex scanning of the carotid
arteries.
Criterion of inclusion was a clinical syndrome indicating a
large-vessel hemispheric stroke that is a total or a partial anterior
circulation syndrome (TACS, PACS)19 to have best chances to
visualize the actual ischemic lesion at neuroradiologic controls.
Criteria of exclusion were:
1. PACS characterized only by higher cerebral dysfunction
alone or by motor deficit confined to the face or to one limb
to avoid treatment to patients with an already predictable
good spontaneous outcome;
2. a lacunar syndrome (LACS)19;
3. age ⬍18 and ⬎90 completed years;
4. stupor or coma;
5. any previous handicap making nonapplicable the neurologic
scale of evaluation at entry18;
6. any uncertainty about the time of onset of stroke;
7. persistent systolic blood pressure ⬎185 mm Hg and/or dia-
stolic blood pressure ⬎110 mm Hg at entry15;
8. rapid regression of symptoms before treatment;
9. other diagnoses from CT;
10. any current contraindication to anticoagulants;
11. cancer or any other severe concurrent disease;
12. pregnancy;
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13. inability to start treatment within the third hour of stroke; and
14. inability to obtain informed consent from patients or their
relatives.
A previous stroke was a matter of exclusion if the patient had
persistent motor or higher cerebral dysfunction at the time of the
qualifying stroke.
Therapeutic Plan
After recruitment, the patients were assigned to receive for 5 days a
pump-assisted infusion of intravenous heparin sodium (24 000 IU
per day dissolved in 1000 mL of saline without initial bolus) or of an
equal quantity of saline. The speed of infusion, either unfractionated
heparin or saline, was 42 mL/hr. Prothrombin time international
normalized ratio (PTINR), partial thromboplastin time ratio (PTTR),
and platelet counts were obtained at 6 hours after the start of infusion
and then every day in both groups of patients. Unfractionated heparin
was regulated aiming to maintain activated thromboplastin time
(PTT) 2.0 to 2.5 times the control ratio. Treatment was immediately
withdrawn in case of any hemorrhage. After 5 days of stroke, both
groups of patients were given oral aspirin (100 mg/day) or oral
anticoagulants (targeted to obtain PTINR between 2.0 and 3.020) in
case of cardiac sources of emboli.
Since admission, both groups of patients received supportive
general care and control of blood pressure, in addition to rehabilita-
tion maneuvers. Systolic blood pressure was aimed to be maintained
120 to165 mm Hg and diastolic blood pressure 70 to 95 mm Hg. In
the control group, 5000 IU of calcium heparin was administered
subcutaneously twice a day for the prevention of deep venous
thrombosis (DVT). Furthermore, compression stockings were used
in both groups to prevent DVT.21
Evaluations After Admission
The etiologic mechanism of stroke was assigned according to the
TOAST criteria.22 CT was repeated between day 4 and day 7 of
stroke, in case of stroke recurrence, and whenever there was
suspected cerebral bleeding.
In case of sudden or unexplained inhospital death, a necropsy
study was obtained. Cerebral bleedings were differentiated in symp-
tomatic or asymptomatic according to the rules of the NINDS trial.15
Extracranial bleedings were defined as major when needing blood
transfusions. CT scans were reviewed by a single neuroradiologist
(G.B.) who was blind to treatments. The functional status at 90⫾10
days of stroke was assigned by phone interview by P.S., neurologist
and head at a rehabilitation center, settled far from our general
hospital. He was blind to the treatments.
To ensure proper blinding, none of the patients had to be sent for
rehabilitation to his center. Phone interviews were collected either by
the caregivers or the patients. A score of 0 to 2 of the mod-
ified Rankin Scale23 was considered as criterion for recovery of
self-independence.
Statistical Analysis
All the data were recorded in a database file and processed for
statistical analyses with the Statistical Package for Social Sciences
(SPSS Inc.) by B.M.C., who is an experienced statistician. Data were
analyzed according to the intention-to-treat principle. All tests were
2-tailed, and probability value ⬍0.05 was considered an indicator of
significance. The minimal number of needed patients was provided
to be approximately 408 according to a trial attempting to ascertain
a difference in favor of heparin of approximately 30% with a power
of 90%.
Results
Study Population
Of 2589 consecutively screened stroke patients by December
31, 2001, 418 patients (16.1%) met the selection criteria.
They were 247 women and 171 men, with a mean age of 70.9
years (range, 22 to 90 years). The vascular risk factors of the
study population were: hypertension in 278 patients (66.5%),
diabetes in 73 (17.5%), smoking in 136 (32.5%), hyperlipid-
emia in 62 (15.1%), and known cardiac diseases in 218
(52.1%).
Atrial fibrillation was found at entry ECG in 173 patients
(41.3%), whereas an appropriate internal carotid artery dis-
ease (stenosis ⬎50% or occlusion) was seen at duplex
scanning in 127 patients (30.4%).
Stroke was a TACS in 204 patients (48.8%) and a PACS in
214 (51.2%).
According to subtype classification,22 stroke was consid-
ered to be cardioembolic in 178 (42.6%), atherothrombotic in
101 (24.2%), and of unknown/undetermined origin in 139
(33.2%).
Figure reports the flow diagram of the study.
Two hundred eight patients were given intravenous heparin
sodium. The 2 groups were well balanced as baseline char-
acteristics by randomization (Table 1).
None of the patients in either group received any treatment
before randomization. The interval stroke to needle was quite
similar in both groups. It was 147 minutes (range, 59 to 178
minutes) in the heparin group and 152 minutes (range, 54 to
180 minutes) in the control group (P⫽0.455, Student t test).
Blood pressure also was similar between groups at time of
starting treatments. It was (systolic/diastolic mm Hg mean
values⫾standard deviation) 137.6/78.2⫾20.3/10.9 in the
heparin group and 139.1/79.5⫾22.7/10.1 in the other group
(P⫽0.477 for systolic and P⫽0.207 for diastolic blood pressure,
Student t test).
 Camerlingo et al Acute Nonlacunar Hemispheric Cerebral Infarction
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Flow diagram of the study.
All the patients assigned to heparin sodium received
planned treatment.
None of the patients in the control group was shifted to
unfractionated heparin.
All of the patients had a second CT, except a woman on
intravenous heparin, who was found at necropsy to have a
large hemorrhagic transformation of the cerebral infarction.
Primary End Point
At 90 days of stroke, the patients recovering self-sufficiency
were 81 of 208 (38.9%) in the heparin sodium group and 60
of 210 (28.6%) in the other group. That difference was
statistically significant (P⫽0.025).
Table 2 shows the rates of the patients per single score on
the modified Rankin Scale.
2417
Safety End Points
Eighty-one patients (19.4%) died within 90 days of stroke.
Thirty-five deaths were recorded in the group treated with
heparin sodium (16.8%) and 46 in the other group (21.9%).
That difference did not achieve statistical significance (P⫽
0.189). The causes of deaths are reported in Table 3. Symp-
tomatic cerebral hemorrhage was seen in 16 patients. Of
those, 13 patients were in the treatment group (6.2%) and 3
patients in the control group (1.4%) (P⫽0.008).
Asymptomatic hemorrhagic transformations of the brain is-
chemia were seen at control CT in 44 patients (23 versus 21,
P⫽0.725).
Table 4 shows the hemorrhagic complications of the brain
we have seen. Major extracranial bleedings were seen in 9
 2418 Stroke November 2005

TABLE 1. Patients’ Characteristics by Group of Treatment TABLE 3. Causes of Deaths

Control, n (%) Heparin, n (%) P Heparin Control
No. 210 208 Stroke itself 15 24
Mean age (range) 71 (23–90) 70 (22–90) 0.752 Brain hematoma 7 1
Men 85 (40.5) 86 (41.3) 0.856 Pneumonia/sepsis 5 7
Women 125 (59.5) 122 (58.6) Pulmonary embolism* 2 6
Rankin score one before stroke 12 (5.7) 14 (6.7) 0.820 Cardiac death 6 8
Median NIHSS at entry (full range) 17 (6–27) 17 (6–28) 0.654 *There were 2 more nonfatal pulmonary embolisms in the heparin group, but
Hypertension 136 (64.8) 142 (68.3) 0.447 no nonfatal pulmonary embolism in the control group.
Diabetes 34 (16.2) 39 (18.7) 0.491
48 hours.3– 6,9,11 Because all of those studies dealing with sys-
Smoking 68 (32.3) 68 (32.7) 0.946
temic thrombolysis beyond 3 hours of the onset of stroke
Any heart disease 103 (49.0) 115 (55.3) 0.201
failed,15,16,24 –28 the time intervals of the previous studies on
Atrial fibrillation 80 (38.1) 93 (44.7) 0.170
heparin appear to be really very long.
Carotid artery disease 60 (28.6) 67 (32.2) 0.418
Another explanation of our results could have been the
TACS 102 (48.6) 102 (49.9) 0.924 anticoagulant regimen of heparin administration. Complete
PACS 108 (51.4) 106 (50.1) anticoagulation was shown to be superior than fixed doses
Cardioembolic subtype 85 (40.5) 93 (44.7) 0.330 because it prevents not only of embolisms to the brain,29 but
Atherothrombotic subtype 48 (22.8) 53 (25.4) also of severity of the strokes occurring during treatment
Unknown/undetermined subtype 77 (36.7) 62 (29.8) of patients with atrial fibrillation.30 Thus, the high rate of
NIHSS indicates National Institute of Health Stroke Scale.15 patients with cardioembolic subtype of stroke we included
could have optimized the effect of heparin. Furthermore, a
patients. Of them, 6 patients received intravenous heparin recent experimental study has demonstrated that steady
(2.9%) and 3 were in the control group (1.4%) (P⫽0.491). plasma concentration of unfractionated heparin can reduce
Those extracranial bleedings occurred in the abdominal the infarct volume after transient focal cerebral ischemia in
muscle wall (4 patients), in the gastrointestinal tract (4 the rat.31
patients), and in a shoulder (1 patient). No death was the In our opinion, timing and dosage of unfractionated hepa-
Downloaded from http://ahajournals.org by on January 29, 2023

result of an extracranial major bleeding. rin and patients’ selection could have concurred together
Finally, none of the patients had platelets decreased below resulting in the success of the study.
100 000/cm3. A possible criticism of our study might be the choice to
accept scores 0 to 2 of the modified Rankin Scale23 as
Discussion criterion for the recovery of self-independence. That choice
Our study suggests that an anticoagulant regimen of intrave- could have apparently enlarged the benefit from intravenous
nous heparin sodium, administered within the first 3 hours of heparin.
the onset of symptoms, could be of benefit for the patients To consider recovery of self-independence, a score ⱕ1
with an acute nonlacunar hemispheric cerebral infarction. (complete recovery of the neurologic deficit) or ⱕ2 (no or
Those patients were more likely to be self-independent and slight neurologic disability) on the modified Rankin Scale23 is
alive by 90 days of stroke. The absolute risk reduction for not without meaning because it was the cause of failure of a
the recovery of self-independence was approximately 10%, large clinical trial.28 NINDS trial accepted grade 0 and 1, but
which would appear to be interesting because of the clinical it included also patients with modest deficit.15 On the con-
severity of the patients included in the study. Possibly, trary, PROACT II trial, which probably selected patients as
intravenous heparin could have been effective because of severe as ours, considered as self-independent the patients
utilization closest to the onset of stroke. To date, information recovering grade 0 to 2.32
on heparin was from studies allowing intervals because stroke Finally, the authors of the original article23 considered
to initiation of treatment was up to 12 hours,10 24 hours,7,8 or scores 0 to 2 as recovery of self-independence. Thus, both the
clinical severity of the patients we selected and the indica-
TABLE 2. Rates of Scores on the Modified Rankin Scale tions from the original paper would be in agreement with our
Heparin, n (%) Control, n (%) criterion.
0 18 (8.6) 12 (5.7)
TABLE 4. Hemorrhagic Complications of the Brain
1 34 (16.3) 23 (10.9)
2 29 (13.9) 25 (11.9) Control, n (%) Heparin, n (%)
3 20 (9.6) 24 (11.4) Symptomatic 3 (1.4) 13 (6.2)
4 39 (18.7) 37 (17.6) Fatal 1 (0.5) 7 (3.4)
5 33 (15.9) 43 (20.5) Nonfatal 2 (0.9) 6 (2.8)
Deaths 35 (16.8) 46 (21.9) Asymptomatic 21 (10.0) 23 (11.0)
 Camerlingo et al Acute Nonlacunar Hemispheric Cerebral Infarction
However, even when considering in our study only the
patients achieving a score of 0 or 1 at 3 months of stroke as
recovery of self-independence, the difference would remain
statistically significant (52 versus 35; P⫽0.0479, ␹2 test).
Thereby, independently from the criteria to tribute recov-
ery of self-independence, intravenous heparin would seem to
be an effective treatment of the acute hemispheric cerebral
infarction. Another matter of criticism might be the open
design of the study, which left to a phone interview the
assessment of the final functional status. However, the
assessment was made by a single physician, skilled of
disability measures, who stayed far from our unit and was
completely blind to the medical records. We used that method
because it was already validated in Italy.33
In addition, a similar procedure was already used in the
up-to-date largest clinical trial on stroke treatment,5 and in a
large clinical trial on thrombolysis too.24
As for thrombolysis, also intravenous heparin was associ-
ated with an increased risk of symptomatic intracranial
hemorrhage. However, our rate did not look high and it was
similar to the one found in the NINDS trial.15 Other trials of
thrombolysis reported greater rates, but they included patients
whose signs started up to 6 hours since stroke.16,24 –28 No
information is available for the clinical trials on intravenous
heparin.3,4
In our study, we observed almost 28.5% patients recover-
ing self-independence in the control group. This should be a
consequence that all the patients were managed in a stroke
unit.34 In conclusion, we think that the main suggestion from
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our study was that it might be another brick to the concept
limit of the 3 hours from onset of stroke to start treatment.
That limit could be valid whichever the treatment really
interfering with the cascade of coagulation, because the
favorable results observed also by another trial, which used a
different agent within the same time interval of stroke.35
However, other data have to be obtained to confirm this
impression.
Addendum
By the time this manuscript was submitted, another trial dealing with
unfractionated heparin and stroke was published (Chamorro A,
Busse O, Obach V, Toni D, Sandercock P, Reverter JC, Cervera A,
Torres F, Davalos A; for the RAPID Investigators. The RAPID
anticoagulation prevents ischemic damage study in acute stroke—
final results from the writing committee. Cerebrovasc Dis.
2005;19:402– 404). That trial, which included patients up to 12 hours
from the onset of stroke, was prematurely interrupted after 67
patients were enrolled. The main result was a trend toward a lower
recurrence rate in the patients treated with unfractionated heparin.
There was no difference in the rate of “hemorrhagic worsening.”
Acknowledgments
The authors thank Daniele Cafini, MD, who is chief of the Legal
Medicine Service of The Ospedali Riuniti di Bergamo.
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