ORIGINAL. CONTRIBUTION
`
`Immediate Anticoagulation With Heparin for
`Immediate Anticoagulation With Heparin for
`First-Ever Ischemic Stroke in the Carotid Artery
`First-Ever Ischemic Stroke in the Carotid Artery
`Territories Observed Within 5 Hours of Onset
`Territories Observed Within 5 Hours of Onset
`Massimo Camerlingo, MD; Luciano Casto, MD; Bruno Censori, MD; Bruno Ferraro, MD;
`Massimo Camerlingo, MD; Luciano Casto, MD; Bruno Censori, MD; Bruno Ferraro, MD;
`GianCarlo C. Gazzaniga, MD; Bruno Cesana, MD; Angelo Mamoli, MD
`GianCarlo C. Gazzaniga, MD; Bruno Cesana, MD; Angelo Mamoli, MD
`
`Objective: To evaluate the safety and possible efficacy
`Objective: To evaluate the safety and possible efficacy
`of heparin sodium anticoagulation within 5 hours of the
`of heparin sodium anticoagulation within 5 hours of the
`onset of first-ever nonlacunar ischemic strokes in the in-
`onset of first-ever nonlacunar ischemic strokes in the in-
`ternal carotid artery territories.
`ternal carotid artery territories.
`
`Design: Pilot study, prospective and open.
`Design: Pilot study, prospective and open.
`
`Setting: Inpatient stroke unit.
`Setting: Inpatient stroke unit.
`
`Patients: Of 360 stroke patients observed during 13
`Patients: Of 360 stroke patients observed during 13
`months, 45 (12.5%) were included in the study.
`months, 45 (12.5%) were included in the study.
`
`Interventions: Heparin sodium was administered in-
`Interventions: Heparin sodium was administered in-
`travenously, starting with a bolus of 10 000 U, followed
`travenously, starting with a bolus of 10 000 U, followed
`by continuous infusion over 4 days at a rate adjusted to
`by continuous infusion over 4 days at a rate adjusted to
`maintain an activated partial thromboplastin time ratio
`maintain an activated partial thromboplastin time ratio
`between 2 and 2.5. The mean interval from stroke to treat-
`between 2 and 2.5. The mean interval from stroke to treat-
`ment was 197 minutes.
`ment was 197 minutes.
`
`Results: Two patients had cerebral hemorrhage, one of
`Results: Two patients had cerebral hemorrhage, one of
`
`which was fatal. None had extracranial major bleeding,
`which was fatal. None had extracranial major bleeding,
`while six had minor bleeding. The conditions of 23 pa-
`while six had minor bleeding. The conditions of 23 pa-
`tients improved, 16 patients were stable, and six patients
`tients improved, 16 patients were stable, and six patients
`worsened by day 1, while 29 patients improved, eight pa-
`worsened by day 1, while 29 patients improved, eight pa-
`tients were stable, and eight patients worsened by day 7.
`tients were stable, and eight patients worsened by day 7.
`Six patients died by the first month and five more by the
`Six patients died by the first month and five more by the
`sixth month. Twenty-one patients were self-sufficient, both
`sixth month. Twenty-one patients were self-sufficient, both
`at 1 and 6 months. Hemorrhagic complications were un-
`at 1 and 6 months. Hemorrhagic complications were un-
`related to any investigated factor. Multivariate analysis in-
`related to any investigated factor. Multivariate analysis in-
`dicated that short-term outcome was predicted only by in-
`dicated that short-term outcome was predicted only by in-
`farct size (P<.0001) and long-term outcome by infarct size
`farct size (P<.0001) and long-term outcome by infarct size
`(P=.002) and large vessel status (P=.0235).
`(P=.002) and large vessel status (P=.0235).
`
`Conclusions: Our study suggests that immediate hepa-
`Conclusions: Our study suggests that immediate hepa-
`rin treatment for ischemic carotid stroke is feasible and
`rin treatment for ischemic carotid stroke is feasible and
`generally safe and that patients whose conditions im-
`generally safe and that patients whose conditions im-
`prove are those with smaller infarct size and no evidence
`prove are those with smaller infarct size and no evidence
`of large vessel obstruction.
`of large vessel obstruction.
`
`(Arch Neurol. 1994;51:462-467)
`(Arch Neurol. 1994;51:462-467)
`
`H EPARIN SODIUM is
`HEPARIN SODIUM is
`
`widely used in the
`widely used in the
`treatment of brain
`treatment of brain
`ischemia1 despite in¬
`ischemia' despite in-
`conclusive available
`conclusive available
`data,2-3 which are derived from several
`data,2'3 which are derived from several
`uncontrolled studies4 8 and few random¬
`uncontrolled studies' and few random-
`ized studies.910 Those studies delayed
`ized studies.'''' Those studies delayed
`initiation of treatment from the onset of
`initiation of treatment from the onset of
`stroke, using heparin as a preventive
`stroke, using heparin as a preventive
`drug against early stroke recurrence or
`drug against early stroke recurrence or
`enlargement of thrombi. By contrast,
`enlargement of thrombi. By contrast,
`experimental data"·12 support the earli¬
`experimental data' I .' support the earli-
`est treatment possible to save ischemie
`est treatment possible to save ischemic
`but still viable brain tissue.
`but still viable brain tissue.
`Because cardiac embolism is a fre¬
`Because cardiac embolism is a fre-
`quent cause of the arterial occlusions
`quent cause of the arterial occlusions
`seen during the first few hours after
`seen during the first few hours after
`stroke,13 patients with early observed
`stroke,' patients with early observed
`stroke might benefit from anticoagula-
`stroke might benefit from anticoagula-
`
`ARCH NEUROUVOL 51, MAY 1994
`462
`
`tion therapy.14 Thus, we have prospec¬
`tion therapy.' Thus, we have prospec-
`tively evaluated the safety and possible
`tively evaluated the safety and possible
`effectiveness of heparin, which was ad¬
`effectiveness of heparin, which was ad-
`ministered within 6 hours of the onset
`ministered within 6 hours of the onset
`of a first-ever nonhemorrhagic stroke in
`of a first-ever nonhemorrhagic stroke in
`the internal carotid artery territories.
`the internal carotid artery territories.
`
`RESULTS
`RESULTS
`
`Of 360 consecutively screened patients,
`Of 360 consecutively screened patients,
`48 were treated within 6 hours of
`48 were treated within 6 hours of
`stroke, and 45 (12.5%) were included in
`stroke, and 45 (12.5%) were included in
`
`See Patients and Methods
`See Patients and Methods
`on next page
`on next page
`
`From the Second Neurological
`From the Second Neurological
`Department, Ospedali Riuniti
`Department, Ospedali Riuniti
`Bergamo (Drs Camerlingo,
`Bergamo (Drs Camerlingo,
`Casto, Censori, Ferraro,
`Casto, Censori, Ferraro,
`Gazzaniga, and Mamoli)
`Gazzaniga, and Mamoli)
`and Ospedale Maggiore
`and Ospedale Maggiore
`Epidemiologic Laboratory,
`Epidemiologic Laboratory,
`Istituto di Ricerca e Cura
`Istituto di Ricerca e Cura
`a Carattere Scientifico
`a Carattere Scientifico
`(Dr Cesana),
`(Dr Cesana),
`Milan, Italy.
`Milan, Italy.
`
`Downloaded From: http://archneur.jamanetwork.com/ by a West Virginia University Library User on 06/21/2015
`
`MYLAN - EXHIBIT 1035
`
`

`

`PATIENTS AND METHODS
`PATIENTS AND METHODS
`
`From February 1, 1991, to March 31,1992, all patients re¬
`From February 1, 1991, to March 31, 1992, all patients re-
`ferred to our stroke unit because of a first-ever, acute neu¬
`ferred to our stroke unit because of a first-ever, acute neu-
`rological deficit of presumed vascular origin, suggesting in¬
`rological deficit of presumed vascular origin, suggesting in-
`volvement of carotid artery territories referred within 5 hours
`volvement of carotid artery territories referred within 5 hours
`of onset. These patients were considered for immediate hepa¬
`of onset. These patients were considered for immediate hepa-
`rin anticoagulation therapy. Those patients underwent a
`rin anticoagulation therapy. Those patients underwent a
`computed tomographic (CT) scan immediately after hos¬
`computed tomographic (CT) scan immediately after hos-
`pital admission.
`pital admission.
`Table 1 summarizes our exclusion criteria. We ex¬
`Table 1 summarizes our exclusion criteria. We ex-
`cluded lacunar syndromes, defined according to Bamford
`cluded lacunar syndromes, defined according to Bamford
`et al,13 because of their peculiar, usually benign prognosis.
`et al,'5 because of their peculiar, usually benign prognosis.
`We also retrospectively excluded treated patients without
`We also retrospectively excluded treated patients without
`demonstration of a recent consistent infarction in the an¬
`demonstration of a recent consistent infarction in the an-
`terior circulation on the second CT scan because of am¬
`terior circulation on the second CT scan because of am-
`biguous location of the brain ischemia. Suitable patients
`biguous location of the brain ischemia. Suitable patients
`underwent a scored neurological examination using the Ca¬
`underwent a scored neurological examination using the Ca-
`nadian Neurological Scale16 and ultrasounds (both extra-
`nadian Neurological Scale and ultrasounds (both extra-
`cranial and transcranial). Patients with poor signal quality
`cranial and transcranial). Patients with poor signal quality
`at transcranial Doppler ultrasounds also were submitted to
`at transcranial Doppler ultrasounds also were submitted to
`cerebral angiography before treatment.
`cerebral angiography before treatment.
`After receiving informed consent from the patients,
`After receiving informed consent from the patients,
`they were treated intravenously with a 10 000-U bolus of
`they were treated intravenously with a 10 000-U bolus of
`heparin sodium, followed by continuous pump-assisted ad¬
`heparin sodium, followed by continuous pump-assisted ad-
`ministration at a rate adjusted to achieve an activated par¬
`ministration at a rate adjusted to achieve an activated par-
`tial thromboplastin time (aPTT) ratio between 2 and 2.5
`tial thromboplastin time (aPTT) ratio between 2 and 2.5
`times the control ratio. The aPTT, together with the pro-
`times the control ratio. The aPTT, together with the pro-
`thrombin time international normalized ratio and platelet
`thrombin time international normalized ratio and platelet
`count, were obtained at 4 hours after administration of the
`count, were obtained at 4 hours after administration of the
`bolus and then every day, up to day 7.5 Heparin therapy
`bolus and then every day, up to day 7.5 Heparin therapy
`
`was discontinued on the fifth day after stroke, and treat¬
`was discontinued on the fifth day after stroke, and treat-
`ment with oral aspirin (325 mg/d) was begun. Patients with
`ment with oral aspirin (325 mg/d) was begun. Patients with
`atrial fibrillation who were self-sufficient after the first month
`atrial fibrillation who were self-sufficient after the first month
`of stroke were then shifted to oral anticoagulation therapy.
`of stroke were then shifted to oral anticoagulation therapy.
`The CNS test was repeated on days 1 and 7, and a second
`The CNS test was repeated on days 1 and 7, and a second
`CT scan was performed by day 4. If hemorrhagic transfor¬
`CT scan was performed by day 4. If hemorrhagic transfor-
`mation of the brain ischemia was suspected, another CT
`mation of the brain ischemia was suspected, another CT
`scan was performed. An increase or decrease of at least 1
`scan was performed. An increase or decrease of at least 1
`point on the CNS test between day 1 and hospital admis¬
`point on the CNS test between day 1 and hospital admis-
`sion and day 7 and hospital admission was considered to
`sion and day 7 and hospital admission was considered to
`show clinical improvement or worsening. Modifications of
`show clinical improvement or worsening. Modifications of
`±0.5 points were considered to show no change. Func¬
`±0.5 points were considered to show no change. Func-
`tional outcome was rated at 1 and 6 months using the
`tional outcome was rated at 1 and 6 months using the
`Rankin17 score. Good outcome was self-sufficiency ( Rankin
`Rankin" score. Good outcome was self-sufficiency ( Rankin
`score, <3), a poor outcome was disability (Rankin score,
`score, <3), a poor outcome was disability (Rankin score,
`S3) or death. All adverse experiences possibly related to
`or death. All adverse experiences possibly related to
`heparin therapy and death were recorded.
`heparin therapy and death were recorded.
`Variables related to outcome at months 1 and 6 ( 2 test),
`Variables related to outcome at months 1 and 6 (x' test),
`death, and hemorrhagic complications (Fisher's Exact Test)
`death, and hemorrhagic complications (Fisher's Exact Test)
`were sought. The investigated variables included age (<70
`were sought. The investigated variables included age (<70
`vs S70 years), sex, history ofhypertension, side of the brain
`vs 70 years), sex, history of hypertension, side of the brain
`ischemia, timing ofstart ofheparin bolus (< 180 or a 180 min¬
`ischemia, timing of start of heparin bolus (<180 or 180 min-
`utes after stroke), CNS score atstudy entry and at day 1 (<6.5
`utes after stroke), CNS score at study entry and at day 1 (<6.5
`vs &6.5), electrocardiogram (normal, atrial fibrillation, or left
`vs 6.5), electrocardiogram (normal, atrial fibrillation, or left
`ventricular hypertrophy), arterial obstruction detected by ul¬
`ventricular hypertrophy), arterial obstruction detected by ul-
`trasound, size ofbrain infarction at CT scan (<3 vs &3 cm in
`cm in
`trasound, size of brain infarction at CT scan (<3 vs
`diameter), prothrombin time international normalized ratio
`diameter), prothrombin time international normalized ratio
`after bolus (< 1.25 vs a 1.25), aPTT ratio after bolus (<4 vs
`after bolus (<1.25 vs 1.25), aPTT ratio after bolus (<4 vs
`>4), and lowest platelet count (<150X 107L vs >150X 107
`and lowest platelet count (<150 X 109/L vs .150 X 109/
`L). The relative risk for significant variables was assigned by
`L). The relative risk for significant variables was assigned by
`an odds ratio test. Finally, the selected variables were entered
`an odds ratio test. Finally, the selected variables were entered
`into a multiple logistic regression analysis.
`into a multiple logistic regression analysis.
`
`Table 1. Exclusion Criteria
`Table 1. Exclusion Criteria
`
`Age <40 and >80 y
`Age <40 and >80 y
`Stupor or coma
`Stupor or coma
`Brain hemorrhage
`Brain hemorrhage
`Canadian Neurological Scale score >8
`Canadian Neurological Scale score >8
`Lacunar syndromes
`Lacunar syndromes
`Regression of signs before treatment
`Regression of signs before treatment
`Contraindications to anticoagulants
`Contraindications to anticoagulants
`Ongoing medication with anticoagulants
`Ongoing medication with anticoagulants
`Cancer or other life-threatening diseases
`Cancer or other life-threatening diseases
`Renal or hepatic failure
`Renal or hepatic failure
`Pregnancy
`Pregnancy
`Lack of informed consent from patients or relatives
`Lack of informed consent from patients or relatives
`Start of treatment with heparin beyond 6 h after stroke
`Start of treatment with heparin beyond 6 h after stroke
`Patients with undetermined or inconsistent lesions on initial
`Patients with undetermined or inconsistent lesions on initial
`computed tomographic scan
`computed tomographic scan
`
`the study. Reasons for exclusion are listed in Table 2.
`the study. Reasons for exclusion are listed in Table 2.
`The demographic characteristics and the risk factors of
`The demographic characteristics and the risk factors of
`the enrolled patients are summarized in Table 3.
`the enrolled patients are summarized in Table 3.
`
`Forty-five patients were included in the analysis. Their
`Forty-five patients were included in the analysis. Their
`mean score on the CNS was 5.0 (range, 1.5 to 8.0) at
`mean score on the CNS was 5.0 (range, 1.5 to 8.0) at
`hospital admission, 5.9 (range, 0.0 to 9.0) on day 1,
`hospital admission, 5.9 (range, 0.0 to 9.0) on day 1,
`and 6.4 (range, 0.0 to 10.0) on day 7. No direct or in¬
`and 6.4 (range, 0.0 to 10.0) on day 7. No direct or in-
`direct signs of acute ischemia18 on the baseline CT
`direct signs of acute ischemia" on the baseline CT
`scan were noted in 41 patients (91.1%).
`scan were noted in 41 patients (91.1%).
`All patients underwent extracranial and transcra¬
`All patients underwent extracranial and transcra-
`nial ultrasound examinations. Eight patients under¬
`nial ultrasound examinations. Eight patients under-
`went cerebral angiography on both carotid sides.
`went cerebral angiography on both carotid sides.
`Twenty-eight patients (62.2%) had obstructions of
`Twenty-eight patients (62.2%) had obstructions of
`symptomatic arterial vessels: seven with obstructions
`symptomatic arterial vessels: seven with obstructions
`of both extracranial internal carotid artery and middle
`of both extracranial internal carotid artery and middle
`cerebral artery stem, seven of internal carotid artery
`cerebral artery stem, seven of internal carotid artery
`alone, four of carotid siphon, 10 of middle cerebral ar¬
`alone, four of carotid siphon, 10 of middle cerebral ar-
`tery alone, and 17 with no detectable obstructions
`tery alone, and 17 with no detectable obstructions
`(but possibly obstructions of the middle cerebral ar¬
`(but possibly obstructions of the middle cerebral ar-
`tery branches, which are undetectable by ultra¬
`tery branches, which are undetectable by ultra-
`sounds19). All of the detected obstructions were occlu¬
`sounds'). All of the detected obstructions were occlu-
`sions, except two cases with tight stenosis of the
`sions, except two cases with tight stenosis of the
`extracranial internal carotid artery. All patients who
`extracranial internal carotid artery. All patients who
`underwent angiography had occlusion of the middle
`underwent angiography had occlusion of the middle
`
`ARCH NEUROUVOL 51, MAY 1994
`463
`
`Downloaded From: http://archneur.jamanetwork.com/ by a West Virginia University Library User on 06/21/2015
`
`

`

`Table 2. Primary Reasons for Exclusion on 360
`Table 2. Primary Reasons for Exclusion on 360
`Observed Strokes*
`Observed Strokes*
`
`Table 4. Clinical Results*
`Table 4. Clinical Results*
`
`Reasons
`Reasons
`Age
`Age
`Stupor-coma
`Stutior-coma
`Recurrence of stroke
`Recurrence of stroke
`Referral time >5 h
`Referral time >5 h
`Hemorrhages
`Hemorrhages
`Vertebro-basilar territory
`• Vertebro-basilar territory
`Regression of signs and CNS score >8
`Regression of signs and CNS score >8
`Lacunar syndromes
`tacunar syndromes
`Ongoing anticoagulants
`Ongoing anticoagulants
`Life-threatening disease or cancer
`Ufe-threatening disease or cancer
`Start of heparin >6 h after stroke
`Start of heparin >6 h after stroke
`No consistent lesion at CT scan
`No consistent lesion at CT scan
`.
`- Total
`Total
`
`No. (%)
`No. (%)
`33(10.5)
`33 (10.5)
`7 (2.2)
`7 (2.2)
`15 (4.7)
`15 (4.7)
`147(46.7)
`147 (46.7)
`28 (8.9)
`28 (8.9)
`25 (7.9)
`25 (7.9)
`7 (2.2)
`7 (22)
`13(4.1)
`13 (4.1)
`4(1.3)
`4 (1.3)
`(1.9)
`6 (1.9)
`27 (8.6)
`27 (8.6)
`3 (0.9)
`3 (0.9)
`315
`315
`
`*CNS indicates Canadian Neurological Scale; CT, computed
`*CNS indicates Canadian Neurological Scale; CT, computed
`tomographic.
`tomographic.
`
`Table 3. Patients' Characteristics (N=45)
`Table 3. Patients' Characteristics (N.45)*
`
`26
`26
`19
`19
`68 (45-80)t
`88(45-80)1
`18 (40)
`18 (40)
`10 (22.2)
`10 (22.2)
`7 (15.5)
`7 (15.5)
`5(11.1)
`5 (11.1)
`
`Sex
`Sex
`M
`M
`F
`Mean age, y (range)
`Mean age, y (range)
`Hypertension, No. (%)
`Hypertension, No. (%)
`Smoker, No. (%)
`Smoker, No. (%)
`Coronary heart disease, No. (%)
`Coronary heart disease, No. (%)
`Diabetes, No. (%)
`Diabetes, No. (%)
`Side of infarction
`Side of infarction
`L
`L
`R
`Mean CNS score at entry (range)
`Mean CNS score at entry (range)
`Atrial fibrillation at entry, No. (%)
`Atrial fibrillation at entry, No. (%)
`Normal CT scan at entry, No. (%)
`Normal CT scan at entry, No. (%)
`Symptomatic vessel obstructions, No. (%)
`Symptomatic vessel obstructions, No. (%)
`Mean time from stroke to heparin, min (range)
`Mean time from stroke to heparin, min (range)
`*CNS indicates Canadian Neurological Scale; CT, computed
`*CNS indicates Canadian Neurological Scale; CT, computed
`tomographic.
`tomographic.
`\There were 22 patients older than 70 years.
`1. There were 22 patients older than 70 years.
`XThere were 30 patients with a score lower than 6.5.
`There were 30 patients with a score lower than 6.5.
`§7ftere were 24 people who received heparin before 180 minutes from
`§There were 24 people who received heparin before 180 minutes from
`stroke.
`stroke.
`
`22
`22
`23
`23
`5.0 (1.5-8.0)
`5.0 (1.5-8.0)$
`16 (35.5)
`16 (35.5)
`41 (91.1)
`41 (91.1)
`28 (62.2)
`28 (62_2)
`197 (60-360)§
`197 (60-360)§
`
`Mean CNS score (range)
`Mean CNS score (range)
`Day 1
`Day 1
`Day 7
`Day 7
`Improved patients, No.
`Improved patients, No.
`Day 1
`Day 1
`Day 7
`Day 7
`Stable patients, No.
`Stable patients, No.
`Day1
`Day 1
`Day 7
`Clay 7
`Worsened patients, No.
`Worsened patients, No.
`Day 1
`Day 1
`Day 7
`Day 7
`Deaths, No.
`Deaths, No.
`Month 1
`Month 1
`Month 6
`Month 6
`Good outcome, No.
`Good outcome, No.
`Month 1
`Month 1
`Month 6
`Month 6
`Poor outcome, No.
`Poor outcome, No.
`Month 1
`Month 1
`Month 6
`Month 6
`CT scan, No.
`CT scan, No.
`Cerebral hematoma
`Cerebral hematoma
`Infarction
`infarction
`a3cm
`3cm
`<3cm
`<3cm
`Stroke recurrence
`Stroke recurrence
`.alter 2 RIO, No.
`after 2 mo, No.
`
`5.9 (0.0-9.0)1
`5.9 (0.0-9.0)1'
`6.4 (0.0-10.0)1;
`6.4 (0.0-10.0)#
`
`23
`23
`29
`29
`
`16
`16
`8
`8
`
`6
`6
`8
`8
`
`6
`6
`11
`11
`
`21
`21
`21
`21
`
`24
`24
`24
`24
`
`2
`2
`
`25
`25
`18
`18
`
`2
`2
`
`*CNS indicates Canadian Neurological Scale; CT, computed
`*CNS indicates Canadian Neurological Scale; CT, computed
`tomographic.
`tomographic.
`t There were 24 patients with a score lower than 6.5.
`T There were 24 patients with a score lower than 6.5
`XThere were 19 patients with a score lower than 6.5.
`$There were 19 patients with a score lower than 6.5
`
`Table 5. Causes of Death
`Table 5. Causes of Death
`
`Ceases of Death
`Causes of Death
`1st month
`1st month
`Cerebral hematoma
`Cerebral hematoma
`Stroke
`Stroke
`Pulmonary embolism
`Pulmonary embolism
`6th month
`6th month
`Pneumonia
`Pneumonia
`Cardiac death
`Cardiac death
`Pulmonary embolism
`Pulmonary embolism
`
`No. of Patients
`No. of Patients
`
`1
`4
`1
`
`2
`2
`1
`
`cerebral artery stem. Twenty-four patients (53.3%)
`cerebral artery stem. Twenty-four patients (53.3%)
`had an abnormal electrocardiogram (16 had atrial fi¬
`had an abnormal electrocardiogram (16 had atrial fi-
`brillation; eight had left ventricular hypertrophy). The
`brillation; eight had left ventricular hypertrophy). The
`heparin bolus increased the mean aPTT ratio from
`heparin bolus increased the mean aPTT ratio from
`0.91 (range, 0.77 to 1.05) to 3.46 (range, 0.98 to 7.0).
`0.91 (range, 0.77 to 1.05) to 3.46 (range, 0.98 to 7.0).
`The mean prothrombin time international normalized
`The mean prothrombin time international normalized
`ratio went from 1.01 (range, 0.85 to 1.34) to 1.40
`ratio went from 1.01 (range, 0.85 to 1.34) to 1.40
`(range, 1.05 to 2.27). Four patients had no response to
`(range, 1.05 to 2.27). Four patients had no response to
`the bolus dose. Platelet counts declined to less than
`the bolus dose. Platelet counts declined to less than
`100X107L only in two patients (97X107L and
`100X 109/L only in two patients (97X 109/L and
`
`89X109/L, respectively) by day 7. Neither patient had
`89X109/1.., respectively) by day 7. Neither patient had
`clinical evidence of adverse effects.
`clinical evidence of adverse effects.
`None of the patients died before day 4, when con¬
`None of the patients died before day 4, when con-
`trol CT scans were scheduled. Heparin was discontin¬
`trol CT scans were scheduled. Heparin was discontin-
`ued before the fifth day of stroke only in patients who
`ued before the fifth day of stroke only in patients who
`developed hemorrhagic complications. The conditions
`developed hemorrhagic complications. The conditions
`of 23 patients (51.1%) were improved, 16 (35.5%)
`of 23 patients (51.1%) were improved, 16 (35.5%)
`were stable, and six (13.3%) were worse by day 1. By
`were stable, and six (13.3%) were worse by day 1. By
`
`ARCH NEUROUVOL 51, MAY 1994
`464
`
`Downloaded From: http://archneur.jamanetwork.com/ by a West Virginia University Library User on 06/21/2015
`
`

`

`Table 6. Statistical Results (Univariate Analysis)
`Table 6. Statistical Results (Univariate Analysis)*
`
`Figure 1. Computed tomographic scan of patient 28 performed 24 hours
`Figure 1. Computed tomographic scan of patient 28 performed 24 hours
`after administration of heparin sodium bolus when the patient became
`after administration of heparin sodium bolus when the patient became
`comatose.
`comatose.
`
`Age
`Age
`Sex
`Sex
`Side of infarction
`Side of infarction
`Hypertension
`Hypertension
`AF on ECG
`AF on ECG
`LVH on ECG
`LVH on ECG
`Heparin start
`Heparin start
`CNS
`CNS
`At entry
`At entry
`At day 1
`At day 1
`Lesion size on CT
`Lesion size on CT
`Vessel obstruction
`Vessel obstruction
`PTINR
`PT INR
`aPTT ratio
`aPTT ratio
`Platelet count
`Platelet count
`
`Age
`Age
`Sex
`Sex
`Side of infarction
`Side of infarction
`Hypertension
`Hypertension
`AF on ECG
`AF on ECG
`LVH on ECG
`LVH on ECG
`Heparin start
`Heparin start
`CNS
`CNS
`At entry
`At entry
`At day 1
`At day 1
`Lesion size on CT
`Lesion size on CT
`Vessel obstruction
`Vessel obstruction
`PTINR
`PT INR
`aPTT ratio
`aPTT ratio
`Platelet count
`Platelet count
`
`r
`
`OR (95% CL)
`OR (95% CL)
`6th Month
`1st Month
`6th Month
`1st Month
`Predictors of Death
`Predictors of Death
`NS
`NS
`NS
`NS
`NS
`NS
`NS
`NS
`NS
`NS
`NS
`NS
`NS
`NS
`
`NS
`NS
`NS
`NS
`NS
`NS
`NS
`NS
`NS
`NS
`10.0(1.6,73.3)
`10.0 (1.6, 73.3)
`NS
`NS
`
`NS
`NS
`NS
`NS
`NS
`NS
`NS
`NS
`NS
`NS
`NS
`NS
`NS
`NS
`Predictors of Poor Outcome
`Predictors of Poor Outcome
`NS
`NS
`NS
`NS
`NS
`NS
`NS
`NS
`NS
`NS
`NS
`NS
`
`NS
`NS
`NS
`NS
`22.0 (2.3,152.9)
`22.0 (2.3, 152.9)
`10.3(1.1,90.9)
`10.3 (1.1, 90.9)
`NS
`NS
`NS
`NS
`NS
`NS
`
`NS
`NS
`NS
`NS
`NS
`NS
`NS
`NS
`NS
`NS
`NS
`NS
`
`NS
`NS
`8.0(1.2,21.5)
`8.0 (1.2, 21.5)
`3.8(1.0,17.1)
`3.8 (1.0, 17.1)
`35.7(5.1,178.5)
`35.7 (5.1, 178.5)
`4.3(1.0,19.7)
`4.3 (1.0, 19.7)
`NS
`NS
`NS
`NS
`NS
`NS
`
`NS
`NS
`5.2(1.2,26.9)
`5.2 (1.2, 26.9)
`5.0(1.2,22.2)
`5.0 (1.2, 22.2)
`12.5(2.5,70.3)
`12.5 (2.5, 70.3)
`8.1 (1.7,42.3)
`8.1 (1.7, 42.3)
`NS
`NS
`NS
`NS
`NS
`NS
`
`-
`
`J
`
`*OR indicates odds ratio; CL, confidence limits; AF, atrial fibrillation;
`*OR indicates odds ratio; CL, confidence limits; AF, atrial fibrillation;
`left ventricular hypertrophy; CNS, Canadian
`ECG, electrocardiogram; LVH,
`ECG, electrocardiogram; LVH, left ventricular hypertrophy; CNS, Canadian
`Neurological Scale; PTINR, prothrombin time international normalized
`Neurological Scale; PT INR, prothrombin time international normalized
`ratio; aPTT, activated partial thromboplastin time; CT, computed
`ratio; aPTT, activated partial thromboplastin time; CT, computed
`tomography; and NS, not significant.
`tomography; and NS, not significant.
`
`Table 7. Statistical Results (Logistic Regression Analysis*
`Table 7. Statistical Results (Logistic Regression Analysis*
`
`OR (95% CL)
`OR (95% CL)
` -'-
`6th Month
`1st Month
`6th Month
`1st Month
`
`NS
`NS
`NS
`NS
`35.7(6.1,207.5)
`35.7 (6.1, 207.5)
`NS
`NS
`
`NS
`NS
`NS
`NS
`9.6(2.1,44.3)
`9.6 (2.1, 44.3)
`5.8(1.2,27.8)
`5.8 (1.2, 27.8)
`
`CNS Score
`CNS Score
`At entry
`At entry
`At day 1
`At day 1
`Lesion size on CT
`Lesion size on CT
`Vessel obstruction
`Vessel obstruction
`
`*OR indicates odds ratio; CL, confidence limits; CNS, Canadian
`*OR indicates odds ratio; CL, confidence limits; CNS, Canadian
`Neurological Scale; CT, computed tomography; and NS, not significant.
`Neurological Scale; CT, computed tomography; and NS, not significant.
`
`month and another five (11.1%) within 6 months, for
`month and another five (11.1%) within 6 months, for
`a total of 11 deaths (24.4%). The timing and causes of
`a total of 11 deaths (24.4%). The timing and causes of
`death are outlined in Table 5.
`death are outlined in Table 5.
`
`Figure 2. Computed tomographic scan of patient 39 performed 48 hours
`Figure 2. Computed tomographic scan of patient 39 performed 48 hours
`after administration of heparin sodium bolus when the patient, after having
`after administration of heparin sodium bolus when the patient, after having
`a dramatic improvement of her right hemiparesis, became drowsy and
`a dramatic improvement of her right hemiparesis, became drowsy and
`hémiplégie.
`hemiplegic.
`
`day 7, the conditions of 29 patients (64.4%) were im¬
`day 7, the conditions of 29 patients (64.4%) were im-
`proved, eight (17.8%) were stable, and eight (17.8%)
`proved, eight (17.8%) were stable, and eight (17.8%)
`were worse. Two patients (4.4%) had homolateral re¬
`were worse. Two patients (4.4%) had homolateral re-
`currence of stroke between 2 and 3 months after the
`currence of stroke between 2 and 3 months after the
`qualifying stroke. At both 1 and 6 months, functional
`qualifying stroke. At both 1 and 6 months, functional
`outcomes were rated as good in 21 patients (46.7%)
`outcomes were rated as good in 21 patients (46.7%)
`(Table 4). Six patients (13.3%) died within the first
`(Table 4). Six patients (13.3%) died within the first
`
`ARCH NEHROLNOL 51, MAY 1994
`465
`
`Downloaded From: http://archneur.jamanetwork.com/ by a West Virginia University Library User on 06/21/2015
`
`

`

`Cerebral hematomas, which were associated with
`Cerebral hematomas, which were associated with
`clinical worsening, were observed in two patients
`clinical worsening, were observed in two patients
`(4.4%) (Figure 1 and Figure 2). One of them died
`(4.4%) (Figure 1 and Figure 2). One of them died
`by day 5. Extracranial bleeding occurred in six pa¬
`by day 5. Extracranial bleeding occurred in six pa-
`tients (13.3%): in four it was in the gastrointestinal
`tients (13.3%): in four it was in the gastrointestinal
`tract; in one, in the genitourinary tract; and in one it
`tract; in one, in the genitourinary tract; and in one it
`was subcutaneous. None of the hemorrhages was life-
`was subcutaneous. None of the hemorrhages was life-
`threatening or required blood transfusion. All hemor¬
`threatening or required blood transfusion. All hemor-
`rhages occurred within 48 hours of receiving the bolus
`rhages occurred within 48 hours of receiving the bolus
`dose.
`dose.
`Clinically silent hemorrhagic infarctions were de¬
`Clinically silent hemorrhagic infarctions were de-
`tected on the second CT scan in four patients (8.9%).
`tected on the second CT scan in four patients (8.9%).
`A CNS score of less than 6.5 at study entry (P=.0084)
`A CNS score of less than 6.5 at study entry (P=.0084)
`and at day 1 (P=.0503), obstruction of large vessels
`and at day 1 (P=.0503), obstruction of large vessels
`(P=.0498), and a brain lesion 3 cm in diameter or
`(P=.0498), and a brain lesion 3 cm in diameter or
`greater at initial CT scan (P<.0001) were associated
`greater at initial CT scan (P<.0001) were associated
`with poor outcomes at 1 month. A CNS score of less
`with poor outcomes at 1 month. A CNS score of less
`than 6.5 at study entry (P=.0194) and at day 1
`than 6.5 at study entry (P=.0194) and at day 1
`(P=.0024), obstruction of large vessels (P=.0049), and
`(P=.0024), obstruction of large vessels (P=.0049), and
`a brain lesion 3 cm in diameter or greater (P=.0005)
`a brain lesion 3 cm in diameter or greater (P=.0005)
`were also associated with poor outcomes at 6 months.
`were also associated with poor outcomes at 6 months.
`Mortality alone during the first month was unrelated
`Mortality alone during the first month was unrelated
`to any investigated variable, whereas death by the
`to any investigated variable, whereas death by the
`sixth month was related to left ventricular hypertro¬
`sixth month was related to left ventricular hypertro-
`phy on electrocardiogram (P=.009), CNS score of less
`phy on electrocardiogram (P..009), CNS score of less
`than 6.5 at day 1 (P=.0018), and arterial obstruction
`than 6.5 at day 1 (P=.0018), and arterial obstruction
`(P=.0349) (Table 6). Hemorrhagic complications
`(P=.0349) (Table 6). Hemorrhagic complications
`were unrelated to any coagulation parameters.
`were unrelated to any coagulation parameters.
`After multivariate analysis (Table 7), infarct size
`After multivariate analysis (Table 7), infarct size
`at initial CT scan was the only independent predictor
`at initial CT scan was the only independent predictor
`of both 1-month (P<.0001) and 6-month (P=.002)
`of both 1-month (PC.0001) and 6-month (P=.002)
`outcomes, and large vessel status was an independent
`outcomes, and large vessel status was an independent
`predictor of 6-month outcome (P=.0235). The number
`predictor of 6-month outcome (P=.0235). The number
`of deaths was insufficient to perform multivariate
`of deaths was insufficient to perform multivariate
`analysis for mortality alone.
`analysis for mortality alone.
`
`COMMENT
`
`Despite the findings of several studies,4"10 the risks-
`Despite the the findings of several studies,'" the risks-
`
`benefits of heparin anticoagulation therapy for
`benefits of heparin anticoagulation therapy for
`ischemie stroke remain to be ascertained. Our pro¬
`ischemic stroke remain to be ascertained. Our