(Stroke. 1999;30:2592.)
© 1999 American Heart Association, Inc.
Original Contributions |
A Randomized Efficacy Trial of Citicoline in Patients With Acute Ischemic Stroke
From Oregon Stroke Center, Oregon Health Sciences University, Portland, Ore (W.M.C.); Forsyth Memorial Hospital, Winston Salem, NC (B.J.W.); Scripps Memorial Hospital, La Jolla, Calif (K.A.S.); University of South Alabama, Mobile (L.A.S., R.E.G.); and Interneuron Pharmaceuticals, Inc, Lexington, Mass.
Correspondence to Dr Wayne M. Clark, Oregon Stroke Center UHS 44, Oregon Health Sciences University, 3181 SW Sam Jackson Park Rd, Portland, OR 97201. E-mail Clarkw{at}ohsu.edu
 |
Abstract |
|---|
 Top Abstract IntroductionSubjects and MethodsResultsDiscussionAppendixReferences |
|---|
Background and Purpose—Citicoline (cytidine-5'-diphosphocholine; CDP-choline) may reduce central nervous system ischemic injury by stabilizing cell membranes and reducing free radical generation. A previous dose-comparison trial in patients with acute stroke found that 500 mg of citicoline appeared to improve neurological outcome with minimal side effects.
Methods—The current trial was a 33-center, randomized,
double-blind, efficacy trial in 394 patients comparing placebo (n=127)
with citicoline (n=267) (500 mg po daily) for 6 weeks, with a 6-week
posttreatment follow-up period. Patients with acute (24 hours)
ischemic strokes clinically assessed to be in the middle
cerebral artery territory with National Institutes of Health Stroke
Scale (NIHSS) 
5 were enrolled.
Results—Mean time to treatment was 12 hours, and mean age was 71
for placebo and 70 for citicoline. Although mean baseline NIHSS were
similar for both groups, there was a higher percentage of placebo
patients with NIHSS <8 (34% vs 22%; P<0.01). The
incidence and type of side effects were similar between the groups. The
planned primary analysis (logistic regression: 5 categories
Barthel) failed the proportional odds assumption and was rendered
unreliable. There were no between-group differences seen on the planned
secondary assessment analyses at 90 days, including the Barthel
Index 95 at 12 weeks (last observation carried forward: placebo 40%;
citicoline 40%) or mortality rate (placebo 18%; citicoline 17%).
However, post hoc analyses in a subgroup of patients with
baseline NIHSS 8 found that citicoline-treated patients were more
likely to have a full recovery (Barthel 95): placebo 21%; citicoline
33%; P=0.05; whereas no difference was seen in patients
with baseline NIHSS<8 (placebo 77%; citicoline 69%;
P>0.1.
Conclusions—The results of this study indicate that citicoline was safe but ineffective in improving the outcome of patients with acute ischemic stroke who were enrolled in this trial. Post hoc analyses indicate that there may be a subgroup of patients with moderate to severe strokes who would benefit.
Key Words: citicoline • stroke • treatment
|
Introduction |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionAppendixReferences |
|---|
Citicoline (cytidine-5-diphosphocholine or CDP-choline) is an essential precursor for the synthesis of phosphatidylcholine, a key component of cell membranes. Although citicoline is a naturally occurring endogenous compound, the sodium salt of citicoline is synthesized for clinical use. During ischemia, phosphatidylcholine is broken down into free fatty acids, which in turn are used to generate free radicals that potentiate ischemic injury.1 The reversible synthetic pathway leading from choline to phosphatidylcholine is outlined in Figure 1A
. Cerebral ischemia and
hypoxia have been shown to reverse this synthetic pathway,
leading to decreased phosphatidylcholine content in the cell membrane
and increased concentrations of free fatty acids2 3 4 (see
Figure 1B). The exogenous administration of citicoline has been
shown in animal models to reduce this cell-membrane breakdown, leading
to increased synthesis of phosphatidylcholine and decreased levels of
free fatty acids5 6 (see Figure 1C).
|
The use of citicoline treatment has been shown to be beneficial in several animal models of ischemia or hypoxia,7 8 9 10 11 12 13 14 including recent studies with reversible focal occlusion15 and in an intracerebral hemorrhage model.16 These studies have found that citicoline treatment decreases free fatty acid concentration, improves neurological signs, decreases neurological deficits, restores animal learning performance, reduces glutamate-mediated injury, preserves phosphatidylcholine levels, and improves neuronal survival.
Citicoline has also been studied in several randomized clinical stroke treatment trials outside the United States,17 18 19 20 with initial time-to-treatment windows of 2 to 14 days. In these studies, doses of citicoline ranging between 250 to 1000 mg per day were found to improve global and neurological function at 90 days and promote earlier motor and cognitive recovery at 14 days. In a previous dose-finding, multicenter, randomized trial in the United States, the effectiveness of 3 doses of citicoline (500 mg, 1000 mg, 2000 mg) versus placebo was evaluated in 259 patients with an acute ischemic stroke ("001A" trial).21 This trial found that both 500 mg and 2000 mg citicoline produced a significant treatment effect compared with placebo when the baseline National Institute of Health Stroke Scale (NIHSS) 22 score was used as a covariate. Since the 500 mg group appeared to have less side effects, this dose was the one chosen for further efficacy evaluations.
The purpose of the current study ("007") was to evaluate the safety and effectiveness of 500 mg citicoline versus placebo in patients who are examined within 24 hours of an acute ischemic stroke.
|
Subjects and Methods |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionAppendixReferences |
|---|
This trial was a randomized, double-blind, placebo-controlled efficacy study of 500 mg of oral citicoline in patients with acute ischemic stroke. Patients for the trial were selected on the basis of eligibility criteria (see Table 1
) from 31 stroke centers in the
United States (See Appendix). The protocol used in this trial was
approved for use by the institutional review board of each
participating institution, and all patients or their legal
representatives signed an informed consent.
|
The primary objective of this study was to determine the effects on recovery of 500 mg of citicoline given orally over a 6-week treatment period and a 6-week follow-up period in patients with acute ischemic stroke. It was hypothesized that citicoline would improve functional, global, and neurological outcome measures when compared with the placebo group.
To be eligible for the study, the patient must have been examined within 24 hours with symptoms consistent with an ischemic stroke clinically assessed to be referable to the middle cerebral artery territory (angiographic confirmation not required). Patients were to have at least 5 points on the NIHSS with at least 2 of these points from the motor sections. For patients who awoke with their symptoms, it was determined that their onset time would start at the time that they awoke from sleep (not when they went to sleep). The rational for allowing patients who awoke with symptoms to be enrolled were that there were no safety concerns with delayed therapy and that prior citicoline trials have effectively used time windows of up to 2 weeks. A baseline CT and/or MRI scan must have been consistent with a diagnosis of stroke. That is, although it did not have to be positive for a stroke, it could not show another diagnosis as a cause for the symptoms, for example, intracerebral hemorrhage or tumor.
All patients who qualified according to the inclusion/exclusion
criteria and for whom informed consent was obtained from either the
patient or family were randomly assigned to 6 weeks of treatment with
either placebo or citicoline (500 mg) in a soft-gelatin capsule
(identical in appearance and consistency). Patients were to
be randomly assigned on a 2:1 basis to receive citicoline (267
patients) or placebo. (127) The patients were randomly assigned within
each center with the use of a blocked randomization. No one at the
local site was aware of the patient’s group assignment. The sample
size was calculated on the basis of the primary outcome measure
(Barthel Index) with 95 defined as a success using an 
of 0.05 and
a power of 80%. Predicted successful response rates based on the prior
dose finding citicoline trial21 were 49% for citicoline
and 33% for placebo. All patients were required to be inpatients at
the start of the study medication treatment but could be discharged at
any time with oral treatment continued through the remainder of the 6
weeks. Patients were seen by study personnel at baseline, 1 week,
hospital discharge, 3 weeks, 6 weeks, and 12 weeks, at which time a
side effect profile, drug accountability, and required efficacy
measures were completed.
The primary outcome measure of this study was functional outcome as
determined by the Barthel Index at 12 weeks.23 For the
primary analysis, it was a priori determined that the
Barthel Index would be classified into 5 strata (death or zero, 5 to
40, 45 to 60, 65 to 80, 85 to 100). Logistic regression
analysis was to be used to determine whether there were
significant differences between the 2 treatment groups in the
distribution of patients within these 5 strata. It was further
determined a priori that to decrease the impact of any baseline
differences in stroke severity, the baseline NIHSS score would be used
as a covariate in the primary analysis. Secondary prespecified
outcome measures included (1) assessments of categorized Barthel Index
at the other weeks, (2) percentage of patients who had a full recovery
(Barthel Index 95 or 100 at 12 weeks), (3) assessment of treatment
differences on the Modified Rankin scale,24 (4) assessment
of treatment differences on neurological, behavioral, and cognitive
function by use of the NIHSS and Mini-Mental State Examination, (5)
assessment of mortality, (6) assessment of treatment differences in the
percentage of patients who had a full recovery defined as an NIHSS
score of 
1, (7) assessment of number of days from stroke to hospital
discharge, (8) determination of the relative rate of improvement for
the Barthel Index, Rankin scale, and NIHSS between the groups.
Additional post hoc outcome analyses were performed on a
subgroup of patients with moderate to large strokes.
All analyses were done with the last observation carried forward (LOCF) for those patients who discontinue early. All analyses were based on the intention-to-treat (ITT) sample. A patient qualified for inclusion in the ITT sample if he/she entered the double-blind phase of the study and was evaluated at least once or died since receiving double-blind medication.25
Figure 2 shows the trial profile for the
study. All a priori treatment comparisons were declared
statistically significant if the p0.05. All of the
analyses presented used the Cochran-Mantel-Haenszel
procedure, with center as the stratification variable.
|
|
Results |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionAppendixReferences |
|---|
Three hundred ninety-four patients were enrolled in the study from June 30, 1996, to June 12, 1997. The randomization blinding was successful, with treatment unblinding occurring in only 1 patient. All analyses were based on the ITT population (see Figure 2
). Table 2 gives the baseline
characteristics for the 2 groups. There was no significant difference
noted in terms of patient age, sex, hemisphere involved by the stroke,
or time to treatment, stroke subtype, or preexisting medical condition.
Although the mean baseline NIHSS was similar between groups, there was
a significantly higher percentage of patients with mild strokes
(baseline NIHSS <8) in the placebo groups (34%) compared with
citicoline (22%) (P<0.01). This baseline imbalance may
have impacted the overall efficacy results in this trial.
|
The primary efficacy analysis was the Barthel Index score
classified into 5 strata analyzed by use of logistic regression
analysis, with the baseline NIHSS score used as a covariate.
The distribution of Barthel Index scores at 12 weeks is shown in Table 3. Unfortunately, the distribution of
patients failed the proportional odds assumption and the primary
planned analysis was rendered unreliable and was therefore not
completed. Table 4 shows results for some
of the planned secondary end points for the study. In the overall
population, no treatment benefit was seen on any of the planned
secondary end points, even when the baseline NIHSS was used as a
covariant. However, the study was only powered to detect
differences on the basis of the primary measure and not these secondary
outcome measures. To determine if citicoline may be beneficial for a
subgroup of patients, post hoc analyses were performed by
quartiles of the NIHSS scores. These post hoc analyses were not
prespecified and involved multiple comparisons. As such, they cannot be
corrected to provide definitive statistical significance but must
instead be viewed as hypothesis generating. In patients with mild
baseline strokes (NIHSS <8), no differences were seen between groups
with very high rates of spontaneous recovery occurring (Barthel 95:
placebo 77%; citicoline 69%; Rankin 1: placebo 53%; citicoline
57% and NIHSS 1: placebo 49%; citicoline 57%). These results
reinforce the importance of matching for the proportion of mild strokes
at baseline. For patients with moderate-to-severe strokes defined as
baseline NIHSS 8, treatment effects were seen on several of the full
recovery end points on post hoc analyses (see Table 5). The two 8 NIHSS groups were well
matched on baseline demographics. In the baseline NIHSS 8 groups,
with a global outcome statistic similar to the NINDS trial that
reflects NIHSS 1, Barthel 95, and Rankin 1, there appears to be
an overall benefit favoring citicoline treatment (odds ratio 1.9;
P=0.04). In an additional post hoc analysis, the
percentage of patients who had large improvements in their NIHSS scores
defined as a 7-point improvement at 12 weeks compared with baseline
was evaluated. A higher percentage (P=0.01) of
citicoline-treated patients had this improvement (42%) compared with
patients receiving placebo (30%).
|
|
|
Table 6 shows the effect of citicoline
treatment on mortality and serious adverse events. There were no
patient deaths reasonably attributed to the study medication in this
trial. There were no serious adverse events (SAEs) reasonably
attributed to the study medication and there were no between-group
differences in the incidence of any of the SAEs. The higher incidence
of central nervous system SAEs (11% vs 19%; P>0.1)
reflected a few patients in the citicoline groups having recurrent
strokes that were believed to be unrelated to the drug. In terms of
other side effects, citicoline appears to be remarkably well tolerated
with no adverse event being significantly more frequently seen in the
citicoline group compared with placebo. The increased incidence of
accidental falling and dizziness reported in the prior 001A
dose-finding study was not seen in the current study.
|
|
Discussion |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionAppendixReferences |
|---|
This study failed to find a benefit for citicoline on any of the planned efficacy end points in the overall study population. These results may have been confounded by a significant baseline imbalance in the baseline stroke severity between groups. This illustrates that despite proper randomization, important baseline imbalances can occur in studies when relatively small numbers of patients are used. The response rate (Barthel Index
95) in the control group overall was
also higher than predicted in our sample size calculations (33% vs
40%); this may have increased the chance of a type II error occurring.
We were also unable to perform the primary planned analysis in
this study, a logistic regression based on a categorized Barthel Index,
because of nonproportional distribution of patients. For this reason,
future citicoline trials will instead utilize a responder
analysis on the basis of the NIHSS. Overall citicoline was very
well tolerated, with no reported side effect being significantly higher
than in the placebo group.
A very high rate of spontaneous recovery regardless of treatment
was seen in mild patients with NIHSS <8, suggesting that it would be
very difficult to detect significant treatment effects in patients with
mild stroke (high likelihood of a type II error). In patients with
moderate-to-severe strokes defined by NIHSS 8, this study found
potential treatment effects with citicoline on several of the efficacy
end points measuring full recovery. Interestingly, the same <8 and 8
NIHSS cutoff has recently been found to be an important predictor of
early stroke recovery.26 In this study, the investigators
found that 45% of patients with initial NIHSS <8 were fully recovered
(NIHSS 0,1) at 48 hours compared with only 2% of those with baseline
NIHSS of 8. On the basis of the high spontaneous recovery
results seen in these 2 studies, it appears that patients with an
NIHSS of <8 probably should not be enrolled in clinical therapeutic
trials until more sensitive measures of outcome are developed.
The current study failed to confirm the results of the previous citicoline dose-finding US trial in the overall population studied.21 That study (001A), involving 259 patients, found that both 500 mg and 2000 mg but not 1000 mg of citicoline produced a significant treatment effect compared with placebo when baseline differences in the NIHSS score were used as a covariate. Because the 2000 mg and 500 mg groups appeared to have equal efficacy and because the 2000 mg group had a higher incidence of mild dizziness, it was decided to use the 500 mg group in the current study. However, after the importance of baseline differences in stroke severity was found in the current study, the previous 001A trial was reanalyzed. It was found that there was a significant imbalance in the 500 mg group; this time with the 500 mg treatment group having a higher percentage of mild strokes (47% vs 38%). In contrast, the stroke severity of the 2 groups was well matched for the 2000 mg group and placebo (35% vs 38%). It therefore appears that the 2000 mg dose may provide the greatest likelihood of therapeutic effect. For this reason, the 2000 mg dose has been chosen for use in a further confirmatory efficacy trial.
The safety and beneficial effects seen with citicoline in moderate-to-severe strokes in the current study are similar to those that have been seen in other randomized, non-US trials. Goyas et al17 studied the effect of intravenous citicoline (750 mg/d for approximately 10 days) within 48 hours of stroke onset in a double-blind, placebo-controlled trial. Citicoline patients showed a significant improvement on a quantified neurological assessment scale rating motor strength, muscular force, sensation, higher cortical function, and ambulation at 90 days. Patients treated with citicoline were significantly (P=0.02) more likely to be ambulatory compared with placebo-treated patients at 90 days (60% vs 24%). A weakness of this study is that it did not use currently accepted measures of neurological evaluation or functional outcome. A second double-blind, placebo-controlled trial evaluating intravenous citicoline (250 mg TID for 10 days) in patients treated within 48 hours of their symptoms was done by Boudouresques and Michel.18 Most of the patients were severely impaired at baseline. With the use of a 5-point recovery rating scale, this study found that a significantly higher percentage of patients had a very good to fairly good recovery with citicoline versus placebo treatment at 10 days after stroke (79% vs 44%). Both of these studies found significantly more fully recovered patients (52% and 48%, respectively) receiving citicoline as compared with placebo (24% and 9%, respectively). In a small double-blind, placebo-controlled study, Corso et al19 treated patients with acute stroke (48 hours) with either 1000 mg/d of intravenous citicoline or placebo for 30 days. In comparison to their baseline assessments, 76% of the citicoline-treated patients demonstrated improvement compared with only 31% of the placebo-treated patients (P<0.01). The largest multicenter, double-blind, placebo-controlled study investigating citicoline in ischemic stroke was completed by Tazaki et al20 in Japan. In this study, patients were treated within 14 days of onset of ischemic stroke symptoms with either 1000 mg/d of intravenous citicoline (n=133) for 14 days or placebo (n=139). A 6-category global improvement rating scale was used as a key end point. The study found that citicoline-treated patients had a significant improvement on day 14 in terms of the global improvement rating scale, with 52% of the citicoline treated patients showing a significant improvement compared with only 26% for those receiving placebo (P<0.01). A major weakness of this publication is that it did not describe in detail the long-term functional outcome results on these patients.
In the above trials, the incidence of side effects associated with citicoline treatment was low. In these placebo-controlled trials, only headache, vertigo, and dizziness were observed more frequently in the citicoline-treated patients compared with placebo (headache: 2.2% citicoline vs 0.3% placebo; vertigo: 1.2% citicoline vs 0.7% placebo; dizziness: 1.0% citicoline vs 0.2% placebo). A direct comparison of these trials with the current study is difficult because of differences in patient populations and efficacy end points. However, they appear to support the possible efficacy of citicoline in both functional and cognitive recovery after stroke.
It is interesting to compare the results and patient demographics of
this study with other recent randomized stroke treatment trials. The
baseline stroke severity in the current study (mean 13) is similar to
that seen in the National Institute of Neurologic Disorders under
3-hour rt-PA trial (mean 14).27 The rate of spontaneous
full recovery on the Barthel Index is also very similar, being 40% in
our trial and 39% in the NINDS trial placebo group. Our baseline
stroke severity was higher than that in the recently reported ECASS II
and ATLANTIS rt-PA trials, both of which had an NIHSS mean of
11.28 29 The high rate of spontaneous full recovery
(Barthel Index 53%) as the result of relative mild strokes has been
offered as an explanation for the failure of these two trials to find a
treatment benefit. Perhaps the most relevant comparison is that of the
recent intra-arterial Prourokinase trial (PROACT
II)30 to our >7 NIHSS subgroup. Both trials
targeted middle cerebral artery (MCA) strokes, although, unlike the
PROACT II trial, we did not confirm MCA occlusion. The baseline NIHSS
severity was similar in the two populations (PROACT II 17; 8 group 15
as was the low rate of full recovery in the placebo groups: PROACT II
32%; 8 group 21%). Direct comparisons of treatment benefits are
difficult, but both trials report an 
9% absolute potential increase
in the rate of full recovery.
In summary, this study suggests that citicoline can be safely used in acute stroke treatment with little or no side effects. Overall, there were no significant differences between citicoline and placebo on the planned efficacy analysis in the total patient cohort treated in this trial. However, citicoline may be beneficial in a subgroup of patients with moderate-to-severe strokes. A large efficacy trial trying to confirm this promising effect in patients with moderate-to severe stroke is currently in progress in North America.
|
Appendix |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionAppendixReferences |
|---|
US Citicoline Stroke Treatment Study IP302-007 Participating Centers
Oregon Health Sciences Center, Portland: Wayne M. Clark, MD, Helmi L. Lutsep, MD, Anne Doherty, RN; 53 patients. Thomas Jefferson University, Philadelphia, Pa: Rodney D. Bell, MD, Jamie Strauss, RN; 9 patients. University of Rochester Medical Center, Rochester, NY: Curtis Benesch, MD, Justine Zentner, MSN, NP; 9 patients. Central Baptist Hospital, Lexington, Ky: William Brooks, MD, Patty Howard, RN, Cyndi Baxter, RN; 15 patients. Fairfax Hospital, Falls Church, Va: David B. Grass, MD, Maureen Burke, RN; 5 patients. Wayne State University, Detroit, Mich: Seemant Chaturvedi, MD, Bryan D. Bertasio, RN; 8 patients. Cox Medical Center, Springfield, Mo: James E. Duff, MD, Tracy Vaughn, RN; 3 patients. Southwestern Vermont Medical Center, Bennington: Keith R. Edwards, MD, Cindy Lewis; 11 patients. Genesis Health Care System, Zanesville, Ohio: John Feerick, MD, Beverly Woodyard, RN; 17 patients. Duke University Medical Center, Durham, NC: Carmelo Graffagninio, MD, Cheryl Mc Clenny, RN; 6 patients. Evanston Hospital, Evanston, Ill: Daniel Homer, MD, Barbara Small, RN, MBA; 9 patients. Pennsylvania Hospital, Philadelphia: Dara G. Jamieson, MD, Concetta Gonnella, COA; 10 patients. University of Texas Medical Branch, Galveston: Thomas A. Kent, MD, William Dalmeida, MS; 8 patients. Daniel freeman Marina Hospital, Marina Del Rey, Calif: David Kudrow, MD, Anthony Duong, BS; 3 patients. Bowman Gray School of Medicine, Winston-Salem, NC: David Lefkowitz, MD, Jean Satterfield; 16 patients. USCD Stroke Center, San Diego, Calif: Patrick D. Lyden, MD, Karen Rapp, RN; 9 patients. Marshfield Clinc, Marshfield, Wis: Kenneth Madden, MD, PhD, Charmaine Matti; 7 patients. Danbury Hospital, Danbury, Conn: Samuel H. Markind, MD, Elizabeth W. Young, RN, John M. Young, RN; 19 patients. St. John’s Hospital, Springfield, Ill: Assa Mayerdorf, MD, Kathy Zeck, RN; 10 patients. St. Luke’s Hospital, Duluth, Minn: David McKee, MD, Julia leLand, RN; 11 patients. University of Texas Medical School at Houston: Lewiss B. Morgenstern, MD, Mary Ann Young, RN; 15 patients. University of Pennsylvania Medical Center, Philadelphia: Eric Raps, MD, Jeanne Dora, RN, MSN; 17 patients. Dartmouth-Hitchcock Medical Center, Lebanon, NH: Alexander G. Reeves, MD, Kathleen Ann Ryan, RN; 7 patients. Hinsdale Hospital, Hinsdale, Ill: Merrell D. Reiss, MD, Eileen Carter, MSN; 14 patients. Saint Luke’s Hospital of Kansas City, Mo: Marilyn M. Rymer, MD, Jolene Price, MSN, SNP; 3 patients. John Glancy Memorial Hospital, Duluth, Ga: Arthur D. Schiff, MD, Elizabeth Flax, RN; 5 patients. Scripps Memorial Hospital, La Jolla, Calif: Kenneth A. Selzer, MD, Jeanine Coffman, RN; 20 patients. St. Vincent’s Medical Center, Bridgeport, Conn: Kenneth C. Siegel, MD, M. Susan Law, RN; 13 patients. Forsyth Memorial Hospital, Winston-Salem, NC: Benjamin J. Williams, MD, William A. Brady, MD, Peggy H. Williams, CRC; 33 patients. University of South Alabama, Mobile: Richard M. Zweifler, MD, Renay Drinkard, RN, MSN; 20 patients. The Valley Hospital, Ridgewood, NJ: Kenneth A. Levin, MD, Joanne Blayman, RN; 10 patients.
|
Acknowledgments |
|---|
The authors would like to thank Valerie Roska for her expert assistance in the preparation of the manuscript.
Received August 13, 1999; revision received September 20, 1999; accepted September 20, 1999.
|
References |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionAppendixReferences |
|---|
1. Kennedy EP. The metabolism and function of complex liquids. Harvey Lect. 1963;57:143–171.
2. Bazan NG Jr. Effects of ischemia and electroconvulsive shock on free fatty acid pool in the brain. Biochim Biophys Acta. 1970;218:1–10.[Medline] [Order article via Infotrieve]
3.
Yatsu FM, Moss SA. Brain lipid changes following
hypoxia. Stroke. 1971;2:587–593.
4. Majeswska MD, Strosznajder J, Lazarewicz J. Effect of ischemic anoxia and barbiturate anesthesia on free radical oxidation of mitochondrial phospholipids. Brain Res. 1976;110:547–557.[Medline] [Order article via Infotrieve]
5. Trovarelli G, DeMedio GE, Dorman RV, Piccinin GL, Horrocks LA, Porcellati G. Effect of cytidine diphosphate choline (CDP-choline) on ischemia-induced alterations of brain lipid in the gerbil. Neurochem Res. 1981;6:821–833.[Medline] [Order article via Infotrieve]
6. Dorman RV, Dabrowiecki Z, DeMedio GE, Trovarelli G, Porcellati G, Horroks LA. Control of lipid metabolism in ischemic brain CDPamines. In: Horroks LA, Ansell GB, Porcellati G, eds. Phospholipids in the Nervous System. Vol I: Metabolism. New York: Raven Press Publishers; 1982:123–135.
7. Weiss GB. Metabolism and actions of CDP-choline as an endogenous compound and administered exogenously as citicoline. Life Sci. 1995;56:637–660.[Medline] [Order article via Infotrieve]
8.
Kakihana M, Fukuda N, Suno M, Nagaoka A. Effects of
CDP-choline on neurologic deficits and cerebral glucose
metabolism in a rat model of cerebral ischemia.
Stroke. 1988;19:217–222.
9. Dorman RV, Dabrowieki Z, Horrocks LA. Effects of CDP choline and CDP ethanolamine on the alterations in rat brain lipid metabolism induced by global ischemia. J Neurochem. 1983;40:276–279.[Medline] [Order article via Infotrieve]
10. Yamamoto M, Shimizu M, Okamiya H. Pharmacological actions of a new TRH analogue, YM-14673, in rats subjected to cerebral ischemia and anoxia. Eur J Pharmacol. 1990;181:207–214.[Medline] [Order article via Infotrieve]
11. Boismare F, Le Poncin Lefitte M, Rapin JR. Hemodynamic, functional, and biochemical effects of hypobaric hypoxia in rats treated with cytidine diphosphocholine. Presented at the Comptes rendus des seances de las Societe de Biologie. 1978;172:651.
12. Hamdorf G, Cervos-Navarro J. Study of the effects of oral administration of CDP-choline on open-field behaviour under conditions of chronic hypoxia. Arzneimittelforschung/Drug Res. 1990;40:519–522.
13. De Medio GE, Brunett M, Dorman RV, Droz B, Horrocks LA, Porcellati G. Phospholipid metabolism during central and peripheral damage and recovery in nervous tissue. Original article series. Birth Defects.. 1983;19:175–187.
14. Mykita S, Golly F, Dreyfus H, Freysz L, Massarelli R. Effect of CDP-choline on hypocampic neurons in culture. J Neurochem. 1986;47:223–231.[Medline] [Order article via Infotrieve]
15. Aronowski J, Strong R, Grotta JC. Citicoline for treatment of experimental focal ischemia: histologic ad behavioral outcome. Neurol Res. 1996;18:570–574.[Medline] [Order article via Infotrieve]
16.
Clark W, Gunion-Rinker L, Lessov N, Hazel K. Citicoline
treatment for experimental intracerebral
hemorrhage in mice. Stroke. 1998;29:2136–2140.
17. Goyas JY, Bastard J, Missoum A. Results after 90 days of stroke treatment with CDP-choline, concerning a double blind test. Presented at the International Symposium: Brain suffering and precursors of phospholipids; January 18, 1980; Paris.
18. Boudouresques AB, Michel B. Therapeutic conduct in light of a cerebral vascular accident and the use of CDP-choline. Presented at the International Symposium: Brain suffering and precursors of phospholipids; January 18, 1980; Paris.
19. Corso A, Arena M, Ventimiglia A, Bizzarro G, Campo G, Radalica F. CDP-choline for cerebrovascular disorders: clinical evaluation and evaluation of electrophysiological symptomology. Clin Ter. 1982;102:379–386.[Medline] [Order article via Infotrieve]
20.
Tazaki Y, Sakai F, Otomo E, Kutsuzawa T, Kameyama M,
Omae T, Fujishima T. Treatment of acute cerebral infarction with a
choline precursor in a multicenter double-blind placebo-controlled
study. Stroke. 1988;19:211–216.
21.
Clark W, Warach S, Pettigrew L, Gammans R, Sabounjian
L. A randomized dose response trial of citicoline in acute
ischemic stroke patients. Neurology. 1997;49:671–678.
22.
Brott T, Adams H, Olinger C. Measurements of acute
cerebral infarction: a clinical examination scale. Stroke. 1989;20:864–870.
23. Mahoney FI, Barthel DW. Functional evaluation: the Barthel index. MD State Med J. 1965;1461–65.
24.
van Swieten JC, Koudstaal PJ, Visser MC, Schouten HJA,
van Gijn J. Interobserver agreement for the assessment of handicap
in stroke patients. Stroke. 1988;19:604–607.
25. Friedman LM, Furberg CD, DeMets DL. Fundamentals of Clinical Trials. 2nd ed. Littleton, Mass: PSG Publishing; 1985.
26.
DeGraba T, Hallenbeck J, Pettigrew K, Dutka A, Kelly B.
Progression in acute stroke: value of the Initial NIH stroke scale
score on patient stratification in future trials. Stroke. 1999;30:1208–1212.
27.
The National Institute of Neurological Disorders, and
Stroke rt-PA Stroke Study Group. Tissue plasminogen
activator for acute ischemic stroke. N
Engl J Med. 1995;333:1581–1587.
28. Hacke W, Kaste M, Fieshchi C, von Kummer R, Davalos A, Meier D, Larrue V, Bluhmki E, Davis S, Donnon G, Schneider D, Diez-Tejedor E, Trouillas P (Second European-Australasian Acute Stroke Study Investigators). Randomized double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASSII). Lancet.. 1998;352:1245–1251.[Medline] [Order article via Infotrieve]
29. Clark W, Albers G. for the ATLANTIS Stroke Study Investigators. The ATLANTIS rt-PA acute stroke trial: final results. Stroke. 1999;30:234. Abstract.
30. Furlan A, Higashida R, Wechsler L, Schulz G. PROACT II: recombinant prourokinase in acute cerebral thromboembolism. Stroke.. 1999;30:234. (Results presented at the 24th International AHA Stroke Conference, February 1999).
31.
Adams H, Bendixen B, Kappelle J, Biller J, Love B,
Gordon D, Marsh E. Classification of subtype of acute ischemic
stroke. Stroke. 1993;24:35–41.
This article has been cited by other articles:
 |
|
 |
|
  The Optimising the Analysis of Stroke Trials (OAST Should Stroke Trials Adjust Functional Outcome for Baseline Prognostic Factors? Stroke, March 1, 2009; 40(3): 888 - 894. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. W. Neumar, J. P. Nolan, C. Adrie, M. Aibiki, R. A. Berg, B. W. Bottiger, C. Callaway, R. S.B. Clark, R. G. Geocadin, E. C. Jauch, et al. Post-Cardiac Arrest Syndrome: Epidemiology, Pathophysiology, Treatment, and Prognostication A Consensus Statement From the International Liaison Committee on Resuscitation (American Heart Association, Australian and New Zealand Council on Resuscitation, European Resuscitation Council, Heart and Stroke Foundation of Canada, InterAmerican Heart Foundation, Resuscitation Council of Asia, and the Resuscitation Council of Southern Africa); the American Heart Association Emergency Cardiovascular Care Committee; the Council on Cardiovascular Surgery and Anesthesia; the Council on Cardiopulmonary, Perioperative, and Critical Care; the Council on Clinical Cardiology; and the Stroke Council Circulation, December 2, 2008; 118(23): 2452 - 2483. [Full Text] [PDF]
|
|
|
|
|
|
M. Ali, P. M.W. Bath, J. Curram, S. M. Davis, H.-C. Diener, G. A. Donnan, M. Fisher, B. A. Gregson, J. Grotta, W. Hacke, et al. The Virtual International Stroke Trials Archive Stroke, June 1, 2007; 38(6): 1905 - 1910. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
The Optimising Analysis of Stroke Trials (OAST) Co Can We Improve the Statistical Analysis of Stroke Trials?: Statistical Reanalysis of Functional Outcomes in Stroke Trials * OAST Supplemental Appendix I: Statistical Tests Compared (see Table I) * OAST Supplemental Appendix II: Supplementary Analyses * OAST Supplemental Appendix III: Trial Data (see Tables II and III) * OAST Supplemental Appendix IV: Results (see Table IV) Stroke, June 1, 2007; 38(6): 1911 - 1915. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. P. Adams Jr, G. del Zoppo, M. J. Alberts, D. L. Bhatt, L. Brass, A. Furlan, R. L. Grubb, R. T. Higashida, E. C. Jauch, C. Kidwell, et al. Guidelines for the Early Management of Adults With Ischemic Stroke: A Guideline From the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: The American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists. Circulation, May 22, 2007; 115(20): e478 - e534. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. P. Adams Jr, G. del Zoppo, M. J. Alberts, D. L. Bhatt, L. Brass, A. Furlan, R. L. Grubb, R. T. Higashida, E. C. Jauch, C. Kidwell, et al. Guidelines for the Early Management of Adults With Ischemic Stroke: A Guideline From the American Heart Association/ American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: The American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists Stroke, May 1, 2007; 38(5): 1655 - 1711. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. S. Elkins, T. Khatabi, L. Fung, J. Rootenberg, and S. C. Johnston Recruiting Subjects for Acute Stroke Trials: A Meta-Analysis Stroke, January 1, 2006; 37(1): 123 - 128. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. B. Young, C. J. Weir, K. R. Lees, and for the GAIN International Trial Steering Committe Comparison of the National Institutes of Health Stroke Scale With Disability Outcome Measures in Acute Stroke Trials Stroke, October 1, 2005; 36(10): 2187 - 2192. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. S. Weaver, J. Leonardi-Bee, F. J. Bath-Hextall, and P. M.W. Bath Sample Size Calculations in Acute Stroke Trials: A Systematic Review of Their Reporting, Characteristics, and Relationship With Outcome Stroke, May 1, 2004; 35(5): 1216 - 1224. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. P. Adams Jr, R. J. Adams, T. Brott, G. J. del Zoppo, A. Furlan, L. B. Goldstein, R. L. Grubb, R. Higashida, C. Kidwell, T. G. Kwiatkowski, et al. Guidelines for the Early Management of Patients With Ischemic Stroke: A Scientific Statement From the Stroke Council of the American Stroke Association Stroke, April 1, 2003; 34(4): 1056 - 1083. [Full Text] [PDF]
|
|
|
|
|
|
D. L. Tirschwell, W.T. Longstreth Jr, K. J. Becker, R. E. Gammans Sr, L. A. Sabounjian, S. Hamilton, and L. B. Morgenstern Shortening the NIH Stroke Scale for Use in the Prehospital Setting Stroke, December 1, 2002; 33(12): 2801 - 2806. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Davalos, J. Castillo, J. Alvarez-Sabin, J. J. Secades, J. Mercadal, S. Lopez, E. Cobo, S. Warach, D. Sherman, W. M. Clark, et al. Oral Citicoline in Acute Ischemic Stroke: An Individual Patient Data Pooling Analysis of Clinical Trials Stroke, December 1, 2002; 33(12): 2850 - 2857. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. M. Clark, L. R. Wechsler, L. A. Sabounjian, and U. E. Schwiderski A phase III randomized efficacy trial of 2000 mg citicoline in acute ischemic stroke patients Neurology, November 13, 2001; 57(9): 1595 - 1602. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Recommendations for Clinical Trial Evaluation of Acute Stroke Therapies Stroke, July 1, 2001; 32(7): 1598 - 1606. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. L. Sacco, J. T. DeRosa, E. C. Haley Jr, B. Levin, P. Ordronneau, S. J. Phillips, T. Rundek, R. G. Snipes, J. L. P. Thompson, and for the GAIN Americas Investigators Glycine Antagonist in Neuroprotection for Patients With Acute Stroke: GAIN Americas: A Randomized Controlled Trial JAMA, April 4, 2001; 285(13): 1719 - 1728. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Uchino, D. Billheimer, and S. C. Cramer Entry Criteria and Baseline Characteristics Predict Outcome in Acute Stroke Trials Stroke, April 1, 2001; 32(4): 909 - 916. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Fisher and W. Schaebitz An Overview of Acute Stroke Therapy: Past, Present, and Future Arch Intern Med, November 27, 2000; 160(21): 3196 - 3206. [Full Text] [PDF]
|
|
|
|
|
|
J. P. Broderick, M. Lu, R. Kothari, S. R. Levine, P. D. Lyden, E. C. Haley, T. G. Brott, J. Grotta, B. C. Tilley, J. R. Marler, et al. Finding the Most Powerful Measures of the Effectiveness of Tissue Plasminogen Activator in the NINDS tPA Stroke Trial Stroke, October 1, 2000; 31(10): 2335 - 2341. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. M. Clark, E. C. Raps, D. C. Tong, and R. E. Kelly Cervene (Nalmefene) in Acute Ischemic Stroke : Final Results of a Phase III Efficacy Study Stroke, June 1, 2000; 31(6): 1234 - 1239. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||