Low-Molecular-Weight Heparin for the Treatment of Acute Ischemic Stroke
Richard Kay, M.D., Ka Sing Wong, M.B., B.S., Yuk Ling Yu, M.D., Yuk Wah Chan, M.Med., Tak Hong Tsoi, M.B., B.S., Anil T. Ahuja, M.D., Fu Luk chan, M.B., B.S., Ka Yeung Fong, M.B., B.S., Chun Bong Law, M.B., Ch.B., Agatha Wong, R.N., and Jean Woo, M.D.
Background Despite doubts about their efficacy and concern abouttheir safety, antithrombotic agents are often used to treatacute ischemic stroke. Recent experience in patients with otherthromboembolic disorders suggests that low-molecular-weightheparin, which requires only subcutaneous administration onceor twice daily, may be more effective and safer than standard(unfractionated) heparin.
Methods We conducted a randomized, double-blind, placebo-controlledtrial comparing two dosages of low-molecular-weight heparinwith placebo in the treatment of ischemic stroke. Patients wererandomly assigned within 48 hours of the onset of symptoms toreceive high-dose nadroparin (4100 anti–factor Xa IU twicedaily), low-dose nadroparin (4100 IU once daily), or placebosubcutaneously for 10 days. The primary measure of outcome wasdeath or dependency regarding activities of daily living sixmonths after randomization. Secondary outcomes were death, hemorrhagictransformation of the infarction, and other complications at10 days, and death or dependency at 3 months.
Results A total of 2750 patients were screened for the study.Among 312 patients randomized, 306 had outcomes that were analyzedat six months. Forty-five patients (45 percent) in the high-dosegroup, 53 patients (52 percent) in the low-dose group, and 68patients (65 percent) in the placebo group died or became dependent.There was a significant dose-dependent effect among the threestudy groups in favor of low-molecular-weight heparin (P = 0.005by the chi-square test for trend). No significant differencesamong the groups in the occurrence of secondary outcomes wereobserved at 10 days.
Conclusions For patients with ischemic stroke treated within48 hours of the onset of symptoms, low-molecular-weight heparinwas effective in improving outcomes at six months.
Ischemic stroke accounts for approximately 85 percent of allstrokes in Europe and North America and for 70 percent of thosein the Far East.1 Established methods of preventing such strokesin patients at high risk include treatment with antiplateletagents, oral anticoagulants, or carotid endarterectomy.2 Foracute episodes, however, no specific treatment has been shownin randomized, controlled trials to improve functional statusor reduce mortality.3,4 Antithrombotic agents, particularlyheparin, have been a popular choice of many physicians for decades,but their benefit is unproved and their use remains controversial.5,6,7,8,9,10,11
Recent clinical studies in patients with venous thrombosis suggestthat low-molecular-weight heparin may be more effective thanstandard unfractionated heparin, with no increase in the riskof bleeding,12,13,14,15 as well as being more bioavailable andsimpler to administer.16 In an open pilot study reported previously,17we gave low-molecular-weight heparin subcutaneously to 55 patientswith acute ischemic stroke and found the treatment well tolerated.In this randomized, double-blind, placebo-controlled study,we sought to test the hypothesis that in the treatment of patientswith acute ischemic stroke, low-molecular-weight heparin issuperior to placebo in reducing death or dependency with regardto activities of daily living six months after a stroke.
Methods
Patients and Study Design
Patients admitted to the four hospitals participating in thestudy who had clinical diagnoses of acute stroke were screenedfor eligibility. They were included in the study if their symptomsof stroke had started during the previous 48 hours (countedfrom the time of awakening, if the symptoms had been noted onwaking from sleep) and if the patient or the patient's familymembers provided written informed consent. Patients were excludedfrom the study if any of the following were present: age over80 years; computed-tomographic (CT) evidence of intracranialhemorrhage; transient neurologic deficits; sustained hypertension,with systolic blood pressure above 180 mm Hg or diastolic bloodpressure above 120 mm Hg; major confounding neurologic or systemicillness (including a previous disabling stroke); a recent majoroperation or known tendency toward bleeding; current anticoagulanttherapy or valvular heart disease necessitating such therapy;and known hypersensitivity or any other adverse reaction toheparin. Patients with strokes of all degrees of severity wereenrolled, except those with no motor deficit and patients inwhom death was considered to be imminent.
Individual investigators at each hospital were responsible forthe recruitment, medical treatment, and follow-up assessmentof patients. Case-record forms were faxed to the study coordinatorfor immediate entry into a computerized data base (FileMakerPro, Claris, Santa clara, Calif.). All personnel involved inthe study remained unaware of the treatment assignments untilthe completion of follow-up for the last patient. No interimanalyses were undertaken. The study protocol was approved bythe ethics committees of the Chinese University of Hong Kongand the University of Hong Kong.
Treatment Schedule
Patients were randomly assigned to one of three treatments (high-doselow-molecular-weight heparin, low-dose low-molecular-weightheparin, or placebo) in blocks of six according to a computer-generatedrandomized schedule. These treatments were administered subcutaneouslytwice daily for 10 days by means of identical syringes filledwith 4100 anti–factor Xa IU of nadroparin calcium (Fraxiparine,Sanofi-Winthrop, Gentilly, France) in 0.4 ml of solution, orthe same volume of placebo. The syringes were contained in sequentiallynumbered boxes that were assigned to the patients consecutively.Patients in the high-dose group received the active drug every12 hours. Patients in the low-dose group received the activedrug in alternation with placebo every 12 hours (the first dosewas always the active drug). The patients in the placebo groupreceived injections of placebo every 12 hours.
Nonstudy medications, such as antihypertensive agents, steroids,and osmotic diuretics, were allowed, but the use of other antithromboticagents, including aspirin, was discouraged. At the end of the10-day treatment period, all the patients were given oral aspirin(100 mg daily) unless it was contraindicated.
Base-Line Assessment and Definitions of Infarct Subtypes
At the base-line assessment, the sex and age of each patientwere recorded and information was collected on the followingvariables: any history of hypertension, diabetes mellitus, anginaor myocardial infarction, stroke or transient ischemic attack,or smoking during the previous year; the patient's level ofconsciousness; the time of onset of symptoms; blood pressure;and other clinical data used to diagnose the subtype of theinfarct18 and whether it had a cardioembolic cause.19
The definitions of the subtypes of cerebral infarction wereadapted, with modifications, from Bamford et al.,18 with theprecondition that a motor deficit had to be present before apatient could be enrolled in the study. A total infarct of theanterior circulation was defined as an ischemic stroke involvinga combination of (1) higher cerebral dysfunction (dysphasiaor visuospatial disorder), (2) homonymous hemianopia, and (3)hemiparesis in at least two of three areas (the face, an arm,and a leg). If the level of consciousness was impaired and formaltesting of higher function or the visual field was impossible,a deficit was assumed to be present. A partial infarct of theanterior circulation was defined as an ischemic stroke involvingtwo of the three components of the total anterior-circulationinfarct or hemiparesis of the face, an arm, or a leg (only oneof the three areas). A lacunar infarct was defined as an ischemicstroke involving hemiparesis in at least two of these areas(the face, an arm, and a leg). Patients with impaired consciousnesswere considered not to have lacunar infarctions but rather tohave total or partial infarcts of the anterior circulation.An infarct of the posterior circulation was defined as an ischemicstroke involving hemiparesis or tetraparesis and brain-stemor cerebellar signs. The validity of this classification systemhas been studied by Anderson et al.,20 and its interobserverreliability has been evaluated by Lindley et al.21
Initial Study Assessment
The initial study assessment was made 10 days after randomization.The causes of any deaths during the first 10 days were documented.Any complication that led to early discontinuation of the studymedication or that was noted at the end of the treatment periodand any use of nonstudy medication during that period were recorded.
Initially, the study protocol did not require CT to be performeda second time at the end of the treatment period. After the49th patient, the protocol was modified to include CT at thispoint so that the risk of hemorrhagic transformation of theinfarct, defined as an area of bleeding within infarcted braintissue, could be measured objectively among patients whose symptomsmight not worsen. Both the first and second CT scans were readby a participating radiologist who was unaware of the treatmentassignment and the patient's degree of progress. At the conclusionof the trial, the CT films were reviewed by another blindedobserver. Disagreements were resolved by a panel comprisingthe second observer and two participating neurologists.
Assessment of Outcome
The primary, prespecified study outcome was "poor outcome,"defined as either death from any cause or dependency with respectto daily activities during the six months after randomization.The method of assessing dependency in the International StrokeTrial was employed.22 Briefly, patients or their care giverswere asked whether the patient had needed help in performingactivities of daily living in the previous two weeks and whetherthe patient considered that he or she had recovered completelyfrom the stroke. Patients were interviewed either in personor over the telephone and were considered to be dependent ifthey said they required help in performing activities of dailyliving and that they had not recovered completely from the stroke.Patients who said they did not need help with activities ofdaily living or considered themselves to have recovered fullywere not regarded as dependent. To validate this measure ofdependency in our cohort of patients, we compared it with theassessments obtained with the Barthel index23 three months afterrandomization.
Secondary study outcomes were death, hemorrhagic transformationof the infarct, and the occurrence of any other complicationwithin the 10 days of treatment, and poor outcome 3 months afterrandomization.
Statistical Analysis
Since the study design involved three groups of patients receivingdosages of active drug (0.8, 0.4, and 0 ml per day) that differedby the same amount, the chi-square test for trend with one degreeof freedom was used to test the significance of group differenceswith respect to the primary and secondary outcomes.24 To testthe association between treatment and outcome, we estimatedrisk ratios and 95 percent confidence intervals. To determinewhether other factors influenced outcomes, we performed a logistic-regressionanalysis that incorporated the base-line characteristics ofthe patients. All the tests were two-tailed, and computationswere made with SAS software (SAS Institute, Cary, N.C.). Toassess the validity of our measure of dependency, we calculatedits sensitivity and specificity 25 with respect to the assessmentsobtained with the Barthel index.
Results
Characteristics of the Patients
From October 1992 through July 1994, 2750 patients were screenedfor the study, 312 of whom (11 percent) were randomized. Allwere Chinese. Four patients were found to be ineligible forthe study before the randomization code was broken (three patientsin the high-dose group because of meningioma, parkinsonism,and hypoglycemia, and one in the low-dose group because of anasopharyngeal carcinoma); these patients were excluded fromall subsequent analyses.
The base-line characteristics of the 308 patients included inthe study were similar in the three groups, as shown in Table 1.
Table 1. Base-line Characteristics of the Study Patients According to Treatment Group.
Events during the 10 Days of Treatment
During the 10-day treatment period, 23 patients (7.5 percent)died, and 28 had complications leading to early discontinuationof the study medication. The causes of death and the types ofcomplications are listed in Table 2. There were no significantdifferences among the three groups in numbers of either deaths(P = 0.84) or complications (P = 0.14). Nonstudy medicationsadministered during this period that could affect the outcomeof stroke are also shown in Table 2.
Table 2. Deaths, Complications, and Use of Nonstudy Medications during the 10-Day Treatment Period, According to Treatment Group.
Except for the first 49 patients, for whom a second CT studywas not required, such a study was performed routinely at theend of the treatment period. Twelve patients died without asecond CT scan, and in three patients scanning was not donea second time because the patient refused to participate orwas discharged early from the hospital (Table 3). Among the245 patients who had second scans, 22 (9.0 percent) had evidenceof hemorrhagic transformation of their infarcts, which was asymptomaticin all but one patient (in the placebo group) and did not immediatelylead to death in any. There were no significant differencesamong the three groups in the proportion of patients who hadhemorrhagic transformation (P = 0.19).
Table 3. Incidence of Hemorrhagic Transformation of the Infarct as Detected on a Second CT Scan at 10 Days, According to Treatment Group.
Outcome at Three Months
By the end of three months after randomization, 42 patients(13.6 percent) had died. Two patients in the high-dose groupcould not be located. The causes of death and the functionalstatus of the remaining 264 patients are shown in Table 4. Therisk ratio for a poor outcome in the high-dose group as comparedwith the placebo group was 0.83 (95 percent confidence interval,0.66 to 1.05), corresponding to a reduction of 17 percent inthe relative risk (95 percent confidence interval, -5 percentto 34 percent). The risk ratio for a poor outcome in the low-dosegroup as compared with the placebo group was 0.95 (95 percentconfidence interval, 0.76 to 1.17). An observed trend favoringthe effect of low-molecular-weight heparin on the outcome atthree months was not statistically significant (P = 0.12).
Table 4. Mortality and Functional Status, According to Treatment Group.
Outcome at Six Months
By the end of six months after randomization, 50 patients (16.2percent) had died. One patient who could not be located at threemonths was found, but another patient in the high-dose groupwas lost to follow-up at six months. Of the 256 remaining patients,191 were seen in person, 63 were contacted by telephone, and2 were contacted by letter. The causes of death and the functionalstatus of these patients are shown in Table 4. Forty-five patients(45 percent) in the high-dose group, 53 patients (52 percent)in the low-dose group, and 68 patients (65 percent) in the placebogroup had poor outcomes. The risk ratio for a poor outcome inthe high-dose group as compared with the placebo group was 0.69(95 percent confidence interval, 0.54 to 0.90), correspondingto a reduction of 31 percent in the relative risk (95 percentconfidence interval, 10 percent to 46 percent). The risk ratiofor a poor outcome in the low-dose group as compared with theplacebo group was 0.81 (95 percent confidence interval, 0.64to 1.02). There was a significant favorable, dose-dependenteffect of low-molecular-weight heparin on the outcome at sixmonths (P = 0.005) (Figure 1). When the two patients lost tofollow-up were included and assumed to have had poor outcomes,the P value was 0.007.
Figure 1. Outcomes of Patients in Each Treatment Group Six Months after Randomization.
There was a significant, dose-dependent reduction in the risk of death or dependency at six months among the patients treated with low-molecular-weight heparin (chi-square for trend = 8.066; P = 0.005).
Between three and six months after randomization, the functionalstatus of 11 patients in the high-dose group, 9 in the low-dosegroup, and 6 in the placebo group improved, whereas in 2, 1,and 7 patients in the respective groups the outcomes worsened.The patient who could not be located at three months but wasfound at six months was alive but dependent. Of the 10 patientswhose conditions deteriorated, none had a change of medicationbetween three and six months: 8 were taking aspirin, 1 in thehigh-dose group was taking ticlopidine because of intoleranceto aspirin, and 1 in the placebo group received no antithromboticprophylaxis because of a hemorrhagic transformation of the infarction.Eight patients died between three and six months after randomization,all of whom had been considered dependent at three months; forthat reason, they did not contribute to the difference amongthe three groups in the percentage of poor outcomes at six months.
Effect of Patients' Characteristics
Logistic regression was used to determine which of the patients'characteristics listed in Table 1 were significant predictorsof the outcome at six months, to adjust the effect of treatmentfor any imbalance in prognostic factors, and to study the degreeto which the effect of treatment was modified by prognosticallyimportant factors. This process indicated that age (P<0.001),a history of diabetes mellitus (P = 0.005), the patient's levelof consciousness (P<0.001), and two of the four infarct subtypes(total infarct of the anterior circulation [P = 0.002] and lacunarinfarct [P = 0.01]) had a significant predictive influence.Including the effect of treatment in a model that containedthese factors decreased the P value for treatment to 0.003.Thus, the effect of treatment was slightly increased after adjustmentfor imbalances in prognostic factors created by randomization.In a subsequent analysis, product terms representing the interactionbetween each prognostic factor and treatment were consideredfor inclusion in the model. The P value for each interactionwas large, indicating that there was no real evidence that anyof these factors affected the size of the treatment effect.
The effects of treatment are shown according to infarct subtypein Table 5.
Table 5. Effect of Treatment at Six Months According to Subtype of Infarct.
Validation and Compliance
Validation of Functional Outcome
At three months, 263 of the 264 patients who were still alivewere available for validation of their functional status. Amongthe 116 patients who had scores of 16 or less on the Barthelindex, 109 were classified as dependent, whereas among the 147patients with scores of more than 16 on that index, 118 wereclassified as independent. Thus, our measure of dependency hada sensitivity of 94 percent and a specificity of 80 percentas compared with a score of 16 or less on the Barthel index,a level above which the majority of patients would be consideredindependent with respect to activities of daily living.26
Compliance
As Table 2 shows, 10 patients in the high-dose group, 7 in thelow-dose group, and 11 in the placebo group did not completethe full 10 days of treatment. At three months, 87 percent ofthe patients still alive were taking aspirin, and at six months81 percent of those still alive were doing so. Five patientswere taking other antithrombotic drugs at three months, andseven patients were doing so at six months. These patients wereequally distributed among the three groups. No patient underwentcarotid endarterectomy.
Discussion
Antithrombotic therapy is commonly prescribed without a clearjustification for patients with acute ischemic stroke. Thisclinical trial suggests that low-molecular-weight heparin mayhave benefits beyond the prevention of deep venous thrombosis.In a meta-analysis of randomized trials of antithrombotic therapyin patients with ischemic stroke (including four trials of lowmolecular-weightheparin or heparinoid in a total of 268 patients),27 a significantreduction in deep venous thrombosis was found, but no reductionin pulmonary embolism or mortality. There were no data on survivalfree of severe disability. In this study, in contrast to previoustrials, we primarily attempted to determine whether treatmentreduced mortality and lessened morbidity. We used modern methodsof study design, randomization, blinding, and outcome analysis.Telephone interviews, regarded as reliable means of assessingstroke outcomes,28,29 ensured that only two patients were lostto follow-up.
The results of this study are consistent with the hypothesisthat low-molecular-weight heparin is helpful in reducing therisk of death or dependency six months after a stroke. A trendfavoring an effect of low-molecular-weight heparin was foundat three months, but the trend was not statistically significantat that point. Between three and six months, more treated patientsthan patients given placebo had improvement, and fewer treatedpatients had a worsening of their condition. We speculate thatantithrombotic treatment may have reduced the volume of theinfarct by limiting the extension of thrombus to the ischemicpenumbra, which could exist for up to 48 hours after ischemicstroke,30 and by maintaining blood flow in that region. Treatedpatients would thus have more potential for survival and recovery.
In this study, base-line characteristics, including all thatwere prognostically important, were distributed evenly amongthe three groups. Because all the personnel involved were unawareof the study assignments, the ancillary care provided duringand after the treatment period was similar in the three groups.The secondary prophylaxis prescribed was equivalent in the threegroups, and subsequent compliance with therapy was balanced.Hence, the only explanation for the favorable responses we observedwas the effect of treatment — which, incidentally, becamemore significant when it was adjusted for imbalances in prognosticfactors created by randomization. However, the study samplewas too small to allow any meaningful analysis of the effectamong subgroups.
The dosage of low-molecular-weight heparin given to the high-dosegroup corresponded to the dose recommended to treat deep venousthrombosis. The treatment was safe; there was no significantdifference between the treated patients and those given placeboin rates of hemorrhagic transformation of the infarct or othercomplications. Further advantages of low-molecular-weight heparinas compared with conventional unfractionated heparin includethe opportunity to administer only one or two subcutaneous dosesdaily, a more predictable anticoagulant response to fixed doses,16and a lower incidence of heparin-induced thrombocytopenia.31Without the need for continuous infusion or laboratory monitoring,earlier mobilization of the patient and even home treatmentbecome possible.
We conclude that low-molecular-weight heparin, given as nadroparinat a dosage of 4100 anti–factor Xa IU twice daily for10 days, was superior to placebo in treating patients with acuteischemic stroke. Our data suggest that for every five patientsso treated, one death or case of dependency may be avoided.Further clinical trials are needed to determine the optimaldosage and duration of treatment and to see whether our resultscan be generalized to other populations.
Supported in part by a grant (MD90208) from the Chinese Universityof Hong Kong and by Sanofi Recherche, Gentilly, France.
We are indebted to Dr. H.P. Adams, Jr., Dr. P. d'Azemar, Dr.W.R. Clarke, Professor M. Gent, Dr. M. Hommel, Ms. G. Perez,Dr. L. Sagnard, Dr. P.A.G. Sandercock, and Dr. A.G.G. Turpiefor advice during the preparation of the manuscript.
Source Information
From the Departments of Medicine (R.K., K.S.W., A.W., J.W.) and Diagnostic Radiology and Organ Imaging (A.T.A.), Prince of Wales Hospital; the Departments of Medicine (Y.L.Y., K.Y.F.) and Diagnostic Radiology (F.L.C.), Queen Mary Hospital; the Department of Medicine and Geriatrics, Kwong Wah Hospital (Y.W.C., C.B.L.); and the Department of Medicine, Pamela Youde Nethersole Eastern Hospital (T.H.T.) — all in Hong Kong.
Address reprint requests to Dr. Kay at the Department of Medicine, Prince of Wales Hospital, Shatin, Hong Kong.
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