Effect of oral nimodipine on cerebral infarction and outcome aftersubarachnoid haemorrhage: British aneurysm nimodipine trial

J D Pickard, G D Murray, R Illingworth, M D M Shaw, G M Teasdale, PM Foy, P R D Humphrey,D A Lang, R Nelson, P Richards, J Sinar, S Bailey, A Skene

Wessex NeurologicalCentre, SouthamptonGeneral Hospital,Southampton S09 4XYJ D Pickard, MCHIR,professor ofclinicalneurological sciencesR Nelson, FRCS, seniorregistrar in neurosurgeryS Bailey, RGN, MedicalResearch Council researchsister

Medical Statistics Unit,Department of Surgery,University of Glasgow,Glasgow GIl 6NTG D Murray, PHD, seniorlecturer in medical statistics

Regional NeurosciencesCentre, Charing CrossHospital, London W6 8RFR Illingworth, FRCS,consultant neurosurgeonP Richards, FRCS, consultantneurosurgeon

Mersey RegionalDepartment of Medical andSurgical Neurology,Walton Hospital, LiverpoolL9 1AEM D M Shaw, FRCS,consultant neurosurgeonP M Foy, FRCS, consultantneurosurgeonP R D Humphrey, MRCP,consultant neurologist

Institute of NeurologicalSciences, SouthernGeneral Hospital, GlasgowG514TFG M Teasdale, FRCS,professor ofneurosurgeryD A Lang, FRCS, registrar inneurosurgeryJ Sinar, FRCS, registrar inneurosurgery

Department ofMathematics, University ofNottingham, NottinghamNG7 IRDA Skene, PHD, senior lecturerin medical statistics

Correspondence to:Professor Pickard.

Br.rlcj7 19'9;298:636-42

AbstractObjective-To determine the efficacy of oral

nimodipine in reducing cerebral infarction andpoor outcomes (death and severe disability) aftersubarachnoid haemorrhage.Design-Double blind, placebo controlled,

randomised trial with three months of follow up andintention to treat analysis. To have an 80% chancewith a significance level of 0-05 of detecting a 50%reduction in an incidence of cerebral infarction of15% a minimum of 540 patients was required.Setting-Four regional neurosurgical units in the

United Kingdom.Patients-In all 554 patients were recruited

between June 1985 and September 1987 out ofa population of 1115 patients admitted with sub-arachnoid haemorrhage proved by the results oflumbar puncture or computed tomography, or both.The main exclusion criterion was admission tothe neurosurgical units more than 96 hours aftersubarachnoid haemorrhage. There were fourbreaks of code and no exclusions after entry. Onepatient was withdrawn and in 130 treatment wasdiscontinued early. All patients were followed up forthree months and were included in the analysis,except the patient who had been withdrawn.Interventions-Placebo or nimodipine 60 mg was

given orally every four hours for 21 days to 276 and278 patients, respectively. Treatment was startedwithin 96 hours after subarachnoid haemorrhage.End points -Incidence of cerebral infarction and

ischaemic neurological deficits and outcome threemonths after entry.Measurements-Demographic and clinical data,

including age, sex, history of hypertension andsubarachnoid haemorrhage, severity ofhaemorrhageaccording to an adaptation of the Glasgow comascale, number and site of aneurysms on angio-graphy, and initial findings on computed tomographywere measured at entry. Deterioration, defined asdevelopment of a focal sign or fall of more than onepoint on the Glasgow coma scale for more than sixhours, was investigated by using clinical criteria andby computed tomography, by lumbar puncture, orat necropsy when appropriate. All episodes ofdeterioration and all patients with a three monthoutcome other than a good recovery were assessedby a review committee.Main results-Demographic and clinical data at

entry were similar in the two groups. In patientsgiven nimodipine the incidence of cerebral infarctionwas 22% (61/278) compared with 33% (92/276) inthose given placebo, a significant reduction of 34%(95% confidence interval 13 to 50%). Poor outcomeswere also significantly reduced by 40% (95%confidence interval 20 to 55%) with nimodipine (20%(55/278) in patients given nimodipine v 33% (91/278)in those given placebo). Adverse reactions werereported in 14 patients given nimodipine and 10 givenplacebo.

Conclusions-Oral nimodipine 60 mg four hourlyis well tolerated and reduces cerebral infarction andimproves outcome after subarachnoid haemorrhage.

IntroductionDespite advances that have reduced considerably

the risks of operation to secure a ruptured cerebralaneurysm the overall mortality and morbidity duringthe management of patients with subarachnoidhaemorrhage who have survived and not beendevastated by the initial ictus has not fallen dramatic-ally. This is mainly because such patients rebleed andhave delayed cerebral ischaemia. The managementdilemma remains the need to weigh the risk ofprecipitating cerebral ischaemia by operation againstthat of rebleeding while awaiting surgery.

Subarachnoid haemorrhage provides the clearestclinical opportunity for pretreating ischaemia, but,although the calcium antagonist nimodipine has beenreported to reduce the incidence of delayed cerebralischaemia after subarachnoid haemorrhage,' 2definitive evidence is lacking. Previous trials weresmall and relied on selecting a subgroup of patientswith cerebral ischaemia presumed to be due to cerebralvasospasm. Ischaemia may be the result of severalfactors35 and cannot be attributed simply to anexaggerated contraction of cerebral arteries (vaso-spasm); thus defining such a subgroup is difficult andignores any potential benefit of treatment in othercauses of ischaemia.Nimodipine has various effects on the cerebral

circulation, not all of which may be beneficial.Cerebrovascular smooth muscle is more sensitivethan systemic arterial smooth muscle to changes inextracellular calcium concentration and to calciumantagonists such as nimodipine.6-8 In addition to beinga moderate cerebral vasodilator, however, nimodipineimpairs cerebrovascular reactivity.9-" Nimodipinedoes not reduce the incidence or severity of cerebralvasospasm detected by angiography in humans orprimates,'2-'7 but it reduces the size of cerebral infarctsin rats when given before but not after occlusion of acerebral artery. 8We therefore conducted a prospective trial to

establish the effect of nimodipine on the incidence ofboth ischaemic events and proved cerebral infarctionand on outcome after subarachnoid haemorrhage.

Patients and methodsSELECTION OF PATIENTS AND DIAGNOSIS

Eligible patients were admitted to one of four centres(in London, Southampton, Liverpool, and Glasgow)within 96 hours after the onset of symptoms and signsof subarachnoid haemorrhage. This time limit wasspecified because our hypothesis was that nimodipineshould be given soon after the bleed to have aprophylactic effect upon subsequent ischaemia. Thediagnosis was confirmed by lumbar puncture or

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computed tomography, or both-angiography was notrequired before admission to the trial. The reasonsfor exclusion were pregnancy; major renal, hepatic, orpulmonary disease; pre-existing cardiac decompensa-tion or a recent (within six months) myocardialinfarction; age below 18 years; a subarachnoidhaemorrhage that produced a coma in the weekpreceding the most recent subarachnoid haemorrhage;and the patient or relative being unwilling to giveconsent. Eligibility for the trial was checked inspecially designed record forms with a check list ofentry and exclusion criteria. A separate record waskept of patients who did not fulfil the entry criteria.Patients' eligibility was rechecked during outcomereview meetings of all the centres. There were noexclusions. Written informed consent was obtainedfrom the patient, care having been taken to avoidundue stress, or from a relative. The ethical committeeof each centre approved the study and the Departmentof Health and Social Security supplied a clinical trialexemption for the drug before the start of the study.

DESIGN OF STUDY

Our aim was to establish with a prospective,multicentre, randomised, double blind, placebocontrolled trial whether oral nimodipine (60 mg everyfour hours) reduced the incidence of episodes ofcerebral ischaemia and cerebral infarction arising anewafter spontaneous intracranial haemorrhage froma cerebral aneurysm. The outcome events to bespecifically examined prospectively were the inci-dences of cerebral infarction and ischaemic deficit andthe outcome three months after the bleed, with theprinciple distinction being between a moderate orgood recovery and a bad outcome (death or severedisability). Each of the centres had experience withsimilar large studies of dipyridamole,'9 antifibrinolytictreatment,20 or computed tomography2l in patientswith subarachnoid haemorrhage. From these resultswe expected that at least 15% of control patients wouldhave a poor outcome attributable to cerebral infarction.A minimum of 540 patients was required for the trial tohave an 80% chance with a significance level of 0 05 ofdetecting a 50% reduction in an incidence of cerebralinfarction of 15%.

RANDOMISATION

Patients were randomised to treatment or placebo byusing separate randomisation lists for each centrebalanced in blocks of four. Bayer UK supplied thepharmacy in each centre with bottles containingtablets of either nimodipine or placebo. Bottles werenumbered consecutively and assigned to eligiblepatients in that order. Each centre was supplied withcards that could break the code for each patientindividually and be used if the doctor in charge of thepatient decided that the code needed to be broken.

TREATMENT

Treatment was started within 96 hours after ictusand routinely continued for 21 days in survivors,unless there were clinical indications for stopping.Nimodipine (or matching placebo) was given as fastrelease tablets containing 30 mg active compound (twotablets given orally every four hours). The dose wasbased on the results of previous studies.' 1322 Tabletswere swallowed with water, or if the patient was unableto swallow the tablets were crushed and washed down anasogastric tube with normal saline. The protocolallowed for adjustment of the dose if hypotensionoccurred, but this was not found to be necessary.Compliance was checked while the patient was in theneurosurgical unit by comparing the number of tabletsprescribed with the number taken. Any patient whomissed more than one third of the daily dose on any day

was deemed to be non-compliant. The protocolallowed for separate analysis of this group, but this wasfound not to be necessary. Plasma samples were takenfrom 35 patients (eight taking placebo, 27 nimodipine)and nimodipine concentrations measured-there wasno evidence of patients given placebo receiving activetreatment, or vice versa.

CLINICAL MONITORING

The severity of subarachnoid haemorrhage wasgraded according to an adaptation of the Glasgow comascale,' which is similar to the scale recently adopted bythe World Federation of Neurosurgical Societies.24Patients whose clinical grade was I had a score on theGlasgow coma scale of 15 and were neurologicallyintact, apart from having cranial nerve palsy. Those ingrade II had a score of 15 and were neurologicallyintact, apart from having cranial nerve palsy, with neckstiffness or headache, or both. Those in grade III had ascore of 13-14 and were with or without neurologicaldeficit and those in grade IV a score of 8-12 with orwithout neurological deficit. Finally, those in grade Vhad a score of 3-7 and were in a coma with or withoutabnormal posturing.Computed tomography was performed within

24 hours after admission to the trial and repeatedwhenever necessary if the patient's clinical conditiondeteriorated at all. Angiography, operation, and otheraspects of management remained the responsibility ofthe consultant in charge of the patient. The causeof subarachnoid haemorrhage was determined byangiography or at necropsy or, in two cases, from thetypical.appearance of a giant aneurysm on a computedtomogram.

Patients were monitored clinically throughout theirtime in hospital: blood pressure, pulse rate, andneurological observations were recorded. Particularattention was paid to the patient's degree of conscious-ness, focal neurological features, and symptoms andsigns suggestive of rebleeding, ischaemia, or anotheradverse event.The minimum criterion to define deterioration was

either development of a focal sign or a decline by morethan one point on the Glasgow coma scale for morethan six hours. The aetiology of deterioration wasinvestigated by using clinical criteria with results fromcomputed tomography whenever possible; whenappropriate it was investigated by lumbar puncture orat necropsy. All episodes of deterioration and allpatients whose outcome at three months was not a goodrecovery were assessed at regular meetings of a reviewcommittee comprising representatives from each of thefour centres. The review committee assessed outcomeblind to allocated treatment. Causes of deteriorationwere classified as rebleed, cerebral ischaemia orinfarction, or other, when the specific complicationwas recorded. The diagnosis of rebleeding or ofischaemia or infarction was classified as definitive orprobable according to whether confirmatory evidencewas available from computed tomography, from anoperation, or at necropsy.A patient with two infarcts was counted once for the

statistical analysis of cerebral infarction. If a patienthad both a rebleed and an infarct he (she) appeared inboth analyses. Deterioration in a patient known to havean intracerebral haematoma was deemed to be due toischaemia if as the new signs developed there was agrowing area of low density surrounding a clot thathad not itself increased on computed tomography.Outcome was assessed at least three months after entryto the trial according to the five point Glasgow outcomescale2' by a doctor who was not responsible for thepatient's early management or by postal or telephoneinquiry when a patient had moved out of the region. Inpatients who were dead or disabled at three months we

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assessed whether the cause was a direct effect ofthe initial bleed, cerebral ischaemia or infarction,rebleeding, hydrocephalus, intracranial haematoma,operative complication, another complication oftreatment, or other. In five cases there was suddendeath with no clinical evidence or evidence fromcomputed tomography, from lumbar puncture, or atnecropsy of the cause; these were classified as suddendeath of unknown cause.

STATISTICAL ANALYSIS

The two treatment groups were compared for ratesof infarction (primary outcome event), poor outcome(secondary outcome event), and rebleeding by usingx2 tests. These analyses were supported by a detailedanalysis that used stepwise logistic regression toadjust the comparisons for the effects of any chanceimbalance in the prognostic factors identified from anearlier study20 with the addition of data from computedtomography. Interaction terms between the prognosticfactors and treatment were included in the models totest whether any treatment effects were confined toparticular subgroups of patients. The prognosticfactors considered in this analysis were age; sex; loss ofconsciousness at ictus; time from haemorrhage toentry; score on the Glasgow coma scale on entry; limbweakness, neck stiffness, and headache (all on en'try);hypertension (defined by a history of hypertension,receiving hypertensive treatment on entry, or adiastolic blood pressure greater than 100 mmHg onentry); angiographic findings (positive, negative, ornot done); and computed tomographic findings(normal, abnormal, or not done).

All clinical data generated during the study wererecorded in the patients' record forms by us- theblue National Cash Register copy was sent monthly toBayer UK (Dr L Porto) to comply with Department of

TABLE I-Demographic data on and indices of severity of initial subarachnoid haemorrhage in patientstreated with nimodipine or placebo. Values are numbers ofpatients unless stated otherwise

Mean (SD) age (years)MenWomenAlcohol abuseDiabetes mellitusChronic airways diseasePeripheral vascular diseaseSmoker (> 10 cigarettes/day)Other cardiovascular diseaseOther diseasesHypertension:

HistoryBeing treated at entryPresent at entryAny feature

Abnormal electrocardiogram on admissionPrevious subarachnoid haemorrhageLoss of consciousness at ictusClinical grade:

IVIIIIVV

Initial computed tomographyTime from ictus to scan (days)Normal resultsCisternal blood (>2 mm thick)Intracerebral haematomaIntraventricular bloodHydrocephalus

AngiographyTime from ictus to angiography (days)Aneurysm:

ProvedMultipleCarotidAnterior cerebralMiddle cerebralPosterior circulation

Spasm presentOperations:No

Time from ictus to operation (days) range)

Patients taking nimodipine(n= 278)

46 (13)1141641245

1202

28

332040712837126

816876197

2731 5

35177588334

2435 5

187406881542054

16510-8 (2-60)

Patients taking placebo(n= 276)

48(12)107169

372

1431133

231635523343

I 545168618336

Health and Social Security (clinical trial exemption)regulations, the pink copy to GDM, and the whitecopies were kept in each centre. GDM and AS (forBayer UK) analysed the data independently.

ResultsBetween June 1985 and September 1987, 554

patients were recruited into the trial out of a totalpopulation of 1115 patients admitted to the fourcentres with a diagnosis of subarachnoid haemorrhage:151 in Southampton, 101 in London, 199 in Glasgow,and 103 in Liverpool. A total of 108 patients did notfulfil the entry criteria for the trial in Southampton,207 did not in Liverpool, 214 in Glasgow, and 32 inLondon. The most- common reason for not fulfillingthe entry criteria was a delay of more than 96 hoursbetween bleeding and admission (317 patients). All buttwo patients were entered within the time limit of96 hours; these two patients remained in the analysis asthey had violated the criterion by less than 24 hours.The mean time from ictus to entry was 1 9 days.One patient withdrew his verbal consent after

randomisation (placebo group) but before he hadsigned the consent form or received any treatment. Hiscase was fully documented and followed up to threemonths (he made a good recovery) but was notincluded in the statistical analysis. There were fourbreaks of code in two centres: sudden hypotensionwith induction of anaesthesia (placebo), jaundice ofunexplained cause (placebo), sudden intraoperativehypotension (placebo), and jaundice shown atnecropsy to have been due to rupture of an aorticaneurysm (nimodipine). Treatment was discontinuedwithin 21 days in 130 patients (70 given nimodipine,60 placebo), the main reason being a negative result onangiography with no evidence ofan imbalance betweentreatments (87 patients).The cases of 272 patients were reviewed by the

committee. No patients were lost to follow up. Allpatients recorded as survivors were known to be alive90 days after entry.

DEMOGRAPHIC AND CLINICAL DATA

The demographic data and various indices ofseverity of subarachnoid haemorrhage (table I) showthe overall comparability of the treatment groups. Thegroup given nimodipine had a higher prevalenceof hypertension, neck stiffness, and non-reactingpupils, factors generally considered prognostic ofpoor outcome. The group given placebo, however,contained more patients with a history of cardio-vascular disease and a higher number of smokers.

129 INTERCENTRE VARIABILITY

12 The overall comparability of the two groups was159 maintained within centres but there were differences72 among the four centres, reflecting different patterns of258 referral, systemic disease, and resources.

276 In London older patients (mean age 50) were enteredearlier (mean 1 4 days, with fewer admissions toolate for entry (14% (19/133)). The patients wereslightly more hypertensive, with a longer duration ofunconsciousness at ictus (in 11% (11/101) it was over

229 24 hours), a lower clinical grade (55% (55/101) had a5-1

good grade), and less neck stiffness (7% (7/101));181 angiography and operations were performed much29 later (mean of 11 and 19 days, respectively).83 In Southampton patients were entered latest15 (2 3 days) and there was a higher prevalence of46 previous subarachnoid haemorrhage (23% (35/151))154 and loss of consciousness at ictus (54% (82/151)) and113 (2-116) less headache (25% (35/142)). Computed tomography

yielded more normal results (25% (37/147)), with

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fewer proved aneurysms (56% (84/151)). Computedtomography in the patients treated with nimodipineyielded fewer normal results (17% (12/72)) than inthose given placebo (33% (25/75)).

In Liverpool the greatest number of patientswere admitted too late for entry (39% (122/310)), theprevalence of loss of consciousness at ictus was lowest(30% (31/103)), lumbar puncture studies were used themost for diagnosis (91% (94/103); range 46-55% in theother centres), and patients had the best overall grade.

In Glasgow the prevalence ofaneurysms was greatest(77% (154/199)), including multiple aneurysms (27%(40/150 angiograms)), and the prevalence of reportedalcohol abuse was lowest (2% (3/199)).

Overall, the earlier computed tomography wasperformed the greater the incidence of significantcisternal blood and hydrocephalus. The incidence ofproved aneurysms was lowest in Southampton andLondon (56 and 60%, respectively).

INFARCTS

Nimodipine reduced significantly the number ofprimary outcome events- that is, the number of allcerebral infarcts-by 34% (table II). The number ofdefinite infarcts was reduced by 37% (61 in placebogroup, 39 in nimodipine; X2 =6-10, df=1; p=0 014).There was no evidence that the time from ictus or entryto first infarct was affected by treatment (ictus toinfarct: nimodipine 9-0 days, range 1-38; placebo8 4 days, range 1-40). Late infarcts seemed to beassociated with later operations, although the numberswere small. The effect of nimodipine was seen bothbefore and after operation and in patients considered tobe too ill for angiography or surgery.The following factors were individually (rather than

independently) associated with the rate of infarction:sex (marginal), loss of consciousness, angiographicfindings, centre (marginal), hypertension, findings oncomputed tomography, and treatment. Adjustingsimultaneously for findings on angiography andcomputed tomography and hypertension removed theeffects of sex, loss of consciousness, and centre, buttreatment remained highly significant (p<0001).There was no evidence of any interactions betweenprognostic factors and treatment.

In summary, there was clear evidence of a reducedincidence of infarction in patients given nimodipine.The difference could not be explained by an imbalancein prognostic factors (indeed, adjusting for theprognostic factors if anything pointed to an enhancedbenefit), and there was no evidence that the benefit oftreatment was confined to a particular subgroup of thepatients.

OUTCOME

Nimodipine reduced significantly the secondaryoutcome event-namely, the incidence of pooroutcome (dead, vegetative state, and severe disability)-from 33% (91 patients) to 20% (55)-that is, by 40%(table II). Given the distribution of outcomes with thefive category Glasgow outcome scale, there wasclear evidence (significant at the 1% level) that thedistribution of outcome changed with treatment:nimodipine shifted the pattern of outcomes towards

TABLE II-Effect of nimodipine on incidence of cerebral infarction and outcome after subarachnoidhaemnorrhage. Values are numbers (percentages) ofpatients unless stated otherwise

Patients taking Patients taking Relative 95%nimodipine placebo reduction Confidence Significance(n=278) (n=276) (%) interval (p value)

Cerebral infarct 61 (22) 92 (33) 34 13 to 50 0-003 (, 899; df= 1)Poor outcome 55 (20) 91 (33) 40 20 to 55 <0 001 (y = 12-41; df= 1)Rebleed 25 (9) 38(14) 35 -5to59 0077(7 3 13;df=1)

the good recovery end of the scale compared withplacebo. One hundred and three patients died within90 days after starting treatment, 43 in the group givennimodipine and 60 in that given placebo (table III).

TABLE iII-Effect of nimodipine on score on Glasgow outcome scalethree months after subarachnoid haemorrhage. Values are numbers ofpatients

Patients taking nimodipine Patients taking placeboOutcome (n=278) (n=276)

Death 43 60Vegetative state 1 2Disability:

Severe 11 29Moderate 24 16

Good recovery 199 169

Mortality in the two groups was not significantlydifferent at the 5% level but had an observed sig-nificance level of 6% (relative reduction 29% (95%confidence interval -i to 50); X2=3 60, df= 1).The principal reason for the improvement in

outcome was a reduction in the number of deathsand patients with disability considered to be due toepisodes of delayed ischaemia. Other causes of death ordisability (initial bleed, rebleeding, intracranialhaematoma, operative complication, hydrocephalus,complications of treatment, other causes, andunknown) were similar in the two groups. In particular,recovery in patients who had sustained a severe initialbleed did not seem to be influenced (table IV).

TABLE iv-Causes of disability and death in patients takingnimodipine or placebo. Values are numbers (percentages) ofpatients*

Disability Death

Patients Patients Patients Patientstaking taking taking taking

nimodipine placebo nimodipine placeboCause (n=278) (n=276) (n=278) (n=276)

Cerebral ischaemia 20 (7) 34(12) 17 (6) 25 (9)Initial bleed 19 (7) 17 (6) 7(3) 10(4)Rebleeding 5 (2) 7 (3) 14 (5) 24 (9)Intracranial haematoma 1 (<1) 1 (<1) 3 (1)Hydrocephalus 1 (<1) 6 (2) 1 (<1) 2 (1)Operative complicationt 8 (3) 6(2) 4 (1) 3 (1)Other 5 (2) 2 (1) I (<1) 7 (3)Unknown 5 (2)

*Patients had more than one cause of disability or death.tComplications of treatment with either nimodipine or placebo did notcause any disability or death.

The following factors were individually related tooutcome: age, sex (marginal), loss of consciousness,score on Glasgow coma scale, angiographic findings,limb weakness, neck stiffness (marginal), hyper-tension, computed tomographic findings, andtreatment. Adjusting simultaneously for age, loss ofconsciousness, score on Glasgow coma scale, andfindings on angiography and computed tomographyremoved the effects of sex, limb weakness, neckstiffness, and hypertension, but treatment remainedhighly significant (p= 0001). There was no evidence ofany interaction between any prognostic factor andtreatment.

In summary, there was clear evidence that treatmentwith nimodipine reduced the incidence of a pooroutcome. This could not be explained by an imbalancein prognostic factors between the treatment groups.There was no evidence that the benefit of treatmentwas confined to any particular subgroup of thepatients.

REBLEEDS

The incidence of rebleeding, either probable ordefinite, in patients treated with nimodipine was 9%

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compared with 14% in patients given placebo (tableII). This difference had an observed significancelevel of 8%. The following factors were individuallyassociated with the risk of rebleeding: age, lossof consciousness, score on Glasgow coma scale(marginal), angiographic findings, hypertensionymarginal), and computed tomographic findings.Adjusting simultaneously for age and angiographicfindings removed the effects of the other variables, andthere was little evidence of an effect of treatment(p=021). This analysis should be given little weightbecause there were too few rebleeds to be confident ofhaving identified relevant factors.

BLOOD PRESSURE

Nimodipine reduced progressively over 21 daysboth systolic (by a mean (SD) of 7 1 (18 5) mmHg;p=005) and diastolic blood pressure (by 3 6(11-0) mmHg; p=0-094). This effect was possiblyslightly more obvious in hypertensive patients, but itwas not significant. Treatment had no consistent effecton the natural tendency of the pulse rate to increaseprogressively for 21 days after a subarachnoidhaemorrhage (from a mean of 76 (12) to 85 (15) beats/minute) or on fluid intake or urine output.

ADVERSE REACTIONS

Twenty seven adverse reactions (17 for nimodipine,10 for placebo) were reported in 24 patients (14 givennimodipine, 10 given placebo). The highest numbersof reported events were for cardiovascular effects andeffects on the liver and bi iary system. Six adversecardiovascular events were reported in the group givennimodipine (three of headache, one of flushing, one ofhypertension, and one of hypotension) and three in thegroup given placebo (two of hypotension and one ofheadache).

Four adverse events concerned with the liverand biliary system were reported in patients givennimodipine (two of jaundice, two of liver functionabnormalities) and five in those given placebo (one ofjaundice, four of liver function abnormalities). Apartfrom two events of rash with nimodipine and one ofrash with placebo all other adverse reactions werereported on only one occasion in both groups. Theadverse reaction was considered to be sufficientlysevere in eight patients taking nimodipine and threetaking placebo for the treatment to be withdrawn.Routine haematological and biochemical laboratorydata were comparable between the two groups.

DiscussionOur results show that oral nimodipine 60 mg every

four hours is well tolerated and reduces cerebralinfarction and improves outcome after subarachnoidhaemorrhage. This effect of treatment is seen in allclinical grades of patients both before and afteroperation. Although it is generally accepted that thepeak incidence of delayed ischaemia is around seven to10 days after the initial bleed, the need for early andalso prolonged treatment was shown by the occurrence

of infarction as soon as the first day and as late as the40th day aftter the initial bleed-only 37% ofepisodes of infarction occurred from the seventh to the10th day.

Deterioration due to cerebral infarction was chosenas the primary outcome event for several reasons.Firstly, given the known actions of nimodipine,we considered that any beneficial effect would beshown through a prophylactic effect" and a reducedoccurrence of such episodes. Secondly, althoughnimodipine might help to preserve neuronal integrityin ischaemia, many other factors, including specifictreatments such as induced hypertension, contributeto the natural recovery of function that occurs in somepatients with delayed ischaemic deterioration.4 As aresult the proportion of patients who are permanentlydisabled owing to ischaemia may provide a lesssensitive assessment of a prophylactic measure.Furthermore, infarction can be diagnosed by clinicalobservation by sequential computed tomography,and at necropsy. We intentionally did not interpretparticular episodes as being due to cerebral vasospasm.Arterial narrowing detected by angiography is only oneof the many factors that lead to cerebral ischaemia aftersubarachnoid haemorrhage. Others include raisedintracranial pressure (haematoma, hydrocephalus);episodes of hypotension, hypoxia, hypovolaemia, orhyponatraemia; predisposing factors (history ofhypertension, advancing age, cigarette smoking); andsurgery to clip the aneurysm.45 Indeed, cerebralvasospasm alone seldom precipitates critical cerebralischaemia unless the cerebral circulation can no longercompensate for proximal arterial constriction bydilatation of distal cerebral arterioles. So many factorscontribute to delayed cerebral ischaemia that anappropriate subgroup would be difficult to define.Anyway, beneficial effect of nimodipine was seen in allthe patients.The assessment ofoutcome by the Glasgow outcome

scale is widely accepted. To avoid unduly relying onthe distinction between good recovery and moderatedisability because such a distinction is particularlysubject to variability in observers we distinguishedpoor outcomes (death, persistent vegetative state, andsevere disability) from good recovery and moderatedisability combined. The effect on outcome wasgreater perhaps than we would have expected from thereduction in the number of cerebral infarcts detectedby computed tomography, given that there are othercauses ofbad outcome. Studies at necropsy have shownthat cerebral infarcts may be small and diffuselydistributed' and hence beyond the resolution ofcomputed tomography. Nimodipine might protectpartially against such minor diffuse infarction.We found no evidence that the beneficial effect ofnimodipine was restricted to men, contrary to a recentstudy of patients with stroke.26

Results compatible with our findings were obtainedin smaller controlled trials (table V) and in uncontrolledstudies.' 322 The pioneering study of Allen et al showedan effect of treatment only when a subgroup of patientswith ischaemic neurological deficits attributed to

IABIE v-Comparison of results of double blind placebo controlled tnrals oforal timodipine treatment in patients with subarachnoid haemorrhage

Dose No No of patients Grade No of patients with bad outcomes Relative(everv four hours of on reduction

Studs Year Place for 21 days) centres Total Exclusions Nimodipine Placebo entry Time Nimodipine Placebo (%)

Allen etal 1983 United States 0 35 mg/kg 5 125 9 56 60 1-2 21 days 1 8 86*Philippon eta!l" 1986 France 60 mg 2 81 11 31 39 1-3 21 days 3 13 71*Neil-D"wer et al 1987 United Kingdom 60 mg 1 75 25 25 25 1-5 3 months 6 12 50Current trial 1989 United Kingdom 6( mg 4 554 0 278 276 1-5 3 months 55 91 40

Petruketal' 1988 Canada 90mg 17 188 34 72 82 3-5 121 days 53 67 10*3 months 44 54 7

*Related to spasm alone.

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vasospasm was defined: a significant benefit was notseen when the whole population was considered.1Similar results have been reported for outcome at threemonths in patients of all clinical grades (table V). 6 27Data from two controlled studies of intravenousnimodipine (1-2 mg/h for seven to 10 days)2829 and fromopen trials (preoperative, topical, and intravenousnimodipine for seven to 14 days followed by oral drugfor up to 21 days) with historical controls'1322 suggestthat outcome in patients with ischaemia associatedwith vasospasm was improved.

Is intravenous nimodipine more effective than oralnimodipine? Although it is difficult to compare thepatient populations, the reduction in the incidence ofbad outcomes with intravenous nimodipine (23% inthe study of Ohman and Heiskanen28 and 36% in thatof Jan et al29) is similar to that in our study (40%).During intravenous infusion (2 mg/h) the mean plasmaconcentration was reported to be 26-6 (1 8) ng/ml,while during oral treatment (45 mg every four hours)the peak plasma concentration an hour after each doseranged from 7 to 96 ng/ml and was 13 2 ng/ml (range<3-38-8 ng/ml) immediately before each tablet wastaken.30 The area under the curve was similar for thetwo methods of administration."' Because proteinbinds 98% of the drug the ratio of cerebrospinal fluid toplasma concentration is only 0 005-the concentrationin cerebrospinal fluid was 0 3 (0 2) ng/ml comparedwith 77 (34) ng/ml in plasma.3' Whether the differencein plasma concentration with oral and intravenousadministration is reflected in the cerebrospinal fluidand whether such a difference affects nimodipine'sefficacy in preventing cerebral infarction remains to bedetermined. Certainly, the available clinical evidencedoes not yet suggest any great difference. Oraladministration permits prolonged treatment, which isuseful if there is a long delay between the bleed andoperation.

Oral nimodipine is well tolerated and in practice hasnot led to problems with interaction with anaestheticagents.'2 3 We found no suggestion of episodes ofsevere hypotension with nimodipine when comparedwith placebo. The mild reduction in blood pressurenoted, particularly in the hypertensive patients,"4 mayhave contributed to the improved outcome.35Would a higher dose have any greater effect? A

Canadian study used 90 mg every four hours and,although it was a smaller study of patients with a poorgrade, showed no significant hypotensive effects,'7 butthe effects on overall outcome were much less clear cutthan in our trial. An unpublished study (Bayer trial No3247/3293) comparing 30, 60, and 90 mg orally everyfour hours did not show additional benefit with the90 mg dose when compared with the 60 mg dose. Intheory, a patient who metabolises nimodipine quicklymight develop ischaemia and would benefit from ahigher dose.

For how long should nimodipine be used? There wasno evidence after nimodipine was discontinued of alate incidence of cerebral infarction compared withplacebo. Any late infarcts seemed to occur after lateoperations. Prophylactic treatment should starttherefore before any operation, whatever its timing.The effect of treatment was independent of whenpatients were given nimodipine within the 96 hoursafter ictus. The experimental data show that pre-treatment within 20-30 minutes after occlusionof the middle cerebral artery in rats is protective.'Cerebral ischaemia after subarachnoid haemorrhage isprogressive so it is not surprising that nimodipine maybe helpful even after clinical deterioration starts,'9but prophylaxis is to be preferred. Patients withnegative results on high quality cerebral angiograms areat low risk of rebleeding or cerebral ischaemia andstopping nimodipine treatment might be considered to

reduce costs. Exploratory analysis suggests, however,that there is still a trend in favour of nimodipine.The mechanism ofthe beneficial effect ofnimodipine

is unclear. The original rationale for using calciumantagonists after subarachnoid haemorrhage was toreduce cerebral arterial spasm as seen on angiography.Our observation that spasm was not seen less often intreated patients accords with previous studies that usedangiography or transcranial Doppler ultrasonographyin patients and primates.'2'7 The data thus suggest thatnimodipine neither prevents nor reverses cerebralvasospasm. Calcium channel blockers such asnimodipine may have an effect on cerebral arteriolesthat are below the limits of resolution of angiographyand transcranial Doppler ultrasonography,6 37 butcerebral blood flow studies do not support such amechanism.27 The brain uses calcium for many otherprocesses in addition to the control of cerebrovascularsmooth muscle, and the diverse effects of calciumantagonists are becoming known.38"4"How should the fact that oral nimodipine 60 mg

every four hours reduces the incidence of cerebralinfarction and improves outcome affect overallmanagement of subarachnoid haemorrhage? Earlysurgery clearly will reduce the incidence of rebleeding,but for most neurosurgical units in the UnitedKingdom more resources are needed to provide sucha service. The proved efficacy of nimodipine anddoctors' ability to assess recovery of normal cerebro-vascular reactivity in individual patients4' willencourage selective early surgery and hence earliertransfer to neurosurgical units. Antifibrinolytic drugsreduce rebleeding in the short term but increasecerebral infarction.20 Nimodipine might reduceischaemic complications produced by antifibrinolyticagents,'7 but, as with the present trial, such a combina-tion should not be used without the benefit of asubstantial randomised double blind trial. Finally,the introduction of nimodipine for subarachnoidhaemorrhage is not displacing another treatment. Theapparent additional expense must, however, be viewedin the context of the overall cost effectiveness ofmanaging a patient with subarachnoid haemorrhagefrom ictus to final outcome and consideration shouldnot be restricted simply to the immediate burden onneurosurgical units' drug budget.

We thank Dr L Porto and Mrs Julia Duffy of Bayer UK fortheir collaboration and punctilious attention to detail; ourcolleagues for permission to enter their patients into the trialand for their enthusiastic support (Mr J Brice and Mr JGarfield in Southampton; Mr M Rice-Edwards in London;Mr J Miles, Mr R V Jeffreys, and Mr G Findlay in Liverpool;and Mr T A H Hide, Mr S Galbraith, Mr J Turner, MrR Johnston, Mr P Stanworth, and Mr D Mendelow inGlasgow); and Mrs Jane Roberts for her help with managingthe trial in Southampton. Bayer UK provided the fundingrequired to support the study in the four centres; the conductof the trial and statistical assessment were our independentresponsibilities.

I Allen GS, Ahn HS, Preziosi TJ, ei al. Cerebral arterial spasm-a controlledtrial of nimodipine in patients with subarachnoid hemorrhage. N EnglJMed1983;308:619-24.

2 Anonymous. Calcium antagonists attd aneurysmal subarachnoid haemorrhage[Editorial]. Lancet 1983;ii: 141-3.

3 Crompton MR. Cerebral infarction following the rupture of cerebral berryaneurysms. Brain 1964;87:263-79.

4 Symon L. Disordered cerebrosascular physiology in aneurysmal subarachnoidhaemorrhage. Acta Neurochir (Wien) 1978;41:7-22.

5 Pickard JD, Matheson M, Patterson J, Wyper D. Prediction of late ischemiccomplications after cerebral aneurysm surgery by the intraoperativemeasurement of cerebral blood flow. 7 Neurosurg 1980;53:305-8.

6 Simeone FA, Vinall P. Mechanisms of contractile response of cerebral artery toexternally-applied fresh blood. I Neurosurg 1975;43:37-47.

7 Brandt L, Andersson KE, Edvinsson L, Ljunggren B. Effects of extracellularcalcium and of calcium antagonists on the contractile responses of isolatedhuman pial and mesenteric arteries. J Cereb Blood Flow Metabol 1981;1:339-47.

8 Kazda S, Towart R. Nimodipine: a new calcium antagonistic drug with apreferential cerebrosvascular action. Acta Neurochir (Wien) 1982;63:259-65.

9 Harper AM\, Craigen L, Kazda S. Effect of the calcium antagonist, nimodipine,

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on cerebral blood flow and mctabolism in the primate. ] Cereh Blood Flo-wMletabol 1981;1:349-56.

10 Harris RJ, Branston NMi, Svmon L, Bayhan M, Watson A. The effects of acalciurn antagonist, nimodipine, upon physiological responses of thecerebral sasculature and its possible influence upon focal cerebral ischemia.Stroke 1982;13:759-66.

11 Haws CH, Heistad DD. Effects of nimodipine on cerebral sasoconstrictorresponses. Am ] Physiol 1984;247:H 170-6.

12 Grotenhuis JA, Bettag WXI, Fiebach BJO, Dabir K. Intracarotid slow bolusinjection of' nimodipine during angiography for treatment of cerebralvasospasm after subarachnoid hemorrhage. ] Neurosurg 1984;61:231-40.

13 Ljunggren B, Brandt L, Saseland H, et al. Outcome in 60 consecutive patientstreated with early aneurysm operation and intravenous nimodipine.7 Neurosurg 1984;61:864-73.

14 Espinosa F, Weir B, Overton r, e al. A randomized placebo-controlleddouble-blind trial of nimodipine after subarachnoid hemorrhage inmonkeys. 1. Clinical and radiological findings. ] Neurosurg 1984;61:231-40.

15 Nosko M, Weir B, Krueger C, et al. Nimodipine and chronic vasospasm inmonkeys. I. Clinical and radiological findings. Neurosurgerv 1985;16:129-36.

16 Philippon J, Grob R, Dagreou F, Guggiari Ni, Rivierez M, Viars P. Preventionof vasospasm in subarachnoid haemorrhage. A controlled study withnimodipine. -cta N'eurochir (Wien) 1986;82: 110-4.

17 Petruk KC, West NI, Mohr G, et al. Nimodipine treatment in poorgrade aneurysm patients. Results of a multicentre, double-blind, placebocontrolled trial. ] Nreurosurg 1988;68:505-17.

18 Gotoh 0, Mohamed AA, McCulloch I, Graham Dl, Harper AM,Teasdale GM. Nimodipine and the hemodvnamic and histopathologicalconsequences of middle cerebral artery occlusion in the rat.]J Cereb BloodFlowMeiab 1986;6:321-31.

19 Shaw MDNi, Foy PM, Conway M, e al. Dipyridamole and post-operativeischemic deficits in aneurysmal subarachnoid hemorrhage. ] Neurosurg1985 ;63:699-703.

20 V'ermeulen NI, Lindsay KW, Cheah MF, ei al. Antifibrinolytic treatment insubarachnoid hemorrhage. N EnglJ]fed 1984;311:432-7.

21 Mohsen F, Pomonis S, Illingworth R. Prediction of delayed cerebral ischaemiaafter subarachnoid haemorrhage by computed tomography. ] Neure'Neurosurg Psychialry 1984;47:1197-202.

22 Auer LM. Acute operation anid preventive nimodipine improve outcome inpatients with ruptured aneurysms. Neurosurgerv 1984;15:57-66.

23 Teasdale GM, Lindsay KW, Allardyce G, Dharker S, Ward P. Standardizedclinical grading of patients with subarachnoid haemorrhage: a uniforminternational system? In: Auer LNI, ed. Timing of aneurysm surgery. Berlin:Walter de Gruvter, 1985:9-14.

24 Teasdale GNI. A universal subarachnoid haemorrhage scale: report of acommittee of the World Federation of Neurosurgical Societies. J NeurolNeurosurgPsychiatry 1988;51:1457.

25 Jennett B, Bond M. Assessment of outcome after severe brain damage. Apractical scale. Lancet 1975;i:480-4.

26 Gielmers HJ, Gorter K, de Weerdt Cj, Wiezer HJA. A controlled trial ofnimodipine in acute ischemic stroke. N EnglJ Med 1988;318:203-7.

27 Neil-Dwver G, Mee E, Dorrance D, Lowe D. Early intervention withnimodipine in subarachnoid haemorrhage. Eur Heart J 1987;8(suppl K):41-7.

28 Ohman J, Heiskanen 0. Effect of nimodipine on the outcome of patients afteraneurvsmal subarachnoid hemorrhage and surgery. J Neurosurg 1988;69:683-6.

29 Jan M,, Buchheit F, Tremoulet M. Therapeutic trial of intravenous nimodipinein patients with established cerebral sasospasm after rupture of intracranialaneurvsms. Neurosurger-e 1988;23:154-7.

30 Vinge E, Andersson KE, Brandt L, Ljunggren B, Nilsson LG, Rosendal-Helgesen S. Pharmacokinetics of nimodipine in patients with aneurysmalsubarachnoid haemorrhage. Eurj Clin Pharmacol 1986;30:421-5.

31 Ramsch KD, AhrG, Tettenborn D, Auer LM. Overview on pharmacokineticsof nimodipine in healthy volunteers and in patients with subarachnoidhaemorrhage. Neurochirurgia (Stutig) 1985;28(suppl 1):74-8.

32 Stulleken EH, Balestrieri FJ, Prough DS, McWhorter JM. The hemodvnamiceffects of nimodipine in patients anesthetised for cerebral aneurysmclipping. Anesthestology 1985;62:346-8.

33 Merin RG. Calcium channel blocking drugs and anesthetics-is the druginteraction beneficial or detrimental? Anesthesiology 1987;66:111-3.

34 Tettenborn D, Dycka J, Volberg E, Dudden P. Blood pressure and heartrate during treatment with nimodipine in patients with subarachnoidhaemorrhage. Neurochirurgia (Stuttg) 1985;28(suppl 1):84-6.

35 O'Neill P, West CR, Chadwick DW, et al. Post-ictal blood pressure inaneurysmal subarachnoid haemorrhage. BrJ Neurosurg 1988;2:153-60.

36 Brandt L, Ljunggren B, Andersson KE, et al. Effects of topical application of acalcium antagonist (nifedipine) on feline cortical pial microvasculatureunder normal conditions and in focal ischemia. J Cereb Blood Flowv Metabol1983;3:44-50.

37 Takavasu M, Bassett JE, Dacey RG. Effects of calcium antagonists onintracerebral penetrating arterioles in rats. J Neurosurg 1988;69: 104-9.

38 Middlemiss DN, Spedding M. A functional correlate for the dihydropyridinebinding site in rat brain. Nature 1985;314:94-6.

39 Pickard JD, Walker V, Vile J, Perry S, Smythe PJ, Hunt R. Oral nimodipinereduces prostaglandin and thromboxane production by arteries chronicallyexposed to a periarterial haematoma and the antifibrinolvtic agenttranexamic acid. J Neurol Neurosurg Psychiatry 1987;50:727-3 1.

40 Phillis JW, O'Regan MH, Walter GA. Effects of nifedipine and felodipine onadenosine and inosine release from the hypoxemic rat cerebral cortex.J Cereb Blood Flouw Metab 1988;8:179-85.

41 Pickard JI), Read DH, Lovick AHJ. Preoperative assessment of cercbro-sascular reactivity following subarachnoid haemorrhage-clinicalcorrelations. In: Auer LM, ed. Ttmtng ofaneurvsm surger,. Berlin: Walter deGruyter, 1985:47-51.

(Accepted 20 December 1988)

Increased risk of atherosclerosis in women after the menopause

Jacqueline C M Witteman, Diederick E Grobbee, Frans J Kok, Albert Hofman, Hans A Valkenburg

Department ofEpidemiology, ErasmusUniversity Medical School,Rotterdam,The NetherlandsJacqueline C M Witteman,MSC, resident in epidemiologyDiederick E Grobbee, MD,senior lecturer in epidemiologyFrans J Kok, PHD, seniorlecturer in epidemiologyAlbert Hofman, MD,professor ofepidemiologyHans A Valkenburg, MD,emeritus professor ofepidemiology

Correspondence to:Miss Witteman.

BrMed7 1989;298:642-4

AbstractAn increase in the incidence of cardiovasculardisease has generally been observed in postmeno-pausal women, but there have been few studies ofthe association between menopausal state andatherosclerosis. In this study 294 premenopausaland 319 postmenopausal women aged 45 to 55 wereexamined radiographically for calcified deposits inthe abdominal aorta, which have been shown torepresent intimal atherosclerosis. Aortic athero-sclerosis was present in eight (3%) of the premeno-pausal women and in 38 (12%) ofthe postmenopausalwomen. After adjustments for age and otherindicators of cardiovascular risk women with anatural menopause had a 3*4 times greater risk ofatherosclerosis than premenopausal women (95%confidence interval 1-2 to 9-7; p<O0O5); women whohad had a bilateral oophorectomy had a 5*5 timesgreater risk (1-9 to 15-8; p<O0OO5). No excess risk ofatherosclerosis was observed among women whohad had a hysterectomy without removal of bothovaries.These results suggest that when oestrogen

production stops, either naturally or after surgery,the risk of atherosclerosis is increased.

IntroductionAn increase in the incidence of cardiovascular

disease after the menopause has generally beenobserved, though not all studies agree with thisfinding.' 2 Non-invasive assessment of atherosclerosis

may help to clarify this issue. Information on the extentof atherosclerosis in premenopausal and postmeno-pausal women has been gained mainly from necropsystudies. Compared with women with intact ovarieswomen who had had bilateral oophorectomy had anexcess of coronary atherosclerosis, which approachedthat in men. We investigated the association betweenmenopausal state and the presence of calcified depositsin the abdominal aorta as seen on lateral radiographs ofthe lumbar spine. The presence of such depositsrepresents true intimal atherosclerosis5 and is a strongpredictor of death from cardiovascular causes.6

Subjects and methodsA population study on chronic diseases was

conducted in Zoetermeer, a suburb of The Haguein The Netherlands, between 1975 and 1978. Allinhabitants of one rural and one urban district whowere aged 5 years and over were invited for a medicalexamination. The response rate among middle agedwomen was 77%. Details of the initial study have beenreported.7 All women aged 45 to 55 without a history ofcardiovascular disease (n=676) were eligible for ourstudy. The lower age limit was 45 because radiographyof the lumbar spine was performed from this ageonwards. The upper age limit of 55 was chosen toinclude sufficient premenopausal and postmenopausalwomen of similar ages.We diagnosed atherosclerosis by radiographic

detection of calcified deposits in the abdominal aorta.6Lateral radiographs of the lumbar spine were available

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