Kamal, Ayeesha Kamran

Khan, Maria

eCommons@AKU

eCommons@AKUSection of Neurology Department of MedicineFebruary 2011What are the therapeutic options for strokessecondary to intracranial large artery stenosisMaria KhanAga Khan UniversityAyeesha Kamran KamalAga Khan UniversityFollow this and additional works at: http://ecommons.aku.edu/pakistan_fhs_mc_med_neurolPart of the Neurology CommonsRecommended CitationKhan, M., Kamal, A. (2011). What are the therapeutic options for strokes secondary to intracranial large artery stenosis. Journal of thePakistan Medical Association, 61(2), 194-5.Available at: http://ecommons.aku.edu/pakistan_fhs_mc_med_neurol/16Warfarin-aspirin symptomatic intracranialdisease trial-wasid and trial of cilostazol insymptomatic intracranial arterial stenosis-TossWhy are these studies important andnoteworthy?Atherosclerotic stenosis of the major intracranialarteries (intracranial internal carotid artery, middle cerebralartery, vertebral artery, basilar artery) is emerging as the mostcommon cause of stroke worldwide. It causes 30% to 50% ofstrokes in Asians and 8% to 10% of strokes in North AmericanCaucasians. Intracranial atherosclerosis preferentially affectsAsians, Hispanics, Far East Asians and Blacks as compared tocarotid bifurcation disease which affects whites more. The riskof recurrent stroke is also higher than for most other strokesubtypes and has been quoted as 15% per year. Since intracranial atherosclerosis is the most frequentbut the most under recognized cause of stroke in ourpopulation, it is important to evaluate the therapeutic optionsfor secondary stroke prevention in this subgroup of patients.Before WASID, there was an uncertainty regardingwhether warfarin was superior to aspirin for secondaryprevention in intracranial disease. Prior studies had shownmixed results and there was a need for a randomized trial in thisregard. The other study TOSS was undertaken to assesswhether cilostazol (which is a phosphodiesterase 3 inhibitorwith both antiplatelet and vasodilating effects) can delay theprogression of intracranial atherosclerosis and hence preventrecurrent events.Who were the participants?WASID was an investigator-initiated, randomized,double-blind, multicenter clinical trial conducted at 59 sites inNorth America. Patients were recruited if they had a TIA or anondisabling stroke that occurred within 90 days beforerandomization and that was attributable to angiographicallyverified 50 to 99 percent stenosis of a major intracranial artery(carotid, middle cerebral, vertebral, or basilar).Patients wereexcluded if they had other causes for stroke like extracraniallarge artery disease or cardioembolic causes. They were alsoexcluded if they had contraindication to Aspirin or Warfarin.Since the study was carried out in North America most of thepatients were whites~58% with only about 30% who wereblacks.Vol. 61, No. 2, February 2011 194Evidence Based MedicineWhat are the therapeutic options for strokes secondaryto intracranial large artery stenosis?Maria Khan, Ayeesha Kamran KamalStroke Service and Vascular Fellowship Program, Aga Khan University Hospital, Karachi, Pakistan.TOSS was also a multicenter, double blind placebocontrolled trial carried out in 5 tertiary hospitals in SouthKorea. Patients with ischaemic strokes within 2 weeks fromonset, and with symptomatic stenosis in the M1 segment ofMCA or basilar artery were eligible for enrolment. Theyexcluded patients with other potential causes of stroke and withanaemia and thrombocytopenia.What was the intervention?In WASID the initially prescribed dose of warfarin (orits placebo) was 5 mg daily, and that of enteric-coated aspirin(or its placebo) was 650 mg twice daily. A total of 569 patientswere randomized, 280 to Aspirin arm and 289 to Warfarin.Both groups were followed up for a period of approximately1.9 years. All patients underwent blood testing for INR on amonthly basis and the dose of warfarin was then adjusted by anunblinded investigator. Patients were contacted monthly todetermine whether outcome events had occurred and wereexamined after every four months. Imaging was done if anevent was suspected.In TOSS participants were randomly given eithercilostazol 100 mg twice daily or matching placebo. Allparticipants got Aspirin 100 mg daily. A total of 135 patientswere randomized, 67 to cilostazol arm and 68 to placebo arm.They were followed at 1, 3, 5 and 6 months.What was the outcome?In WASID, the primary end point (which wasischaemic stroke, brain haemorrhage or death from vascularcauses) occurred in 22.1 percent of the patients in the aspiringroup and 21.8 percent of those in the warfarin group (hazardratio, 1.04; 95 percent confidence interval, 0.73 to 1.48;P=0.83). There were no significant differences between the twogroups in terms of the secondary endpoints either. Warfaringroup had significantly more cardiac events compared to thosegetting aspirin (rate, 2.9 percent in the aspirin group vs. 7.3percent in the warfarin group; hazard ratio, 0.40; 95 percentconfidence interval, 0.18 to 0.91; P=0.02). Also, majorhaemorrhages occurred significantly more often amongpatients assigned to warfarin (3.2 percent in the aspirin groupvs. 8.3 percent in the warfarin group; hazard ratio, 0.39; 95percent confidence interval, 0.18 to 0.84; P=0.01).In TOSS the primary outcome was the progression ofsymptomatic stenosis on MRA at 6 months. The extent ofstenosis was graded and progression was defined as worseningof stenosis by 1 or more grades on final MRA. The progressionof stenosis assessed by TCD was used as a secondary outcomemeasure. During the follow up period no clinical events(strokes or TIAs) occurred. The progression on MRA wassignificantly less frequent in the cilostazol group than in theplacebo group (p=.008). TCD evaluations were also similarwith less frequent progression in the cilostazol group.What were the conclusions?Before WASID it was thought that certain high-riskpatients such as those with severe stenosis, vertebrobasilardisease and those who have failed anticoagulation wouldbenefit from warfarin. In WASID, however, patients withsevere stenosis or those previously on antithrombotic therapydid not benefit from warfarin. Patients with basilar arterystenosis in WASID did appear to have a lower rate of theprimary end point on warfarin, but there was no difference inthe rate of stroke in the territory of the basilar artery betweenpatients on aspirin versus warfarin and there was no clearevidence of a benefit of warfarin over aspirin for patients withvertebrobasilar stenosis.TOSS concluded that cilostazol combined with aspirinmay prevent the progression of intracranial atheroscleroticlesions although whether this translates into clinical effectscannot be judged from this trial.How does this impact our clinical practice?Intracranial atherosclerosis is a greatly under-recognized cause of ischaemic stroke in our population.Currently available data does not prove a clear superiority ofany one antithrombotic agent over the others. The threeagents evaluated so far for this disease entity are aspirin,warfarin and cilostazol. Till more data becomes available,aspirin alone is sufficient for secondary stroke prevention inlarge artery atherosclerotic disease, although cilostazolshows promise. It is, therefore, important to recognize thatother risk factors must be aggressively managed in thesepatients as they may have a greater effect on slowing the rateof progression of this disease.Recommended Reading1. Kasner SE, Lynn MJ, Chimowitz MI, Frankel MR, Howlett-Smith H,Hertzberg VS, et al. Warfarin Aspirin Symptomatic Intracranial Disease(WASID) Trial Investigators. Warfarin vs aspirin for symptomatic intracranialstenosis: subgroup analyses from WASID. Neurology 2006; 67: 1275-8.2. Kwon SU, Cho YJ, Koo JS, Bae HJ, Lee YS, Hong KS, et al. CilostazolPrevents the Progression of the Symptomatic Intracranial Arterial Stenosis.The Multicenter Double-Blind Placebo-Controlled Trial of Cilostazol inSymptomatic Intracranial Arterial Stenosis. Stroke 2005; 36: 782-6.195 J Pak Med Assoc

What are the therapeutic options for strokes secondary to intracranial large artery stenosis

eCommons@AKUDepartment of Medicine Department of MedicineFebruary 2011What are the therapeutic options for strokessecondary to intracranial large artery stenosis?Maria KhanAga Khan UniversityAyeesha Kamran KamalAgha Khan University, ayeesha.kamal@aku.eduFollow this and additional works at: http://ecommons.aku.edu/pakistan_fhs_mc_med_medPart of the Neurology CommonsRecommended CitationKhan, M., Kamal, A. (2011). What are the therapeutic options for strokes secondary to intracranial large artery stenosis?. JPMA. TheJournal of the Pakistan Medical Association, 61(2), 194-195.Available at: http://ecommons.aku.edu/pakistan_fhs_mc_med_med/388Warfarin-aspirin symptomatic intracranialdisease trial-wasid and trial of cilostazol insymptomatic intracranial arterial stenosis-TossWhy are these studies important andnoteworthy?Atherosclerotic stenosis of the major intracranialarteries (intracranial internal carotid artery, middle cerebralartery, vertebral artery, basilar artery) is emerging as the mostcommon cause of stroke worldwide. It causes 30% to 50% ofstrokes in Asians and 8% to 10% of strokes in North AmericanCaucasians. Intracranial atherosclerosis preferentially affectsAsians, Hispanics, Far East Asians and Blacks as compared tocarotid bifurcation disease which affects whites more. The riskof recurrent stroke is also higher than for most other strokesubtypes and has been quoted as 15% per year. Since intracranial atherosclerosis is the most frequentbut the most under recognized cause of stroke in ourpopulation, it is important to evaluate the therapeutic optionsfor secondary stroke prevention in this subgroup of patients.Before WASID, there was an uncertainty regardingwhether warfarin was superior to aspirin for secondaryprevention in intracranial disease. Prior studies had shownmixed results and there was a need for a randomized trial in thisregard. The other study TOSS was undertaken to assesswhether cilostazol (which is a phosphodiesterase 3 inhibitorwith both antiplatelet and vasodilating effects) can delay theprogression of intracranial atherosclerosis and hence preventrecurrent events.Who were the participants?WASID was an investigator-initiated, randomized,double-blind, multicenter clinical trial conducted at 59 sites inNorth America. Patients were recruited if they had a TIA or anondisabling stroke that occurred within 90 days beforerandomization and that was attributable to angiographicallyverified 50 to 99 percent stenosis of a major intracranial artery(carotid, middle cerebral, vertebral, or basilar).Patients wereexcluded if they had other causes for stroke like extracraniallarge artery disease or cardioembolic causes. They were alsoexcluded if they had contraindication to Aspirin or Warfarin.Since the study was carried out in North America most of thepatients were whites~58% with only about 30% who wereblacks.Vol. 61, No. 2, February 2011 194Evidence Based MedicineWhat are the therapeutic options for strokes secondaryto intracranial large artery stenosis?Maria Khan, Ayeesha Kamran KamalStroke Service and Vascular Fellowship Program, Aga Khan University Hospital, Karachi, Pakistan.TOSS was also a multicenter, double blind placebocontrolled trial carried out in 5 tertiary hospitals in SouthKorea. Patients with ischaemic strokes within 2 weeks fromonset, and with symptomatic stenosis in the M1 segment ofMCA or basilar artery were eligible for enrolment. Theyexcluded patients with other potential causes of stroke and withanaemia and thrombocytopenia.What was the intervention?In WASID the initially prescribed dose of warfarin (orits placebo) was 5 mg daily, and that of enteric-coated aspirin(or its placebo) was 650 mg twice daily. A total of 569 patientswere randomized, 280 to Aspirin arm and 289 to Warfarin.Both groups were followed up for a period of approximately1.9 years. All patients underwent blood testing for INR on amonthly basis and the dose of warfarin was then adjusted by anunblinded investigator. Patients were contacted monthly todetermine whether outcome events had occurred and wereexamined after every four months. Imaging was done if anevent was suspected.In TOSS participants were randomly given eithercilostazol 100 mg twice daily or matching placebo. Allparticipants got Aspirin 100 mg daily. A total of 135 patientswere randomized, 67 to cilostazol arm and 68 to placebo arm.They were followed at 1, 3, 5 and 6 months.What was the outcome?In WASID, the primary end point (which wasischaemic stroke, brain haemorrhage or death from vascularcauses) occurred in 22.1 percent of the patients in the aspiringroup and 21.8 percent of those in the warfarin group (hazardratio, 1.04; 95 percent confidence interval, 0.73 to 1.48;P=0.83). There were no significant differences between the twogroups in terms of the secondary endpoints either. Warfaringroup had significantly more cardiac events compared to thosegetting aspirin (rate, 2.9 percent in the aspirin group vs. 7.3percent in the warfarin group; hazard ratio, 0.40; 95 percentconfidence interval, 0.18 to 0.91; P=0.02). Also, majorhaemorrhages occurred significantly more often amongpatients assigned to warfarin (3.2 percent in the aspirin groupvs. 8.3 percent in the warfarin group; hazard ratio, 0.39; 95percent confidence interval, 0.18 to 0.84; P=0.01).In TOSS the primary outcome was the progression ofsymptomatic stenosis on MRA at 6 months. The extent ofstenosis was graded and progression was defined as worseningof stenosis by 1 or more grades on final MRA. The progressionof stenosis assessed by TCD was used as a secondary outcomemeasure. During the follow up period no clinical events(strokes or TIAs) occurred. The progression on MRA wassignificantly less frequent in the cilostazol group than in theplacebo group (p=.008). TCD evaluations were also similarwith less frequent progression in the cilostazol group.What were the conclusions?Before WASID it was thought that certain high-riskpatients such as those with severe stenosis, vertebrobasilardisease and those who have failed anticoagulation wouldbenefit from warfarin. In WASID, however, patients withsevere stenosis or those previously on antithrombotic therapydid not benefit from warfarin. Patients with basilar arterystenosis in WASID did appear to have a lower rate of theprimary end point on warfarin, but there was no difference inthe rate of stroke in the territory of the basilar artery betweenpatients on aspirin versus warfarin and there was no clearevidence of a benefit of warfarin over aspirin for patients withvertebrobasilar stenosis.TOSS concluded that cilostazol combined with aspirinmay prevent the progression of intracranial atheroscleroticlesions although whether this translates into clinical effectscannot be judged from this trial.How does this impact our clinical practice?Intracranial atherosclerosis is a greatly under-recognized cause of ischaemic stroke in our population.Currently available data does not prove a clear superiority ofany one antithrombotic agent over the others. The threeagents evaluated so far for this disease entity are aspirin,warfarin and cilostazol. Till more data becomes available,aspirin alone is sufficient for secondary stroke prevention inlarge artery atherosclerotic disease, although cilostazolshows promise. It is, therefore, important to recognize thatother risk factors must be aggressively managed in thesepatients as they may have a greater effect on slowing the rateof progression of this disease.Recommended Reading1. Kasner SE, Lynn MJ, Chimowitz MI, Frankel MR, Howlett-Smith H,Hertzberg VS, et al. Warfarin Aspirin Symptomatic Intracranial Disease(WASID) Trial Investigators. Warfarin vs aspirin for symptomatic intracranialstenosis: subgroup analyses from WASID. Neurology 2006; 67: 1275-8.2. Kwon SU, Cho YJ, Koo JS, Bae HJ, Lee YS, Hong KS, et al. CilostazolPrevents the Progression of the Symptomatic Intracranial Arterial Stenosis.The Multicenter Double-Blind Placebo-Controlled Trial of Cilostazol inSymptomatic Intracranial Arterial Stenosis. Stroke 2005; 36: 782-6.195 J Pak Med Assoc

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