Kamal, Ayeesha Kamran

Khan, Maria

eCommons@AKU

eCommons@AKUDepartment of Medicine Department of MedicineDecember 2010What are the current therapeutic options forhaemorrhagic strokes?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. (2010). What are the current therapeutic options for haemorrhagic strokes?. JPMA. The Journal of the PakistanMedical Association, 60(12), 1065-1067.Available at: http://ecommons.aku.edu/pakistan_fhs_mc_med_med/386The  Factor Seven for Acute Haemorrhagic StrokeTrial (FAST) and Intensive Blood Pressure Reduction inAcute Cerebral Haemorrhage trial (INTERACT). Why are these studies important andnoteworthy?Intracerebral haemorrhage (ICH) is the mostdevastating form of stroke carrying a mortality of up to 40%at one month. In our part of the world the levels ofuncontrolled hypertension pose a greater risk of ICH for ourpopulation where ICH is about 30% of all strokes comparedto 14% in developed countries. There is evidence to suggest that haematomaexpansion occurs in as many as 70% of patients. Thisexpansion translates into increased disability and death.Most of this expansion is within the initial three hours. Alsoearly elevation of blood pressure (BP) is very common afterICH and many studies have highlighted an associationbetween elevated BP post ICH and poor outcomes. Thereason for this is postulated to be an increase in both the sizeof the haematoma and perilesional oedema.Factor VIIa activates factor X on the surface ofactivated platelets and leads to accelerated coagulation andthus limits rebleed and haematoma expansion. A prior study(published in NEJM in 2005) had demonstrated thatrecombinant activated Factor VII (rFVIIa) when givenwithin four hours of symptom onset limited the growth ofICH. In the FAST trial, the investigators evaluated theeffects of two dose of rFVIIa on rates of death and disabilityafter ICH.The Intensive Blood Pressure Reduction In AcuteCerebral Haemorrhage Trial (INTERACT) was arandomized controlled trial undertaken to determine theeffects of early intensive BP lowering on haematomagrowth and perihaematomal oedema. A pilot phase of thisstudy had demonstrated that such lowering of BP was safeand limited haematoma expansion in patients treated withinsix hours of symptom onset. In the next phase the authorshave reported the effects of early intensive BP lowering onhaematoma growth over 72 hours and also investigated theeffects of this treatment on perihaematomal oedema. A thirdphase of the study is currently underway to assess whetherthis therapy translates into clinical benefit or not. Who were the participants?The FAST trial was a multicenter, randomized,double- blind, placebo- controlled trial conducted betweenMay 2005 and February 2007 at 122 sites in 22 countries.Most of these were European countries and the US, with nocontribution from South East Asia. China and Singaporecontributed small numbers. Patients older than 18 yearswith acute ICH documented by CT within 3 hours ofsymptom onset were eligible to get enrolled. They excludedpatients who had a GCS of 5 or less (indicating severe ICH),those who had a surgical evacuation planned within 24hours, those who were on anticoagulation and those whohad a history of recent thromboembolism (and thereforecontraindication to rFVIIa).For INTERACT 404 patients were recruited forma network of hospital sites in China, South Korea, andAustralia during 2005 and 2007. They include patients>18 years of age with CT confirmed spontaneous ICHand elevated systolic BP (>2 readings of >150 and <220mm Hg recorded >2 min apart). A prerequisite was thecapacity to start randomly assigned treatment within 6hours of ICH in a monitored environment. They excludedpatients with a clear indication or contraindication to BPlowering, those with a recent ischaemic stroke, thosewho were deeply comatose or were planned for an earlyVol. 60, No. 12, December 2010 1065Evidence Based MedicineWhat are the current therapeutic options for haemorrhagic strokes?Maria Khan, Ayeesha Kamran KamalDepartment of Neurology, Director Stroke Service and Vascular Fellowship Program, Aga Khan University Hospital, Karachi, Pakistan.neurosurgical intervention.What was the intervention?In FAST the patients underwent block randomizationaccording to site to receive a single intravenous dose ofplacebo (268 patients) or of rFVIIa at a dose of 20 µg (276patients) or 80 µg (297 patients) per kilogram. Treatmentwas administered within 1 hour after the baseline CT scanand no later than 4 hours after the onset of symptoms.Follow up CT scans were performed at 24 and 72 hours andvolumes of intracerebral haemorrhage, intraventricularhaemorrhage, and oedema were calculated. The primaryoutcome measure was the score on mRS at day 90.In INTERACT, patients were randomly assigned toreceive either an early intensive BP-lowering treatmentstrategy (203 patients) or the recommended best practicestandard of BP lowering (201 patients) at the time that of theAmerican Heart Association guidelines published in 1999.For patients allocated to the intensive group, the goal was toachieve a systolic BP of 140 mm Hg within 1 hour ofrandomization and subsequently to maintain this target levelfor the next 7 days.  For patients allocated to the guidelinegroup, treatment was recommended to achieve a targetsystolic BP of 180 mm Hg. The outcomes for the presentinvestigation were the absolute and proportional increasesin haematoma and perihaematomal oedema volumes duringthe first 72 hours after ICH. CT was repeated at 24 and 72hours of symptom onset. For this 151 patients were includedfrom the intensive arm and 145 from the standard care arm,as the rest did not have 3 CT scans.What was the outcome?In FAST the estimated mean increase in the volumeof intracerebral haemorrhage was 26% in the placebo groupand 11% in the group receiving 80 µg of rFVIIa perkilogram thus proving that factor VI does limit haematomaexpansion. The increase in the volume of  haematoma was3.8 ml less in the group receiving 80 µg of rFVIIa than inthe placebo group (95% confidence interval [CI], 6.7 to 0.9;P = 0.009). The intraventricular haemorrhage volumedoubled in the placebo arm but remained unchanged in thefactor VII arms, but this difference did not reach statisticalsignificance and the final lesion volumes were also similarin the three groups. Despite the significant haematomaexpansion in the placebo arm compared to the active arm,the primary outcome measure (the proportion of patientswho died or were severely disabled) did not differsignificantly among the three groups. The distribution ofoutcomes on the modified Rankin scale and the medianscores on the Barthel index were similar among the threegroups. However, there was an absolute increase of 5% inthe frequency of arterial thromboembolic serious adverseevents in the group receiving 80 µg of  rFVIIa per kilogramas compared with the placebo group (P = 0.04).In INTERACT, early intensive BP loweringsignificantly reduced BP levels during the treatment. Comparedwith the guideline group, the intensive group showed significantdifferences of 3.15 mL (95% CI, 1.00 to 5.30 mL;  P=0.004) and2.45 mL (95% CI, 0.75 to 4.16 mL; P=0.005) less meanabsolute haematoma  growth at 24 and 72 hours, respectively.The mean difference in absolute increase over 72 hours was2.80 mL (95% CI, 1.04 to 4.56 mL; P=0.002). However, therewas no significant difference in the mean perihaematomaloedema growth between the two groups.What were the conclusions?In FAST, rFVIIa given within 4 hours after theonset of symptoms of intracerebral haemorrhagesignificantly reduced growth of the haematoma but failedto improve survival or functional outcome at 90 days.There was also an absolute increase of 5% in arterialthromboembolic serious adverse events in the groupreceiving 80 µg of rFVIIa per kilogram as compared withthe placebo group (9% vs. 4%). Although this is a negativetrial there are some important things that need to beconsidered. Firstly, there were important randomizationimbalances in the trial. Secondly, the patients who wereincluded had relatively small haemorrhages (meanvolume~22-24 ml) and were neurologically very intactwith GCS of 14 and NIHSS of around 13. What is notknown is whether those with larger haemorrhages or thosewith higher risk of re-bleed for various reasons wouldbenefit more from this therapy.INTERACT has demonstrated that early intensiveBP lowering does attenuate haematoma growth in patientswith ICH. It does not have a significant effect on the growthof perihaematomal oedema. Whether this radiologicalfinding translates into clinical benefit is yet to be evaluated.Do corticosteroids have a role in ICH?A Cochrane review published in 2008 on use ofcorticosteroids in primary ICH concluded that there is noevidence of a beneficial or adverse effect of corticosteroidsin patients with ICH whereas there is some evidence thatcorticosteroids increase the risk of serious adverse effects.How does this impact our clinical practice?Before FAST and INTERACT, there was little dataregarding therapy in ICH. Now at least targets have beenidentified. Recombinant factor VIIa shows promise but itneeds to be evaluated in patients with larger haematomasand in those with higher risk of re-bleed. Till then its use isnot recommended. 1066 J Pak Med AssocEarly intensive BP lowering also has impact onlimiting haematoma growth. But till the next phase of thistrial is completed, we cannot conclude whether thistranslates into clinical benefit or not. Besides this kind ofaggressive BP management requires dedicated stroke unitswhich in our current setup are not available. Till more datacomes out, standard recommendations for ICH managementshould be followed.Corticosteroid use is very frequent in our setup.What must be borne in mind is that there is no evidenceto suggest their benefits and they carry a risk of adverseeffects. Therefore their use is not recommended inpatients with ICH.Recommended Reading1. Mayer SA, Brun NC, Begtrup K, Broderick J, Davis S, Diringer MN,Skolnick BE, Steiner T; FAST Trial Investigators. Efficacy and safety ofrecombinant activated factor VII for acute intracerebral hemorrhage. N Engl JMed 2008; 358: 2127-37.2. Anderson CS, Huang Y, Arima H, Heeley E, Skulina C, Parsons MW,et al. INTERACT Investigators. Effects of early intensive bloodpressure-lowering treatment on the growth of hematoma andperihematomal edema in acute intracerebral hemorrhage: the IntensiveBlood Pressure Reduction in Acute Cerebral Haemorrhage Trial(INTERACT). Stroke 2010; 41: 307-12. 3. Feigin VL, Anderson N, Rinkel GJE, Algra A, Jan van Gijn, et al.Corticosteroids for aneurysmal subarachnoid haemorrhage and primaryintracerebral haemorrhage Cochrane Review, October 2008.Vol. 60, No. 12, December 2010 1067

English

What are the current therapeutic options for haemorrhagic strokes?

eCommons@AKUSection of Neurology Department of MedicineDecember 2010What are the current therapeutic options forhaemorrhagic strokesMaria 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. (2010). What are the current therapeutic options for haemorrhagic strokes. Journal of the Pakistan MedicalAssociation, 60(12), 1065-7.Available at: http://ecommons.aku.edu/pakistan_fhs_mc_med_neurol/18The  Factor Seven for Acute Haemorrhagic StrokeTrial (FAST) and Intensive Blood Pressure Reduction inAcute Cerebral Haemorrhage trial (INTERACT). Why are these studies important andnoteworthy?Intracerebral haemorrhage (ICH) is the mostdevastating form of stroke carrying a mortality of up to 40%at one month. In our part of the world the levels ofuncontrolled hypertension pose a greater risk of ICH for ourpopulation where ICH is about 30% of all strokes comparedto 14% in developed countries. There is evidence to suggest that haematomaexpansion occurs in as many as 70% of patients. Thisexpansion translates into increased disability and death.Most of this expansion is within the initial three hours. Alsoearly elevation of blood pressure (BP) is very common afterICH and many studies have highlighted an associationbetween elevated BP post ICH and poor outcomes. Thereason for this is postulated to be an increase in both the sizeof the haematoma and perilesional oedema.Factor VIIa activates factor X on the surface ofactivated platelets and leads to accelerated coagulation andthus limits rebleed and haematoma expansion. A prior study(published in NEJM in 2005) had demonstrated thatrecombinant activated Factor VII (rFVIIa) when givenwithin four hours of symptom onset limited the growth ofICH. In the FAST trial, the investigators evaluated theeffects of two dose of rFVIIa on rates of death and disabilityafter ICH.The Intensive Blood Pressure Reduction In AcuteCerebral Haemorrhage Trial (INTERACT) was arandomized controlled trial undertaken to determine theeffects of early intensive BP lowering on haematomagrowth and perihaematomal oedema. A pilot phase of thisstudy had demonstrated that such lowering of BP was safeand limited haematoma expansion in patients treated withinsix hours of symptom onset. In the next phase the authorshave reported the effects of early intensive BP lowering onhaematoma growth over 72 hours and also investigated theeffects of this treatment on perihaematomal oedema. A thirdphase of the study is currently underway to assess whetherthis therapy translates into clinical benefit or not. Who were the participants?The FAST trial was a multicenter, randomized,double- blind, placebo- controlled trial conducted betweenMay 2005 and February 2007 at 122 sites in 22 countries.Most of these were European countries and the US, with nocontribution from South East Asia. China and Singaporecontributed small numbers. Patients older than 18 yearswith acute ICH documented by CT within 3 hours ofsymptom onset were eligible to get enrolled. They excludedpatients who had a GCS of 5 or less (indicating severe ICH),those who had a surgical evacuation planned within 24hours, those who were on anticoagulation and those whohad a history of recent thromboembolism (and thereforecontraindication to rFVIIa).For INTERACT 404 patients were recruited forma network of hospital sites in China, South Korea, andAustralia during 2005 and 2007. They include patients>18 years of age with CT confirmed spontaneous ICHand elevated systolic BP (>2 readings of >150 and <220mm Hg recorded >2 min apart). A prerequisite was thecapacity to start randomly assigned treatment within 6hours of ICH in a monitored environment. They excludedpatients with a clear indication or contraindication to BPlowering, those with a recent ischaemic stroke, thosewho were deeply comatose or were planned for an earlyVol. 60, No. 12, December 2010 1065Evidence Based MedicineWhat are the current therapeutic options for haemorrhagic strokes?Maria Khan, Ayeesha Kamran KamalDepartment of Neurology, Director Stroke Service and Vascular Fellowship Program, Aga Khan University Hospital, Karachi, Pakistan.neurosurgical intervention.What was the intervention?In FAST the patients underwent block randomizationaccording to site to receive a single intravenous dose ofplacebo (268 patients) or of rFVIIa at a dose of 20 µg (276patients) or 80 µg (297 patients) per kilogram. Treatmentwas administered within 1 hour after the baseline CT scanand no later than 4 hours after the onset of symptoms.Follow up CT scans were performed at 24 and 72 hours andvolumes of intracerebral haemorrhage, intraventricularhaemorrhage, and oedema were calculated. The primaryoutcome measure was the score on mRS at day 90.In INTERACT, patients were randomly assigned toreceive either an early intensive BP-lowering treatmentstrategy (203 patients) or the recommended best practicestandard of BP lowering (201 patients) at the time that of theAmerican Heart Association guidelines published in 1999.For patients allocated to the intensive group, the goal was toachieve a systolic BP of 140 mm Hg within 1 hour ofrandomization and subsequently to maintain this target levelfor the next 7 days.  For patients allocated to the guidelinegroup, treatment was recommended to achieve a targetsystolic BP of 180 mm Hg. The outcomes for the presentinvestigation were the absolute and proportional increasesin haematoma and perihaematomal oedema volumes duringthe first 72 hours after ICH. CT was repeated at 24 and 72hours of symptom onset. For this 151 patients were includedfrom the intensive arm and 145 from the standard care arm,as the rest did not have 3 CT scans.What was the outcome?In FAST the estimated mean increase in the volumeof intracerebral haemorrhage was 26% in the placebo groupand 11% in the group receiving 80 µg of rFVIIa perkilogram thus proving that factor VI does limit haematomaexpansion. The increase in the volume of  haematoma was3.8 ml less in the group receiving 80 µg of rFVIIa than inthe placebo group (95% confidence interval [CI], 6.7 to 0.9;P = 0.009). The intraventricular haemorrhage volumedoubled in the placebo arm but remained unchanged in thefactor VII arms, but this difference did not reach statisticalsignificance and the final lesion volumes were also similarin the three groups. Despite the significant haematomaexpansion in the placebo arm compared to the active arm,the primary outcome measure (the proportion of patientswho died or were severely disabled) did not differsignificantly among the three groups. The distribution ofoutcomes on the modified Rankin scale and the medianscores on the Barthel index were similar among the threegroups. However, there was an absolute increase of 5% inthe frequency of arterial thromboembolic serious adverseevents in the group receiving 80 µg of  rFVIIa per kilogramas compared with the placebo group (P = 0.04).In INTERACT, early intensive BP loweringsignificantly reduced BP levels during the treatment. Comparedwith the guideline group, the intensive group showed significantdifferences of 3.15 mL (95% CI, 1.00 to 5.30 mL;  P=0.004) and2.45 mL (95% CI, 0.75 to 4.16 mL; P=0.005) less meanabsolute haematoma  growth at 24 and 72 hours, respectively.The mean difference in absolute increase over 72 hours was2.80 mL (95% CI, 1.04 to 4.56 mL; P=0.002). However, therewas no significant difference in the mean perihaematomaloedema growth between the two groups.What were the conclusions?In FAST, rFVIIa given within 4 hours after theonset of symptoms of intracerebral haemorrhagesignificantly reduced growth of the haematoma but failedto improve survival or functional outcome at 90 days.There was also an absolute increase of 5% in arterialthromboembolic serious adverse events in the groupreceiving 80 µg of rFVIIa per kilogram as compared withthe placebo group (9% vs. 4%). Although this is a negativetrial there are some important things that need to beconsidered. Firstly, there were important randomizationimbalances in the trial. Secondly, the patients who wereincluded had relatively small haemorrhages (meanvolume~22-24 ml) and were neurologically very intactwith GCS of 14 and NIHSS of around 13. What is notknown is whether those with larger haemorrhages or thosewith higher risk of re-bleed for various reasons wouldbenefit more from this therapy.INTERACT has demonstrated that early intensiveBP lowering does attenuate haematoma growth in patientswith ICH. It does not have a significant effect on the growthof perihaematomal oedema. Whether this radiologicalfinding translates into clinical benefit is yet to be evaluated.Do corticosteroids have a role in ICH?A Cochrane review published in 2008 on use ofcorticosteroids in primary ICH concluded that there is noevidence of a beneficial or adverse effect of corticosteroidsin patients with ICH whereas there is some evidence thatcorticosteroids increase the risk of serious adverse effects.How does this impact our clinical practice?Before FAST and INTERACT, there was little dataregarding therapy in ICH. Now at least targets have beenidentified. Recombinant factor VIIa shows promise but itneeds to be evaluated in patients with larger haematomasand in those with higher risk of re-bleed. Till then its use isnot recommended. 1066 J Pak Med AssocEarly intensive BP lowering also has impact onlimiting haematoma growth. But till the next phase of thistrial is completed, we cannot conclude whether thistranslates into clinical benefit or not. Besides this kind ofaggressive BP management requires dedicated stroke unitswhich in our current setup are not available. Till more datacomes out, standard recommendations for ICH managementshould be followed.Corticosteroid use is very frequent in our setup.What must be borne in mind is that there is no evidenceto suggest their benefits and they carry a risk of adverseeffects. Therefore their use is not recommended inpatients with ICH.Recommended Reading1. Mayer SA, Brun NC, Begtrup K, Broderick J, Davis S, Diringer MN,Skolnick BE, Steiner T; FAST Trial Investigators. Efficacy and safety ofrecombinant activated factor VII for acute intracerebral hemorrhage. N Engl JMed 2008; 358: 2127-37.2. Anderson CS, Huang Y, Arima H, Heeley E, Skulina C, Parsons MW,et al. INTERACT Investigators. Effects of early intensive bloodpressure-lowering treatment on the growth of hematoma andperihematomal edema in acute intracerebral hemorrhage: the IntensiveBlood Pressure Reduction in Acute Cerebral Haemorrhage Trial(INTERACT). Stroke 2010; 41: 307-12. 3. Feigin VL, Anderson N, Rinkel GJE, Algra A, Jan van Gijn, et al.Corticosteroids for aneurysmal subarachnoid haemorrhage and primaryintracerebral haemorrhage Cochrane Review, October 2008.Vol. 60, No. 12, December 2010 1067

What are the current therapeutic options for haemorrhagic strokes

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What are the current therapeutic options for haemorrhagic strokes

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