Hematoma growth and outcomes in intracerebral hemorrhage the INTERACT1 study

DOI 10.1212/WNL.0b013e318260cbba; Published online before print June 27, 2012;2012;79;314Neurology Candice Delcourt, Yining Huang, Hisatomi Arima, et al.The INTERACT1 studyHematoma growth and outcomes in intracerebral hemorrhage :January 3, 2013This information is current as of/content/79/4/314.full.html located on the World Wide Web at:The online version of this article, along with updated information and services, isrights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.All since 1951, it is now a weekly with 48 issues per year. Copyright © 2012 by AAN Enterprises, Inc. ® is the official journal of the American Academy of Neurology. Published continuously NeurologyHematoma growth and outcomes in intracerebral hemorrhageThe INTERACT1studyCandice Delcourt,MD Yining Huang,MD Hisatomi Arima,MD,PhDJohn Chalmers,PhD,FRACPStephen M.Davis,MD,FRACPEmma L.Heeley,PhD Jiguang Wang,MD Mark W.Parsons,PhD,FRACPGuorong Liu,MD Craig S.Anderson,PhD,FRACPFor the INTERACT1InvestigatorsABSTRACTObjective:Uncertainty exists over the size of potential beneficial effects of medical treatmentstargeting hematoma growth in intracerebral hemorrhage (ICH).We report associations of hema-toma growth parameters on clinical outcomes in the pilot phase,Intensive Blood Pressure Reduc-tion in Acute Cerebral Hemorrhage Trial (INTERACT1)( NCT00226096).Methods:In randomized patients with both baseline and 24-hour brain CT (n ϭ335),associationsbetween measures of absolute and relative hematoma growth and 90-day poor outcomes of death and dependency (modified Rankin Scale score 3–5)were assessed in logistic regression models,with data reported as odds ratios (OR)and 95%confidence intervals (CI).Results:A total of 10.7mL (1SD)increase in hematoma volume over 24hours was stronglyassociated with poor outcome (adjusted OR 1.72,95%CI 1.19–2.49;p ϭ0.004).An associa-tion was also evident for relative growth (adjusted OR 1.67,95%1.22–2.27;p ϭ0.001for 1SD increase).The analyses were adjusted for age,sex,achieved systolic blood pressure,elevated NIH Stroke Scale score (Ն14),hematoma location,baseline hematoma volume,intraventricular extension,antithrombotic therapy,baseline glucose,time from ICH to baseline CT scan,and time from baseline to repeat CT scan.A 1mL increase in hematoma growth was associated with a 5%(95%CI 2%–9%)higher risk of death or dependency.Conclusion:Medical treatments,such as rapid intensive blood pressure lowering,could achieveϳ2–4mL absolute attenuation of hematoma growth.There is hope that this could translate into modest but still clinically worthwhile (ϳ10%–20%better chance)outcome from ICH.Neurology ®2012;79:314–319GLOSSARYBP ؍blood pressure;CI ϭconfidence interval;FAST ϭFactor VII for Acute hemorrhagic Stroke Trial;GCS ϭGlasgow Coma Scale;ICH ϭintracerebral hemorrhage;INTERACT1ϭIntensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial;IVH ϭintraventricular hemorrhage;mRS ϭmodified Rankin Scale;NIHSS ϭNIH Stroke Scale;OR ϭodds ratio;rFVIIa ϭrecombinant activated factor VIIa.Although intracerebral hemorrhage (ICH)affects over 1million people in the world each year,1most of whom either die or are left seriously disabled,there is still no routinely available medical therapy that has been proven to improve outcome.Various factors that have been shown to influence outcome in ICH,including age,initial hematoma volume,hematoma growth,neurologic deficit,intraventricular extension,and infratentorial location.2–4Among these factors,hematoma growth is the major focus of therapeutic attention as it is the only modifiable factor which occurs in most patients.5–8However,there is uncertainty over the clinical significance of any potential effect of medical treatments that target hematoma growth in ICH.There has only been one detailed analysis of the relationship between hematoma growth and outcome,4a pooling of 115patients from the recombinant activated factor VIIa (rFVIIa)trials (patients treated with placebo,enrolled in 1of 3trials investigating the safety,From The George Institute for Global Health (C.D.,H.A.,J.C.,E.L.H.,C.S.A.),Royal Prince Alfred Hospital,University of Sydney,Australia;Department of Neurology (Y.H.),Peking University First Hospital,China;Department of Neurology (S.M.D.),Royal Melbourne Hospital,University of Melbourne,Australia;Shanghai Institute for Hypertension (J.G.W.),China;Department of Neurology (M.W.P.),John HunterHospital,Hunter Medical Research Institute,Newcastle,Australia;and Department of Neurology (Y.L.),Baotou Central Hospital,Baotou,China.Coinvestigators are listed on the Neurology ®Web site at .Study funding :Supported by the National Health and Medical Research Council of Australia (Program Grant 358395).Go to for full disclosures.Disclosures deemed relevant by the authors,if any,are provided at the end of this article.Editorial,page 298Supplemental data at Supplemental DataCorrespondence &reprint requests to Dr.Anderson:canderson@.audosage,and proof-of-concept of rFVIIa)and 103untreated patients from a population-based study in greater Cincinnati/northern Kentucky.Although this study demonstrated an independent prognostic effect of hema-toma growth on both mortality and func-tional outcome after acute ICH,the subsequent pivotal Factor VII for Acute hem-orrhagic Stroke Trial(FAST)9failed to show a clear improvement in clinical outcomes de-spite there being an attenuation of hematoma expansion of approximately4–5mL.Finally, the pilot phase of the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial(INTERACT1)showed beneficial effects on hematoma growth(ϳ2mL)but not on any clinical outcome.10Our aim was to quantify as-sociations of hematoma growth parameters ac-cording to achieved blood pressure(BP)levels between1and24hours postrandomization on death and functional outcomes among all par-ticipants in INTERACT1.METHODS Standard protocol approvals,registra-tions,and patient consents.The study protocol was ap-proved by appropriate ethics committees at each site and registered with (NCT00226096).Written in-formed consent was obtained from each patient or their legal surrogate in situations in which they were unable to do so. Study design.The design of INTERACT1has been described in detail elsewhere.10,11Briefly,404patients were recruited from a network of hospital sites in China,South Korea,and Australia during2005and2007.Eligible patients were agedՆ18years with CT-confirmed spontaneous ICH and elevated systolic BP (2measurements ofՆ150mm Hg andՅ220mm Hg recorded Ն2minutes apart)with the capacity to start randomly assigned BP-lowering treatment within6hours of ICH in a suitably mon-itored environment.Patients on antithrombotic agents(i.e.,an-tiplatelets or anticoagulation)were eligible for the trial. Exclusion criteria were a clear indication for,or contraindication to,intensive BP lowering;ICH secondary to a structural cerebral abnormality or thrombolysis;recent ischemic stroke;deep coma (Glasgow Coma Scale score[GCS]3–5);significant prestroke disability or medical illness;and early planned neurosurgical in-tervention.Patients were randomly assigned to receive either an early intensive BP-lowering treatment strategy(140mm Hg sys-tolic goal)or the recommended standard of BP lowering at the time(Յ180mm Hg systolic).Assessments included use of the NIH Stroke Scale(NIHSS)on enrollment,at24and72hours, and at7days,and the modified Rankin Scale(mRS,dependency defined as scores3–5)at28and90days after randomization. CT analyses.Cerebral CT was performed using standardized techniques at baseline and24Ϯ3hours later.For each patient, uncompressed digital images were supplied to a central labora-tory in DICOM format on a CD-ROM identified only by the patient’s unique study number.Hematoma volume and location were determined independently by2trained neurologists blind to clinical data,treatment,and date and sequence of CT using computer-assisted multislice planimetric and voxel threshold techniques in MIStar version3.2(Apollo Medical Imaging Technology,Melbourne,Australia).Statistical analysis.We excluded69patients without a24-hour CT or were missing90-day outcome data.Hematoma growth was treated both as a categorical variable,using categories commonly used in the literature,and as a continuous variable,to evaluate the impact of modest incremental changes in volume on outcomes.Baseline differences between the included and ex-cluded patients were assessed using the␹2test for categorical variables and the Wilcoxon test for continuous variables.Average achieved systolic BP levels in individual patients from1to24 hours postrandomization were used.Absolute and relative hema-toma growth at24hours was categorized into4“clinically mean-ingful”groups based on what has been used elsewhere5and on the distribution of the data:for absolute change,this was as“no growth,”“minimal change”(Յ5mL),“moderate change”(5.1–12.5mL),and“massive change”(Ͼ12.5mL);and for relative change,“no growth,”“minimal change”(Յ33%),“moderate change”(34%–50%),and“massive change”(Ͼ50%)was used. Logistic regression models were used to estimate odds ratios (OR)and95%confidence intervals(CI)for a1SD increase in growth(10.7mL for absolute increase).The analyses were ad-justed for age,sex,achieved systolic BP during the first24hours, elevated NIHSS score(Ն14),hematoma location,baseline he-matoma volume,intraventricular hemorrhage(IVH),anti-thrombotic therapy,baseline glucose,time from ICH to baseline CT scan,and time from baseline to repeat CT scan.Associations and95%CI for subgroups were estimated by treating the OR as “floating absolute risks,”12and the testing for trends was under-taken using median values in each group.Estimates of associa-tions for hematoma growth as a continuous variable required values to be log-transformed to remove skewness by the addition of the value1.1,and to eliminate negative values which may have arisen because of genuine shrinkage in hematoma or minor between-group sequential CT measurement error.Associations of hematoma growth on death or dependency by3different hematoma locations were compared by adding an interaction term to the statistical model.All analyses were performed using SAS version9.2(SAS Institute).RESULTS Among the404patients included in INTERACT1,there were346(86%)with sequential CTs(baseline and24hours)and335(83%)with clinical outcome data.The table shows that the base-line characteristics were broadly similar between in-cluded and excluded patients:mean age62years, most male with ICH in a deep location(basal ganglia or thalamus),and about one-fifth with IVH;and pa-tients had similar levels of neurologic severity(me-dian NIHSS and median GCS scores).Of the69 excluded patients,none died but6had some form of neurosurgical intervention before the24-hour CT scan.Overall,60%of patients had evidence of hema-toma growth,and it was clinically significant (Ͼ33%)in24%of patients.Figure1shows that strong associations were evident between relative and absolute hematoma growth and death or dependencyat90days(pϭ0.0008andϽ0.0001,respectively). With absolute and proportional growth as continu-ous measures,the respective OR(per1SD increase)at90days for the key outcomes were as follows:for death or dependency,1.72(95%CI1.19–2.49)and 1.67(95%CI1.22–2.27);death1.24(95%CI 0.90–1.72)and1.26(95%CI0.86–1.83);and for dependency alone,1.10(95%CI0.88–1.42)and 1.40(95%CI1.06–1.85)(figure2).A1SD abso-lute increase in hematoma volume corresponded to an increase of10.7mL,which equated to a1mL hematoma growth being associated with a5%(95% CI2%–9%)higher chance of being dead or depen-dent at90days.Conversely,any intervention that could reduce hematoma growth by2–4mL could equate to a10%–20%reduction in the risk of death or dependency at90days.In INTERACT1,a1.7 and a3.4mL absolute difference in hematoma growth for patients randomized within6and4 hours,respectively,would be expected to translate into at least8.2%and15.8%relative reductions in the chances of a poor outcome.Hematoma location had no independent influence on effects of hema-toma growth on outcomes(figure3).These results did not change with2further adjusted analysis:the first related to the exclusion of3participants who were taking warfarin at the time of entry in the study and the other related to the inclusion of new-onset IVH observed among59patients(23%of256pa-tients without IVH at baseline)on the repeat24-hour CT scan as a covariate into the statistical model. DISCUSSION These data from the INTERACT1 study reaffirm the importance of hematoma growth as a key determinant of death and dependency in ICH.There was a near continuous(linear)associa-tion between hematoma growth and outcome,with every1mL of hematoma growth estimated to be associated with5%increase in the odds of death and dependency.This association took account of other influencing factors such as age,sex,BP,clinical sever-ity,baseline volume,location of hematoma,and presence of IVH.However,potentially more relevant to clinical practice is the observation that growth in hematoma volumes greater than5mL is clearly clin-ically significant.These analyses were able to confirm the pooled data from the preliminary rFVIIa trials and observa-tional Cincinnati study,where a1mL increase in hematoma volume was associated with a7%relative increase in the risk of death or worsening of disability (1-point increase on the mRS)at90days.4In the2 major rFVIIa trials,treatment with rFVIIa at80␮g per kg resulted in a3.8mL reduction in hematoma growth compared to placebo,which equated to a 50%overall relative reduction in hematoma growth. However,there were discordant clinical outcomes between the2clinical trials13,14;the second pivotalAbbreviations:BPϭblood pressure;GCSϭGlasgow Coma Scale;NIHSSϭNIH Stroke Scale.a Data are n(%),mean(SD),or median(interquartile range).b Scores range from0(normal)to42(coma with quadriplegia).c Scores range from3(deep coma)to15(normal).study did not confirm the earlier finding of a signifi-cant reduction in death and disability with the hemo-static therapy.Various explanations for this unexpected result have included an imbalance in the randomized allocation of groups,an increase in arte-rial thromboembolic events from rFVIIa offsetting beneficial effects,the inclusion of very elderly pa-tients at high risk of non-neurologic causes of death,and the play of chance resulting in better outcomes for the placebo group.13,14In INTERACT1,a 10–14mm Hg difference in systolic BP between randomized groups in the first 24hours of treatment for patients included within 6hours is expected to translate into at least an 8.5%relative reduction in poor outcome in ICH,which could not be detected reliably in a study with a sam-ple size of only 400.However,secondary analysis of this study indicated that an earlier (Ͻ4hours)initia-tion of treatment to lower BP could be expected to produce greater effects on ICH growth (15.8%rela-tive reduction in poor outcomes).Although the cur-rent analysis has not identified any significant interaction between time to treatment and efficacy,the power to show such an interaction was limited by the small sample size,and observational studies show that most hematoma growth occurs soon after stroke onset.5Thus,intensive BP lowering appears to have an ability to attenuate hematoma growth at between 2mL (0–6hours)and 4mL (0–4hours),which could result in between 10%and 20%increased chances of survival free of disability in ICH.We recognize the potential for selection bias to influence our data as these analyses pertain to a clini-cal trial population in which patients with more se-vere ICH (e.g.,low GCS)or requiring early decompressive surgery were excluded.Moreover,pa-tients with missing data are likely to have had more severe deficits,died early,and by inference had larger hematoma volumes than on average in the analysis cohort.Also,baseline ICH volume in INTERACT1was relatively small (9vs about 22mL in the rFVIIa trials).Thus,a bias toward smaller hematomas which are less likely to increase in size and have a better prognosis in these analyzes may have overestimated the efficacy of BP lowering and for such treatment to be not directly extrapolated to all cases of ICH.An-other possible source of bias is that INTERACT1included predominantly Chinese participants with a higher proportion of deep ICH than Western popu-lations and who may have a different response to BP-lowering treatment.However,our analysis does not suggest any difference in the relationship between he-matoma growth and death and dependency between Chinese and Western patients.Finally,the analysis did not include several biochemical (e.g.,cholesterol)and hematologic (e.g.,platelet and coagulation)pa-Odds ratios (OR)(95%confidence interval [CI])are adjusted for age,sex,achieved systolic blood pressure during the first 24hours,elevated NIH Stroke Scale score (Ն14),blood glucose,time from onset to the first CT,time from the first to the second CT,hematoma location,baseline hematoma volume,intraventricular extension,and antithrombotic therapy.Solid boxes represent estimates of OR on death or dependency.Centers of boxes are placed at the estimates of OR;areas of the boxes are proportional to the reciprocal of the variance of the estimates.Vertical lines represent 95%CI.rameters known to predict hematoma growth be-cause they were not routinely measured in such a pragmatic clinical trial.This study not only reinforces the strength of associ-ation between hematoma growth and clinical outcome in ICH,but it also confirms the assumptions underly-ing the sample size calculations underlying the ongoing second(main phase)INTERACT2study,11originally powered on the basis of the pooled analysis of the rFVIIa trials and Cincinnati study.4The finding thatProportional increase in hematoma volume was log-transformed to remove skewness after adding the value1.1to eliminate negative values.Odds ratios (OR)represent a difference of a SD(10.7mL for absolute increase and0.42for log-transformed proportional increase).Odds ratios and p values were controlled for age,sex,achieved systolic blood pressure during the first24hours,elevated NIH Stroke Scale score(Ն14),blood glucose,time from onset to the first CT,time from the first to the second CT,hematoma location,baseline hematoma volume,intraventricular extension,and antithrombotic therapy. Solid boxes represent estimates of OR on outcomes.Centers of boxes are placed at the estimates of OR;areas of the boxes are proportional to the reciprocal of the variance of the estimates.Horizontal lines represent95%confidence intervals(95%CI).Odds ratios(OR)and p values were controlled for age,sex,achieved systolic blood pressure during the first24hours,elevated NIH Stroke Scale score (Ն14),blood glucose,time from onset to the first CT,time from the first to the second CT,baseline hematoma volume,intraventricular extension,and antithrombotic therapy.Diamonds represent the estimates and95%confidence intervals(95%CI)of overall effects.Other conventions as for figure2. p Homogeneity tested the consistency of effects across different locations of hematoma.BP lowering significantly attenuates hematoma growth suggests a direct biological benefit of this treatment strategy,which is now being tested for clinical benefit in larger,adequately powered trials.11,15AUTHOR CONTRIBUTIONSC.D.,H.A.,J.C.,E.L.H.,and C.A.contributed to the concept and ratio-nale for the study.H.A.and E.L.H.contributed to data analysis.C.D., H.A.,E.L.H.,and C.A.contributed to the interpretation of the results. All authors participated in the drafting and approval of the final manu-script and take responsibility for the content and interpretation of this article.DISCLOSUREC.Delcourt and Y.Huang report no disclosures.H.Arima holds a Future Fellowship from the Australian Research Council.J.Chalmers holds re-search grants from Servier as chief investigator for ADVANCE-ON,ad-ministered through the University of Sydney.S.Davis,E.Heeley,and J. Wang report no disclosures.M.Parsons holds a Future Fellowship from the Australian Research Council.G.Liu reports no disclosures.C.Ander-son holds a Senior Principal Research Fellowship from the National Health and Medical Research Council of Australia.Go to for full disclosures.Received September7,2011.Accepted in final form December8,2011.REFERENCES1.Qureshi AI,Tuhrim S,Broderick J,Batjer H,Hondo H,Hanley D.Spontaneous intracerebral haemorrhage.N Engl J Med2001;344:1450–1460.2.Hemphill JC,Bonovich D,Besmertis L,Manley G,John-ston SC.The ICH score:a simple,reliable grading scale for intracerebral haemorrhage.Stroke2001;32:891–897. 3.Broderick J,Brott TG,Duldner J,Tomsick T,Huster G.Volume of intracerebral hemorrhage:a powerful and easy-to-use predictor of30-day mortality.Stroke1993;24:987–993.4.Davis S,Hennerici M,Brun N,Diringer M,Mayer S,Begtrup M.Hematoma growth is a determinant of mortal-ity and poor outcome after intracerebral hemorrhage.Neu-rology2006;66:1175–1181.5.Broderick J,Diringer M,Hill M,et al.Determinants ofintracerebral hemorrhage growth:an exploratory analysis.Stroke2007;38:1072–1075.6.Ohwaki K,Yano E,Nagashima H,Hirata M,Nakagomi T,Tamura A.Blood pressure management in acute intracere-bral hemorrhage:relationship between elevated blood pressure and hematoma enlargement.Stroke2004;35: 1364–1367.7.Fujii Y,Takeuchi S,Sasaki O,Minakawa T,Tanaka R.Multivariate analysis of predictors of hematoma enlarge-ment in spontaneous intracerebral hemorrhage.Stroke 1998;29:1160–1166.8.Kazui S,Minematsu K,Yamamoto H,Sawada T,Yamagu-chi T.Predisposing factors to enlargement of spontaneous intracerebral hematoma.Stroke1997;28:2370–2375. 9.Mayer S,Brun N,Begtrup K,et al.Efficacy and safety ofrecombinant activated factor VII for acute intracerebral hemorrhage.N Engl J Med2008;358:2127–2137.10.Anderson CS,Huang Y,Wang JG,et al.Intensive bloodpressure reduction in acute cerebral haemorrhage trial (INTERACT):a randomised pilot ncet Neurol 2008;7:391–399.11.Delcourt C,Huang Y,Wang J,et al.The second(main)phase of an open,randomised,multicentre study to investi-gate the effectiveness of an intensive blood pressure reduction in acute cerebral haemorrhage trial(INTERACT2).Int J Stroke2010;5:110–116.12.Easton D,Peto J,Babiker A.Floating absolute risk:analternative to relative risk in survival and case-control anal-ysis avoiding an arbitrary reference group.Stat Med1991;10:1025–1035.13.Mayer S,Brun NC,Begtrup K,et al.Recombinant acti-vated factor VII for acute intracerebral hemorrhage.N Engl J Med2005;352:777–785.14.Mayer S,Davis S,Skolnick B,et al.Can a subset of intra-cerebral hemorrhage patients benefit from hemostatic ther-apy with recombinant activated factor VII?Stroke2009;40:833–840.15.Qureshi AI,Palesch YY.Antihypertensive Treatment ofAcute Cerebral Hemorrhage(ATACH)II:design,meth-ods,and rationale.Neurocrit Care Epub2011May28.Refresh Your Annual Meeting Experience with New2012AAN On Demand●More than600hours of cutting-edge educational content and breakthrough scientific research ●Online access within24hours of end of program●Mobile streaming for most iPad®,iPhone®,and Android®devices●USB Flash Drive offers convenient offline access(shipped after the Annual Meeting)●Enhanced browser,search,and improved interface for better overall experienceGet a great value with special pricing on AAN On Demand and the Syllabi on CD.Learn more at /view/ondemand2.DOI 10.1212/WNL.0b013e318260cbba; Published online before print June 27, 2012;2012;79;314Neurology Candice Delcourt, Yining Huang, Hisatomi Arima, et al.studyHematoma growth and outcomes in intracerebral hemorrhage : The INTERACT1January 3, 2013This information is current as ofServices Updated Information &/content/79/4/314.full.html including high resolution figures, can be found at:Supplementary Material3e318260cbba.DC3.html /content/suppl/2013/01/03/WNL.0b013e318260cbba.DC2.html /content/suppl/2012/06/28/WNL.0b013e318260cbba.DC1.html /content/suppl/2012/06/28/WNL.0b01Supplementary material can be found at:References /content/79/4/314.full.html#ref-list-1This article cites 14 articles, 8 of which can be accessed free at:Citationsls /content/79/4/314.full.html#related-ur This article has been cited by 2 HighWire-hosted articles:Subspecialty Collections/cgi/collection/outcome_research Outcome researchage /cgi/collection/intracerebral_hemorrh Intracerebral hemorrhagezed_controlled_consort_agreement /cgi/collection/clinical_trials_randomi agreement)Clinical trials Randomized controlled (CONSORT following collection(s):This article, along with others on similar topics, appears in the Permissions & Licensing/misc/about.xhtml#permissions tables) or in its entirety can be found online at:Information about reproducing this article in parts (figures,Reprints/misc/addir.xhtml#reprintsus Information about ordering reprints can be found online:。