Secondary Prevention after Ischemic Strokeor Transient Ischemic AttackSripal Bangalore, MD, MHA,a Lee Schwamm, MD,b Eric E. Smith, MD, MPH,c Inder M. Singh, MD, MS,d

Steering CommaNew York Univ niversity ofCalgary, Alberta rham, NC;fAhmanson-UCL r, and HarvardMedical School,

presented with transient ischemic attack.

cal Research Center, Theork University School of

CLINICAL RESEARCH STUDYFunding: See last page of article.Conicts of Interest: See last page of article.

Catheterization Laboratory, Cardiovascular CliniLeon H. Charney Division of Cardiology, New YCONCLUSIONS: In patients surviving an ischemic stroke or transient ischemic attack, adherence to evidence-based secondary prevention discharge measures were consistently less for patients with transient ischemicattack, thus representing a missed opportunity at instituting preventive measures to reduce the risk ofrecurrent stroke. 2014 Elsevier Inc. All rights reserved. The American Journal of Medicine (2014) 127, 728-738KEYWORDS: Secondary prevention; Stroke; Transient ischemic attacksAuthorship: SRequests for r

MHA, FACC, FA

0002-9343/$ -seehttp://dx.doi.org/1e Gregg C. Fonarow, MD,f Deepak L. Bhatt, MD, MPH;g for the Get With the Guidelines-Stroittee and Investigators

ersity Medical Center, New York; bMassachusetts General Hospital, Boston; cHotchkiss Brain Institute, U, Canada; dMercy Heart and Vascular Institute, Sacramento, Calif; eDuke Clinical Research Institute, DuA Cardiomyopathy Center, Los Angeles, Calif; gBrigham and Womens Hospital Heart & Vascular CenteBoston, Mass.

ABSTRACT

BACKGROUND: Patients with stroke or transient ischemic attack are at increased risk of recurrent stroke.Transient ischemic attack is a harbinger for stroke merely hours to days after the initial transient ischemicattack. There is thus a narrow window of opportunity to initiate evidence-based therapies for secondaryprevention of stroke. Our objective was to assess hospital adherence at discharge to secondary preventionmeasures after transient ischemic attack or ischemic stroke.METHODS: Observational study of patients in the Get With The Guidelines-Stroke registry from 2007 to2011. Patients were divided into 2 cohorts based on presentation: transient ischemic attack versus ischemicstroke. Adherence to evidence-based secondary prevention and other quality measures were assessed.RESULTS: Among the 858,835 patients with transient ischemic attack or ischemic stroke, 259,319 (30%)patients presented with a transient ischemic attack and 599,516 (70%) patients presented with an ischemicstroke. After adjusting for patient and hospital characteristics, adherence to secondary prevention measureswas consistently lower for the transient ischemic attack cohort (vs ischemic stroke cohort), who had lowerodds of being discharged on antithrombotics (odds ratio [OR] 0.63; 95% condence interval [CI],0.59-0.66; P

increased risk of major adverse

a stroke or transientrecurrent stroke, but alsorbidity and mortality.8,9

entive measures after aat aggressive secondaryployed at the time offor transient ischemicowed in clinical practicedy, using data from theregistry, we aimed toprevention measures athemic attack or ischemicfor patients with tran-

ic stroke; and evaluateriod from 2007 to 2011.

oke (GWTG-Stroke)

Study Cohort

injury, or those with syclassied as ischemic str2 cohorts: transient ischemstudy period was from Ja

Patients were excludewith missing data on >admitted to the hospitaischemic attack; 3) theyhad an in-hospital stroke;missing or they left agahospital, or were dischar

Secondary PreventioMeasuresThe outcome measure oondary prevention measincluded performance msures. The discharge peantithrombotic medicatioplatelet agents (aspirin,

ICA

ic ake,

risk of stroke merely havintofor

35 pwe-basgefora mevenrecu

nt IsThe GWTG-Stroke program is a voluntary qualityimprovement program across the US, which collects infor-mation on stroke admission. The methods of the GWTG-Stroke program have been described previously.10-12

Briey, for each hospitalization for stroke or transientischemic attack, information on patient demographics,medical history, in-hospital diagnostic work-up, treatment,emphasize aggressive secondaryprevention measures after eitherischemic attack, not only to reduceto reduce related cardiovascular moThe narrow time window for prevtransient ischemic attack dictates thprevention strategies must be emdischarge during index admissionattack. However, whether this is follis not well characterized. In this stuGet With The Guidelines-Strokeassess the adherence to secondaryhospital discharge after transient iscstroke; compare rates of adherencesient ischemic attack and ischemtemporal trends during the study pe

METHODS

Get With The Guidelines-StrProgramcardiovascular events (w22% at 1year),4-7 with the risk of adversecardiovascular events similar tothat of patients with documentedischemic stroke.5

Randomized trials have shownthat aggressive secondary preven-tion measures after an ischemicstroke or a transient ischemicattack can substantially reduce therisk of recurrent ischemic stroke.The American Heart Association/American Stroke Association(AHA/ASA) guidelines for thesecondary prevention of stroke

the initial TIA, leof opportunitybased therapiestion of stroke.

Among the 858,8ischemic stroke,ence to evidencevention discharconsistently lessthus representingat instituting prreduce the risk ofTransient ischemic attack is a harbinger for stroke, with a90-day stroke rate of w11% and with a recurrent transientischemic attack rate ofw13%.1-3 In addition, approximatelyone quarter of ischemic strokes are preceded by a transientischemic attack, often merely hours or days before theischemic stroke.2 There is thus a narrow time window forprevention of ischemic stroke aftera transient ischemic attack.2 Inaddition to the increased risk ofischemic stroke, patients with tran-sient ischemic attack have an

CLINICAL SIGNIF

Transient ischemharbinger for stro

Bangalore et al Secondary Prevention after Stroke/Transiedischarge medications, counseling, and disposition wereclopidogrel) and anticoagulants (heparin and warfarin); 2)anticoagulation (warfarin, heparin, or other anticoagulants)for atrial brillation (paroxysmal or persistent); 3) lipid-lowering agents for patients with low-density lipoproteincholesterol (LDL) >100 mg/dL; 4) smoking cessationcounseling provided at or before discharge for currentsmokers; 5) stroke education; and 6) weight loss education

for patients with a body mf interest was adherence to sec-ures at hospital discharge. Thiseasures and other quality mea-rformance measures included: 1)ns at discharge, including anti-aspirin/dipyridamole, ticlopidine,graphic evidence of ischemicmptoms lasting >24 hours, wereoke.14 Patients were grouped intoic attack and ischemic stroke. Thenuary 1, 2007 to October 3, 2011.d if: 1) they were enrolled at sites25% of patients; 2) they werel without at least one transientwere transfer-in and -outs; 4) they5) their discharge destination wasinst medical advice, died in theged to hospice (Figure 1).

n and Other Quality-of-careFor the purpose of this analysis,patients in the GWTG-Strokeregistry with a diagnosis of tran-sient ischemic attack or ischemicstroke were included. Transientischemic attack was dened assymptoms that were present at thetime of hospital arrival, lasting

The730measures included: 1) antihypertensive treatment withangiotensin-converting enzyme inhibitor (ACEi) orangiotensin receptor blockers (ARB), beta-blockers, cal-cium channel blockers, or diuretics; 2) LDL documentation;3) intensive statin therapy; and 4) recommendationsregarding diabetes management (medications or diet) inpatients with diabetes.

Statistical AnalysisMultivariable logistic regression analyses were performedto evaluate the adjusted relationship between the 2 patientgroups and the secondary prevention measures and out-comes. All models used a Generalized Estimating Equationapproach to account for within-hospital clustering and wereadjusted for patients baseline characteristics. In addition,the hospital characteristics such as the geographic region,number of beds in the hospital, annual number of strokedischarge, annual intravenous tissue plasminogen activatorvolume, and teaching status were included in the model.

A time-trend analysis was performed to evaluate thechange over time in the core discharge measures. Aninteraction of time-by-patient group was included in themodel to assess whether the temporal trends were different

Figure 1 Patient selection. LAMA left against mtPA tissue plasminogen activator.American Journal of Medicine, Vol 127, No 8, August 2014between ischemic stroke and transient ischemic attack pa-tients after adjusting for baseline covariates described above.

All statistical analyses were performed using SASversion 9.2 (SAS Institute, Cary, NC). All P values were2-sided, with P

Table 1 Baseline Characteristics of Patients with IS or TIA

Variable Overall (n 858,835) TIA (n 259,319) IS (n 599,516) P-valueDemographic

Age 69.98 14.42 69.94 14.63 70.00 14.63 .1399Sex, male 47.15 42.90 48.98

patients (Table 2). Transient ischemic attack patients were

0.73; P 0), but wereless likely to have atrial brillation, diabetes, hypertension,or be smokers, when compared with patients presenting withan ischemic stroke (Table 1). Patients with transientischemic attack had lower total cholesterol, LDL choles-terol, and higher high-density lipoprotein cholesterol whencompared with patients with an ischemic stroke.

In-hospital Treatment and Quality of CarePatients presenting with transient ischemic attack hadshorter symptom onset to arrival time (115 minutes vs 187minutes), with 51% of patients presenting within 2 hours ofsymptoms (Table 2). In patients arriving within 3 hours ofsymptom onset, transient ischemic attack patients were lesslikely to receive computed tomography scan within 25minutes of arrival when compared with the ischemic stroke

Heart rate 79.68 16Systolic blood pressure 156.92 29Diastolic blood pressure 82.86 18BMI 28.14 6.BMI body mass index; CAD coronary artery disease; EMS em

NIH National Institutes of Health; PVD peripheral vascular disease; T*Off-hours dened as holiday or before 7 AM or after 6 PM from MondaTable 1 Continued

Variable Overall (n

732statin for LDL >100 mg/dL (75.0% vs 82.8%), and lesslikely to receive stroke education (73.5% vs 79.4%) andweight loss recommendations (52.2% vs 55.1%) (Table 2).In addition, transient ischemic attack patients were lesslikely to be prescribed an ACEi or an ARB, beta-blocker, ora calcium channel blocker or receive intensive statin therapyat discharge when compared with the ischemic stroke pa-tients (Table 2).

Quality of Care: Multivariable AnalysesIn the multivariable model adjusted for patient/hospitalcharacteristics and accounting for the clustering of datawithin hospitals, adherence to secondary prevention95% CI, 0.85-0.90; P

Table 2 Hospital Characteristics, In-hospital Treatment, Secondary Prevention, and Other Quality-of-care Measures

Variable Overall (n 858,835) TIA (n 259,319) IS (n 599 516) P-valueHospital characteristics

Number of beds* 347 (240-503) 327 (227-470) 353 (248-522)

es: M

juste

Lo95

0.0.0.0.0.0.0.68 0.71 100 0.70 0.Intensive statin therapy (since 2010) 0.76 0.Diabetes medications or ADA diet 1.01 0.

OutcomesDischarge home 7.84 7.Able to ambulate independently (among non-missing) 4.43 4.Able to ambulate independently or with assistance(among non-missing)

5.89 5.

LOS 3 days 4.55 4.ACEi angiotensin-converting enzyme inhibitors; ADA American Diabetes

CI condence interval; CT computed tomography; DVT deep vein thrombohospital stay; ND not documented; OR odds ratio; Ref reference; TIA 86 0.91

7 tonce t

nt IsFigure 2 (A) Adherence to antithrombotics at discharge 200at discharge 2007 to 2011. AF atrial brillation. (C) Adhere

Bangalore et al Secondary Prevention after Stroke/Transiepatients with transient ischemic attack having a stroke,15 andmany of them within hours to days following a transientischemic attack.2 There is thus a narrow time window forinstituting preventive measures including medication, strokeeducation, and counseling in patients with transientischemic attack; and this is at the time of admission for theindex transient ischemic attack. In the Early use of eXistingPREventive Strategies for Stroke (EXPRESS) study, astrategy of urgent assessment and early initiation of existingtreatment in patients with transient ischemic attack reducedthe 90-day risk of recurrent stroke by about 80%.18 Inaddition, urgent assessment and treatment of patients withtransient ischemic attack reduced subsequent hospital bed-days, acute costs, and 6-month disability.19 The AHA/ASAguideline for secondary prevention of stroke therefore placesspecial emphasis on secondary prevention to prevent recur-rent strokes and cardiovascular events.8 These include (butare not limited to) blood pressure reduction (Class I) even inpatients without a documented history of hypertension (ClassIIa); glycemic control in patients with diabetes (Class I);statin therapy with intensive lipid lowering in patients whohave evidence of atherosclerosis, an LDL level 100 mg/dL(Class I); smoking cessation (Class I); antiplatelet therapywith aspirin (Class I); and anticoagulation in patients withparoxysmal or permanent atrial brillation (Class I).8,9 Thesemeasures have been shown to reduce the risk of recurrentstroke and cardiovascular events. However, the performancemeasures endorsed by the National Quality Forum is focused

2007 to 2011.2011. (B) Adherence to anticoagulation for atrial brillationo statins at discharge for low-density lipoprotein >100 mg/dLchemic Attack 735on patients with ischemic stroke and has largely ignoredpatients with transient ischemic attack; a critical gap thatneeds to be urgently addressed.

A Missed OpportunityThe results of the present study suggest that in patientspresenting with a clinically less dramatic event such as thosewith a transient ischemic attack, the hospital adherence tosecondary prevention measures was consistently inferior,with lower odds of being discharged on antithrombotics,anticoagulants for atrial brillation, statins, or to receivedysphagia screening, LDL cholesterol measurement, smokingcessation counseling, stroke education, or weight loss rec-ommendations. This represents a missed opportunity atsecondary prevention, as the window for prevention of arecurrent stroke or transient ischemic attack is narrow forthese patients. Since the inception of the GWTG-Strokeprogram, there have been considerable improvements inadherence to these core discharge measures. In the presentstudy, adherence to antithrombotics for patients with transientischemic attack at discharge increased from 94.7% in 2007 to97.1% in 2011. Similarly, the adherence to anticoagulation foratrial brillation at discharge increased from 88.1% to 90.8%and for statins from 62.6% to 85.7%. Although these adher-ence rates for the transient ischemic attack cohort haveimproved in recent years, they were consistently lowercompared with the ischemic stroke cohort. There is, thus,

scharation

TheFigure 3 (A) Adherence to smoking cessation counselling at di2007 to 2011. (C) Adherence to weight management recommend736room for improvement, and efforts must be directed toclose this gap in adherence. Although the adherence todischarge measures was consistently lower for most mea-sures for a transient ischemic attack patient, they were nodifferent for antihypertensive medication usage whencompared with ischemic stroke patients. In addition, thereis controversy about the optimal antihypertensive agent forstroke prevention with the AHA/ASA guidelines advo-cating diuretics or a combination of diuretics with anACEi. In our study, only 20% were on diuretics and 46%on an ACEi or an ARB. Interestingly, the second mostcommon antihypertensive agents used (after ACEi/ARB)were beta-blockers, where the data are rather weak forstroke prevention,20-22 and beta-blockers have beenrelegated to fourth-line agents by major national andinternational hypertension guidelines.23,24

STUDY LIMITATIONSOur data are from a prospective registry of patients from avoluntary quality-reporting program; therefore, adherence toguideline-recommended secondary prevention therapiesmay be higher in these hospitals than in hospitals notparticipating in GWTG-Stroke. If so, it is possible that thedifference in quality of care between transient ischemicattack and ischemic stroke might be even greater innonparticipating hospitals. However, this is still the largestseries reporting secondary prevention after an ischemic stroke

to 2011.ge 2007 to 2011. (B) Adherence to stroke education at discharges at discharge 2007 to 2011. (D) Trends in defect-free care 2007American Journal of Medicine, Vol 127, No 8, August 2014or transient ischemic attack, with data from close to a millionpatients from more than 1500 acute care hospitals. Our dataassessed secondary prevention measures at the time of hos-pital discharge and do not provide data on adherence/compliance with these recommendations post discharge.Reecting a focus of GWTG-Stroke on acute thrombolytictherapy in the emergency department, only transient ischemicattack patients with ongoing symptoms at the time of acti-vation of emergency medical services or admission to theemergency department were included in the registry; there-fore, patients presenting with past resolved transient ischemicattacks are not included in our analysis. However, we have noreason to think that quality of care would be better in patientspresenting with past resolved transient ischemic attacks, andwe suspect that, if different, it would be worse rather thanbetter. Moreover, disparity in the use of evidence-basedtherapies could merely be a reection of physician assess-ment of increased risk of adverse effect for a particular patientsubgroup or a reection of patient choice, which is notcaptured in the database. Moreover, although the relativedifference between the patients cohorts for secondary pre-vention and quality-of-care measures were large, in somecases the absolute differences were rather small.

CONCLUSIONSData from over close to a million patients with ischemicstroke or transient ischemic attack suggest that the hospital

nt Isadherence to evidence-based secondary prevention andother quality-of-care measures at the time of discharge isconsistently lower for patients with transient ischemic attackwhen compared with patients with ischemic stroke. Theadherence to these discharge measures has increased inGWTG-Stroke program from 2007 to 2011 but is stillconsistently lower for the transient ischemic attack cohort.Efforts must be made to close these treatment gaps andmake use of the narrow treatment window available for suchpatients to prevent recurrent cerebrovascular and cardio-vascular events.

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Funding: The GWTG-Stroke program is provided by the AHA/American Stroke Association. The GWTG-Stroke program is currentlysupported in part by a charitable contribution from Janssen PharmaceuticalCompanies of Johnson & Johnson. GWTG-Stroke has been funded in thepast through support from Boehringer Ingelheim, Merck, Bristol-MyersSquib/Sano Pharmaceutical Partnership, and the AHA PharmaceuticalRoundtable. The industry sponsors of GWTG-Stroke had no role in thedesign and conduct of the study; in the collection, analysis, and interpre-tation of the data; or in the preparation, review, or approval of themanuscript.

Conicts of Interest: SB, EES, IMS, and LL report no disclosures. LSreports the following: Serves as the unpaid chair of the AHA GWTGStroke Clinical Working Group; serves as a Stroke Systems of Care ExpertConsultant and measure development expert to the Joint Commission,Coverdell Registry/MA Dept of Public Health; is on the steering com-mittee for the Medtronic Victory AF trial, and the DSMB for the Novo-Nordisk DEVOTE trial. He receives research funding from NINDS andPCORI. GCF reports the following: EmploymentUCLA Employee,which holds a patent on stroke retriever devices National Institutes ofHealthGrants and grants pending. DLB discloses the following re-lationships: Advisory Board, Elsevier; Practice Update Cardiology,Medscape Cardiology, Regado Biosciences; Board of Directors: BostonVA Research Institute, Society of Cardiovascular Patient Care; Chair:American Heart Association Get With The Guidelines Steering Commit-tee; Data Monitoring Committees: Duke Clinical Research Institute;Harvard Clinical Research Institute; Mayo Clinic; Population HealthResearch Institute; Honoraria: American College of Cardiology (Editor,Clinical Trials, Cardiosource), Belvoir Publications (Editor in Chief,Harvard Heart Letter), Duke Clinical Research Institute (clinical trialsteering committees), Harvard Clinical Research Institute (clinical trial

chemic Attack 737steering committee), HMP Communications (Editor in Chief, Journal of

Invasive Cardiology); Population Health Research Institute (clinical trialsteering committee), Slack Publications (Chief Medical Editor, CardiologyTodays Intervention), WebMD (CME steering committees); Other:Clinical Cardiology (Associate Editor); Journal of the American Collegeof Cardiology (Section Editor, Pharmacology); Research Grants: Amarin,

AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, Roche,Sano Aventis, The Medicines Company; Unfunded Research: FlowCo,PLx Pharma, Takeda.

Authorship: All authors had access to the data and a role in writing themanuscript.

738 The American Journal of Medicine, Vol 127, No 8, August 2014

Secondary Prevention after Ischemic Stroke or Transient Ischemic AttackMethodsGet With The Guidelines-Stroke (GWTG-Stroke) ProgramPatient Selection and Study CohortSecondary Prevention and Other Quality-of-care MeasuresStatistical Analysis

ResultsBaseline CharacteristicsIn-hospital Treatment and Quality of CareQuality of Care: Multivariable AnalysesTime Trend

DiscussionPrevention of Recurrent StrokeA Missed Opportunity

Study LimitationsConclusionsReferences