Rationale, Design, and Implementation of Aggressive Risk Factor Management in the Stenting and Aggressive Medical Management for Prevention of Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) Trial
2012; Lippincott Williams & Wilkins; Volume: 5; Issue: 5 Linguagem: Inglês
10.1161/circoutcomes.112.966911
ISSN1941-7705
AutoresTanya N. Turan, Michael Lynn, Azhar Nizam, Bethany F Lane, Brent M. Egan, Ngoc‐Anh Le, Maria F. Lopes‐Virella, Kathie L. Hermayer, Oscar Benavente, Carole L. White, W. Virgil Brown, Michelle F. Caskey, Meghan R. Steiner, Nicole Vilardo, Andrew Stufflebean, Colin P. Derdeyn, David Fiorella, Scott Janis, Marc I. Chimowitz,
Tópico(s)Health Systems, Economic Evaluations, Quality of Life
ResumoHomeCirculation: Cardiovascular Quality and OutcomesVol. 5, No. 5Rationale, Design, and Implementation of Aggressive Risk Factor Management in the Stenting and Aggressive Medical Management for Prevention of Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) Trial Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBRationale, Design, and Implementation of Aggressive Risk Factor Management in the Stenting and Aggressive Medical Management for Prevention of Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) Trial Tanya N. Turan, MD, MS, Michael J. Lynn, MS, Azhar Nizam, MS, Bethany Lane, RN, MSN, Brent M. Egan, MD, Ngoc-Anh Le, PhD, Maria F. Lopes-Virella, MD, PhD, Kathie L. Hermayer, MD, MS, Oscar Benavente, MD, Carole L. White, PhD, RN, W. Virgil Brown, MD, Michelle F. Caskey, BA, Meghan R. Steiner, MS, Nicole Vilardo, BA, Andrew Stufflebean, BA, Colin P. Derdeyn, MD, David Fiorella, MD, PhD, Scott Janis, PhD, Marc I. Chimowitz, MBChB and for the SAMMPRIS Investigators. Tanya N. TuranTanya N. Turan From the Medical University of South Carolina, Charleston (T.N.T., B.M.E., M.F.L.-V., K.L.H., M.F.C., M.R.S., A.S., M.I.C.); Emory University, Atlanta, GA (M.J.L., A.N., B.L, N.-A.L., W.V.B.,); Atlanta VAMC, Decatur, GA (N.-A.L, W.V.B.); University of British Columbia, Vancouver, Canada (O.B.); University of Texas Health Science Center at San Antonio (C.L.W.); Dartmouth Medical School, Hanover, NH (N.V.); Washington University, St. Louis, MI (C.P.D.); State University of New York at Stony Brook (D.F.); National Institute of Neurological Disorders and Stroke, Bethesda, MD (S.J.). , Michael J. LynnMichael J. Lynn From the Medical University of South Carolina, Charleston (T.N.T., B.M.E., M.F.L.-V., K.L.H., M.F.C., M.R.S., A.S., M.I.C.); Emory University, Atlanta, GA (M.J.L., A.N., B.L, N.-A.L., W.V.B.,); Atlanta VAMC, Decatur, GA (N.-A.L, W.V.B.); University of British Columbia, Vancouver, Canada (O.B.); University of Texas Health Science Center at San Antonio (C.L.W.); Dartmouth Medical School, Hanover, NH (N.V.); Washington University, St. Louis, MI (C.P.D.); State University of New York at Stony Brook (D.F.); National Institute of Neurological Disorders and Stroke, Bethesda, MD (S.J.). , Azhar NizamAzhar Nizam From the Medical University of South Carolina, Charleston (T.N.T., B.M.E., M.F.L.-V., K.L.H., M.F.C., M.R.S., A.S., M.I.C.); Emory University, Atlanta, GA (M.J.L., A.N., B.L, N.-A.L., W.V.B.,); Atlanta VAMC, Decatur, GA (N.-A.L, W.V.B.); University of British Columbia, Vancouver, Canada (O.B.); University of Texas Health Science Center at San Antonio (C.L.W.); Dartmouth Medical School, Hanover, NH (N.V.); Washington University, St. Louis, MI (C.P.D.); State University of New York at Stony Brook (D.F.); National Institute of Neurological Disorders and Stroke, Bethesda, MD (S.J.). , Bethany LaneBethany Lane From the Medical University of South Carolina, Charleston (T.N.T., B.M.E., M.F.L.-V., K.L.H., M.F.C., M.R.S., A.S., M.I.C.); Emory University, Atlanta, GA (M.J.L., A.N., B.L, N.-A.L., W.V.B.,); Atlanta VAMC, Decatur, GA (N.-A.L, W.V.B.); University of British Columbia, Vancouver, Canada (O.B.); University of Texas Health Science Center at San Antonio (C.L.W.); Dartmouth Medical School, Hanover, NH (N.V.); Washington University, St. Louis, MI (C.P.D.); State University of New York at Stony Brook (D.F.); National Institute of Neurological Disorders and Stroke, Bethesda, MD (S.J.). , Brent M. EganBrent M. Egan From the Medical University of South Carolina, Charleston (T.N.T., B.M.E., M.F.L.-V., K.L.H., M.F.C., M.R.S., A.S., M.I.C.); Emory University, Atlanta, GA (M.J.L., A.N., B.L, N.-A.L., W.V.B.,); Atlanta VAMC, Decatur, GA (N.-A.L, W.V.B.); University of British Columbia, Vancouver, Canada (O.B.); University of Texas Health Science Center at San Antonio (C.L.W.); Dartmouth Medical School, Hanover, NH (N.V.); Washington University, St. Louis, MI (C.P.D.); State University of New York at Stony Brook (D.F.); National Institute of Neurological Disorders and Stroke, Bethesda, MD (S.J.). , Ngoc-Anh LeNgoc-Anh Le From the Medical University of South Carolina, Charleston (T.N.T., B.M.E., M.F.L.-V., K.L.H., M.F.C., M.R.S., A.S., M.I.C.); Emory University, Atlanta, GA (M.J.L., A.N., B.L, N.-A.L., W.V.B.,); Atlanta VAMC, Decatur, GA (N.-A.L, W.V.B.); University of British Columbia, Vancouver, Canada (O.B.); University of Texas Health Science Center at San Antonio (C.L.W.); Dartmouth Medical School, Hanover, NH (N.V.); Washington University, St. Louis, MI (C.P.D.); State University of New York at Stony Brook (D.F.); National Institute of Neurological Disorders and Stroke, Bethesda, MD (S.J.). , Maria F. Lopes-VirellaMaria F. Lopes-Virella From the Medical University of South Carolina, Charleston (T.N.T., B.M.E., M.F.L.-V., K.L.H., M.F.C., M.R.S., A.S., M.I.C.); Emory University, Atlanta, GA (M.J.L., A.N., B.L, N.-A.L., W.V.B.,); Atlanta VAMC, Decatur, GA (N.-A.L, W.V.B.); University of British Columbia, Vancouver, Canada (O.B.); University of Texas Health Science Center at San Antonio (C.L.W.); Dartmouth Medical School, Hanover, NH (N.V.); Washington University, St. Louis, MI (C.P.D.); State University of New York at Stony Brook (D.F.); National Institute of Neurological Disorders and Stroke, Bethesda, MD (S.J.). , Kathie L. HermayerKathie L. Hermayer From the Medical University of South Carolina, Charleston (T.N.T., B.M.E., M.F.L.-V., K.L.H., M.F.C., M.R.S., A.S., M.I.C.); Emory University, Atlanta, GA (M.J.L., A.N., B.L, N.-A.L., W.V.B.,); Atlanta VAMC, Decatur, GA (N.-A.L, W.V.B.); University of British Columbia, Vancouver, Canada (O.B.); University of Texas Health Science Center at San Antonio (C.L.W.); Dartmouth Medical School, Hanover, NH (N.V.); Washington University, St. Louis, MI (C.P.D.); State University of New York at Stony Brook (D.F.); National Institute of Neurological Disorders and Stroke, Bethesda, MD (S.J.). , Oscar BenaventeOscar Benavente From the Medical University of South Carolina, Charleston (T.N.T., B.M.E., M.F.L.-V., K.L.H., M.F.C., M.R.S., A.S., M.I.C.); Emory University, Atlanta, GA (M.J.L., A.N., B.L, N.-A.L., W.V.B.,); Atlanta VAMC, Decatur, GA (N.-A.L, W.V.B.); University of British Columbia, Vancouver, Canada (O.B.); University of Texas Health Science Center at San Antonio (C.L.W.); Dartmouth Medical School, Hanover, NH (N.V.); Washington University, St. Louis, MI (C.P.D.); State University of New York at Stony Brook (D.F.); National Institute of Neurological Disorders and Stroke, Bethesda, MD (S.J.). , Carole L. WhiteCarole L. White From the Medical University of South Carolina, Charleston (T.N.T., B.M.E., M.F.L.-V., K.L.H., M.F.C., M.R.S., A.S., M.I.C.); Emory University, Atlanta, GA (M.J.L., A.N., B.L, N.-A.L., W.V.B.,); Atlanta VAMC, Decatur, GA (N.-A.L, W.V.B.); University of British Columbia, Vancouver, Canada (O.B.); University of Texas Health Science Center at San Antonio (C.L.W.); Dartmouth Medical School, Hanover, NH (N.V.); Washington University, St. Louis, MI (C.P.D.); State University of New York at Stony Brook (D.F.); National Institute of Neurological Disorders and Stroke, Bethesda, MD (S.J.). , W. Virgil BrownW. Virgil Brown From the Medical University of South Carolina, Charleston (T.N.T., B.M.E., M.F.L.-V., K.L.H., M.F.C., M.R.S., A.S., M.I.C.); Emory University, Atlanta, GA (M.J.L., A.N., B.L, N.-A.L., W.V.B.,); Atlanta VAMC, Decatur, GA (N.-A.L, W.V.B.); University of British Columbia, Vancouver, Canada (O.B.); University of Texas Health Science Center at San Antonio (C.L.W.); Dartmouth Medical School, Hanover, NH (N.V.); Washington University, St. Louis, MI (C.P.D.); State University of New York at Stony Brook (D.F.); National Institute of Neurological Disorders and Stroke, Bethesda, MD (S.J.). , Michelle F. CaskeyMichelle F. Caskey From the Medical University of South Carolina, Charleston (T.N.T., B.M.E., M.F.L.-V., K.L.H., M.F.C., M.R.S., A.S., M.I.C.); Emory University, Atlanta, GA (M.J.L., A.N., B.L, N.-A.L., W.V.B.,); Atlanta VAMC, Decatur, GA (N.-A.L, W.V.B.); University of British Columbia, Vancouver, Canada (O.B.); University of Texas Health Science Center at San Antonio (C.L.W.); Dartmouth Medical School, Hanover, NH (N.V.); Washington University, St. Louis, MI (C.P.D.); State University of New York at Stony Brook (D.F.); National Institute of Neurological Disorders and Stroke, Bethesda, MD (S.J.). , Meghan R. SteinerMeghan R. Steiner From the Medical University of South Carolina, Charleston (T.N.T., B.M.E., M.F.L.-V., K.L.H., M.F.C., M.R.S., A.S., M.I.C.); Emory University, Atlanta, GA (M.J.L., A.N., B.L, N.-A.L., W.V.B.,); Atlanta VAMC, Decatur, GA (N.-A.L, W.V.B.); University of British Columbia, Vancouver, Canada (O.B.); University of Texas Health Science Center at San Antonio (C.L.W.); Dartmouth Medical School, Hanover, NH (N.V.); Washington University, St. Louis, MI (C.P.D.); State University of New York at Stony Brook (D.F.); National Institute of Neurological Disorders and Stroke, Bethesda, MD (S.J.). , Nicole VilardoNicole Vilardo From the Medical University of South Carolina, Charleston (T.N.T., B.M.E., M.F.L.-V., K.L.H., M.F.C., M.R.S., A.S., M.I.C.); Emory University, Atlanta, GA (M.J.L., A.N., B.L, N.-A.L., W.V.B.,); Atlanta VAMC, Decatur, GA (N.-A.L, W.V.B.); University of British Columbia, Vancouver, Canada (O.B.); University of Texas Health Science Center at San Antonio (C.L.W.); Dartmouth Medical School, Hanover, NH (N.V.); Washington University, St. Louis, MI (C.P.D.); State University of New York at Stony Brook (D.F.); National Institute of Neurological Disorders and Stroke, Bethesda, MD (S.J.). , Andrew StufflebeanAndrew Stufflebean From the Medical University of South Carolina, Charleston (T.N.T., B.M.E., M.F.L.-V., K.L.H., M.F.C., M.R.S., A.S., M.I.C.); Emory University, Atlanta, GA (M.J.L., A.N., B.L, N.-A.L., W.V.B.,); Atlanta VAMC, Decatur, GA (N.-A.L, W.V.B.); University of British Columbia, Vancouver, Canada (O.B.); University of Texas Health Science Center at San Antonio (C.L.W.); Dartmouth Medical School, Hanover, NH (N.V.); Washington University, St. Louis, MI (C.P.D.); State University of New York at Stony Brook (D.F.); National Institute of Neurological Disorders and Stroke, Bethesda, MD (S.J.). , Colin P. DerdeynColin P. Derdeyn From the Medical University of South Carolina, Charleston (T.N.T., B.M.E., M.F.L.-V., K.L.H., M.F.C., M.R.S., A.S., M.I.C.); Emory University, Atlanta, GA (M.J.L., A.N., B.L, N.-A.L., W.V.B.,); Atlanta VAMC, Decatur, GA (N.-A.L, W.V.B.); University of British Columbia, Vancouver, Canada (O.B.); University of Texas Health Science Center at San Antonio (C.L.W.); Dartmouth Medical School, Hanover, NH (N.V.); Washington University, St. Louis, MI (C.P.D.); State University of New York at Stony Brook (D.F.); National Institute of Neurological Disorders and Stroke, Bethesda, MD (S.J.). , David FiorellaDavid Fiorella From the Medical University of South Carolina, Charleston (T.N.T., B.M.E., M.F.L.-V., K.L.H., M.F.C., M.R.S., A.S., M.I.C.); Emory University, Atlanta, GA (M.J.L., A.N., B.L, N.-A.L., W.V.B.,); Atlanta VAMC, Decatur, GA (N.-A.L, W.V.B.); University of British Columbia, Vancouver, Canada (O.B.); University of Texas Health Science Center at San Antonio (C.L.W.); Dartmouth Medical School, Hanover, NH (N.V.); Washington University, St. Louis, MI (C.P.D.); State University of New York at Stony Brook (D.F.); National Institute of Neurological Disorders and Stroke, Bethesda, MD (S.J.). , Scott JanisScott Janis From the Medical University of South Carolina, Charleston (T.N.T., B.M.E., M.F.L.-V., K.L.H., M.F.C., M.R.S., A.S., M.I.C.); Emory University, Atlanta, GA (M.J.L., A.N., B.L, N.-A.L., W.V.B.,); Atlanta VAMC, Decatur, GA (N.-A.L, W.V.B.); University of British Columbia, Vancouver, Canada (O.B.); University of Texas Health Science Center at San Antonio (C.L.W.); Dartmouth Medical School, Hanover, NH (N.V.); Washington University, St. Louis, MI (C.P.D.); State University of New York at Stony Brook (D.F.); National Institute of Neurological Disorders and Stroke, Bethesda, MD (S.J.). , Marc I. ChimowitzMarc I. Chimowitz From the Medical University of South Carolina, Charleston (T.N.T., B.M.E., M.F.L.-V., K.L.H., M.F.C., M.R.S., A.S., M.I.C.); Emory University, Atlanta, GA (M.J.L., A.N., B.L, N.-A.L., W.V.B.,); Atlanta VAMC, Decatur, GA (N.-A.L, W.V.B.); University of British Columbia, Vancouver, Canada (O.B.); University of Texas Health Science Center at San Antonio (C.L.W.); Dartmouth Medical School, Hanover, NH (N.V.); Washington University, St. Louis, MI (C.P.D.); State University of New York at Stony Brook (D.F.); National Institute of Neurological Disorders and Stroke, Bethesda, MD (S.J.). and for the SAMMPRIS Investigators. From the Medical University of South Carolina, Charleston (T.N.T., B.M.E., M.F.L.-V., K.L.H., M.F.C., M.R.S., A.S., M.I.C.); Emory University, Atlanta, GA (M.J.L., A.N., B.L, N.-A.L., W.V.B.,); Atlanta VAMC, Decatur, GA (N.-A.L, W.V.B.); University of British Columbia, Vancouver, Canada (O.B.); University of Texas Health Science Center at San Antonio (C.L.W.); Dartmouth Medical School, Hanover, NH (N.V.); Washington University, St. Louis, MI (C.P.D.); State University of New York at Stony Brook (D.F.); National Institute of Neurological Disorders and Stroke, Bethesda, MD (S.J.). Originally published1 Sep 2012https://doi.org/10.1161/CIRCOUTCOMES.112.966911Circulation: Cardiovascular Quality and Outcomes. 2012;5:e51–e60IntroductionThe value of comprehensive intensive atherosclerotic risk factor control in patients with coronary artery disease is well established. In 2007, the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial demonstrated that among patients with stable coronary disease, intensive management of vascular risk factors was as good as endovascular intervention plus intensive medical management for preventing cardiac ischemic events.1 Yet, despite the fact that atherosclerotic risk factor control in patients with stroke or transient ischemic attack is recommended by guidelines,2 a multimodal approach to prevention has not previously been tested in patients with atherosclerotic stroke. Older atherosclerotic stroke prevention trials comparing carotid revascularization with medical therapy, such as North American Symptomatic Carotid Endarterectomy Trial (NASCET)3 and Asymptomatic Carotid Atherosclerosis Study (ACAS),4 were performed in an era before statins and angiotensin converting enzyme inhibitors became standard of care, and therefore risk factor control was not adequate by today's standards. Even recent trials comparing carotid revascularization procedures5,6 had little emphasis on risk factor control in their design and therefore had little impact on blood pressure and cholesterol measures at 1 year.7,8 Among stroke prevention trials in patients with heterogeneous causes of stroke, several trials have studied the effects of specific risk factor medications9–11 or of intensive control of a particular risk factor, such as blood pressure,12 but no stroke prevention trials have used a mutimodal aggressive risk factor approach.Among patients with intracranial atherosclerosis, which may be the most common cause of stroke worldwide,13 risk factor control is also believed to be important for stroke prevention. The Warfarin Aspirin Symptomatic Intracranial Disease (WASID) trial, in which patients with symptomatic intracranial stenosis were managed with either warfarin or aspirin and usual risk factor management,14 showed that patients with poorly controlled blood pressure and elevated cholesterol during follow-up had significantly higher rates of recurrent stroke and other vascular events,15 suggesting that aggressive management of vascular risk factors may benefit these patients. However, the impact of multimodal aggressive risk factor control as a primary treatment strategy in patients with intracranial stenosis had not been assessed. Endovascular treatment of intracranial stenosis was also an emerging, yet unproven, therapy. Therefore, in an effort to study these 2 treatment strategies, the Stenting and Aggressive Medical Management for Prevention of Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) trial was designed to compare aggressive medical management alone versus aggressive medical management plus percutaneous transluminal angioplasty and stenting. Thus, the SAMMPRIS trial became the first multicenter stroke prevention trial to encorporate multimodal, protocol-driven risk factor control in the design. This article focuses on the rationale, design, and implementation of the intensive risk factor management protocols in SAMMPRIS and describes the challenges in implementing these protocols during the trial and how the challenges have been managed.Overall SAMMPRIS DesignThe overall design of SAMMPRIS has been described previously.16 In brief, SAMMPRIS is an ongoing investigator-initiated and designed Phase III randomized, multicenter trial funded by the National Institute of Neurological Disorders and Stroke in which eligible patients were randomized at 50 sites to aggressive medical therapy alone or percutaneous transluminal angioplasty and stenting using the Wingspan stent system plus aggressive medical therapy. The main eligibility criteria were TIA or nondisabling stroke within 30 days prior to enrollment caused by 70% to 99% stenosis of a major intracranial artery (middle cerebral artery, carotid, vertebral, or basilar). The primary outcome is stroke or death within 30 days after enrollment or after a revascularization procedure for the qualifying lesion performed during the follow-up period or stroke in the territory of the qualifying artery beyond 30 days. Aggressive medical therapy includes aspirin 325 mg/day during the entire follow-up period (estimated mean follow-up of ≈32 months), clopidogrel 75 mg per day for 90 days after enrollment, and aggressive risk factor management primarily targeting systolic blood pressure (SBP) <140 mm Hg (<130 if diabetic) and low-density lipoprotein cholesterol (LDLc) <70 mg/dL. Risk factor management of both primary and secondary targets (see Table 1) is performed by the study neurologist and coordinator at each site, assisted by an innovative, evidence-based, educational, lifestyle modification program (INTERxVENT) that is administered at regularly scheduled times to all patients throughout the study.Table 1. SAMMPRIS Risk Factor Targets and Their MeasurementRisk FactorGoalMeasurementPrimary risk factors LDLc<70 mg/dLCentral lab- Direct LDL measurement* Systolic blood pressure<140 mm Hg (<130 if diabetic)Using standardized device provided to siteSecondary risk factors Non-HDLc<100 mg/dLCentral lab HbA1c<7.0%Local lab SmokingCessationSelf reported (PACE score†) Weight managementFor initial BMI of 25–27 kg/m2: target BMI 27 kg/m2: target 10% weight lossHeight at baseline Physical activity≥30 min of moderate exercise 3 or more times per weekSelf reported (PACE score†)SAMMPRIS indicates Stenting and Aggressive Medical Management for Prevention of Recurrent Stroke in Intracranial Stenosis; LDLc, low-density lipoprotein cholesterol; LDL, low-density lipoprotein; HDLc, high-density lipoprotein cholesterol; and HbA1c, hemoglobin A1c.*Measured by homogeneous enzymatic method (www.sekisui diagnostics.com).†Physician-based Assessment and Counseling for Exercise (PACE) questionaire is performed for smoking and exercise.The target sample size in SAMMPRIS was 764 patients, but enrollment was stopped early by National Institute of Neurological Disorders and Stroke on the basis of recommendation by the independent Data Safety Monitoring Board on April 5, 2011 due primarily to safety concerns regarding the periprocedural stroke and death risk in the percutaneous transluminal angioplasty and stenting group.17 At the time when enrollment was stopped, 451 patients had been enrolled and the primary event rate in the medical arm was substantially lower than anticipated.17 Follow-up with aggressive medical management of all enrolled patients will continue until March 2013, after which the final outcome and risk factor data will be available for analysis.Rationale for Incorporating Aggressive Risk Factor ManagementAggressive management of vascular risk factors was incorporated into the SAMMPRIS design for several reasons: (1) In the WASID study14 (which included patients with stroke or TIA within the previous 90 days that was due to 50% to 99% intracranial stenosis) risk factors were managed by the study neurologist in association with the patient's primary care physician. National guidelines for treatment of risk factors were provided to the neurologist at each site, but no specific protocols to address risk factors were followed. Table 2 (reproduced from Chaturvedi et al15) shows how often risk factors exceeded prespecified target goals at baseline and year 1 (study period: 1999–2003) in WASID. Some progress was made in treating cholesterol and smoking within the first year, but not in lowering blood pressure. Many patients still had uncontrolled vascular risk factors, suggesting that simply providing guidelines for risk factor control was not sufficient to achieve the desired targets. Failure to achieve risk factor targets in WASID appeared to have important clinical consequences, because good control of blood pressure and cholesterol levels during follow-up was associated with reductions in the risk of stroke, myocardial infarction and vascular death.15 (2) Other secondary prevention stroke trials of patients with heterogeneous causes of stroke had shown that treatment of elevated LDLc11 and blood pressure10 reduced the risk of recurrent stroke. (3) Among patients with stable coronary artery disease, intensive risk factor management alone was shown to be as good as endovascular intervention plus either usual medical management or intensive medical management in preventing cardiac ischemic events.1,18 (4) If usual medical management was compared with stenting plus usual medical management in SAMMPRIS and the stenting arm was found to be superior, stenting would become the standard of care for these patients. It would then be very difficult to perform a subsequent trial to determine whether aggressive medical management alone could obviate the need for stenting. Thus, it was critical to determine within SAMMPRIS whether aggressive medical therapy obviated the need for stenting.Table 2. Control of Vascular Risk Factors in WASIDRisk FactorBaseline (%)Year 1 Visit (%)SBP ≥140 mm Hg5150Cholesterol ≥200 mg/dL5037*LDLc ≥100 mg/dL7158*LDLc ≥70 mg/dL9488†HDLc 7%‡6456Smoking2117§No alcohol5568*WASID indicates Warfarin Aspirin Symptomatic Intracranial Disease; SBP, systolic blood pressure; LDLc, low-density lipoprotein cholesterol; and HDLc, high-density lipoprotein cholesterol.P values comparing percentage at baseline and 1 year.*P<0.001†P<0.05‡Diabetics only.§P<0.01Rationale for Specific Risk Factor TargetsSystolic Blood PressureThe Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure recommends a target SBP of <140 mm Hg (<130 mm Hg in diabetics)19 and the American Heart Association/American Stroke Association (AHA/ASA) also endorses this blood pressure target for stroke patients.2 In WASID during a mean follow-up of 1.8 years, 23% of patients with mean SBP ≥140 mm Hg had a recurrent ischemic stroke compared with 15% of patients with mean SBP <140 mm Hg (hazard ratio, 1.63; 95% confidence interval [CI], 1.11–2.40; P=0.01),15,20 supporting the use of the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure target in SAMMPRIS.Low-Density Lipoprotein cholesterolAt the time of WASID, the Second Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel (ATP) II) recommended targeting LDLc <100 mg/dL.21 In WASID during a mean follow-up of 1.8 years, 19% of patients with a mean LDLc ≥100 mg/dL had a recurrent ischemic stroke compared with 11% of patients with a mean LDLc <100 mg/dL (hazard ratio, 1.72; 95% CI, 1.04–2.85; P=0.03).15,20 Since the completion of WASID, the NCEP guidelines were updated to include a target LDLc of <70 mg/dL for very high-risk patients.22,23 In WASID, only 10% of patients achieved a mean LDLc <70 mg/dL by the end of Year 2, but the data was strongly suggestive of the fact that achieving an LDLc <70 mg/dL was highly beneficial, as 23% of patients with a mean LDLc ≥70 mg/dL during follow-up had a primary end point (stroke, vascular death, or MI) compared with 7% of patients with an LDLc <70 mg/dL (P=0.09),15 supporting the use of the NCEP target for very high-risk patients in SAMMPRIS.Non-High-Density Lipoprotein CholesterolNon-HDLc was selected as a secondary target in SAMMPRIS because the NCEP ATP III guidelines considered it an important secondary target and recommended achieving a target of 200 mg/dL. In WASID, there was an association between elevated non-HDLc ≥130 mg/dL (the NCEP ATP II recommended target at the time of WASID follow-up) and a higher risk of recurrent stroke (hazard ratio, 1.94; 95% CI, 1.15–3.27; P=0.01).15,20 Evidence at the time of the SAMMPRIS design did not support specific target levels for other cholesterol subfractions, such as HDLc.Hemoglobin A1cHemoglobin A1c (HbA1c) <7.0% was selected as a secondary target for diabetic patients in SAMMPRIS because the American Diabetes Association24 and the ASA/AHA Stroke Council25 guidelines endorsed this target. In WASID, 26% of patients with a mean HbA1c ≥7.0% had a recurrent stroke compared with 15% patients with mean HbA1c <7.0% (hazard ratio, 1.7; 95% CI, 0.81–3.58; P=0.15).20Smoking CessationSmoking cessation was chosen as a risk factor target because the US Department of Health and Human Services Surgeon General's most recent report on the effects of smoking concluded that there was sufficient evidence to establish a causal relationship between smoking and stroke,26 and because the AHA/ASA Stroke Council recommended strongly advising every patient with stroke or TIA who has smoked in the last year to quit.25Weight ManagementWeight Management was included because the 2006 Update of the AHA Scientific Statement on Obesity and Heart Disease From the Obesity Committee of the Council on Nutrition, Physical Activity, and Metabolism27 listed obesity as an independent modifiable risk factor for stroke; and recommended a combination of diet, physical activity, and behavior therapy to achieve a BMI of 27 kg/m2.Physical ActivityThe physical activity target was included based on the AHA/ASA Stroke Prevention Guidelines statement recommendation that patients with ischemic stroke or TIA who are capable of engaging in physical activity participate in at least 30 minutes of moderate-intensity physical exercise most days.25Rationale for Incorporating a Lifestyle Modification ProgramSeveral studies have shown a large gap between recommended target levels for risk factors and those achieved in clinical practice.15,28–30 Although cardiac rehabilitation programs designed to address this risk factor treatment gap exist at most large hospitals, not all healthcare facilities offer this service. Commercially available lifestyle modification programs have emerged to help patients and employees of large corporations achieve risk factor targets. These programs have improved the achievement of risk factor targets in a variety of populations, including patients who have previously suffered a stroke or TIA and those with multiple risk factors.31–33Design and Implementation of the Risk Factor Protocols in SAMMPRISThe design of risk factor management in SAMMPRIS included the following strategies to help control risk factors: providing study medications to subjects, providing medication titration algorithms for the primary risk factors to study investigators, standardizing the measurement of primary risk factor levels, providing an innovative lifestyle management program to subjects, and central oversight of risk factor performance.The Risk Factor Team includes the patient's study neurologist, the patient's study coordinator, and the patient's INTERxVENT lifestyle coach. The neurologist and coordinator follow protocols for the primary risk factors and collaborate with the patient's outside physicians to achieve secondary risk factor targets using national guidelines, which include general recommendations for lifestyle modification and medication use. The lifestyle coach recommends and reinforces specific healthy lifestyle behaviors.Study MedicationsMedications necessary to achieve the primary risk factor targets (LDLc and SBP) were provided to subjects free of charge to enhance compliance. To achieve the LDLc target of <70 mg/dL, rosuvastatin was selected as the lipid-lowering agent for various reasons. The NCEP III22 and ASA/AHA Stroke Council guidelines25 recommended statins for the treatment of hypercholesterolemia, and there was evidence that statins offered pleiotropic benefits such as stabilizing atherosclerotic plaques, enhancing endothelial function, decreasing oxidative stress and inflammation, inhibiting thrombosis, and possibly having neuroprotective effects.34,35 Rosuvastati
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