AHA/ASA Guideline Guidelines for the Prevention of Stroke in ...

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Furie et al Prevention of Stroke in Patients With Stroke and TIA 231Table 3.Recommendations for Treatable Vascular Risk FactorsRisk FactorHypertensionDiabetesLipidsRecommendationsBP reduction is recommended for both prevention of recurrent stroke and prevention of other vascular events inpersons who have had an ischemic stroke or TIA and are beyond the first 24 hours (Class I; Level of Evidence A).Because this benefit extends to persons with and without a documented history of hypertension, thisrecommendation is reasonable for all patients with ischemic stroke or TIA who are considered appropriate for BPreduction (Class IIa; Level of Evidence B).An absolute target BP level and reduction are uncertain and should be individualized, but benefit has beenassociated with an average reduction of approximately 10/5 mm Hg, and normal BP levels have been defined as120/80 mm Hg by JNC 7 (Class IIa; Level of Evidence B).Several lifestyle modifications have been associated with BP reduction and are a reasonable part of acomprehensive antihypertensive therapy (Class IIa; Level of Evidence C). These modifications include saltrestriction; weight loss; consumption of a diet rich in fruits, vegetables, and low-fat dairy products; regularaerobic physical activity; and limited alcohol consumption.The optimal drug regimen to achieve the recommended level of reduction is uncertain because direct comparisonsbetween regimens are limited. The available data indicate that diuretics or the combination of diuretics and anACEI are useful (Class I; Level of Evidence A).The choice of specific drugs and targets should be individualized on the basis of pharmacological properties,mechanism of action, and consideration of specific patient characteristics for which specific agents are probablyindicated (eg, extracranial cerebrovascular occlusive disease, renal impairment, cardiac disease, and diabetes)(Class IIa; Level of Evidence B). (New recommendation)Use of existing guidelines for glycemic control and BP targets in patients with diabetes is recommended for patientswho have had a stroke or TIA (Class I; Level of Evidence B). (New recommendation)Statin therapy with intensive lipid-lowering effects is recommended to reduce risk of stroke and cardiovascularevents among patients with ischemic stroke or TIA who have evidence of atherosclerosis, an LDL-C level 100mg/dL, and who are without known CHD (Class I; Level of Evidence B).For patients with atherosclerotic ischemic stroke or TIA and without known CHD, it is reasonable to target areduction of at least 50% in LDL-C or a target LDL-C level of 70 mg/dL to obtain maximum benefit (Class IIa;Level of Evidence B). (New recommendation)Patients with ischemic stroke or TIA with elevated cholesterol or comorbid coronary artery disease should beotherwise managed according to NCEP III guidelines, which include lifestyle modification, dietary guidelines, andmedication recommendations (Class I; Level of Evidence A).Patients with ischemic stroke or TIA with low HDL-C may be considered for treatment with niacin or gemfibrozil(Class IIb; Level of Evidence B).Class/Level ofEvidence*Class I; Level AClass IIa; Level BClass IIa; Level BClass IIa; Level CClass I; Level AClass IIa; Level BClass I; Level BClass I; Level BClass IIa; Level BClass I; Level AClass IIb; Level BCHD indicates coronary heart disease; HDL, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; NCEP III, The Third Report of the NationalCholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Cholesterol in Adults; and SPARCL, Stroke Prevention by AggressiveReduction in Cholesterol.*See Tables 1 and 2 for explanation of class and level of evidence.aerobic physical activity; and limited alcoholconsumption.5. The optimal drug regimen to achieve the recommendedlevel of reduction is uncertain because directcomparisons between regimens are limited. The availabledata indicate that diuretics or the combination ofdiuretics and an ACEI are useful (Class I; Level ofEvidence A). The choice of specific drugs and targetsshould be individualized on the basis of pharmacologicalproperties, mechanism of action, and considerationof specific patient characteristics for which specificagents are probably indicated (eg, extracranial cerebrovascularocclusive disease, renal impairment, cardiacdisease, and diabetes) (Class IIa; Level of EvidenceB). (New recommendation; Table 3)B. DiabetesDiabetes is estimated to affect 8% of the adult population inthe United States. 26 Prevalence is 15% to 33% in patients withischemic stroke. 27–29 Diabetes is a clear risk factor for firststroke, 30–34 but the data supporting diabetes as a risk factorfor recurrent stroke are more sparse. Diabetes mellitus appearsto be an independent predictor of recurrent stroke inpopulation-based studies, 35 and 9.1% of recurrent strokeshave been estimated to be attributable to diabetes. 36,37 Diabeteswas a predictor of the presence of multiple lacunarinfarcts in 2 stroke cohorts. 38,39Normal fasting glucose is defined as glucose 100 mg/dL(5.6 mmol/L), and impaired fasting glucose has been definedas a fasting plasma glucose of 100 mg/dL to 125 mg/dL(5.6 mmol/L to 6.9 mmol/L). 26 A fasting plasma glucose level126 mg/dL (7.0 mmol/L), or A1C 6.5%, or a casualplasma glucose 200 mg/dL (11.1 mmol/L) in the setting ofsymptoms attributable to hyperglycemia meets the thresholdfor the diagnosis of diabetes. 26 A hemoglobin A 1c (HbA 1c )level 7% is defined as inadequate control of hyperglycemia.Diet, exercise, oral hypoglycemic drugs, and insulin arerecommended to gain glycemic control. 26Three major randomized clinical trials of intensive glucosemanagement in persons with diabetes with a history ofcardiovascular disease, stroke, or additional vascular riskDownloaded from stroke.ahajournals.org by on March 8, 2011
232 Stroke January 2011factors have all failed to demonstrate a reduction in cardiovascularevents or death in the groups receiving intensiveglucose therapy. In the Action to Control Cardiovascular Riskin Diabetes (ACCORD) trial, 10 251 patients with type 2diabetes and vascular disease or multiple risk factors wererandomly assigned to an intensive treatment program targetinga glycohemoglobin level of 6% versus a standardprogram with a goal HbA 1c level of 7% to 7.9%. 39 The trialwas halted after a mean of 3.5 years of follow-up because ofan increased risk of death in patients randomized to theintensive treatment program (HR, 1.22; 95% CI, 1.01 to1.46). There was no significant difference in the rate ofnonfatal stroke (HR, 1.06; 95% CI, 0.75 to 1.50; P0.72) orin the primary end point, which was a composite of nonfatalheart attack, nonfatal stroke, and death due to a cardiovascularcause (HR, 0.90; 95% CI, 0.78 to 1.04; P0.16). TheAction in Diabetes and Vascular Disease (ADVANCE) trialalso failed to show a benefit in secondary prevention ofcardiovascular events. In this trial 11 140 patients with type 2diabetes and a history of macrovascular disease or anotherrisk factor were randomly assigned to intensive glucosecontrol (target 6.5%) or standard glucose control (targetHbA 1c 7%). 40 Thirty-two percent of subjects had a historyof major macrovascular disease, including 9% with a historyof stroke. There was no significant reduction in the occurrenceof macrovascular events alone (HR, 0.94; 95% CI, 0.84to 1.06; P0.32) or nonfatal stroke (3.8% in both treatmentarms). In contrast to the ACCORD trial, there were nosignificant differences in the rate of deaths between the studygroups. Finally, the Veterans Affairs Diabetes Trial, consistingof 1791 veterans with type 2 diabetes assigned tointensive blood glucose treatment or standard treatment,found no significant difference between the 2 groups in anycomponent of the primary outcome, which consisted of timeto occurrence of a major cardiovascular event, or in the rateof death due to any cause (HR, 1.07; 95% CI, 0.81 to 1.42;P0.62). 40 The results of these trials indicate the glycemictargets should not be lowered to HbA 1c 6.5% in patientswith a history of cardiovascular disease or the presence ofvascular risk factors.Among patients who have had a stroke or TIA and havediabetes, guidelines have been established for glycemiccontrol 41 and BP management. 14Recently the use of pioglitazone has been evaluated in5238 patients with type 2 diabetes and macrovascular disease.In the PROspective pioglitAzone Clinical Trial In macroVascularEvents (PROactive), there was no significant reductionin the primary end point of all-cause death or cardiovascularevents in patients randomly assigned to pioglitazone comparedwith placebo (HR, 0.78; 95% CI, 0.60 to 1.02). 42,43Remarkably, among patients who entered PROactive with ahistory of stroke, pioglitazone therapy was associated with a47% relative risk reduction in recurrent stroke (HR, 0.53;95% CI, 0.34 to 0.85), and a 28% relative risk reduction instroke, MI, or vascular death (HR, 0.72; 95% CI, 0.53 to1.00). Conversely, rosiglitazone, another of the thiazolidinedioneclass of drugs, has been linked to the occurrenceof heart failure and possible fluid retention, which led to theUS Food and Drug Administration (FDA) requiring a boxedwarning for this class of drugs in 2007. An increased risk ofMI or cardiovascular death with the use of rosiglitazone hasbeen suspected but not conclusively proven. The InsulinResistance Intervention after Stroke (IRIS) trial is an ongoingstudy funded by the National Institute for NeurologicalDisorders and Stroke (NINDS) in which patients with TIA orstroke are randomly assigned to pioglitazone or placebo for aprimary outcome of stroke and MI.Recommendation1. Use of existing guidelines for glycemic control andBP targets in patients with diabetes is recommendedfor patients who have had a stroke or TIA (Class I;Level of Evidence B). (New recommendation; Table 3)C. LipidsLarge epidemiological studies in which ischemic and hemorrhagicstrokes were distinguishable have shown a modestassociation of elevated total cholesterol or low-density lipoproteincholesterol (LDL-C) with increased risk of ischemicstroke and a relationship between low LDL-C and greaterrisk of ICH. 44–46 With regard to other lipid subfractions,recent studies have independently linked higher serum triglyceridelevels with occurrence of ischemic stroke 47,48 andlarge-artery atherosclerotic stroke, 49 as well as associatinglow high-density lipoprotein cholesterol (HDL-C) with riskof ischemic stroke. 50 A meta-analysis of 90 000 patientsincluded in statin trials showed that the larger the reduction inLDL-C, the greater the reduction in stroke risk. 51 It wasunclear, however, up until recently what beneficial role, ifany, that statins played in stroke patients without establishedcoronary heart disease (CHD), with regard to vascular riskreduction, particularly prevention of recurrent stroke. 52A retrospective subset analysis of 3280 subjects in theMedical Research Council/British Heart Foundation HeartProtection Study (HPS) with a remote (mean, 4.3 years)history of symptomatic ischemic cerebrovascular diseaseshowed that simvastatin therapy yielded a 20% reduction inmajor vascular events (HR, 0.80; 95% CI, 0.71 to 0.92). 53 Forthe end point of recurrent strokes, simvastatin exerted no netbenefit (HR, 0.98; 95% CI, 0.79 to 1.22), being associatedwith both a nonsignificant 19% reduction in ischemic strokeand a nonsignificant doubling of hemorrhagic stroke (1.3%simvastatin, 0.7% placebo; HR, 1.91; 95% CI, 0.92 to 3.96;4.3% simvastatin versus 5.7% placebo; P0.0001). Giventhe exploratory nature of this post hoc subgroup analysis ofHPS, it remained unclear whether stroke patients woulddefinitively benefit from statin treatment to lessen futurevascular risk (including recurrent stroke), especially thosewithout known CHD. 54In the Stroke Prevention by Aggressive Reduction inCholesterol Levels (SPARCL) study, 4731 persons withstroke or TIA, LDL-C levels between 100 mg/dL and 190mg/dL, and no known history of CHD were randomlyassigned to 80 mg of atorvastatin daily versus placebo. 55During a median follow-up of 4.9 years, fatal or nonfatalstroke occurred in 11.2% who received atorvastatin versus13.1% who received placebo (5-year absolute reduction inrisk, 2.2%; HR, 0.84; 95% CI, 0.71 to 0.99; P0.03). TheDownloaded from stroke.ahajournals.org by on March 8, 2011
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