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 255istics of patients with SCD that have been associated withincreased risk of ischemic stroke include prior TIA (RR, 56;95% CI, 12 to 285, P0.001), 423 greater degree of anemia(RR, 1.85 per 1 g/dL decrease in steady-state hemoglobin;95% CI, 1.32 to 2.59; P0.001), 423,425 prior acute chestsyndrome (a new infiltrate on chest x-ray associated with 1 ormore new symptoms: fever, cough, sputum production, dyspnea,or hypoxia) within 2 weeks (RR, 7.03; 95% CI, 1.27 to4.48; P0.001), 423 annual rate of acute chest syndrome (RR,2.39 per event per year; 95% CI, 1.27 to 4.48; P0.005), 423increased leukocyte count at age 1 year (20.7910 9 /L instroke group versus 17.2110 9 /L in those without stroke;P0.05), 425 nocturnal hypoxemia (HR, mean Sao 2 96%,5.6; 95% CI, 1.8 to 16.9; P0.0026), 426 and higher systolicBP (RR, 1.31/10-mm Hg increase; 95% CI, 1.03 to 1.67;P0.33). 423,424The most common mechanism of ischemic stroke inSCD patients appears to be large-artery arteriopathy, 427,428which is believed to be due to intimal hyperplasia relatedto repeated endothelial injury, 429 but other mechanisms ofstroke can occur. Low protein C and S levels have beenassociated with ischemic stroke, 430 and other markers ofhypercoagulability have been reported in SCD patients,albeit not directly linked to stroke. 431,432 Cerebral venoussinus thrombosis is another mechanism of brain ischemiareported in SCD patients. 433 Cardiac disease causing cerebralembolus is either rare or underreported. Becausemechanisms other than large-artery arteriopathy can resultin stroke in SCD patients, and data on the possibleinteraction between SCD-specific risk factors and vascularrisk factors (eg, diabetes or hyperlipidemia) are not available,identification and treatment of other potential strokemechanisms and traditional risk factors should be consideredand an appropriate diagnostic workup undertaken.Recommendations for treatment of SCD patients withlarge-artery arteriopathy are largely based on stroke preventionstudies performed in a pediatric population. TheStroke Prevention Trial in Sickle Cell Anemia (STOP) trialwas a randomized, placebo-controlled trial that showedtransfusion was effective for primary prevention of strokein children with SCD and high transcranial Dopplervelocities. 434 The STOP results are not directly applicableto these guidelines and are summarized in the AHAstatements on primary prevention 13 and management ofstroke in infants and children. 435 For secondary strokeprevention there are no randomized controlled trials tosupport transfusion in adults or children. A retrospectivemulticenter review of SCD patients with stroke, eitherobserved or transfused, suggested that regular blood transfusionsufficient to suppress native hemoglobin S formationreduced recurrent stroke risk. The transfusion targetmost often used is the percentage of hemoglobin S as afraction of total hemoglobin assessed just before transfusion.Reduction of hemoglobin S to 30% (from a typicalbaseline of 90% before initiating regular transfusions) wasassociated with a significant reduction in the rate ofrecurrent stroke during a mean follow-up of 3 yearscompared with historical controls followed for an unknownduration (13.3% versus 67% to 90%; P0.001). 436Most of the patients in this series were children, and it isnot clear whether adults have the same untreated risk orbenefit from treatment. In addition to the effects oftransfusion therapy on clinical events, transfusion has beenassociated with less progression of large-vessel stenoseson angiography (P0.001) 437 and decreased incidence ofsilent infarcts seen on MRI in SCD patients with elevatedtranscranial Doppler velocities (P0.001) compared withpatients who did not receive transfusions. 438 Regulartransfusions are associated with long-term complications,especially iron overload, making long-term use problematic.Some experts recommend using transfusion for 1 to 3years after stroke, a presumed period of higher risk forrecurrence, then switching to other therapies.Other therapies for secondary stroke prevention in adultSCD patients also have limited evidence to support theirefficacy. Several small studies of secondary stroke preventionin children and young adults with SCD and stroke reportedencouraging results using hydroxyurea to replace regularblood transfusion after 3 years of transfusion therapy. 439–441Hydroxyurea has been reported to decrease transcranialDoppler velocities from baseline in SCD patients(P0.001) 442 and may improve cerebral vasculopathy 443 aswell. A phase III randomized clinical trial comparing longtermtransfusion with transfusion followed by hydroxyurea inchildren with SCD (Stroke With Transfusions Changing toHydroxyurea [SWiTCH]) is currently under way. Bone marrowtransplantation can be curative from a hematologicperspective for a small number of SCD patients with asuitable donor and access to expert care but is usuallyundertaken in young children, not adults. Stroke and otherbrain-related concerns are frequently cited as reasons forundertaking bone marrow transplantation. Experience is limited,but both clinical and subclinical infarctions have beenreported to be arrested by this procedure. 444 Surgical bypassoperations have also been reported to have successfullyimproved outcomes in a few small series of SCD patientswith moyamoya vasculopathy, but no randomized or controlleddata are available. 445,446 Given the lack of systematicexperience with antiplatelet agents, anticoagulants, and antiinflammatoryagents for secondary stroke prevention in SCDpatients, specific stroke prevention medications cannot berecommended outside of general treatment recommendations.Preliminary data from animal studies suggest that statins maydecrease endothelial tissue factor expression in SCD, 447 butuntil further evidence of the benefit of statins in SCD patientshas been demonstrated, risk factor reduction with statins andantihypertensives can only be recommended on the basis oftheir importance in the general population.Recommendations1. For adults with SCD and ischemic stroke or TIA,the general treatment recommendations citedabove are reasonable with regard to control of riskfactors and the use of antiplatelet agents (Class IIa;Level of Evidence B).2. Additional therapies that may be considered toprevent recurrent cerebral ischemic events in patientswith SCD include regular blood transfusionsto reduce hemoglobin S to
256 Stroke January 2011hemoglobin, hydroxyurea, or bypass surgery incases of advanced occlusive disease (Class IIb; Levelof Evidence C) (Table 10).F. Cerebral Venous Sinus ThrombosisThe estimated annual incidence of cerebral venous thrombosis(CVT) is 3 to 4 cases per 1 million population. 448Although CVT accounts for 1% of all strokes, it is animportant diagnostic consideration because of the differencesin its management from that of arterial strokes. 448Early anticoagulation is often considered as both treatmentand early secondary prophylaxis for patients with CVT,although controlled trial data remain limited to 2 studies.449,450 The first trial compared dose-adjusted unfractionatedheparin (UFH; partial thromboplastin time at least 2times control) with placebo. The study was terminated earlyafter only 20 patients had been enrolled, because of thesuperiority of heparin therapy (P0.01). Eight of the 10patients randomly assigned to heparin recovered completely,and the other 2 patients had only mild neurological deficits. Inthe placebo group, only 1 patient had a complete recovery; 3patients died. 449 The same research group also reported aretrospective study of 43 patients with cerebral venous sinusthrombosis associated with intracranial bleeding; 27 of thesepatients were treated with dose-adjusted heparin. The mortalityrate in the heparin group was considerably lower than inthe nonanticoagulation group. 449A more recent and slightly larger randomized study ofcerebral venous sinus thrombosis (n59) compared nadroparin(90 anti–Xa U/kg twice daily) with placebo. 450 After 3months of follow-up, 13% of patients in the anticoagulationgroup and 21% in the placebo group had poor outcomes(RRR, 38%; PNS). Two patients in the nadroparin groupdied, compared with 4 patients in the placebo group. Patientswith intracranial bleeding were included, and no new symptomaticcerebral hemorrhages occurred in either group.In a Cochrane meta-analysis of these 2 trials, anticoagulanttherapy was associated with a pooled relative risk of death of0.33 (95% CI, 0.08 to 1.21) and death or dependency of 0.46(95% CI, 0.16 to 1.31). No new symptomatic ICHs wereobserved in either study. One major gastrointestinal hemorrhageoccurred after anticoagulant treatment. Two controlpatients (on placebo) had a diagnosis of probable pulmonaryembolism (one fatal). 451 On the basis of these 2 trials, the useof anticoagulation with heparin or LMWH given acutely inthe setting of CVT is recommended, regardless of thepresence of hemorrhagic conversion.No randomized trial data exist to guide duration of anticoagulationtherapy. For an initial event, periods between 3 and12 months have been reported. Patients with inherited thrombophiliaoften undergo anticoagulation for longer periodsthan someone with a transient (reversible) risk factor such asoral contraceptive use. Given the absence of data on durationof anticoagulation in patients with CVT, it is reasonable tofollow the externally established guidelines set for patientswith extracerebral DVT, which includes anticoagulationtreatment for 3 months for first-time DVT in patients withtransient risk factors and at least 3 months for an unprovokedfirst-time DVT and anticoagulation for an indefinite period inpatients with a second unprovoked DVT. 452 Antiplatelettherapy is generally given indefinitely after discontinuation ofwarfarin.Given the relatively high proportion of pregnancy-relatedCVT, which ranges from 15% to 31%, 453 the risk forrecurrent CVT during subsequent pregnancies is a commonlyencountered question. Sixty-three pregnancies in patientswith prior CVT have been reported in the literature, including21 with pregnancy-related CVT, with normal delivery and norecurrence of CVT. Although this suggests that future pregnanciesare not an absolute contraindication, given the scarcityof available data, decisions about future pregnanciesmust be individualized. 454Recommendations1. Anticoagulation is probably effective for patientswith acute CVT (Class IIa; Level of Evidence B).2. In the absence of trial data to define the optimalduration of anticoagulation for acute CVT, it isreasonable to administer anticoagulation for at least3 months, followed by antiplatelet therapy (ClassIIa; Level of Evidence C) (Table 10).G. Fabry DiseaseFabry disease is a rare X-linked inherited deficiency of thelysosomal enzyme -galactosidase, which causes lipid depositionin the vascular endothelium and results in progressivevascular disease of the brain, heart, skin, and kidneys. 455Stroke may occur due to dolichoectasia of the vertebral andbasilar arteries, cardioembolism, or small-vessel occlusivedisease. 455–457 Fabry disease may be underdiagnosed as acause of seemingly cryptogenic stroke in the young. 458Antiplatelet agents are believed to be useful in preventingischemic events related to existing vascular disease, 458 but thedisease itself was untreatable and the prognosis quite pooruntil recombinant -galactosidase A became available. Inrandomized controlled trials, administration of intravenous-galactosidase (also known as agalsidase beta) at a dose of1 mg/kg every other week reduced new and cleared oldmicrovascular endothelial deposits in the kidneys, heart, andskin 459 and modestly reduced the composite of renal, cardiac,or cerebrovascular events or death (HR, 0.47; 95% CI, 0.21 to1.03). 460 Enzyme replacement therapy also leads to clinicalimprovements in kidney function, 460,461 but the impact oncardiac function has been inconsistent. 462,463 Enzyme replacementtherapy has been shown to have a favorable effect oncerebral blood flow, 464 but the risk of stroke appears substantialdespite therapy. 465 Earlier intervention or higher enzymedoses or both may be needed for stroke prevention, and thisis an area of active research. 466 The major adverse effects ofrecombinant -galactosidase A infusions are fever and rigors,which may occur in 25% to 50% of treated patients but maybe minimized with slow infusion rates and premedicationwith acetaminophen and hydroxyzine. An expert panel recommendedenzyme replacement therapy for all male patientsstarting at age 16 and all other patients if there is evidence ofsymptoms or progressive organ involvement. 467Recommendations1. For patients with ischemic stroke or TIA and Fabrydisease, -galactosidase enzyme replacement ther-Downloaded from stroke.ahajournals.org by on March 8, 2011
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