— Efficacy of Aspirin Plus Extended-Release Dipyridamole in Preventing Recurrent Stroke in High-Risk Populations Ralph L, Sacco, MS, MD; Juhani Sivenius, MD, PhD; Hans-Christoph Diener, MD, PhD Objective: To assess the efficacy of aspirin plus extended release dipyridamole compared with aspirin alone for the prevention of recurrent stroke among high-risk groups. Design: A post hoc analysis was conducted using data from the European Stroke Prevention Study 2. Rates of annual strokes and vascular events were determined for the aspirin plus extended-release dipyridamole group $50) and the aspirin-only group (n=1649),and were ed by risk subgroup and univariate risk factors. Stroke models from the Framingham Study and the Stroke Prognostic Instrument Il were applied to subjects in the European Stroke Prevention Study 2 to categorize pa- dents into risk groups Results: Compared with aspirin alone, aspirin plus ex- tended-release dipyridamole demonstrated a more pro- nounced efficacy in reducing the risk forstroke and vas- cular events among patients younger than 70 years; those with hypertension, prior stroke, oF transient ischemic at- tack; current smokers; and those with any prior cardio- vascular disease. Relative hazard reductions favored the combination of aspirin plus extended-release dipyridam- ole, and were greatest for the high-risk Framingham Study group and the moderate-risk Stroke Prognostic Instrt- ‘ment II subgroup. Conelusion: Aspirin plus extended-release dipyridam- ole is more effective than aspirin alone at preven stroke, and the difference in efficacy increases in high risk patients. Arch Neurol. 2005;62:403-408 Author Affiliations: Departments of Neurology and Epidemiology; Collegeof Physicians and Surgeons and the Mailman School of Public Health, Columbia University. Neurological Institute, New York, NY (Dr Saceo) Department af Neuroscience and Neurology, Kuopio University Hoop Research and Rehabilitation CCentet Neuron, Kuopio, Finland (Dr Sivenius): and Department of Neurology, University Hospital Essen, Essen, Germany (Dr Diener) Financial Disclosure: Drs Sacco and Diener have received honoraria as consultants and speakers from Bochringer Ingelheim, and Bristol-Myers Squibb Drsivenis has received honoraria from Boehringer Ingelheim, Downloaded From: https: ‘TROKE IS THE THIRD LEADING. cause of death in most devel- coped countries and a lead- ing cause of serious loi term disability. In the United 750000 persons have a stroke at- nnually, of whom about 200000 have re- current stroke.! Among patients with fist stroke, S0% to 85% survive.» These pa- s face a 5% to 15% risk for recurrent roke in the first year follow stroke, during which the highes {stsin the weeks immediately following the {initial event? Because age is an impor- tant nonmodifiable risk factor for stroke, thedecline instroke-related mortality com” bined with the increase in life expec- tancy for the US population will certainly increase the number of persons at risk for recurrent stroke and stroke’s related dis- ability and medical care costs." Fortunately, observational epidemio- logical studies and controlled clinical trials have provided substantial evidence that the risk of recurrent ischemic stroke can be re- state he acute risk ex- Brain Sanot-Synthelabo, duced.” Various modifiable risk factors, such as hypertension, cardiac disease, and dysipi ds antiplatelet agents have demonstrated ellicacy for preventing recurrent stroke, including aspirin, ticlopidine hydrochlo” ride, clopidogrel bisulfate,and aspirin plus extended-release dipyridamole. The stud- {es that produced these findings have re- sulted in updates to the guidelines for secondary stroke prevention from the American Heart Association and the Amer- ‘can College of Chest Physicians.” as, can he controlled to help re- the risk for recurrent stroke. Four CME course available at www.archneurol.com Despite the revised recommendations, expert opinion varies considerably regard- {ng the relative efficacy of anuiplatelet agents forprevention of recurrent stroke." This un- certainty is largely a result of the absence of direct comparisons of combination an- Luplatelet therapy and the matked variabil- ity in the choice of primary end points for individual tals.* Moreover, certain agents of combinations of agents may be pre- (©2003 American Medical Association. AI rights reserved, jamanetvrork.com/ on 02/26/2022Table 1. In the Europe ons of Vascular Risk Vi Stroke Prevention Study 2 Trial Detiaton Por ensbrovszular — Praraoe oT Ho history otischami hat isa or Ml or slecocardoraphic evidence of coronary Ischamic signs or rsdal signs of previous intron Pwo ‘Ahstory of PVD, th absance of or more paihaa pu (crt, radial, femora (2 poplalanay), rhe presnce of for mora acest mums (eats or femoral ay) history of ypartnsion,basaine sso ‘ood pressure 160 mm i, basine| dst bloodpressure >08 rm Hor cunt antnypertnsive eament at ncn (onraly acting antihypertensive agents, angiotonsa-canvaring enzo Inbar sureties nthe absence ot cara tare, tacks in th absence (of HD, or ealu chanel acer in the absence of HD) story of ypachoestrlaia. tel choetl vel = 200 mg (275 mmol} or cure teatmert with Inpopdemic ages at bassine Cardiovascular ease IHD, PVD, earacflure,orypertnion Ta ‘toca turbans ofthe aaa ‘alan hat ested shia neurologjal df rcovrng vtin 24h without funcional inpaimant at standard Clea maurolgcal waminaion Soke ‘Atal turbans ofthe arab ‘aun ht reeled ncn neuolgial defi iasting >24 Death occuring win approximately 24 h ‘ar the appearance of ymptoms- ober Cardovecuar death ined deste Strobl tocar aythmi, homorhage, and paiheral vascllepathy, nd oter nora eae nied thos aba to misestaneous ‘aus sucha labetes alte and real alute Fe of onal stot, nonfatal Mor ‘ascular desth where ace dith Incudes fatal ero, atl Ml, death de to other veel evans ada are usualy witha 30d ofthe eer, susen ath, hemecthagjic dea roncrebral {aa leding), or dea of uncertain Unknown ease aecaring within 24h after the onset of symptors Hypotension Fypectlesterlemia Sutden death Vasu vent obrvtion: IHD, shame hat eae: Ml, myoeardal inaction Vb, pecporal vascular deat TIA arse share atch. ferred in patients with varying degrees of risk for recur- rent stroke and cardiovascular outcomes. To assess the efficacy of aspirin plus extended- release dipyridamole compated with aspirin alone to pre- vent recurrent stroke, we performed post hoc analyses of the European Stroke Prevention Study 2 (ESPS-2) tal (Our aim was to evaluate the reduction in risk for recur- rent stroke in various risk factor subgroups and in sub- groups at high risk for recurrent stroke estimated from externally validated measurement scores. ——_ Ss}. The ESPS-2 was a multicenter, randomized, placsbo- Conioled, double-hind,2-by-2 factorial ral desighed to a sess the salty and ellicacy of low-dose aspiin, extended Felease dipyridamole, and the 2 agents combined for the Secondary prevention ofischemicstroke,Thefull dtl the Stady design are described by Diener anid colleges ri, the study population comprised 6602 patients older than 18 ers (etn tg, 68.7 eats) who had experienced a trannent chemi atack (TTA) (24%) oran scheme stroke (76%) within the preceding 3 months Patents were randomly assigned to reese aspirin alone (30 mg/d), extended release dipyridam- dlealone (400 mld), the 2 agents na combined ormltion, or placebo, and were followed upcrery3 months for 2 years Primary end points were stoke (sal and nonfatal) and death from al causes ‘A baseline, various data were collected regarding demo- traphice and vascular actors sch history of hype Son diabetes melts, myocardial nection (MD, ert Smoking, stroke or TIA. These variables ere dined by bie tory through sujet interview and Bscline medical record re ‘iow. Any tudioytlar dstee Was defined us person = ingetpetcncad crc bre cr having hypertension, iechemic Stele, o peripheral vuculrdisece Deiibisol ve Cala risk factors rom ESPS-2 are listed in Table ¥ We conducted our post hoc analysis vith extemal stroke smodels rom the Framingham Study" and the Stroke Prognos- te nsirament It" (SPL) to compute estimated risk cate go- Ties based on the ESPS-2 baseline varables. We converted the Fisk variables to isk scores using the method inthe Framing- tam study." The Framingham stroke risk score was devel oped from the Praminghatn cohort to calculate an estimated probability of stoke (primary frst seo) im men and women For the Framingham study model, he 10-year stroke prob: ability was classed aslow (20.15) orhigh (20.15) using the iolawing arable: gs astolicbood pressure, anthyperen- sive therapy, diabetes lites cigarette smoke, crdhovasct inr disease, ria ibilation and lel ventricular hypertrophy The SPL was developed specially to predict stoke or death mong ok of TIA survivors The SP1-2 model, which uses few predictive varbles and recalculated point scores forall Component variables, va developed rom the Women's Esto: gemfor Stroke Trial cohort and itenhanced performance has een demonstrated and validated in ater external cohorts The SPL? score was lsfed 35 low (0-3), middle (7), oF high (6-15) wing the following varsle: congestive eae sre, diabetes melt, prior sted, older than 70 year, stroke for arolment event severe hypertension, and coronary a ter dense Soke iskscoeswefecalclated according oibese Imodel for cach subject in ESPS-2, and subjects were catego ‘ed int ik sua based on these scores. he new males crinined the anna stoke and vas lar event tes forthe apirinalone group (9=1689) and the aspirin pls extended-release dipyridamole group (11650), Stated bythe patents isksubyroup and univariate isk a: tor Subjects wating sline data (n=105) fork model Staifcaton (raminghar Sty oFSP1-2) were ciminated from this analis Annus event rates were defined asthe number of fist events divided bythe total numberof patient-years in the study. The primary focus a the aid wan stoke out comes (sal or nonlatal). Stoke or vascular event were de- fined asthe fist occurrence of nonfatal stroke, nonfatal Mle ‘ascula death. Vascular death was defined as fatal stroke, l- TSIM death eto ther asclareventsor cardi re st ally within 30 days of the event, sudden death, hemorhagic death oncereral fatal bleeding) or death of uncertain orn (©2003 American Medical Association. AI rights reserved, Downloaded From: https:/jamanetwork.com/ on 02/26/2022Table 2. Annual Stoke Rates and RHRs inthe European Stoke Prevention Study 2 Trlal, Salted by Baseline Univariate Risk Factors ‘spina Pus ls ator No.of subjects Eendet Release Opyitamolet Aspirin Alone RMA (Lower Upper). % Pat igo Ty No io a3 52 3805,521) 1 Yee 1285 a3 102 18 Sex Ne 1153 54 2 24304, 425) 05 Female 38 50 69 71.8(-06,482) 8 Hypertension| No a 46 57 195 (159,441) 2 ee i010 57 ao 738 (76, 51) ot Diabetes metus No m8 50 67 25.4(66,414) 1 vee a3 69 ar 235 (-150,559) aT Previous Ml lo ans 51 68 24969, 400) ot Yee 2a 66 108 25.8 (108,567) 16 i iain No ‘000 49 68 221 87,417) 06 vee 196 113 136 184(-570,575) st Ay cavaseur disease No 720 36 a4 182(-300,522) 46 vee 266 56 19 713 (84. 422) on? Curent sme tio ait 53 67 197 (26,372) 8 vee 785 50 a5 409 (102,611) ot Prior stoke a TIA io ait 50 57 r22(144,327) 38 vee 285 et 110 445 206,513), 01 uaiyng event TR 76 36 4 112(409,475) 8 Stoke 220 56 at 718(89,427) 06 Abbraviations: CL, condone iit Ml, myocardial infarction: BHR, elas haar radutn, TA, wansientichemie tack, “Data ae que a anal pateriage of subjecsin eat group who experienced a stoke, known cause occurring within 24 hours after the onset of symp: toms. Relative hazard reductions were calelated using Cox pro portional hazards models, Es} Overall, the ESPS.2 results demonstrated that the combi- nation of aspirin plus extended-release dipyridamole com- pared with aspirin alone among TIA or stroke pat Superior in reducing the risk of stroke (relative risk re- duction, 239%; 95% confidence interval, 9%-37%; P=.006) and stroke or vascular events (relative isk reduction, 22%; 95% confidence interval, 7%-36%; P=.003), The efficacy of aspirin plus extended-release dipyridamole compared with aspirin alone for various baseline subgroups is shown for the outcome of stroke in Table 2 and for the out- come of stroke or vascular events (including vascular death) in Fable 3. Compared with aspirin alone, treatment with aspirin plus extended-release dipyridamole resulted in sub- stantial relative hazard reductions for stroke within some of the specific risk factor subgroups. Relative hazard rates favored the combination therapy in each of these sub- groups, with a more pronounced efficacy observed among, those younger than 70 years; those with hypertension, prior MI, prior stroke or TIA, and any prior cardiovascular dis- cease; and current smokers. The greatest relative hazard re- duction (44.6%) was found among patients witha stroke or TIA before the qualifying event. Patients with a history of MI who were treated with aspirin plus extended- release dipyridamole had a 36.8% relative hazard reduc- tion of stroke compared with those taking aspirin alone Patients with any prior eardiovascular disease had a 27.3% lower stroke hazard while taking aspirin plus extended- release dipyridamole compared with aspirin alone. The rela- tive hazard reduction for stroke was 11.2% for those with TIA as a qualilying event and 27.8% for those random- ized after stroke The combined outcome of stroke of vascular events is shown in Table 3. The results show that patients using as- pirin plus extended-release dipyridamole experience sub- stantial relative hazard reductions for the end points of stroke or vascular events. Greater relative hazard reduc- lions were found among those with prior stroke or TIA, previous Ml, and among current smokers. The relative haz ard reduction was 24.8% for those with TLA as a quail {ng event and 18.6% for those randomized afer stroke. Some subgroups, such as those with atrial fibrillation, were small, which resulted in wide confidence intervals The baseline ESPS-2 cohort stratified into low- and high-risk groups according to the Framingham stroke risk (©2003 American Medical Association. AI rights reserved,Table 3, Ann Salted by Baseline Univariate Risk Factors 3! Combined Stroke or Vascular Event Rates and RHRS in the European Stroke Prevention Study 2 Trial, ls ator No.otsubjets stand. Re FRR (Lower, Upper), Pat igetoy No a1 46 67 312087, 482) ot Yee 1235, 134 154 117 (107,208) 28 Sex Ne 1358, 79 102 21.9(07,380) ot Female 38 78 95 178(-82,375) 16 Hypertension| No wa 64 1a 187 (109,408) 19 ee ‘910 80 113 71.0(21,.962) 03 Diabetes metus No 223 73 oz 205 (2,347) we vee a3 109 138 205 (178,464) 2 Previous Ml lo aos 73 ao 194023, 334) 3 Yee 281 139 213 339(-38,579) or i iain No 000 72 a2 217(64,352) 1 vee 196 ai 232 136(-022,475) 57 Ay cavaseur disease No 730, 30 52 243 (258,548) 28 vee 266 a 114 199183. 336) cs Curent sme tio att a os 171 (14,223) or vee 735 13 103 2.1 (191508) 08 Prior stoke a TIA io at 15 as 91 (-130,269) 30 vee 385 80 142 37.7(085,541) one uaiving event TR 78 ar 63 248 173,517) 21 Stoke 20 a0 14 186 (14.329) of Abbrvition: See Table 2. “Dats ae gen anal parantage of eubjetsin each group who expand a srke or accu vent Table 4, Annual Stoke Rates and RHRs by Risk Group In Subjects inthe European Stroke Prevention Study 2 Trl Treated With Aspirin Alone or Aspirin Plus Extended-Release Dipyridamole “spin Pe sx or0up Not subjects Exendes-alease Opyidamolet Aspirin Alone* AR (Lower, Upper). % Pal Framingham sake ik sear Low 3 a4 a8 123(-304.410) 2 High 173 10 10 302 (103,487) 08 P12 ek sore tow 126 32 ar 11a¢320.414) 8 Moderate sant 63 a6 3 (128,508) ne High 200, 109 132 172(-303,508) ry ‘Abbrvition: CL, condance lm RH, lative hazard reduston PL, Soke Prognoste Intuent “Dats ae gen smn petearage of eubjctsin each group Wo xpeiened score or the SPI-2 score is shown in Table 4. The an- nual risk for recurrent stroke among those aspirin increased from 3.8% in the low-risk group to 10.19% inthe high-risk group for the Framingham score, and from 3.7% to 13.2% for the SPL-2 score. Relative hazard re ductions favored the combination of aspirin plus ex- ended-release dipyridamole inall the subgroups, and were greatest for the high-risk Pramingham group and the mod- isk SPL-2 subgroup. Numbers in the highest-risk cated with (©2005 American Medical Assoc group, however, were small. Results were similar for the stroke or vascular events outcome, as shown in Table 5. —_ Ss ]_ Guidelines from the American Heart Association, the American College of Chest Physicians, and the Euro- pean Stroke Initiative state that aspirin alone, aspirin plus extended-release dipyridamole, o clopidogrel is an ac- jon, All rights reservedTable 5. Annual Combined stroke or Vascular Event Rates and RHRs by Risk Group in Subjects Inthe European Stroke Prevention ‘Study 2 Trial Treated With Aspirin Alone or Aspirin Plus Extended-Re sx or0up oot subjects Exendes-alease Opyidamole* Api Alone* RAR (Lovet, Upperct).%~ __P Value Framingham sake ik sear Low usa 4 so s74ci7. 423) 0 High 13 1a 143 206 (27,352) 3 P12 ek sore tow 16 a2 49 138(-283,307) 2 Moderate unt a5 131 215 (81,427) 08 High 20 198 a5 76 (-879,38:) 7 ‘bbrvntion: See Table & “Data as ghen anal parentage of eubjectsn each group who expaencd srko or accu vet ceptable option for first-line therapy to prevent recur= rent stroke,"" Pew data are available regarding how these recommendations translate into clinical practice and which factorsalfect the choice of antiplatelet drugs in pa- dents with a recent ischemic cerebrovascular event. In a recent study from the Vienna Stroke Register, investi gators determined that the most important [actor pro- ‘moting the use of clopidogrel was therapy with aspirin before the index event. High interhospital variability was, found regarding the use of aspirin plus extended- release dipyridamole. The relationship between aspirin and clopidogrel also varied significantly between depart- ‘ments within a hospital. Thus, the most prominent fac- tor influencing the use of clopidogrel or aspirin plus ex- tended-release dipyridamole was the practitioners’ divergent interpretation of the existing evidence. Other main factors were higher costs (clopidogrel), individual experiences, and adverse effects (aspirin plus extended- release dipyridamole). For the secondary prevention of stroke, alternatives ex- {st for aspirin, Clopidogrel and aspirin plus extended- release dipyridamole are more effective than aspirin alone.”**" Adding dipyridamole to aspirin or substitut- ing aspirin with clopidogrel is more expensive than aspi- rinalone in preventing stroke, but these changes in therapy could he more cost-efective in high-risk patients, these patients can be identified.” It seems that inthe long term, aspirin plus extended-release dipyridamole is more effec” live and less costly compared with aspitin alone." Thus, the type of outcome to be prevented, such as recurrent stroke, MI, or other vascular events, and the relative im- pact of other concomitant risk factors also enter into the physician's decision-making process. Clinicians should assess the stroke patients greatest risk before determining long-term treatment to prevent vascular events, The most common vascular event dur- ing the first few years following a stroke or TIA is a re- current nonfatal stroke, which often results in signili- cant disability and reduction in quality of life” Recent antiplatelet studies, such as the Canadian American Ticlo- pidine Study, the Ticlopidine Aspirin Stroke Study, the Clopidogrel vs Aspirin in Patients at Risk of Ischemic Events trial, and ESPS-2, have clearly demonstrated the high risk for recurrent stroke, compared with the lower risk for ML" Therefore, from a clinical perspective, real- ‘ment must focus on preventing subsequent ischemic strokes. Consequently, the antiplatelet agent that is most elfective for preventing stroke will likely result inthe great cst benefit for patients with a history of stroke of TIA. Stroke patients often have other vascular conditions, such as Ml or prior stroke, and multiple risk factors, such as hypertension and diabetes mellitus. When choosing, alternative antiplatelet therapy, the severity of vascular risk factors can influence the clinician to consider more aggressive medications. Our post hoe analysis of the ESPS-2 data shows that the combination of aspirin plus extended-release dipyridamole is significantly more ef- fective than aspirin alone in the prevention of recurrent stroke and stroke oF vascular events for various baseline risk factors. Patients with priorstroke or TIA, those who experienced a previous MI, and current smokers who used aspirin plus extended-release dipyridamole had greater hazard reductions for stroke and stroke or vascular events than those who took aspirin alone, The reductions ob- served among patients with prior cardiovascular disease are noteworthy because some have claimed that aspirin plus extended-release dipyridamole is less effective among, patients with other cardiovascular conditions, In addition, aspirin plus extended-release dipyridam- ole seems to provide greater protection for those patients with a higher risk for stroke based on predicted stroke prob- abilities from external stroke models. For diabetes melli- ts and atrial fibrillation, we did not observe a significant benefit or aspirin plus extended-release dipyridamole com- pared with aspirin alone. Its dificult to make any con- clusions about the atrial fibrillation subgroup because the numbers of patients randomized were small. Moreover, the results of the European Aural Fibrillation Trial that demonstrated the efficacy of oral anticoagulants led to a protocol modification and change in practice in many of the participating ESPS-2 sites during the conduct of the trial, Analysis of the ESPS-2 data set has shown that the 2-year risk of first stroke for baseline atrial fibrillation sub- {jects was greatestamong those treated with placebo (23.4%) compared with aspirin alone (19.2%) and extended- release dipyridamole plus aspirin (17.39%). Limitations of our post hoc analysis exist. The del nitions of the baseline vascular risk factors were based on data available at randomization into ESPS-2 and may be skewed because of older classification schemes. The (©2003 American Medical Association. AI rights reserved,use of the Framingham model to stratily patients into low and high risk may have some limitations because it was originally designed to predict first stroke. Some of the variables in the original Framingham model were not available in the baseline ESPS-2 data set and may have reduced the accuracy ofthe stroke risk scores. The model, however, seemed to competently discriminate the risk for stroke recurrence among the treatment groups. Al- though the risk of stroke recurrence increased across the 3 eategories of the SPI-2, it was originally designed to pre- dict stroke or any death. The lower efficacy of extended- release dipyridamole plus aspirin vsaspirin alone among, the highest-risk group may reflect the lower impact of antiplatelet agents on any death after stroke. This post hoc analysis of ESPS-2 data adds tothe grow- ing information supporting the efficacy of combination therapy with antiplatelet agents, particularly in higher- risk stroke patients, Aspirin plus extended-release di- pyridamole is more effective than aspirin alone at pre- venting stroke, and the difference in efficacy increases im higher-risk patients, The baseline vascular risk for the stroke patient is one important consideration when mak- ing decisions regarding the most effective antiplatelet regi- men to prevent a stroke. Accepted for Publication: July 15, 2004 Correspondence: Ralph L_ Sacco, MS, MD, Departments of Neurology and Epidemiology, College of Physicians and Surgeons and the Mailman School of Public Health, Co- lumbia University, Neurological Institute, 710 W 168th St, New York, NY 10032 (RLS1@columbia.edu). Author Contributions: Study concept and design: Sacco and Diener. Acquisition of data: Sivenius and Diener. Analy sis and interpretation of data: Sacco and Diener. Drafting of the manuscript: Sacco and Diener. Critical revision of the manuscrip for important intellectual content: Sacco, Sive- nus, and Diener. Statistical analysis: Sacco. Obtained unding: Sacco. Administrative, technical, and material sup- port: Sacco and Diener. Study supervision: Sacco. Punding/Support: This study was supported by Boch- ringer Ingelheim, Ridgefield, Conn. (wermiyTeD) ARCH RETROCVOL —_ Ess} 1. arin Ha Aesocaton Hu Dist and Stoke Stati: 2008 Update Da, Tes: Aneean Heat Asai; 201 2, Dist HE Ringe .Anstrombate scandy prvntian ater stoke. Cur Treat Options Canova Med 200220440 3. Weimar, Zl Koerg Diner HO. Pring unconaoaome and su val ater ctschami sbo. J Meu 202 24088 405, 4 Saco AL. araminE Baceck JP, American Hea AsocitionPover- ‘an Confers, N-peenion nd habitation stole: acs. Soke ‘aoraasg07 1617, 5, Wal PA, Cg GP Eaton JD a HA Skit Statement pening i= chemi tok pens wih pr sokeand ast scumi ata Soke ‘con toma, 6. Anitvmboi Tris” Colsboron,Cosbratve mete-anaijeis frn- aise ilo apt sry fer proven of exh myocar ian, and son igh i ates NAL 2002-26718, 1 bar Aarne Eason JD. Seca, Tea tobe nd trom bale thipy isha sls_ Chest 2001254835515, 8 Albers GW. Goce endo in ample vis whch eutomes ae most aleant ook ies? Neary 2000544021028 hear: Cua Fr Sven) Sr. Loner European Stoke Prevention Stud 2: spydanale an acta acid ih senda re ‘entn of ska Neral Ser 105-1 10, Wol PA. Agosino RB, Belzger Al Kal W.Pobbiy f srk: 2 isk proeomeFanngham Sty, Soke 1001-22312-78 1, Kern WL Vacos OM ase LA ta The Sot Prono stunt I: lineal redcsnisrumert fatness and nandis= sing ischemic soe. Sate 200 3155-162 12 Keran WN, rw Sass MeL A progaste tm or tans ‘haa ce mor ato. Aon tr ed 001918352597. 18, ek W, Kast ogous Jt a Europaan Soke lie acte Conta ESI Wig Caries Erpean Stoke tae Recom- mendations for Soke Managemen update 2008, Crtrvas Dis. 2003 year 14, Last, Land W Mule Mena Soe Sty Group. Curent state sof secondanypevron ate a eebrovascl vr. Sook 20012: aco. 268. 15, Worn. Eason 0. Dipyidamse pls spi increase das ‘rch euro 10861087002 16 Hankey Suton CLM, Dutbbin DWV. Tennis oaspin to prever Sela ade sis cur even inpatens aig isk asc ers {Leste of te vez om randomized wa. Sat, 200031 rian 17, Hanley 6 Warow CP. Tesman and scondry preenon of stk ence esis, ard ete on indus nd paplatons. Lance. 080354: ‘srs. 18, Sarin Gaspor LM, Bounanauc H.Casttecva ragenens aed a saan prevention of sla or a ‘oh mM 2000160-2072-278, (©2003 American Medical Association. AI rights reserved, Downloaded From: https:/jamanetwork.com/ on 02/26/2022