Published online before print January 10, 2008, doi: 10.1161/STROKEAHA.107.511501
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(Stroke. 2008;39:258.)
© 2008 American Heart Association, Inc.
Advances in Stroke 2007 |
Advances in Prevention and Health Services Delivery 2007
From the Department of Medicine (Neurology) (L.B.G.), Duke Center for Cerebrovascular Disease, Center for Clinical Health Policy Research, Duke University and Veterans Administration Medical Center, Durham, NC, USA; and the Stroke Prevention Research Unit (P.M.R.), University Department of Clinical Neurology, Radcliffe Infirmary, Oxford, UK.
Correspondence to Larry B. Goldstein, MD, Box 3651, Duke University Medical Center, Durham, NC 27710. E-mail golds004{at}mc.duke.edu
Key Words: health care • health services delivery • prevention
The last year has seen advances in both primary and secondary prevention of stroke, including significant steps forward in our understanding of the risks and benefits of anticoagulation in nonvalvular atrial fibrillation (AF) and in assessment of the benefits of urgent treatment after transient ischemic attack (TIA) and minor stroke.
Nonvalvular AF affects about 1% of the population with its prevalence increasing sharply with age. AF is associated with a 5-fold increase in stroke risk.1 Although warfarin is effective in the secondary prevention of ischemic stroke in the majority of patients with nonvalvular AF,2 uncertainties remain about the optimal use of warfarin in routine clinical practice in the primary prevention setting. Research published in 2007 helps to resolve several outstanding questions.
A systematic review analyzed the efficacy and safety of antithrombotic agents in the primary prevention of stroke in patients with nonvalvular AF.3 This review added 13 recent randomized trials to a previous meta-analysis of all published trials with a mean follow-up of 3 months or longer. Compared with the control, adjusted-dose warfarin (6 trials, 2900 participants) reduced stroke by 64% (95% CI, 49 to 74), whereas antiplatelet agents (8 trials, 4876 participants) reduced risk by 22% (95% CI, 6 to 35). Adjusted-dose warfarin was substantially more efficacious than antiplatelet therapy (12 trials, 12 963 participants; relative risk reduction 39%; 95% CI, 22 to 52). Absolute increases in major extracranial hemorrhages were small (
0.3% per year). Thus, warfarin was substantially more efficacious than antiplatelet therapy.
Because the absolute risk of stroke varies widely among patients with nonvalvular AF, the overall results of trials and meta-analyses of antithrombotic treatment cannot necessarily be generalized to all individuals.4 To balance the benefits and risks of chronic antithrombotic prophylaxis, it is important to estimate the absolute risk of stroke for individual patients. Another recent systematic review addressed this question and evaluated all studies that had used multivariate regression techniques to identify independent risk factors for stroke in patients with nonvalvular AF.5 Among 7 studies (including 6 entirely independent cohorts), prior stroke or TIA (relative risk [RR] 2.5; 95% CI, 1.8 to 3.5), increasing age (RR 1.5 per decade; 95% CI, 1.3 to 1.7), a history of hypertension (RR 2.0; 95% CI, 1.6 to 2.5), and diabetes mellitus (RR 1.7; 95% CI, 1.4 to 2.0) were the strongest, most consistent independent predictors of stroke. Observed absolute stroke rates for nonanticoagulated patients with single independent risk factors were in the range of 6% to 9% per year for prior stroke/TIA, 1.5% to 3% per year for history of hypertension, 1.5% to 3% per year for age >75 years, and 2.0 to 3.5% per year for diabetes. Female sex was inconsistently associated with stroke risk. Evidence that either heart failure or coronary artery disease were independently predictive of stroke was inconclusive.
Persons age >75 years account for more than half of all cases of stroke related to AF and the prevalence of AF is about 12% in this age group. Several studies have shown that the risk of serious anticoagulation-associated hemorrhage rises with age.6,7 Because the elderly are under-represented in most of the randomized trials, particularly those conducted in a primary care setting, concern has long been expressed regarding the applicability of trial evidence to older patients.8–11 Reinforcing this concern, another study published in 2007 highlighted the dramatic increase in incidence of anticoagulant-associated intracerebral hemorrhage in the elderly population in recent years.12 Joint American and European guidelines recommend anticoagulation in the presence of 2 or more risk factors for stroke in the setting of atrial fibrillation (one of which is age 
75), but suggest that patients in this age group who are at increased risk of bleeding can be treated with a lower international normalized ratio target than was used in the randomized trials.13
Two trials published in 2007 have provided much needed data on the safety and efficacy of warfarin versus aspirin in elderly patients. The first was a small open label study in ambulatory, cognitively intact patients aged 80 to 89 years with nonvalvular AF who were randomized to receive dose-adjusted warfarin (international normalized ratio 2.0 to 3.0) or aspirin 300 mg.14 During 1 year of follow-up in 75 patients (aspirin 39; warfarin 36, mean age 83.9 years), dose-adjusted warfarin was significantly better tolerated with fewer adverse events (mainly bleeding) than aspirin (13 versus 2, P=0.002). The second, much larger trial (Birmingham Atrial Fibrillation Treatment of the Aged study, BAFTA) was a prospective, randomized open-label trial with blinded evaluation of end points (PROBE design) in patients aged 75 years or over with nonvalvular AF treated in a primary care setting.15 The trial included 973 patients (mean age 81.5 years) assigned to warfarin (target international normalized ratio 2 to 3) or aspirin (75 mg per day). During a mean follow-up of 2.7 years, there were 24 primary events (21 strokes, 2 other intracranial hemorrhages, and 1 systemic embolus) in subjects assigned to warfarin and 48 primary events (44 strokes, 1 other intracranial hemorrhage, and 3 systemic emboli) in subjects assigned to aspirin (annual risk 1.8% versus 3.8%; RR 0.48; 95% CI, 0.28 to 0.80; P=0.003). The annual risk of extracranial hemorrhage was 1.4% for warfarin versus 1.6% for aspirin-treated subjects. Thus, the results of each of these trials support the use of anticoagulation therapy for people aged over 75 who have nonvalvular AF and no contraindications to treatment.
The advent and widespread use of modern neuroimaging technologies is leading to a reconsideration of the traditional definition of TIA as a high proportion of patients experiencing transient focal neurological symptoms from presumed ischemia have actually had permanent tissue injury.16 TIA patients are often managed nonemergently. An observational study conducted several years ago found that one-third of patients with a first-ever physician diagnosed TIA were not hospitalized and had no diagnostic studies over the first month.17 Several studies published within the last year support the notion that TIA needs to be considered as a medical emergency warranting rapid evaluation and the institution of appropriate treatment.
A systematic review and meta-analysis was conducted to develop overall estimates of the risk of stroke within 2 and 7 days after TIA.18 The 18 identified independent studies included data on 10 126 TIA patients and found 7-day risks ranging from 0% to 12.8% with substantial heterogeneity between studies (P<0.0001). This heterogeneity was almost completely explained by differences in study methodology, setting, and treatments. The pooled risk of stroke was substantial and calculated to be 3.1% (95% CI, 2.0 to 4.1) at 2-days and 5.2% (95% CI, 3.9 to 6.5) at 7 days.
From the standpoint of health services delivery, it is important to be able to identify subgroups of TIA patients who are at relatively higher short-term risk of stroke that could potentially be prevented though rapid intervention. Several different prognostic scoring systems have been developed. The prediction of the 2-day risk of stroke using the California and ABCD scores were evaluated and validated in 4 independent cohorts of patients diagnosed with TIA in emergency department settings.19 The 2 systems similarly predicted stroke risk at 2 days, 7 days and 90 days (c statistic 0.60 to 0.81). A unified score (ABCD2) based on 5 factors (age 60 years [1 point]; blood pressure 140/90 mm Hg [1 point]; unilateral weakness [2 points] or speech impairment without weakness [1 point]; duration 60 minutes [2 points] or 10 to 59 minutes [1 point]; and diabetes [1 point]) was derived and validated. The ABCD2 had better predictive capacity than either of the other 2 systems and can be used to identify TIA patients at a high (score 6 to 7, 8.1% risk), moderate (score 4 to 5, 4.1% risk), and low (score 0 to 3, 1.0% risk) likelihood of stroke over the ensuing 2 days. The score, however, cannot be used to specifically identify TIA patients with 50% carotid stenosis or atrial fibrillation,20 and its use in selecting TIA patients not in need of urgent evaluation needs to be confirmed in a prospective study.
Despite the high short-term risk of stroke in patients with TIA, there have been few studies showing a difference in outcomes with rapid evaluation. The Early use of Existing PREventive Strategies for Stroke (EXPRESS) project, a nested substudy of the population-based Oxford Vascular Study, evaluated the impact of urgent specialist clinic assessment and immediate treatment as compared with routine assessment by primary care physicians of TIA patients not admitted to hospital.21 The study used a before-after design with independent, blinded audit of all strokes occurring within 90 days. Although there was no significant difference in stroke risk of TIA patients treated in-hospital between the 2 periods, the 90-day stroke risk in patients referred to the study clinic fell from 10.3% to 2.1% (adjusted hazard ratio 0.20; 95% CI, 0.08 to 0.49; P=0.0001) with more rapid assessment and treatment. A second study evaluated the impact of a hospital-based TIA evaluation clinic with 24-hour access.22 The observed 90-day stroke rate was 1.24% (95% CI, 0.72 to 2.12), whereas the rate predicted from ABCD2 scores was 5.96%. Although not prospective randomized trials, these 2 studies support the urgent evaluation of TIA patients.
It is known that patients with TIA or minor nondisabling stroke related to a high-grade ipsilateral carotid stenosis benefit from early carotid endarterectomy.23 There are only limited data comparing the effects of specific medical interventions begun soon after TIA. In a factorial design, the Fast Assessment of Stroke and TIA to prevent Early Recurrence (FASTER) trial was designed to evaluate the effects of clopidogrel plus aspirin versus aspirin and simvastatin versus placebo begun within 24 hours of TIA or minor stroke.24 The trial was stopped early because of increased use of statins in the potential study population before TIA and slow recruitment. There was a nonsignificant reduction in the 90-day risk of stroke with clopidogrel+aspirin (risk ratio 0.7; 95% CI, 0 to 1.2) and a nonsignificant increase in stroke risk in those given simvastatin (risk ratio 1.3; 95% CI, 0.7 to 2.4) with no interaction between the 2 interventions (P=0.64). The results of FASTER are inconclusive and additional larger studies comparing urgent interventions for patients with TIA are needed.
Disclosures
None.
Received November 30, 2007; accepted December 3, 2007.
References
1. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: The Framingham study. Stroke. 1991; 22: 983–988.
2. European Atrial Fibrillation Trial Study Group. Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke. Lancet. 1993; 342: 1255–1262.[Medline] [Order article via Infotrieve]
3. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med. 2007; 146: 857–867.
4. Rothwell PM. External validity of randomised controlled trials: "To whom do the results of this trial apply?". Lancet. 2005; 365: 82–93.[CrossRef][Medline] [Order article via Infotrieve]
5. Hart RG, Pearce LA, Albers GW, Connolly SJ, Friday GH, Gage BF, Go AS, Goldstein LB, Gronseth G, Halperin JL, Hylek EM, Lip GYH, Sherman DG, Singer DE, van Walraven C. Independent predictors of stroke in patients with atrial fibrillation: a systematic review. Neurology. 2007; 69: 546–554.
6. Palareti G, Leali N, Coccheri S, Poggi M, Manotti C, D’Angelo A, Pengo V, Erba N, Moia M, Ciavarella N, Devoto G, Berrettini M, Musolesi S. Bleeding complications of oral anticoagulant treatment: An inception-cohort, prospective collaborative study (ISCOAT). Italian study on complications of oral anticoagulant therapy. Lancet. 1996; 348: 423–428.[CrossRef][Medline] [Order article via Infotrieve]
7. Fang MC, Chang Y, Hylek EM, Rosand J, Greenberg SM, Go AS, Singer DE. Advanced age, anticoagulation intensity, and risk for intracranial hemorrhage among patients taking warfarin for atrial fibrillation. Ann Intern Med. 2004; 141: 745–752.
8. Sweeney KG, Gray DP, Steele R, Evans P. Use of warfarin in non-rheumatic atrial fibrillation: a commentary from general practice. Br J Gen Pract. 1995; 45: 153–158.[Medline] [Order article via Infotrieve]
9. Marine JE, Goldhaber SZ. Controversies surrounding long-term anticoagulation of very elderly patients in atrial fibrillation. Chest. 1998; 113: 1115–1118.
10. Morgan SV. Between the devil and the deep blue sea–balancing the risks and potential benefits of warfarin for older people with atrial fibrillation. Age & Ageing. 2004; 33: 544–547.
11. Garcia-Honrubia A, Roldan V, Climent V, Sogorb F, Marin F. Antiplatelet versus anticoagulant therapies in advanced age: An unfinished task. Int J Cardiol. 2006; 110: 271–272.[CrossRef][Medline] [Order article via Infotrieve]
12. Flaherty ML, Kissela B, Woo D, Kleindorfer D, Alwell K, Sekar P, Moomaw CJ, Haverbusch M, Broderick JP. The increasing incidence of anticoagulant-associated intracerebral hemorrhage. Neurology. 2007; 68: 116–121.
13. Fuster V, Ryden LE, Cannom DS, Crijns HJ, Curtis AB, Ellenbogen KA, Halperin JL, Le Heuzey JY, Kay GN, Lowe JE, Olsson SB, Prystowsky EN, Tamargo JL, Wann S, Smith SC Jr, Jacobs AK, Adams CD, Anderson JL, Antman EM, Hunt SA, Nishimura R, Ornato JP, Page RL, Riegel B, Priori SG, Blanc JJ, Budaj A, Camm AJ, Dean V, Deckers JW, Despres C, Dickstein K, Lekakis J, McGregor K, Metra M, Morais J, Osterspey A, Zamorano JL. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation. Circulation. 2006; 114: e257–e354.
14. Rash A, Downes T, Portner R, Yeo WW, Morgan N, Channer KS. A randomised controlled trial of warfarin versus aspirin for stroke prevention in octogenarians with atrial fibrillation (WASPO). Age & Ageing. 2007; 36: 151–156.
15. Mant J, Hobbs FD, Fletcher K, Roalfe A, Fitzmaurice D, Lip GY, Murray E. Warfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (the Birmingham atrial fibrillation treatment of the aged study, BAFTA): A randomised controlled trial. Lancet. 2007; 370: 493–503.[CrossRef][Medline] [Order article via Infotrieve]
16. Easton JD, Albers GW, Caplan LR, Saver JL, Sherman DG. Reconsideration of TIA terminology and definitions. Neurology. 2004; 62 (suppl. 6): S29–S34.
17. Goldstein LB, Bian J, Samsa GP, Bonito AJ, Lux LJ, Matchar DB. New TIA and stroke: Outpatient management by primary care physicians. Arch Intern Med. 2000; 160: 2941–2946.
18. Giles MF, Rothwell PM. Risk of stroke early after transient ischemic attack: a systematic review and meta-analysis. Lancet Neurology. 2007; 6: 1063–1072.[Medline] [Order article via Infotrieve]
19. Johnston SC, Rothwell PM, Nguyen-Huynh MN, Giles MF, Elkins JS, Bernstein AL, Sidney S. Validation and refinement of scores to predict very early stroke risk after transient ischaemic attack. Lancet. 2007; 369: 283–292.[CrossRef][Medline] [Order article via Infotrieve]
20. Koton S, Rothwell PM. Performance of the abcd and abcd2 scores in TIA patients with carotid stenosis and atrial fibrillation. Cerebrovascular Diseases. 2007; 24: 231–235.[Medline] [Order article via Infotrieve]
21. Rothwell PM, Giles MF, Chandratheva A, Marquardt L, Geraghty O, Redgrave JN, Lovelock CE, Binney LE, Bull LM, Cuthbertson FC, Welch SJ, Bosch S, Carasco-Alexander F, Silver LE, Gutnikov SA, Mehta Z. Effect of urgent treatment of transient ischaemic attack and minor stroke on early recurrent stroke (EXPRESS study): A prospective population-based sequential comparison. Lancet. 2007; 370: 1432–1442.[CrossRef][Medline] [Order article via Infotrieve]
22. Lavallee PC, Meseguer E, Abboud H, Cabrejo L, Olivot JM, Simon O, Mazighi M, Nifle C, Niclot P, Lapergue B, Klein IF, Brochet E, Steg PG, Leseche G, Labreuche J, Touboul PJ, Amarenco P. A transient ischaemic attack clinic with round-the-clock access (SOS-TIA): feasibility and effects. Lancet Neurology. 2007; 6: 953–960.[CrossRef][Medline] [Order article via Infotrieve]
23. Rothwell PM, Eliasziw M, Gutnikov SA, Warlow CP, Barnett HJ. Endarterectomy for symptomatic carotid stenosis in relation to clinical subgroups and timing of surgery. Lancet. 2004; 363: 915–924.[CrossRef][Medline] [Order article via Infotrieve]
24. Kennedy J, Hill MD, Ryckborst KJ, Eliasziw M, Demchuk AM, Buchan AM, for the FI. Fast assessment of stroke and transient ischaemic attack to prevent early recurrence (FASTER): A randomised controlled pilot trial. Lancet Neurology. 2007; 6: 961–969.[CrossRef][Medline] [Order article via Infotrieve]
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