Supplementary webappendix This webappendix formed part of the original submission and has been peer reviewed. We post it as supplied by the authors. Supplement to: Hart RG, Diener H-C, Coutts SB, et al, for the Cryptogenic Stroke/ESUS International Working Group. Embolic strokes of undetermined source: the case for a new clinical construct. Lancet Neurol 2014; 13: 429 38.
Supplement Tables Table 1. Features of patient cohorts meeting ESUS criteria* N mean male HTN diabetes prior PFO Comments age (%) (%) (%) stroke (%) Santamaria et al. (2012)(1) 89 71 yrs 54 66 28 23 5%^ Consecutive stroke unit inpatients; average baseline NIHSSS = 9. Bang et al. (2003)(2) 37 61 yrs 46 68 41 32 Young stroke cohort from South Korea; BI at 1 week = 85. ESUS = embolic stroke of undetermined cause; HTN = hypertension; PFO = patent foramen ovale; NIHSSS = National Institutes of Health Stroke Scale score; BI = Barthel Index. *Case series of patients with cryptogenic stroke with sufficient diagnostic evaluation to exclude proximal occlusive arterial disease and major cardioembolic sources (including covert paroxysmal atrial fibrillation and excluding lacunar infarcts. ^PFO with atrial septal aneurysm. References for Supplement Table 1: 1. Santamaria E, Penalba A, Garcia-Berrocoso T, et al. Biomarker level improves the diagnosis of embolic source in ischemic stroke of unknown origin. J Neurol 2012; 259: 2538-45. 2. Bang OY, Lee PH, Joo SY, et al. Frequency and mechanisms of stroke recurrence after cryptogenic stroke. Ann Neurol 2003; 54: 227-34. 1
Table 2. Stroke recurrence rates in patients diagnosed with cryptogenic stroke+ Study criteria/cohort N / mean age Randomized trial (warfarin vs. aspirin); ages 30-85 with ischemic stroke within 30 days and warfarin eligible, 1991-2000. Criteria for 295 / ~64yrs cryptogenic modeled after the NINDS Stroke Data Bank and TOAST, but no details 129 reported 166 WARSS (1)* all cryptogenic age stratified (2) - <60 yrs old - >60 yrs old German Stroke Study Registry (3,4) All without PFO Age stratified - <65 yrs old - >65 yrs old European PFO/ASA Study (5) Roma La Sapienza series (6) CODICA Study (7) TULIPS registry Japan (8) Multicenter prospective registry 2002-2007; TOAST criteria used. Various subgroups of cryptogenic stroke and TIA patients reported Prospective trial testing ASA; ages 18-55 with cryptogenic stroke within 90 days, 1996-2000, TOAST criteria for cryptogenic Cryptogenic acute stroke or TIA within 1 wk from a TEE-based case series 1992-1999. Criteria for cryptogenic: Amarenco et al. NEJM 1994; 331: 1474-9 Prospective study of cryptogenic acute stroke (80%) or TIA within 30 days at 17 Spanish hospitals 2000-2005. 21% given warfarin. TOAST criteria for cryptogenic. Prospective study of patients with cryptogenic stroke (1999-2002) followed 1 yr; 74% antiplatelet, 9% anticoagulated. 548 / 61yrs mean f/u 2yrs 2.4yrs Stroke rate 5.8%/yr* on ASA 2.5%/yr* on ASA 8.3%/yr* on ASA 2.8%/yr on APT 325 2%/yr 233 4.2%/yr 581 / 43yrs 3.2yrs 1.3%/yr on ASA 86 / 47yrs 2.8yrs 4.5%/yr# 486 / 56yrs 2.0yrs 2.9%/yr^ 189 / 72yrs 1 yr 7.8%/yr Ankara (9) Prospective follow-up; 31% anticoagulated 87 / 69yrs 0.5 yrs 9.2%/0.5yrs Palomeras Soler (10) Stroke registry data published in Spanish with English abstract. 14 lost-to-follow-up; 96% antiplatelet therapy 121 / 71yrs 1yr 2.8%/yr Rochester, MN (11) Erlangen Stroke Project (12) Population-based 1985-1989, 36% cryptogenic, but diagnostic evaluation not extensive. Population-based 1994-1998, 35% cryptogenic by modified TOAST, but no details about diagnostic evaluation. 164 / NR ~3.2yrs 21% @ 2yrs** 188 / 75yrs ~2yrs 14% @ 2yrs Canada (13) Two research imaging cohorts 333 / NR 90 d 1.2% @ 90 days^^ Chile (14) Prospective stroke unit 76 / 62 yrs ~2yrs 2.5%/yr f/u = follow-up; yrs = years; ASA = acetyl salicylic acid; APT = antiplatelet therapy; NR = not reported. + An additional relatively small study is not included due to a markedly outlying result: Bang et al.(715) reported a 30% stroke recurrence rate in the first year in 37 patients (mean age = 61 yrs) with cryptogenic stroke. *Only the combined rate of recurrent stroke or death was reported, i.e. no published information on the combination of stroke, MI or vascular death; 70% of events among aspirin-assigned participants were strokes in the entire study cohort,(16) but the fraction in those with cryptogenic stroke has not been reported. Applying 70% to the reported 2-year rate of stroke or death of 16.5% for cryptogenic stroke patients taking aspirin, the estimated annualized stroke rate is 5.8%/yr. #Variety of antithrombotic therapies: aspirin, warfarin and no treatment. ^79% antiplatelet agents, 21% warfarin. Ischemic stroke (vs. TIA) as the ischemic event was the only independent predictor of stroke recurrence (odds ratio = 3.3, p=0.003). (7) **15% taking warfarin. Some fraction of recurrent strokes (<20%) were early, during the initial 30 days. Mean age not provided, but likely quite old. The 5-yr mortality rate was 48.6%.(11) ^^ MRI demonstrated new subclinical brain infarcts in 15% at 90 days.(13) Summary of key studies: The Warfarin-Aspirin Recurrent Stroke Study (WARSS) randomized patients between 30 and 85 years-old with recent (<30 days) ischemic stroke and who were eligible to receive warfarin anticoagulation to aspirin 325mg/d or adjusted-dose warfarin 2
(target INR 1.4-2.8, median = 1.9) and followed for two years.(1) Among 2206 participants entered at U.S. centers during the 1990s, the mean age was 63 years; 29% had prior stroke or TIA. Twenty-six percent (n=576) were deemed cryptogenic based on application of TOAST criteria by local investigators; no data on the frequency of diagnostic tests was reported. For cryptogenic stroke patients, the primary outcome of ischemic stroke or death occurred in 15.0% assigned to warfarin vs. 16.5% assigned to aspirin over two years (HR 0.92, 95%CI 0.6-1.4).(1) Among all participants, recurrent strokes made up 73% of the primary outcome events,(16) but this fraction was not published for the subset with cryptogenic stroke. Extrapolating from all participants, the recurrent stroke rate is estimated as about 5.8% per year for those with cryptogenic stroke. The relatively low achieved intensity of anticoagulation in WARSS is noteworthy regarding the relative efficacy of anticoagulation vs. antiplatelet agents in patient with cryptogenic stroke. In subgroup analyses involving those with cryptogenic stroke, the rate of recurrent ischemic stroke or death was 2.5 times higher among those who were over age 60 years (mean age = 72 years) at entry: 22% over two years.(2) For participants with cryptogenic stroke whose CT showed an embolic topography (338/561 = 60% of all cryptogenic strokes), the two-year rate of recurrent ischemic stroke or death was 11.9% with warfarin vs.17.8% with aspirin (HR=0.66, 95%CI 0.4-1.2).(16) The German Stroke Study Registry (2002-2007) was a prospective study carried-out at 17 German Neurology Departments and is of interest because of being multi-center and using extensive contemporary diagnostic evaluation to determine stroke etiology.(3,4,17) Further, the recurrent stroke rate from these neurology-based hospitalized patients are more likely to be similar to a randomized trial cohort than those from population-based series. There were 1,438 patients with cryptogenic stroke or TIA included in the registry, but only subgroups have been reported. In one report,(3) 339 patients with cryptogenic ischemic stroke (80%) or TIA (20%) were selected who underwent specialized coagulation testing (mean age 53 years); no specific criteria for cryptogenic stroke were provided, but other publications from the Registry cited the modified TOAST criteria. During a mean follow-up of 2.5 years (14% received anticoagulation, 85% antiplatelet therapy), ischemic stroke recurred in 19 (2.2%/yr), but 5 were early, during the initial hospitalization; ischemic stroke after discharge for the index stroke occurred in 1.7%/yr. Five additional patients had hemorrhagic strokes during follow-up. Eight patients died (1%/yr), six of nonvascular causes. In a second report of 548 patients with cryptogenic stroke (79%) or TIA (21%) without patent foramen ovale (modified TOAST criteria cited for definition of cryptogenic etiology) followed for a mean of 28.4 months; the mean age was 61 yrs and 93% received antiplatelet drugs at discharge.(4) The recurrence stroke rate was 2.8%/yr during the entire follow-up period - 4.0%/yr during the first year and 2.4%/yr thereafter.(4) For those >65 years old, the stroke rate was 4.2%/yr (95%CI 2.4,6.0) vs. ~2%/yr for younger patients. Stroke rates for additional patients with patent foramen ovale were confounded by frequent use of anticoagulation and percutaneous closure. No data on myocardial infarction or death was provided.(4) In the European PFO/ASA Study (1996-2000) (5), there were 23 ischemic strokes, 1 cerebral hemorrhage, 1 systemic embolism, 3 MIs, 6 deaths, and 13 TIAs among 581 3
young (mean age = 43 years, all <55 years per study protocol) cryptogenic ischemic stroke patients all followed on aspirin 300mg daily. The VITAmins TO Prevent Stroke (VITATOPS) trial tested B vitamin supplements for secondary prevention of vascular events in 8184 patients (mean age 63 years) with recent TIA (17% of participants) or ischemic (71%)/hemorrhagic (10%) stroke with a mean follow-up of 3.4 years.(18) Among 1008 patients with ischemic stroke of uncertain/unknown cause (not defined), the composite of stroke, myocardial infarction or vascular death occurred in 8.2% (annualized estimate 2.4% per year).(18) Separate results for recurrent stroke are not available. References for Supplement Table 2. 1. Mohr JP, Thompson JLP, Lazar RM, et al. A comparison of warfarin and aspirin for the prevention of recurrent ischemic stroke. N Engl J Med 2001; 345: 1444-51. 2. Homma S, DiTullio MR, Sacco RL, et al. Age as a determinant of adverse events in medically treated cryptogenic stroke patients with patent foramen ovale. Stroke 2004; 35: 2145-9. 3. Weber R, Goertler M, Benemann, Diener HC, et al. Prognosis after cryptogenic cerebral ischemia in patients with coagulopathies. Cerebrovasc Dis 2009; 28: 611-7. 4. Weimar C, Holle DN, Benemann J, et al. Current management and risk of recurrent stroke in cerebrovascular patients with right-to-left cardiac shunt. Cerebrovasc Dis 2009; 28: 349-56. 5. Mas J-L, Arquizan C, Lamy C, et al. Recurrent cerebrovascular events associated with patent foramen ovale, atrial septal aneurysm, or both. N Engl J Med 2001; 345: 1740-6. 6. De Castro S, Cartoni D, Fiorelli M, et al Morphological and functional characteristics of patent foramen ovale and their embolic implications. Stroke 2000; 31: 2407-13. 7. Serena J, Marti-Fabregas J, Santamaria E, et al. Recurrent stroke and massive right-to-left shunt. Results from the prospective Spanish multicenter (CODICA) study. Stroke 2008; 39: 3131-6. 8. Soda T, Nakayasu J, Maeda M, et al. Stroke recurrence within the first year followig cerebral infarction Tottori University Lacunar Infarction Prognosis Study (TULIPS). Acta Neurol Scand 2004: 110: 343-9. 9. Sumer MM, Erturk O. Ischemic stroke subtypes: risk factors, functional outcome, and recurrence. Neurol Sci 2002; 22: 449-54. 10. Palomeras Soler E, Fossas Felip P, et al. Cryptogenic infarct. A follow-up period of 1 year study. Neurologica [Spanish] 2009; 24: 304-8. 11. Petty GW, Brown RD, Whisnant JP, et al. Ischemic stroke subtypes. A population-based study of functional outcome, survival and recurrence. Stroke 2000; 31: 1062-8. 12. Kolominsky-Rabas PL, Weber J, Gefeller O, et al. Epidemiology of ischemic stroke subtypes according to TOAST criteria. Stroke 2001: 32: 2735-40. 13. Bal S, Patel SK, Almekhlafi M, Modi J, Demchuk AM, Coutts SB. High rate of magnetic resonance imaging stroke recurrence in cryptogenic transient ischemic attack and minor stroke patients. Stroke 2012; 43: 3387-8. 14. Vallejos J, Jaramillo A, Reyes A, et al. Prognosis of cryptogenic ischemic stroke: A prospective single-center study in Chile. J Stroke Cerebrovas Dis 2012; 21: 621-8. 15. Bang OY, Lee PH, Joo SY, et al. Frequency and mechanisms of stroke recurrence after cryptogenic stroke. Ann Neurol 2003; 54: 227-34. 16. Sacco RL, Prabhakaran S, Thompson JLP, et al. Comparison of warfarin vs. aspirin for the prevention of recurrent stroke or death: Subgroup analyses from the Warfarin-Aspirin Recurrent Stroke Study. Cerebrovas Dis 2006; 22: 4-12. 4
17. Grau AJ, Weimar C, Buggle F, et al. Risk factors, outcome, and treatment in subtypes of ischemic stroke. The German Stroke Data Bank. Stroke 2001; 32: 2559-66. 18. VITATOPS Trial Study Group. B vitamins in patients with recent transient ischaemic attack or stroke in the VITAmins TO Prevent Stroke (VITATOPS) trial: a randomised, double-blind, parallel, placebo-controlled trial. Lancet Neurol 2010; 9: 855-65. 5