Arvind Chandratheva

Effect of urgent treatment of transient ischaemic attack and minor stroke on early recurrent stroke (EXPRESS study): a prospective population-based sequential comparison.

BACKGROUND The risk of recurrent stroke is up to 10% in the week after a transient ischaemic attack (TIA) or minor stroke. Modelling studies suggest that urgent use of existing preventive treatments could reduce the risk by 80-90%, but in the absence of evidence many health-care systems make little provision. Our aim was to determine the effect of more rapid treatment after TIA and minor stroke in patients who are not admitted direct to hospital. METHODS We did a prospective before (phase 1: April 1, 2002, to Sept 30, 2004) versus after (phase 2: Oct 1, 2004, to March 31, 2007) study of the effect on process of care and outcome of more urgent assessment and immediate treatment in clinic, rather than subsequent initiation in primary care, in all patients with TIA or minor stroke not admitted direct to hospital. The study was nested within a rigorous population-based incidence study of all TIA and stroke (Oxford Vascular Study; OXVASC), such that case ascertainment, investigation, and follow-up were complete and identical in both periods. The primary outcome was the risk of stroke within 90 days of first seeking medical attention, with independent blinded (to study period) audit of all events. FINDINGS Of the 1278 patients in OXVASC who presented with TIA or stroke (634 in phase 1 and 644 in phase 2), 607 were referred or presented direct to hospital, 620 were referred for outpatient assessment, and 51 were not referred to secondary care. 95% (n=591) of all outpatient referrals were to the study clinic. Baseline characteristics and delays in seeking medical attention were similar in both periods, but median delay to assessment in the study clinic fell from 3 (IQR 2-5) days in phase 1 to less than 1 (0-3) day in phase 2 (p<0.0001), and median delay to first prescription of treatment fell from 20 (8-53) days to 1 (0-3) day (p<0.0001). The 90-day risk of recurrent stroke in the patients referred to the study clinic was 10.3% (32/310 patients) in phase 1 and 2.1% (6/281 patients) in phase 2 (adjusted hazard ratio 0.20, 95% CI 0.08-0.49; p=0.0001); there was no significant change in risk in patients treated elsewhere. The reduction in risk was independent of age and sex, and early treatment did not increase the risk of intracerebral haemorrhage or other bleeding. INTERPRETATION Early initiation of existing treatments after TIA or minor stroke was associated with an 80% reduction in the risk of early recurrent stroke. Further follow-up is required to determine long-term outcome, but these results have immediate implications for service provision and public education about TIA and minor stroke.

Population-based study of risk and predictors of stroke in the first few hours after a TIA

Background: Several recent guidelines recommend assessment of patients with TIA within 24 hours, but it is uncertain how many recurrent strokes occur within 24 hours. It is also unclear whether the ABCD2 risk score reliably identifies recurrences in the first few hours. Methods: In a prospective, population-based incidence study of TIA and stroke with complete follow-up (Oxford Vascular Study), we determined the 6-, 12-, and 24-hour risks of recurrent stroke, defined as new neurologic symptoms of sudden onset after initial recovery. Results: Of 1,247 first TIA or strokes, 35 had recurrent strokes within 24 hours, all in the same arterial territory. The initial event had recovered prior to the recurrent stroke (i.e., was a TIA) in 25 cases. The 6-, 12-, and 24-hour stroke risks after 488 first TIAs were 1.2% (95% confidence interval [CI]: 0.2–2.2), 2.1% (0.8–3.2), and 5.1% (3.1–7.1), with 42% of all strokes during the 30 days after a first TIA occurring within the first 24 hours. The 12- and 24-hour risks were strongly related to ABCD2 score (p = 0.02 and p = 0.0003). Sixteen (64%) of the 25 cases sought urgent medical attention prior to the recurrent stroke, but none received antiplatelet treatment acutely. Conclusion: That about half of all recurrent strokes during the 7 days after a TIA occur in the first 24 hours highlights the need for emergency assessment. That the ABCD2 score is reliable in the hyperacute phase shows that appropriately triaged emergency assessment and treatment are feasible.

Influence of general practice opening hours on delay in seeking medical attention after transient ischaemic attack (TIA) and minor stroke: prospective population based study.

Objective To assess the influence of general practice opening hours on healthcare seeking behaviour after transient ischaemic attack (TIA) and minor stroke and feasibility of clinical assessment within 24 hours of symptom onset. Design Population based prospective incidence study (Oxford vascular study). Setting Nine general practices in Oxfordshire. Participants 91 000 patients followed from 1 April 2002 to 31 March 2006. Main outcome measures Events that occurred overnight and at weekends (out of hours) and events that occurred during surgery hours. Results Among 359 patients with TIA and 434 with minor stroke, the median (interquartile range) time to call a general practitioner after an event during surgery hours was 4.0 (1.0-45.5) hours, and 68% of patients with events during surgery hours called within 24 hours of onset of symptoms. Median (interquartile range) time to call a general practitioner after events out of hours was 24.8 (9.0-54.5) hours for patients who waited to contact their registered practice compared with 1.0 (0.3-2.6) hour in those who used an emergency general practitioner service (P<0.001). In patients with events out of hours who waited to see their own general practitioner, seeking attention within 24 hours was considerably less likely for events at weekends than weekdays (odds ratio 0.10, 95% confidence interval 0.05 to 0.21): 70% with events Monday to Friday, 33% on Sundays, and none on Saturdays. Thirteen patients who had events out of hours and did not seek emergency care had a recurrent stroke before they sought medical attention. A primary care centre open 8 am-8 pm seven days a week would have offered cover to 73 patients who waited until surgery hours to call their general practitioner, reducing median delay from 50.1 hours to 4.0 hours in that group and increasing those calling within 24 hours from 34% to 68%. Conclusions General practitioners’ opening hours influence patients’ healthcare seeking behaviour after TIA and minor stroke. Current opening hours can increase delay in assessment. Improved access to primary care and public education about the need for emergency care are required if the relevant targets in the national stroke strategy are to be met.

ABCD2 Score Predicts Severity Rather Than Risk of Early Recurrent Events After Transient Ischemic Attack

Background and Purpose— The ABCD2 score predicts the early risk of stroke after transient ischemic attack (TIA). However, data on the severity of recurrent events would also be useful. Do patients with high scores also have more severe early recurrent strokes, perhaps further justifying hospital admission? Do patients with low scores have a low early risk of recurrent TIA as well as recurrent stroke? Methods— We completed a prospective, population-based study in Oxfordshire, England, of 500 consecutive patients presenting with TIA from April 1, 2002, by using multiple methods of case ascertainment (Oxford Vascular Study). Recurrent TIA, minor stroke, and major stroke (National Institutes of Health Stroke Scale score >3 at the time of first assessment) were identified by face-to-face follow-up. Predictive value was expressed as the area under the receiver operating characteristic curve. Results— Of 500 patients with TIA, 55 had a recurrent TIA (11.0%; 95% CI, 8.3% to 13.7%) and 50 had a recurrent stroke (10.0%; 95% CI, 7.5% to 12.0%) within 7 days. The ABCD2 score was highly predictive of major recurrent stroke (area under the receiver operating characteristic curve=0.80; 95% CI, 0.72 to 0.87, P<0.0001), weakly predictive of minor stroke (area under the receiver operating characteristic curve=0.57; 95% CI, 0.43 to 0.71, P=0.26), and inversely related to risk of recurrent TIA (area under the receiver operating characteristic curve=0.37; 95% CI, 0.29 to 0.44, P=0.001) (overall heterogeneity, P<0.0001). The score predicted stroke-related disability, length of stay for recurrent stroke, and hence, overall acute hospital care costs. Conclusions— The ABCD2 score predicts severity of recurrent events after TIA, high scores being associated with major recurrent stroke and low scores with high rates of recurrent TIA. These findings have implications for cost-benefit analyses of policies on hospital admission for patients with high scores and for the advice given to patients with low scores.

Population-based study of capsular warning syndrome and prognosis after early recurrent TIA

Objective: Many guidelines recommend emergency assessment for patients with ≥2 TIAs within 7 days, perhaps in recognition of the capsular warning syndrome. However, it is unclear whether all patients with multiple TIAs are at high early risk of stroke and whether treatable underlying pathologies are more prevalent in this group. Methods: We studied clinical characteristics, Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification, and risk of stroke in 1,000 consecutive patients with incident and recurrent TIAs in a prospective, population-based study (Oxford Vascular Study). Results: Of 1,000 patients with TIAs, 170 had a further TIA within 7 days (105 within 24 hours). Multiple TIAs were not associated with carotid stenosis or atrial fibrillation, and much of the 10.6 (95% confidence interval [CI] 6.5−15.9) risk of stroke during the 7 days after the first TIA was due to patients with small-vessel disease (SVD) etiology (10 of 24 vs 8 of 146, odds ratio [OR] = 12.3, 95% CI 3.7–41.9, p < 0.0001), particularly those with motor weakness (i.e., capsular warning syndrome) compared with hemisensory events (9 of 15 [60%], 95% CI 35.3–84.7 vs 1 of 9 [11.1%], 95% CI 0–31.7, p = 0.03). The 7-day risk of stroke after a recurrent TIA was similar to the risk after a single TIA in patients with non-SVD TIA (8 of 146 [5.5%] vs 76 of 830 [9.2%], OR = 0.58, 95% CI 0.25–1.3, p = 0.20). Of the 9 patients with stroke after a capsular warning syndrome, all had the recurrent TIA within 24 hours after the first TIA, and the subsequent stroke occurred within 72 hours of the second TIA in 8. The ABCD2 scores of all preceding TIAs were ≥4 in all 9 patients with capsular warning syndrome before stroke. Conclusions: Capsular warning syndrome is rare (1.5% of TIA presentations) but has a poor prognosis (7-day stroke risk of 60%). Otherwise, recurrent TIA within 7 days is not associated with a greater stroke risk than that after a single TIA.

Poor performance of current prognostic scores for early risk of recurrence after minor stroke.

Background and Purpose— The ABCD2 score predicts the early risk of stroke after transient ischemic attack. The early risk of recurrence after minor stroke is as high but the only validated prognostic scores for use in minor stroke predict long-term risk of recurrence: the Essen Stroke Risk Score and the Stroke Prognosis Instrument II. Methods— We determined the prognostic value of the ABCD2 score, Essen Stroke Risk Score, and Stroke Prognosis Instrument II in a prospective population-based study in Oxfordshire, UK, of all incident and recurrent stroke (Oxford Vascular Study). Minor stroke was defined as an National Institutes of Health Stroke Scale score ≤5 at the time of first assessment. The 90-day risks of recurrent stroke were determined in relation to each score. Areas under the receiver operator curves indicated predictive value. Results— Of 1247 first events in the study period, 488 were transient ischemic attacks, 520 were minor strokes, and 239 were major strokes. The ABCD2 score was modestly predictive (area under the receiver operator curve, 0.64; 0.53 to 0.74; P=0.03) of recurrence at 7 days after minor stroke and at 90 days (0.62; 0.54 to 0.70; P=0.004). Neither Essen Stroke Risk Score (0.50; 0.42 to 0.59; P=0.95) nor Stroke Prognosis Instrument II (0.48; 0.39 to 0.60; P=0.92) were predictive of 7-day or 90-day risk of recurrent stroke. Of the traditional vascular risk factors, etiologic classification (Trial of ORG 10172 in Acute Stroke Treatment) and variables in the ABCD2 score, only blood pressure >140/90 mm Hg (hazard ratio, 2.75; 1.18 to 6.38; P=0.02) and large artery disease (hazard ratio, 2.21; 1.00 to 4.88; P=0.05) were predictive of 90-day risk. Conclusions— The predictive power of the ABCD2 score is modest in patients with minor stroke, and neither the Essen Stroke Risk Score nor the Stroke Prognosis Instrument II predicts early recurrence. More reliable early risk prediction after minor stroke is required.

Preliminary evidence of a high risk of bleeding on aspirin plus clopidogrel in aspirin-naïve patients in the acute phase after TIA or minor ischaemic stroke.

Background: Aspirin plus clopidogrel (A+C) may be more effective than aspirin only (AO) acutely after TIA and minor stroke, but the risk of bleeding in the acute phase is uncertain. We determined this risk, focusing particularly on aspirin-naïve patients. Methods: We studied consecutive referrals to the EXPRESS study clinic from 1/4/02 to 31/3/08. A 30- to 90-day course of A+C was given to patients presenting acutely. Bleeding events were identified by face-to-face follow-up, diagnostic coding, and blood transfusion data. Unpublished data from the FASTER pilot trial were also studied. Results: Among 633 EXPRESS patients treated with aspirin (+/– clopidogrel), there were 12 spontaneous bleeds (6 minor, 6 major/life-threatening) within 90 days after assessment, with a higher risk for A+C vs. AO (8/247 vs. 4/386, p = 0.047 overall; 5/247 vs. 1/386, p = 0.03 for major/life-threatening bleeds). The excess of major/life-threatening bleeds on A+C vs. AO was seen in aspirin-naïve patients, (4/137 vs. 0/273, p = 0.01), but not in prior-aspirin patients (1/110 vs. 1/113, p = 0.98). All symptomatic bleeds in the FASTER pilot also occurred in aspirin-naïve patients randomized to A+C (6/104 vs. 0/94, p = 0.03). In a pooled analysis, major/life-threatening bleeding on A+C occurred in 9/241 aspirin-naïve patients (90-day risk = 4.8%, 1.6–8.0) versus 1/204 prior-aspirin patients (p = 0.009). Conclusion: Although based on relatively few outcomes, the high risk of major bleeding on A+C acutely after TIA or minor stroke in aspirin-naïve patients is a cause for concern. The potential risk to patients is sufficient to mandate detailed monitoring of bleeding risk in ongoing trials and stratify results by whether patients were aspirin-naïve.

Low risk of rebound events after a short course of clopidogrel in acute TIA or minor stroke

Objective: The combination of aspirin and clopidogrel is indicated after acute coronary events and possibly for a short period after TIA or minor ischemic stroke. Early discontinuation of clopidogrel results in a transient rebound increase in risk of recurrence in acute coronary syndromes, but there are no published data on any similar rebound effect in patients with TIA or stroke that might inform the design of clinical trials of aspirin and clopidogrel in the acute phase. Methods: A 30-day course of aspirin and clopidogrel (both 75 mg daily) was given to high-risk patients with TIA or minor ischemic stroke seen acutely in the EXPRESS study clinic from April 1, 2002, to March 31, 2009. Clopidogrel was stopped after 30 days and aspirin continued. Recurrent events were ascertained at face-to-face follow-up. Results: A total of 320 patients were prescribed a 30-day course of aspirin and clopidogrel acutely after TIA or minor stroke. There were 5 recurrent ischemic strokes and 7 TIAs during the aspirin and clopidogrel treatment period, but no strokes and 4 TIAs during the 30 days after stopping clopidogrel. A similar temporal trend in stroke risk was seen in the 487 patients prescribed aspirin alone in the acute phase, with 12 and 5 strokes in the equivalent time periods. The upper 95% confidence intervals of the observed 0% risk of stroke during the 30 days after stopping clopidogrel was 1.15% overall. Conclusion: Although larger studies are required, our findings suggest there is unlikely to be a large rebound effect after discontinuation of a 30-day course of clopidogrel in acute TIA and minor ischemic stroke. However, planned trials of aspirin and clopidogrel in the acute phase after TIA or stroke should still follow-up beyond the cessation of clopidogrel treatment.

Utility of current thrombophilia screening in young patients with stroke and TIA

Introduction Approximately 40% of strokes in young adults are cryptogenic. The diagnostic yield of thrombophilia screening remains controversial. We aimed to determine utility of current thrombophilia testing for young patients with stroke and transient ischaemic attack (TIA). Methods We present a retrospective review of all patients with stroke and TIA ≤60 years presenting to University College London Hospital stroke unit and daily TIA clinic from 1 January 2015 to 1 August 2016. Consecutive clinical records and thrombophilia tests, including factor V Leiden (FVL), prothrombin G20210A mutation (PGM), antiphospholipid antibody (APA), and protein S, C and antithrombin (AT) levels, were reviewed. Results The mean age of 628 patients with stroke and TIA was 49.1 years (SD 9.2). Thrombophilia testing was performed in 360 (57%) patients, including 171 with stroke and 189 with TIA. Positive tests were found in 50 (14%) patients, of whom 24 patients were <50 years. Positive results were found in 36 (10%) with acute ischaemic stroke, 4 (1%) with haemorrhagic stroke and 10 (3%) with TIA. Thirteen patients (4%) had homozygous/heterozygous FVL or PGM, and 27 (7.5%) had positive APA (anticardiolipin antibody, anti-β2 glycoprotein antibody or lupus anticoagulant). Of 27 (7.5%) patients with protein C, S or AT deficiency, 10 (2.8%) had primary deficiency, presumed hereditary with other secondary causes excluded. 9% of patients with protein C, S or AT and 27% with APA were followed by confirmatory testing. Conclusion Thrombophilia testing was positive in only 14% of cases overall. Thrombophilia mutations and protein C, S or AT abnormalities were found rarely and were very uncommon in patients with TIA. Follow-up of abnormal results was generally poor for all groups, which further limited the impact of the thrombophilia testing policy.

Undertreatment of Vascular Risk Factors in Patients with Monocular Ischaemic Visual Loss

Background and Purpose: Ischaemic visual loss is often considered a lower risk factor than other transient ischaemic attacks (TIA). We aimed to determine the recurrence risk, prevalence and management of vascular risk factors in these patients. Methods: The study took place in the University College Hospital London daily TIA clinic, main referral centre for North-Central London and Moorfields Eye Hospital. Consecutive records for patients with transient (< 24 h) or permanent (> 24 h) ischaemic visual loss were reviewed during the period January 2014–October 2016. Patients diagnosed with temporal arteritis were excluded. Results: Of 400 patients, 224 (56%) were male with mean age 64.5 years (SD 15.1); 263 patients (65.8%) presented with transient and 137 patients (34.2%) with permanent ischaemic visual loss; 51.3% had hypertension (HTN), 35.3% hypercholesterolaemia, 14.5% diabetes, 11.8% ischaemic ocular events, 10.0% ischaemic heart disease, 7.3% atrial fibrillation (AF), 6.3% TIA, 5.3% stroke, and 12.3% were smokers. Median vascular risk factors were 2 (range 1–6), but 122 (30.5%) had ≥3. Those with diabetes (p < 0.001), HTN (p = 0.008), previous myocardial infarction (p = 0.005), or ≥3 vascular risk factors (p = 0.012) were more likely to present with permanent visual loss, while patients with history of transient events, TIA (p = 0.002), or ocular (p = 0.002) presented with transient visual loss. Ninety-day recurrence was 10.5%; this was higher in patients with ≥3 risk factors (hazard ratio 1.42, 95% CI 0.95–2.11, p = 0.111). Patients with past TIA were more likely to be on secondary prevention than those with ocular ischaemia; 60.0 vs. 34.1% received antiplatelets and 76.0 vs. 43.9% statins. At presentation, only 55.2% (16 patients) with known AF were anticoagulated, despite all of them having CHADSVASC ≥1. Conclusions: Approximately one-third of patients with ocular ischaemia had ≥3 vascular risk factors with recurrences higher in these patients. Yet only half of those with previous ischaemic ocular events were on antiplatelets or statins. These patients should be investigated and treated as aggressively as other forms of TIA or stroke.