Late functional improvement and 5-year poststroke outcomes: a population-based cohort study.

BACKGROUND: Late functional improvement between 3 and 12 months poststroke occurs in about one in four patients with ischaemic stroke, more commonly in lacunar strokes. It is unknown whether this late improvement is associated with better long-term clinical or health economic outcomes. METHODS: In a prospective, population-based cohort of 1-year ischaemic stroke survivors (Oxford Vascular Study; 2002-2014), we examined changes in functional status (modified Rankin Scale (mRS), Rivermead Mobility Index (RMI), Barthel Index (BI)) from 3 to 12 months poststroke. We used Cox regressions adjusted for age, sex, 3-month disability and stroke subtype (lacunar vs non-lacunar) to examine the association of late improvement (by ≥1 mRS grades, ≥1 RMI points and/or ≥2 BI points between 3 and 12 months) with 5-year mortality and institutionalisation. We used similarly adjusted generalised linear models to examine association with 5-year healthcare/social-care costs. RESULTS: Among 1288 one-year survivors, 1135 (88.1%) had 3-month mRS >0, of whom 319 (28.1%) demonstrated late functional improvement between 3 and 12 months poststroke. Late improvers had lower 5-year mortality (aHR per mRS=0.68, 95% CI 0.51 to 0.91, p=0.009), institutionalisation (aHR 0.48, 0.33 to 0.72, p<0.001) and healthcare/social care costs (margin US$17 524, -24 763 to -10 284, p<0.001). These associations remained on excluding patients with recurrent strokes during follow-up (eg, 5-year mortality/institutionalisation: aHR 0.59, 0.44 to 0.79, p<0.001) and on examining late improvement per RMI and/or BI (eg, 5-year mortality/institutionalisation with RMI/BI: aHR 0.73, 0.58 to 0.92, p=0.008). CONCLUSION: Late functional improvement poststroke is associated with lower 5-year mortality, institutionalisation rates and healthcare/social care costs. These findings should motivate patients and clinicians to maximise late recovery in routine practice, and to consider extending access to proven rehabilitative therapies during the first year poststroke.

Ten-year risks of recurrent stroke, disability, dementia and cost in relation to site of primary intracerebral haemorrhage: population-based study.

BACKGROUND: Patients with primary intracerebral haemorrhage (ICH) are at increased long-term risks of recurrent stroke and other comorbidities. However, available estimates come predominantly from hospital-based studies with relatively short follow-up. Moreover, there are also uncertainties about the influence of ICH location on risks of recurrent stroke, disability, dementia and quality of life. METHODS: In a population-based study (Oxford Vascular Study/2002-2018) of patients with a first ICH with follow-up to 10 years, we determined the long-term risks of recurrent stroke, disability, quality of life, dementia and hospital care costs stratified by haematoma location. RESULTS: Of 255 cases with primary ICH (mean/SD age 75.5/13.1), 109 (42.7%) had lobar ICH, 144 (56.5%) non-lobar ICH and 2 (0.8%) had uncertain location. Annual rates of recurrent ICH were higher after lobar versus non-lobar ICH (lobar=4.0%, 2.7-7.2 vs 1.1%, 0.3-2.8; p=0.02). Moreover, cumulative rate of dementia was also higher for lobar versus non-lobar ICH (n/% lobar=20/36.4% vs 16/20.8%, p=0.047), and there was a higher proportion of disability at 5 years in survivors (15/60.0% vs 9/31.0%, p=0.03). The 10-year quality-adjusted life years (QALYs) were also lower after lobar versus non-lobar ICH (2.9 vs 3.8 for non-lobar, p=0.04). Overall, the mean 10-year censor-adjusted costs were £19 292, with over 80% of costs due to inpatient hospital admission costs, which did not vary by haematoma location (p=0.90). CONCLUSION: Compared with non-lobar ICH, the substantially higher 10-year risks of recurrent stroke, dementia and lower QALYs after lobar ICH highlight the need for more effective prevention for this patient group.

Disentangling the multiple links between renal dysfunction and cerebrovascular disease.

Chronic kidney disease (CKD) has a rapidly rising global prevalence, affecting as many as one-third of the population over the age of 75 years. CKD is a well-known risk factor for cardiovascular disease and, in particular, there is a strong association with stroke. Cohort studies and trials indicate that reduced glomerular filtration rate increases the risk of stroke by about 40% and that proteinuria increases the risk by about 70%. In addition, CKD is also strongly associated with subclinical cerebrovascular abnormalities, vascular cognitive impairment and dementia. The mechanisms responsible for these associations are currently unclear. CKD is associated with traditional risk factors such as hypertension, diabetes mellitus and atrial fibrillation, but non-traditional risk factors such as uraemia, oxidative stress, mineral and bone abnormalities, and dialysis-related factors, such as changes in cerebral blood flow or cardiac structure, are also postulated to play a role. Kidney disease can also impact and complicate the treatments used in acute stroke and in secondary prevention. In this review, we will outline our current understanding of the epidemiology and pathophysiology of cerebrovascular disease in CKD.

Long-Term Risk of Stroke After Transient Global Amnesia in Two Prospective Cohorts.

Background and Purpose- Transient global amnesia (TGA) is known as a benign syndrome, but recent data from neuroradiological studies support an ischemic cause in some cases, which might suggest an increased susceptibility to cerebrovascular events. We determined the long-term risk of stroke after a first TGA in 2 independent prospective cohorts. Methods- In 2 independent prospective cohorts of patients with TGA (OXVASC [Oxford Vascular Study], population-based; NU (Northern Umbria) cohort, TGA registry), cardiovascular risk factors and long-term outcomes, including stroke and major cardiovascular events, were identified on follow-up. Cardiovascular risk factors were treated according to primary prevention guidelines. In OXVASC, the age-/sex-adjusted risk of stroke during follow-up was compared with that expected from the rate in the underlying study population. Results- Among 525 patients with TGA (425 NU and 100 OXVASC), mean (SD) age was 65.1 (9.5) years and 42.5% male. Hypertension (58.1%), dyslipidemia (40.4%), and smoking (36.4%) were the most frequent cardiovascular risk factors. The risk of stroke was similar in the 2 cohorts, with a pooled annual risk of 0.6% (95% CI, 0.4-0.9) and a 5-year cumulative risk of 2.7% (1.1-4.3). Moreover, the stroke risk in OXVASC cases was no greater than that expected in the underlying study population (adjusted relative risk=0.73; 0.12-4.54; P=0.74). Conclusions- TGA does not carry an increased risk of stroke, at least when cardiovascular risk factors are treated according to primary prevention guidelines.

Late functional improvement after lacunar stroke: a population-based study.

BACKGROUND: Recovery in function after stroke involves neuroplasticity and adaptation to impairments. Few studies have examined differences in late functional improvement beyond 3 months among stroke subtypes, although interventions for late restorative therapies are often studied in lacunar stroke. Therefore, we compared rates of functional improvement beyond 3 months in patients with lacunar versus non-lacunar strokes. METHODS: In a prospective, population-based cohort of 3-month ischaemic stroke survivors (Oxford Vascular Study; 2002-2014), we examined changes in functional status (modified Rankin Scale (mRS), Rivermead Mobility Index (RMI), Barthel Index (BI)) in patients with lacunar versus non-lacunar strokes from 3 to 60 months poststroke, stratifying by age. We used logistic regression adjusted for age, sex and baseline disability to compare functional improvement (≥1 mRS grades, ≥1 RMI points and/or ≥2 BI points), particularly from 3 to 12 months. RESULTS: Among 1425 3-month survivors, 234 patients with lacunar stroke did not differ from others in 3-month outcome (adjusted OR (aOR) for 3-month mRS >2 adjusted for age/sex/National Institutes of Health Stroke Scale score/prestroke disability: 1.14, 95% CI 0.75 to 1.74, p=0.55), but were more likely to demonstrate further improvement between 3 months and 1 year (aOR (mRS) adjusted for age/sex/3-month mRS: 1.64, 1.17 to 2.31, p=0.004). The results were similar on restricting analyses to patients with 3-month mRS 2-4 and excluding recurrent events (aOR (mRS): 2.28, 1.34 to 3.86, p=0.002), or examining BI and RMI (aOR (RMI) adjusted for age/sex/3-month RMI: 1.78, 1.20 to 2.64, p=0.004). CONCLUSION: Patients with lacunar strokes have significant potential for late functional improvement from 3 to 12 months, which should motivate patients and clinicians to maximise late improvements in routine practice. However, since late recovery is common, intervention studies enrolling patients with lacunar strokes should be randomised and controlled.

Physiological correlates of beat-to-beat, ambulatory, and day-to-day home blood pressure variability after transient ischemic attack or minor stroke.

BACKGROUND AND PURPOSE: Visit-to-visit and day-to-day variability in systolic blood pressure (SBP) are associated with an increased risk of stroke, more strongly than variability on 24-hour ambulatory BP monitoring, but underlying physiological mechanisms are unclear. We related potentially relevant physiological characteristics to beat-to-beat, ambulatory, and day-to-day BP variability to identify underlying mechanisms and potential therapeutic targets. METHODS: BP variability (coefficient of variation [CV]) on 1-month home BP monitoring (3 sitting readings, 3× daily), on 24-hour ambulatory BP monitoring, and on 5-minute beat-to-beat monitoring was related to BP reactivity (to mental arithmetic), arterial aging (aortic stiffness: carotid-femoral pulse wave velocity; aortic pulsatility), heart rate variability (CV of normal-to-normal R-R interval), and orthostatic responses. RESULTS: In 223 patients within 6 weeks of a transient ischemic attack or minor stroke, beat-to-beat and home SBP-CVs were associated with response to arithmetic (beat-to-beat odds ratio per SD=1.64; P<0.0001 and home BP monitoring, 1.41; P=0.025), aortic stiffness (1.84; P<0.0001 and 1.31; P=0.04), aortic pulsatility (1.98; P<0.0001 and 1.61; P<0.0001), and heart rate variability-CV of normal-to-normal R-R interval (1.34; P=0.03 and 1.35; P=0.03), independently of age, sex, and aortic BP. Orthostatic BP changes were associated only with SBP-CV on home BP monitoring (0.62; P=0.002). In contrast, no physiological measures were associated with within-day BP variability on awake ambulatory BP monitoring except response to mental arithmetic (1.40; P=0.01). CONCLUSIONS: Beat-to-beat and day-to-day SBP variability, but not variability on ambulatory BP monitoring, had similar physiological correlates, suggesting common underlying mechanisms and identifying potentially treatable targets that may be responsible for the relationship between SBP variability and stroke risk.

The effect of antihypertensive treatment on headache and blood pressure variability in randomized controlled trials: a systematic review.

Antihypertensive drugs reduce headache but it is unclear whether there are differences between drug classes. Calcium channel blockers (CCBs) decrease variability in systolic blood pressure (SBPV) and stroke risk more than other classes, possibly due to decreased vascular tone. If so, there might be a correlation between drug-class effects on variability in SBP and on headache. We determined antihypertensive class effects on SBPV and headache during follow-up in a systematic review of randomized controlled trials. We determined pooled estimates of treatment effect on group variability in BP (variance ratio, VR) and on the odds ratio for headache (OR) by random-effects meta-analysis. Antihypertensive drugs reduced the incidence of headache compared to placebo (OR = 0.75, 95% CI 0.69-0.82, p < 0.0001, 198 comparisons, 43,672 patients), but there was significant heterogeneity between drug classes (p = 0.0007) with a greater effect of beta-blockers compared to placebo (VR = 0.49, 0.33-0.68, p < 0.0001, 16 trials) or all other drug classes (OR = 0.73, 0.62-0.85, p = 0.0002, 49 trials) and a lack of effectiveness of CCBs (vs. placebo-OR = 0.95, 0.79-1.15, 65 trials; vs. other drugs-OR = 1.19, 1.05-1.35, p = 0.009, 101 trials). Drug-class effects on headache were opposite to effects on variability in SBP (vs. other drugs: CCB-VR = 0.81, 0.71-0.85, p < 0.0001; beta-blocker VR = 1.17, 1.07-1.28, p < 0.0001), but were unrelated to differences in mean SBP. Antihypertensive drugs reduce headache but the effect differs between classes, corresponding to their effects on SBPV and the risk of stroke. This may partly be explained by consistent antihypertensive class effects on vascular tone in the peripheral (variability) and cerebrovascular circulations (headache).

Effect of dose and combination of antihypertensives on interindividual blood pressure variability: a systematic review.

BACKGROUND AND PURPOSE: Recent studies have shown that visit-to-visit blood pressure variability is a powerful risk factor for stroke, is reduced by calcium channel blockers and diuretics, and increased by ß-blockers. However, it is unknown whether these effects are dose-dependent and persist in combination with other drugs. METHODS: Cochrane and Medline databases were searched for systematic reviews and randomized controlled trials of antihypertensive drugs. Eligible trials randomized all patients to a combination of drug classes or different doses of the same drug. Baseline and follow-up data for mean (SD) systolic blood pressure (SBP) and diastolic blood pressure were extracted. Differences in interindividual variance (SD2) in blood pressure were expressed as a ratio (VR). Estimates were pooled by random-effects meta-analysis. RESULTS: Calcium channel blockers reduced interindividual variability in SBP when added to another agent (VR, 0.75; 95% CI, 0.64 to 0.87; P=0.0002; 12 trials; 1565 patients) with a smaller reduction with diuretics (VR, 0.85; 0.71 to 1.01; P=0.07; 17 trials; 3217 patients). Adding other agents to calcium channel blockers did not significantly affect SBP variability (VR, 1.06; 0.83 to 1.34; P=0.65; 12 trials; 1460 patients) despite a 5.8-mm Hg reduction in mean SBP. Randomization to a higher dose of calcium channel blockers reduced SBP variability (VR, 0.84; 0.74 to 0.94; P=0.004; 25 trials; 2179 patients), whereas randomization to a higher dose of ß-blockers increased SBP variability (VR, 1.31; 1.01 to 1.69; P=0.034; 6 trials; 486 patients). CONCLUSIONS: Effects of antihypertensive drugs on SBP variability are dose-dependent and persist when used in combinations. Use of a high dose of a calcium channel blocker alone or in combination with other agents is therefore likely to be particularly effective in prevention of stroke.

Effects of ß-blocker selectivity on blood pressure variability and stroke: a systematic review.

OBJECTIVES: ß-Blockers increase variability in systolic blood pressure (SBP), which probably explains their lesser effectiveness in preventing stroke vs myocardial infarction compared with other agents. This increase in variability in blood pressure (BP) may be particularly marked on non-cardioselective agents, potentially calling into question the widespread first-line use of propranolol in migraine with aura, elderly patients with essential tremor or anxiety, and other groups at risk of stroke. METHODS: We determined ß-blocker subclass effects on variability in BP and stroke risk in a systematic review of randomized controlled trials (RCTs) comparing different types of ß-blocker with placebo or other agents. We determined pooled estimates of the effect of treatment on group variability in BP (ratio of the variances [VR]) and on the risk of stroke vs myocardial infarction during follow-up. RESULTS: Compared with other antihypertensives, variability in SBP was increased more by nonselective ß-blockers (VR=1.34, 1.13-1.59, p =0.002, 25 comparisons, 9,992 patients) than by ß1-selective agents (VR=1.09, 95% confidence interval 1.00-1.19, p =0.053, 68 comparisons, 40,746 patients; difference-p =0.038). In direct comparisons, variability in SBP was also significantly lower with ß1-selective vs nonselective ß-blockers (VR=0.81, 0.68-0.97, p =0.03, 18 comparisons, 954 patients). In comparisons with other antihypertensives, the increase in stroke risk with nonselective ß-blockers ([OR]=2.29, 1.32-3.96, p =0.002) was more marked than with ß1-selective agents (OR=1.24, 1.08-1.42, p =0.003, difference-p =0.03), as was the risk of stroke relative to the risk of myocardial infarction: OR=1.50 (0.93-2.42) vs 0.99 (0.82-1.19). CONCLUSION: Use of ß1-selective rather than nonselective agents may be advisable when ß-blockers are indicated for patients at risk of stroke.