Alastair J.S. Webb

Effects of antihypertensive-drug class on interindividual variation in blood pressure and risk of stroke: a systematic review and meta-analysis

INTRODUCTION Unexplained differences between classes of antihypertensive drugs in their effectiveness in preventing stroke might be due to class effects on intraindividual variability in blood pressure. We did a systematic review to assess any such effects in randomised controlled trials. METHODS Baseline and follow-up data for mean (SD) of systolic blood pressure (SBP) were extracted from trial reports. Effect of treatment on interindividual variance (SD2) in blood pressure (a surrogate for within-individual variability), expressed as the ratio of the variances (VR), was related to effects on clinical outcomes. Pooled estimates were derived by use of random-effects meta-analysis. FINDINGS Mean (SD) SBP at follow-up was reported in 389 (28%) of 1372 eligible trials. There was substantial heterogeneity between trials in VR (p<1 x 10(-40)), 68% of which was attributable to allocated drug class. Compared with other drugs, interindividual variation in SBP was reduced by calcium-channel blockers (VR 0.81, 95% CI 0.76-0.86, p<0.0001) and non-loop diuretic drugs (0.87, 0.79-0.96, p=0.007), and increased by angiotensin-converting enzyme (ACE) inhibitors (1.08, 1.02-1.15, p=0.008), angiotensin-receptor blockers (1.16, 1.07-1.25, p=0.0002), and beta blockers (1.17, 1.07-1.28, p=0.0007). Compared with placebo only, interindividual variation in SBP was reduced the most by calcium-channel blockers (0.76, 0.67-0.85, p<0.0001). Effects were consistent in parallel group and crossover design trials, and in analyses of dose-response. Across all trials, effects of treatment on VR of SBP (r2=0.372, p=0.0006) and on mean SBP (r2=0.328, p=0.0015) accounted for effects on stroke risk (eg, odds ratio 0.79, 0.71-0.87, p<0.0001, for VR< or =0.80), and both remained significant in a combined model. INTERPRETATION Drug-class effects on interindividual variation in blood pressure can account for differences in effects of antihypertensive drugs on risk of stroke independently of effects on mean SBP. FUNDING None.

Increased Cerebral Arterial Pulsatility in Patients With Leukoaraiosis: Arterial Stiffness Enhances Transmission of Aortic Pulsatility

Background and Purpose— Arterial stiffening reduces damping of the arterial waveform and hence increases pulsatility of cerebral blood flow, potentially damaging small vessels. In the absence of previous studies in patients with recent transient ischemic attack or stroke, we determined the associations between leukoaraiosis and aortic and middle cerebral artery stiffness and pulsatility. Methods— Patients were recruited from the Oxford Vascular Study within 6 weeks of a transient ischemic attack or minor stroke. Leukoaraiosis was categorized on MRI by 2 independent observers with the Fazekas and age-related white matter change scales. Middle cerebral artery (MCA) stiffness (transit time) and pulsatility (Goslings index: MCA-PI) were measured with transcranial ultrasound and aortic pulse wave velocity and aortic systolic, diastolic, and pulse pressure with applanation tonometry (Sphygmocor). Results— In 100 patients, MCA-PI was significantly greater in patients with leukoaraiosis (0.91 versus 0.73, P<0.0001). Severity of leukoaraiosis was associated with MCA-PI and aortic pulse wave velocity (Fazekas: &khgr;2=0.39, MCA-PI P=0.01, aortic pulse wave velocity P=0.06; age-related white matter change: &khgr;2=0.38, MCA-PI P=0.015; aortic pulse wave velocity P=0.026) for periventricular and deep white matter lesions independent of aortic systolic blood pressure, diastolic blood pressure, and pulse pressure and MCA transit time with MCA-PI independent of age. In a multivariate model (r2=0.68, P<0.0001), MCA-PI was independently associated with aortic pulse wave velocity (P=0.016) and aortic pulse pressure (P<0.0001) and inversely associated with aortic diastolic blood pressure (P<0.0001) and MCA transit time (P=0.001). Conclusions— MCA pulsatility was the strongest physiological correlate of leukoaraiosis, independent of age, and was dependent on aortic diastolic blood pressure and pulse pressure and aortic and MCA stiffness, supporting the hypothesis that large artery stiffening results in increased arterial pulsatility with transmission to the cerebral small vessels resulting in leukoaraiosis.

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 &bgr;-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 &bgr;-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 β-blocker selectivity on blood pressure variability and stroke A systematic review

Objectives: β-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 β-blocker subclass effects on variability in BP and stroke risk in a systematic review of randomized controlled trials (RCTs) comparing different types of β-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 β-blockers (VR=1.34, 1.13–1.59, p =0.002, 25 comparisons, 9,992 patients) than by β1-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 β1-selective vs nonselective β-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 β-blockers ([OR]=2.29, 1.32–3.96, p =0.002) was more marked than with β1-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 β1-selective rather than nonselective agents may be advisable when β-blockers are indicated for patients at risk of stroke. Neurology® 2011;77:731–737

Resolution of Intraventricular Hemorrhage Varies by Ventricular Region and Dose of Intraventricular Thrombolytic The Clot Lysis: Evaluating Accelerated Resolution of IVH (CLEAR IVH) Program

Background and Purpose— The Clot Lysis: Evaluating Accelerated Resolution of IVH (CLEAR IVH) program is assessing the efficacy of intraventricular recombinant tissue-type plasminogen activator (rtPA) for spontaneous intraventricular hemorrhage (IVH). This subanalysis assesses the effect of dose of rtPA by region on clearance of IVH. Methods— Sixty-four patients within 12 to 24 hours of spontaneous IVH were randomized to placebo or 0.3 mg, 1 mg, or 3 mg of rtPA twice daily through an extraventricular drain. Twelve subregions of the ventricles were scored from 0 to 4. Effect of dose on IVH clearance to 50% of baseline score was compared by survival analysis for all regions combined and by subregion. Models including ventricular region, dose, and baseline score were compared by Cox proportional hazards. Results— IVH score reduced faster across all regions with increasing rtPA dose (clearance to 50%: log-rank P<0.0001; placebo—11.43 days, 95% CI, 5.68–17.18; 0.3 mg—3.19 days, 1.00–5.38; 1 mg—3.54 days, 0.45–6.64; 3 mg—2.59 days, 1.72–3.46). In the combined models, dose and baseline score were independently associated with reduction in IVH score, which was quickest in the midline ventricles, then the anterior half of the lateral ventricles and slowest in the posterior half of the lateral ventricles (clearance to 50%: P<0.0001; rtPA dose: hazard ratio, 1.47, 1.30–1.67; midline versus anterolateral hazard ratio, 1.71, 1.08–2.71; midline versus posterolateral hazard ratio, 4.05, 2.46–6.65; baseline score hazard ratio, 0.96, 0.91–1.01) with a significant interaction between dose and ventricular region (P=0.005). Conclusions— rtPA accelerates resolution of IVH. This effect is dose-dependent, is greatest in the midline ventricles, and least in the posterolateral ventricles. Clinical Trial Registration— URL: www.clinicaltrials.gov. Unique identifier: NCT00650858.

Accuracy of the ABC/2 Score for Intracerebral Hemorrhage: Systematic Review and Analysis of MISTIE, CLEAR-IVH, and CLEAR III

Background and Purpose— The ABC/2 score estimates intracerebral hemorrhage (ICH) volume, yet validations have been limited by small samples and inappropriate outcome measures. We determined accuracy of the ABC/2 score calculated at a specialized reading center (RC-ABC) or local site (site-ABC) versus the reference-standard computed tomography–based planimetry (CTP). Methods— In Minimally Invasive Surgery Plus Recombinant Tissue-Type Plasminogen Activator for Intracerebral Hemorrhage Evacuation-II (MISTIE-II), Clot Lysis Evaluation of Accelerated Resolution of Intraventricular Hemorrhage (CLEAR-IVH) and CLEAR-III trials. ICH volume was prospectively calculated by CTP, RC-ABC, and site-ABC. Agreement between CTP and ABC/2 was defined as an absolute difference up to 5 mL and relative difference within 20%. Determinants of ABC/2 accuracy were assessed by logistic regression. Results— In 4369 scans from 507 patients, CTP was more strongly correlated with RC-ABC (r2=0.93) than with site-ABC (r2=0.87). Although RC-ABC overestimated CTP-based volume on average (RC-ABC, 15.2 cm3; CTP, 12.7 cm3), agreement was reasonable when categorized into mild, moderate, and severe ICH (&kgr;=0.75; P<0.001). This was consistent with overestimation of ICH volume in 6 of 8 previous studies. Agreement with CTP was greater for RC-ABC (84% within 5 mL; 48% of scans within 20%) than for site-ABC (81% within 5 mL; 41% within 20%). RC-ABC had moderate accuracy for detecting ≥5 mL change in CTP volume between consecutive scans (sensitivity, 0.76; specificity, 0.86) and was more accurate with smaller ICH, thalamic hemorrhage, and homogeneous clots. Conclusions— ABC/2 scores at local or central sites are sufficiently accurate to categorize ICH volume and assess eligibility for the CLEAR-III and MISTIE III studies and moderately accurate for change in ICH volume. However, accuracy decreases with large, irregular, or lobar clots. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: MISTIE-II NCT00224770; CLEAR-III NCT00784134.

Validation of the Montreal Cognitive Assessment Versus Mini-Mental State Examination Against Hypertension and Hypertensive Arteriopathy After Transient Ischemic Attack or Minor Stroke

Background and Purpose— Lack of reduced cognitive impairment with blood pressure (BP) lowering in trials may reflect use of the Mini-Mental State Examination (MMSE), which is insensitive to mild cognitive impairment after cerebrovascular events compared with the Montreal Cognitive Assessment. We determined relationships between impairment on MMSE versus Montreal Cognitive Assessment (MoCA) with the major physiological determinant of vascular cognitive impairment: hypertension and hypertensive arteriopathy. Methods— Cognitive impairment in consecutive patients 6 months after transient ischemic attack or minor stroke was defined as significant, mild, or none (MMSE<23, 23–26, ≥27; MoCA<20, 20–24, ≥25) and related to 20 premorbid systolic BP readings, home BP measurement (3 measurements, 3×daily for 1 month), and hypertensive arteriopathy (creatinine, stroke versus transient ischemic attack, leukoaraiosis) by ordinal regression. Results— Of 463 patients, 45% versus 28% had at least mild cognitive impairment on the MoCA versus MMSE (P<0.001). Hypertensive arteriopathy was more strongly associated with cognitive impairment on the MoCA than MMSE (creatinine: odds ratio=3.99; 95% confidence interval, 2.06–7.73 versus 2.16, 1.08–4.33; event: 1.53, 1.06–2.19 versus 1.23, 0.81–1.85; leukoaraiosis: 2.09, 1.42–3.06 versus 1.34, 0.87–2.07). Premorbid and home BP measurement systolic BP were more strongly associated with impairment on vascular subdomains of the MoCA than MMSE (odds ratio/10 mm Hg: visuospatial 1.29 versus 1.05; attention 1.18 versus 1.07; language 1.22 versus 0.91; naming 1.07 versus 0.86). Conclusions— The stronger relationship between impairment on the MoCA with hypertensive arteriopathy, independent of age, indicates a greater sensitivity for vascular-origin cognitive impairment. Use of MoCA should improve sensitivity for cognitive impairment and treatment effects in future studies.

Blood Pressure Variability and Risk of New-Onset Atrial Fibrillation. A Systematic Review of Randomized Trials of Antihypertensive Drugs

Background and Purpose— Increased visit-to-visit variability in blood pressure (BP) is a powerful risk factor for stroke, but the mechanism is uncertain. We hypothesized that BP variability might affect the risk of new atrial fibrillation (AF). Methods— We did a systematic review of large randomized controlled trials reporting new-onset AF by treatment allocation, excluding studies in heart failure and acute myocardial infarction. Estimates of the risk of new AF by treatment allocation were related to effects of treatment on group variability in BP. Results— Of 94 eligible randomized controlled trials, 14 reported rates of new AF. Although there was considerable heterogeneity between trials in effects of treatment on variance ratio (P<0.0001), lower variance ratio was unrelated to new-onset AF either on meta-analysis (OR=1.02; 95% CI 0.90 to 1.15; 125 878 patients; 13 comparisons) or on metaregression (log OR versus log variance ratio of systolic blood pressure r2=0.109, P=0.270). Angiotensin receptor blockers tended to reduce new-onset AF (OR 0.85; 95% CI 0.71 to 1.01; P=0.067; 4 trials; 47 482 patients) with significant reductions in 2 individual trials but had no consistent reduction on variability in BP. Conclusions— Effects of randomized treatment on variability in BP are unrelated to risk of new-onset AF, suggesting that other mechanisms account for the link between variability and stroke risk. However, a lower incidence of AF in patients randomized to angiotensin receptor blockers may explain reductions in stroke risk in some trials.

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.

Seasonal variation in Guillain-Barré syndrome: a systematic review, meta-analysis and Oxfordshire cohort study

Introduction Evidence for seasonal variation in incidence and subtype of Guillain-Barré syndrome (GBS) is contradictory, but has implications for provision of neurological services and understanding pathogenesis. Methods We searched PubMed and EMBASE between inception and January 2014, including all studies reporting seasonal incidence of GBS. We included a retrospective cohort study of patients with GBS at the John Radcliffe Hospital, Oxford 2001–2012 and determined the seasonal variation in GBS incidence and length of stay. The incidence rate ratio (IRR) for winter versus summer was pooled across studies by fixed and random effects meta-analysis weighted by inverse variance, stratified by geographical region, infectious prodrome and GBS subtype. Results Across 9836 patients from 42 studies there was a 14% increased risk of GBS in winter versus summer (IRR=1.14, 1.02–1.27, p=0.020), with significant heterogeneity between studies (I2=77%, p<0.0001), including significant seasonal variation in Oxford (n=140; p=0.037) for winter versus summer (IRR=1.92, 1.18–3.11, p=0.004) but a non-significantly reduced length of stay for winter versus other seasons (15 vs 21 days, p=0.08). Across all studies, there was greater seasonal variation with respiratory prodrome (IRR=3.06, 1.84–5.11, p<0.0001) than diarrhoeal prodrome (IRR=1.10, 0.60–2.00, p=0.76) and a greater incidence in winter in Western countries (IRR=1.28), the Far East (IRR=1.20) and Middle East (IRR=1.12), with a lower incidence in the Indian subcontinent (IRR=0.86) and Latin America (IRR=0.75). Discussion Incidence of GBS was greater in winter than summer, but this was not evident in all geographical regions. This is likely to be related to regional variation in prodromal illnesses.