Effects of alteplase for acute stroke according to criteria defining the European Union and United States marketing authorizations: individual-patient-data meta-analysis of randomized trials

Background: The recommended maximum age and time window for intravenous alteplase treatment of acute ischemic stroke differs between the Europe Union and United States. Aims: We compared the effects of alteplase in cohorts defined by the current Europe Union or United States marketing approval labels, and by hypothetical revisions of the labels that would remove the Europe Union upper age limit or extend the United States treatment time window to 4.5 h. Methods: We assessed outcomes in an individual-patient-data meta-analysis of eight randomized trials of intravenous alteplase (0.9 mg/kg) versus control for acute ischemic stroke. Outcomes included: excellent outcome (modified Rankin score 0–1) at 3–6 months, the distribution of modified Rankin score, symptomatic intracerebral hemorrhage, and 90-day mortality. Results: Alteplase increased the odds of modified Rankin score 0–1 among 2449/6136 (40%) patients who met the current European Union label and 3491 (57%) patients who met the age-revised label (odds ratio 1.42, 95% CI 1.21−1.68 and 1.43, 1.23−1.65, respectively), but not in those outside the age-revised label (1.06, 0.90−1.26). By 90 days, there was no increased mortality in the current and age-revised cohorts (hazard ratios 0.98, 95% CI 0.76−1.25 and 1.01, 0.86–1.19, respectively) but mortality remained higher outside the age-revised label (1.19, 0.99–1.42). Similarly, alteplase increased the odds of modified Rankin score 0-1 among 1174/6136 (19%) patients who met the current US approval and 3326 (54%) who met a 4.5-h revised approval (odds ratio 1.55, 1.19−2.01 and 1.37, 1.17−1.59, respectively), but not for those outside the 4.5-h revised approval (1.14, 0.97−1.34). By 90 days, no increased mortality remained for the current and 4.5-h revised label cohorts (hazard ratios 0.99, 0.77−1.26 and 1.02, 0.87–1.20, respectively) but mortality remained higher outside the 4.5-h revised approval (1.17, 0.98–1.41). Conclusions: An age-revised European Union label or 4.5-h-revised United States label would each increase the number of patients deriving net benefit from alteplase by 90 days after acute ischemic stroke, without excess mortality

Protein-truncating variants in BSN are associated with severe adult-onset 2 obesity, type 2 diabetes and fatty liver disease

Obesity is a major risk factor for many common diseases and has a substantial heritable component. To identify novel genetic determinants, we performed exome-sequence analyses for adult body mass index (BMI) in up to 587,027 individuals. We identified rare, loss-of-function variants in two genes (BSN and APBA1) with effects substantially larger than well-established obesity genes such as MC4R. In contrast to most other obesity-related genes, rare variants in BSN and APBA1 were not associated with normal variation in childhood adiposity. Furthermore, BSN protein-truncating variants (PTVs) magnified the influence of common genetic variants associated with BMI, with a common polygenic score exhibiting an effect twice as large in BSN PTV carriers than non-carriers. Finally, we explored the plasma proteomic signatures of BSN PTV carriers as well as the functional consequences of BSN deletion in human iPSC-derived hypothalamic neurons. Collectively, our findings implicate degenerative processes in synaptic function in the etiology of adult53 onset obesity

Rare coding variants in CHRNB2 reduce the likelihood of smoking

Human genetic studies of smoking behavior have been thus far largely limited to common variants. Studying rare coding variants has the potential to identify drug targets. We performed an exome-wide association study of smoking phenotypes in up to 749,459 individuals and discovered a protective association in CHRNB2, encoding the β2 subunit of the α4β2 nicotine acetylcholine receptor. Rare predicted loss-of-function and likely deleterious missense variants in CHRNB2 in aggregate were associated with a 35% decreased odds for smoking heavily (odds ratio (OR) = 0.65, confidence interval (CI) = 0.56–0.76, P = 1.9 × 10−8). An independent common variant association in the protective direction (rs2072659; OR = 0.96; CI = 0.94–0.98; P = 5.3 × 10−6) was also evident, suggesting an allelic series. Our findings in humans align with decades-old experimental observations in mice that β2 loss abolishes nicotine-mediated neuronal responses and attenuates nicotine self-administration. Our genetic discovery will inspire future drug designs targeting CHRNB2 in the brain for the treatment of nicotine addiction

Body fat distribution and systolic blood pressure in 10,000 adults with whole‐body imaging: UK Biobank and Oxford BioBank

Objective This study aimed to quantify the associations of regional fat mass and fat‐free mass with systolic blood pressure. Methods This analysis combined individual participant data from two large‐scale imaging studies: UK Biobank and Oxford BioBank. In both studies, participants were interviewed and measured, and they underwent dual‐energy x‐ray absorptiometry imaging. Linear regression was used to relate systolic blood pressure to anthropometric measures of adiposity (BMI, waist circumference, and waist to hip ratio) and dual‐energy x‐ray absorptiometry–derived measures of body composition (visceral android fat, subcutaneous android fat, subcutaneous gynoid fat, and fat‐free mass). Results Among 10,260 participants (mean age 49; 96% white), systolic blood pressure was positively associated with visceral android fat (3.2 mmHg/SD in men; 2.8 mmHg/SD in women) and fat‐free mass (1.92 mmHg/SD in men; 1.64 mmHg/SD in women), but there was no evidence of an association with subcutaneous android or gynoid fat. Associations of systolic blood pressure with BMI were slightly steeper than those with waist circumference or waist to hip ratio; these associations remained unchanged following adjustment for fat‐free mass, but adjustment for visceral android fat eliminated associations with waist circumference and waist to hip ratio and more than halved associations with BMI. Conclusions This analysis indicates that visceral fat is the primary etiological component of excess adiposity underlying the development of adiposity‐related hypertension

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

What are the risks of intracerebral haemorrhage due to alteplase after acute ischaemic stroke? Results from an individual patient data meta-analysis of randomised trials

Background: Randomised trials have shown that alteplase improves the odds of a good stroke outcome when delivered within 4.5 hours of acute ischaemic stroke. Alteplase also increases the risk of intracerebral haemorrhage, but the factors determining the proportional and absolute risks are uncertain. Methods: We used data from the Stroke Thrombolysis Trialists’ (STT) meta-analysis of individual patient data from 9 randomised trials of alteplase versus placebo (or open control) involving 6,756 patients. We pre-specified assessment of 3 definitions of intracerebral haemorrhage: type 2 parenchymal haemorrhage (PH-2) within 7 days; SITS-MOST haemorrhage within 24-36 hours (PH-2 with at least 4 point deterioration in NIHSS); and fatal intracerebral haemorrhage within 7 days. We used logistic regression, stratified by trial, to model the log odds of intracerebral haemorrhage on allocation to alteplase, treatment delay, age, and stroke severity. Exploratory analyses assessed mortality after intracerebral haemorrhage and examined the absolute risks of intracerebral haemorrhage in the context of functional outcome at 90-180 days. Findings: Alteplase increased the odds of PH-2 haemorrhage (231/3391 [6.8%] among patients allocated alteplase vs 44/3365 [1.3%] among patients allocated control; odds ratio [OR] 5.55, 95% CI 4.01–7.70; absolute excess 5.5% [95% CI 4.6% - 6.4%]); SITS-MOST haemorrhage (124/3391 [3.7%] vs 19/3365 [0.6%]; OR 6.67, 4.11-10.84; absolute excess 3.1% [2.4% - 3.8%]); and of fatal intracerebral haemorrhage (91/3391 [2.7%] vs 13/3365 [0.4%]; OR 7.14, 3.98–12.79; absolute excess 2.3% [1.7% - 2.9%]). However defined, the proportional increase in intracerebral haemorrhage was similar irrespective of treatment delay, age or baseline stroke severity, but the absolute excess risk of intracerebral haemorrhage increased with increasing stroke severity: for SITS-MOST intracerebral haemorrhage the absolute excess risk ranged from 1.5% (95% CI 0.8-2.6%) for strokes with NIHSS 0-4 to 3.7% (95% CI 2.1-6.3%) for NIHSS ≥22 (trend p=0.01). For those treated within 4.5 hours, the absolute increase in the proportion (6.8%) achieving a modified Rankin score of 0 or 1 (excellent outcome) exceeded the absolute increase in risk of fatal intracerebral haemorrhage (2.2%) and the increased risk of any death within 90 days (0.9%). Interpretation: Among patients treated with alteplase the net outcome is predicted both by time to treatment (with faster time increasing the proportion achieving an excellent outcome) and stroke severity (with more severe stroke increasing the absolute risk of intracerebral haemorrhage). Although, on average, within 4.5 hours of stroke, the probability of achieving an excellent outcome clearly exceeds the risk of death, early treatment is especially important for those with severe strokes

Balancing the risk of major bleeding against vascular disease risk in people without atherosclerotic disease

Background and aims: In the primary prevention setting, low-dose aspirin reduces major vascular events (MVEs) by approximately 11% but increases major bleeding (MB) by 40–50%, implying that net benefit will be most evident when the MVE-to-MB ratio is >4. This study aimed to derive cross-validated risk scores for MB and MVE and use the MVE-to-MB ratio to identify groups who may derive differing net benefits from treatment. Methods: 431 167 UK Biobank participants without known atherosclerotic cardiovascular disease at baseline were followed through record linkage for incident MVEs (myocardial infarction, non-haemorrhagic stroke, transient ischaemic attack, arterial revascularisation or vascular death) and MB (gastrointestinal and intracranial bleeds with hospital admission for ≥2 days). Risk scores were derived for MVE and MB using Cox proportional hazards models with cross-validation. Ratios of observed MVE-to-MB rates were calculated across risk categories. Results: During a median follow-up of 12 years, 18 310 participants suffered an MVE and 5352 an MB. MB risk was highest among participants with frailty, prior bleeds, cancer, liver disease or renal dysfunction, with a 4.3-fold difference in risk between the highest and lowest fifths of MB risk (HR 4.3, 95% CI 3.87 to 4.77). The MVE-to-MB ratio was ≤2.6 in the highest MB risk groups and ≥4 in lower MB risk categories. Conclusions: The derived models using routinely available disease history and laboratory measurements improved distinction of the MVE-to-MB ratio compared with using conventional models for MB risk including vascular risk factors. Such models can help identify those with moderate MVE risk but low MB risk who may benefit from low-dose aspirin

Angiotensin receptor blockers and β blockers in Marfan syndrome: an individual patient data meta-analysis of randomised trials

Angiotensin receptor blockers; Marfan syndromeBloquejadors dels receptors d'angiotensina; Síndrome de MarfanBloqueadores de los receptores de angiotensina; Síndrome de MarfanBackground Angiotensin receptor blockers (ARBs) and β blockers are widely used in the treatment of Marfan syndrome to try to reduce the rate of progressive aortic root enlargement characteristic of this condition, but their separate and joint effects are uncertain. We aimed to determine these effects in a collaborative individual patient data meta-analysis of randomised trials of these treatments. Methods In this meta-analysis, we identified relevant trials of patients with Marfan syndrome by systematically searching MEDLINE, Embase, and CENTRAL from database inception to Nov 2, 2021. Trials were eligible if they involved a randomised comparison of an ARB versus control or an ARB versus β blocker. We used individual patient data from patients with no prior aortic surgery to estimate the effects of: ARB versus control (placebo or open control); ARB versus β blocker; and indirectly, β blocker versus control. The primary endpoint was the annual rate of change of body surface area-adjusted aortic root dimension Z score, measured at the sinuses of Valsalva. Findings We identified ten potentially eligible trials including 1836 patients from our search, from which seven trials and 1442 patients were eligible for inclusion in our main analyses. Four trials involving 676 eligible participants compared ARB with control. During a median follow-up of 3 years, allocation to ARB approximately halved the annual rate of change in the aortic root Z score (mean annual increase 0·07 [SE 0·02] ARB vs 0·13 [SE 0·02] control; absolute difference –0·07 [95% CI –0·12 to –0·01]; p=0·012). Prespecified secondary subgroup analyses showed that the effects of ARB were particularly large in those with pathogenic variants in fibrillin-1, compared with those without such variants (heterogeneity p=0·0050), and there was no evidence to suggest that the effect of ARB varied with β-blocker use (heterogeneity p=0·54). Three trials involving 766 eligible participants compared ARBs with β blockers. During a median follow-up of 3 years, the annual change in the aortic root Z score was similar in the two groups (annual increase –0·08 [SE 0·03] in ARB groups vs –0·11 [SE 0·02] in β-blocker groups; absolute difference 0·03 [95% CI –0·05 to 0·10]; p=0·48). Thus, indirectly, the difference in the annual change in the aortic root Z score between β blockers and control was –0·09 (95% CI –0·18 to 0·00; p=0·042). Interpretation In people with Marfan syndrome and no previous aortic surgery, ARBs reduced the rate of increase of the aortic root Z score by about one half, including among those taking a β blocker. The effects of β blockers were similar to those of ARBs. Assuming additivity, combination therapy with both ARBs and β blockers from the time of diagnosis would provide even greater reductions in the rate of aortic enlargement than either treatment alone, which, if maintained over a number of years, would be expected to lead to a delay in the need for aortic surgery.Marfan Foundation, the Oxford British Heart Foundation Centre for Research Excellence, and the UK Medical Research Council