Citations

ImportanceIncreased white matter hyperintensity (WMH) volume is a common magnetic resonance imaging (MRI) finding in both autosomal dominant Alzheimer disease (ADAD) and late-onset Alzheimer disease (LOAD), but it remains unclear whether increased WMH along the AD continuum is reflective of AD-intrinsic processes or secondary to elevated systemic vascular risk factors.ObjectiveTo estimate the associations of neurodegeneration and parenchymal and vessel amyloidosis with WMH accumulation and investigate whether systemic vascular risk is associated with WMH beyond these AD-intrinsic processes.Design, Setting, and ParticipantsThis cohort study used data from 3 longitudinal cohort studies conducted in tertiary and community-based medical centers—the Dominantly Inherited Alzheimer Network (DIAN; February 2010 to March 2020), the Alzheimer’s Disease Neuroimaging Initiative (ADNI; July 2007 to September 2021), and the Harvard Aging Brain Study (HABS; September 2010 to December 2019).Main Outcome and MeasuresThe main outcomes were the independent associations of neurodegeneration (decreases in gray matter volume), parenchymal amyloidosis (assessed by amyloid positron emission tomography), and vessel amyloidosis (evidenced by cerebral microbleeds [CMBs]) with cross-sectional and longitudinal WMH.ResultsData from 3960 MRI sessions among 1141 participants were included: 252 pathogenic variant carriers from DIAN (mean [SD] age, 38.4 [11.2] years; 137 [54%] female), 571 older adults from ADNI (mean [SD] age, 72.8 [7.3] years; 274 [48%] female), and 318 older adults from HABS (mean [SD] age, 72.4 [7.6] years; 194 [61%] female). Longitudinal increases in WMH volume were greater in individuals with CMBs compared with those without (DIAN: t = 3.2 [P = .001]; ADNI: t = 2.7 [P = .008]), associated with longitudinal decreases in gray matter volume (DIAN: t = −3.1 [P = .002]; ADNI: t = −5.6 [P < .001]; HABS: t = −2.2 [P = .03]), greater in older individuals (DIAN: t = 6.8 [P < .001]; ADNI: t = 9.1 [P < .001]; HABS: t = 5.4 [P < .001]), and not associated with systemic vascular risk (DIAN: t = 0.7 [P = .40]; ADNI: t = 0.6 [P = .50]; HABS: t = 1.8 [P = .06]) in individuals with ADAD and LOAD after accounting for age, gray matter volume, CMB presence, and amyloid burden. In older adults without CMBs at baseline, greater WMH volume was associated with CMB development during longitudinal follow-up (Cox proportional hazards regression model hazard ratio, 2.63; 95% CI, 1.72-4.03; P < .001).Conclusions and RelevanceThe findings suggest that increased WMH volume in AD is associated with neurodegeneration and parenchymal and vessel amyloidosis but not with elevated systemic vascular risk. Additionally, increased WMH volume may represent an early sign of vessel amyloidosis preceding the emergence of CMBs.

Abstract Background Obesity is associated with an increased risk of developing recurrent atrial fibrillation (AF) after catheter ablation (CA). However, the current data on weight loss interventions show inconsistent results in preventing the recurrence of AF after CA. Methods We conducted a systematic search in MEDLINE and EMBASE to identify studies that reported the outcome of recurrence of AF after CA in obese patients undergoing weight interventions. The subgroup analysis included: (1) Weight loss versus no weight loss, (2) >10% weight loss versus <10% weight loss, (3) <10% weight loss versus no weight loss, (4) Follow‐up <12 months, and (5) Follow‐up >12 months after CA. Mantel–Haenszel risk ratios with a 95% confidence interval (CI) were calculated using a random effects model and for heterogeneity, I 2 statistics were reported. Results A total of 10 studies (one randomized controlled trial and nine observational studies) comprising 1851 patients were included. The recurrence of AF was numerically reduced in the weight loss group (34.5%) versus no weight loss group (58.2%), but no statistically significant difference was observed (risk ratio [RR] = 0.76; 95% CI: 0.49–1.18, p = .22). However, there was a statistically significant reduction in recurrence of AF with weight loss versus no weight loss at follow‐up >12 months after CA (RR = 0.47; 95% CI: 0.32–0.68, p < .0001). At follow‐up >12 months after CA, both >10% weight loss versus <10% weight loss (RR = 0.49; 95% CI: 0.31–0.80, p = .004) and <10% weight loss versus no weight loss (RR = 0.39; 95% CI: 0.31–0.49, p < .00001) were associated with a statistically significant reduction in recurrent AF. Conclusion In patients with AF undergoing CA, weight loss is associated with reducing recurrent AF at > 12 months after ablation and these benefits are consistently seen with both >10% and <10% weight loss. The benefits of weight loss in preventing recurrent AF after CA should be examined in larger studies with extended follow‐up duration.

AbstractThe association of psychosocial risk factors with cardiovascular disease is well‐established, and there is a growing recognition of their influence on atrial fibrillation (AF) . A recent National Heart, Lung, and Blood Institute workshop called for transforming AF research to integrate social determinants of health. There is limited data examining the impact of psychosocial risk factors (PSRFs) on outcomes in patients with an established diagnosis of AF. Catheter ablation for AF has been shown to improve arrhythmia burden and quality of life compared with medical treatment alone. It is unknown how PSRFs affect clinical outcomes in patients undergoing AF ablation. It is important to understand this relationship, especially given the increasing adoption of catheter ablation in clinical practice.

Abstract ELEVATE-RR demonstrated noninferior progression-free survival and lower incidence of key adverse events (AEs) with acalabrutinib vs ibrutinib in previously treated chronic lymphocytic leukemia. We further characterize AEs of acalabrutinib and ibrutinib via post hoc analysis. Overall and exposure-adjusted incidence rate was assessed for common Bruton tyrosine kinase inhibitor–associated AEs and for selected events of clinical interest (ECIs). AE burden scores based on previously published methodology were calculated for AEs overall and selected ECIs. Safety analyses included 529 patients (acalabrutinib, n = 266; ibrutinib, n = 263). Among common AEs, incidences of any-grade diarrhea, arthralgia, urinary tract infection, back pain, muscle spasms, and dyspepsia were higher with ibrutinib, with 1.5- to 4.1-fold higher exposure-adjusted incidence rates. Incidences of headache and cough were higher with acalabrutinib, with 1.6- and 1.2-fold higher exposure-adjusted incidence rate, respectively. Among ECIs, incidences of any-grade atrial fibrillation/flutter, hypertension, and bleeding were higher with ibrutinib, as were exposure-adjusted incidence rates (2.0-, 2.8-, and 1.6-fold, respectively); incidences of cardiac events overall (the Medical Dictionary for Regulatory Activities system organ class) and infections were similar between arms. Rate of discontinuation because of AEs was lower for acalabrutinib (hazard ratio, 0.62; 95% confidence interval, 0.41-0.93). AE burden score was higher for ibrutinib vs acalabrutinib overall and for the ECIs atrial fibrillation/flutter, hypertension, and bleeding. A limitation of this analysis is its open-label study design, which may influence the reporting of more subjective AEs. Overall, event-based analyses and AE burden scores demonstrated higher AE burden overall and specifically for atrial fibrillation, hypertension, and hemorrhage with ibrutinib vs acalabrutinib. This trial was registered at www.clinicaltrials.gov as #NCT02477696.

Abstract Background and Aims Colchicine is an anti-inflammatory drug that may prevent post-operative atrial fibrillation (POAF). The effect of this drug has been inconsistently shown in previous clinical trials. We aimed to compare the efficacy and safety of colchicine vs. placebo to prevent POAF in patients undergoing cardiac surgery. Methods and results A systematic search of EMBASE, MEDLINE, SCOPUS, ClinicalTrials.gov, and the Cochrane Library for randomized controlled trials (RCTs) was conducted from inception till April 2023. The primary outcome was the incidence of POAF after any cardiac surgery. The secondary outcome was the rate of drug discontinuation due to adverse events and adverse gastrointestinal events. Risk ratios (RR) were reported using the Mantel Haenszel method. A total of eight RCTs comprising 1885 patients were included. There was a statistically significant lower risk of developing POAF with colchicine vs. placebo (RR: 0.70; 95% CI: 0.59–0.82; P &lt; 0.01, I2 = 0%), and this effect persisted across different subgroups. There was a significantly higher risk of adverse gastrointestinal events (RR: 2.20; 95% CI: 1.38–3.51; P &lt; 0.01, I2 = 55%) with no difference in the risk of drug discontinuation in patients receiving colchicine vs. placebo (RR: 1.33; 95% CI: 0.93–1.89; P = 0.11, I2 = 0%). Conclusion This meta-analysis of eight RCTs shows that colchicine is effective at preventing POAF, with a significantly higher risk of adverse gastrointestinal events but no difference in the rate of drug discontinuation. Future studies are required to define the optimal duration and dose of colchicine for the prevention of POAF.

7514 Background: Pirtobrutinib is a highly selective, non-covalent (reversible) BTKi. Here, we report updated results of pirtobrutinib in patients (pts) with cBTKi pre-treated relapsed/refractory (R/R) MCL and more than 3 years follow-up from start of enrollment. Methods: Pts with cBTKi pre-treated R/R MCL received pirtobrutinib monotherapy in a multicenter phase 1/2 BRUIN trial (NCT03740529). Efficacy was assessed in the prespecified primary efficacy cohort that comprised the first 90 enrolled pts who had measurable disease, had received a prior cBTKi, and had no known central nervous system involvement. The primary endpoint was overall response rate (ORR) as assessed by independent review committee. Secondary endpoints included duration of response (DOR) and safety. A data cut of 29 July 2022 was utilized. Results: Among MCL pts who received a prior cBTKi (n=90), median age was 70 years (range, 46-87), median prior lines of therapy were 3 (range, 1-8), 82% discontinued a prior cBTKi due to disease progression, and 78% had intermediate/high risk sMIPI score. Of samples available, 17/36 (47%) had TP53 mutations and 25/34 (74%) had Ki67 ≥30%. The ORR was 57% (95% CI, 46-67), including 19% complete responses (n=17) and 38% partial responses (n=34). At a median follow-up time of 13 months, the median DOR among the 51 responding pts was 17.6 months (95% CI, 7.3-27.2). The 12- and 18-month estimated DOR rates were 58% (95% CI, 41-72) and 45% (95% CI, 27-61), respectively. ORR and DOR by subgroups are shown in the Table. The median progression-free survival was 7.4 months (95% CI, 5.3–13.3). The median overall survival was 23.5 months (95% CI, 15.9-NE). In the MCL safety cohort (n=166), the most frequent treatment-emergent adverse events (TEAE) were fatigue (31%), diarrhea (22%), and anemia (17%). The most common Grade ≥3 TEAE was neutropenia (15%). Grade ≥3 TEAE of hemorrhage (3%) and atrial fibrillation/flutter (2%) were infrequent. Only 5 (3%) pts discontinued due to a treatment-related AE. Conclusions: Pirtobrutinib continues to show durable efficacy and a favorable safety profile in heavily pre-treated R/R MCL pts with prior cBTKi therapy. Responses were observed in pts with high-risk disease features including pts with blastoid/pleomorphic variants, elevated Ki67 index, and TP53 mutations. Clinical trial information: NCT03740529 . [Table: see text]

Abstract Aims Haematopoietic stem cell transplantation (HSCT) is a potentially curative therapy for several malignant and non-malignant haematologic conditions. Patients undergoing HSCT are at an increased risk of developing atrial fibrillation (AF). We hypothesized that a diagnosis of AF would be associated with poor outcomes in patients undergoing HSCT. Methods and results The National Inpatient Sample (2016–19) was queried with ICD-10 codes to identify patients aged &gt;50 years undergoing HSCT. Clinical outcomes were compared between patients with and without AF. A multivariable regression model adjusting for demographics and comorbidities was used to calculate the adjusted odds ratio (aOR) and regression coefficients with corresponding 95% confidence intervals and P-values. A total of 50 570 weighted hospitalizations for HSCT were identified, out of which 5820 (11.5%) had AF. Atrial fibrillation was found to be independently associated with higher inpatient mortality (aOR 2.75; 1.9–3.98; P &lt; 0.001), cardiac arrest (aOR 2.86; 1.55–5.26; P = 0.001), acute kidney injury (aOR 1.89; 1.6–2.23; P &lt; 0.001), acute heart failure exacerbation (aOR 5.01; 3.54–7.1; P &lt; 0.001), cardiogenic shock (aOR 7.73; 3.17–18.8; P &lt; 0.001), and acute respiratory failure (aOR 3.24; 2.56–4.1; P &lt; 0.001) as well as higher mean length of stay (LOS) (+2.67; 1.79–3.55; P &lt; 0.001) and cost of care (+67 529; 36 630–98 427; P &lt; 0.001). Conclusion Among patients undergoing HSCT, AF was independently associated with poor in-hospital outcomes, higher LOS, and cost of care.