The Role of Race and Ethnicity in the Clinical Outcomes of Severe Hemophilia A Patients with Inhibitors.

Abstract Background: Repeatedly, it has been observed that inhibitors to factor VIII are more frequent in African American (AA) and Hispanic (H) patients with severe congenital hemophilia A than in Caucasian (C) patients. Large retrospective reviews have shown that the mortality rates between African American and Caucasian patients with hemophilia have been similar, although non-whites had significantly more bleeding complications, need for hospitalizations and joint limitations. One possible explanation suggested that whites were more likely to receive aggressive treatment strategies such as home infusion. In none of the above reviews were patients stratified by inhibitor status. Few non-white patients have been included in large studies of inhibitor development and natural history. The purpose of this study was to evaluate the impact of race and ethnicity on the clinical characteristics and outcomes of inhibitors in patients with severe hemophilia A. Methods: This is a retrospective review of the repository database of the Hemophilia and Thrombosis Research Society (HTRS). Due to skewed distributions, non-parametric Kruskal-Wallis tests were used to test for racial differences. Results: The HTRS database captured data from 658 hemophilia patients since January 2000. Within the HTRS registry, there were 562 patients with severe hemophilia A: 68.1% (n=383) Caucasian, 21.0% (n=118) African American, and 10.9% (n=61) Hispanic. In comparison to Caucasians, Hispanics had a higher age at hemophilia diagnosis (p-value &lt;0.01), while there was not a significant difference with African-Americans (p-value =0.53). Amongst those subjects with a prior history of inhibitors, African-Americans and Hispanics had a higher family history of inhibitor development: 13.7% of C, 26.3% of AA (pwhite = 0.02), and 41.2% of H (pwhite = &lt;0.01). In patients with a history of inhibitors, Caucasians reported the lowest prevalence of a history of Intracranial Hemorrhage (ICH): 15.8% of C, 29.8% of AA (pwhite = 0.03), and 20.6% of H (pwhite = 0.52). African-Americans reported the lowest rate of receiving ITT (64.9%), followed 76.5% in Hispanics and 84.9% in Caucasians. African-Americans also had the lowest success rate of ITT, 30.4% as compared to 35.3% in Hispanics and 60.3% in Caucasians. In comparison to African-Americans, Caucasians did not have a significantly higher rate of unrestricted function (p=0.13), while the rate was significantly higher in Hispanics (p=0.02). Conclusion: While the HTRS database did not assess overall bleeding complications, it did show a significantly higher incidence of ICH in African-Americans versus Caucasian inhibitor patients, which could not be confirmed in non-inhibitor patients. It also appears, that fewer African-Americans and Hispanics are receiving immune tolerance therapy and that they have a lower success rate than Caucasians. However, there were insufficient patients studied to reach statistically significant conclusions. Hispanics did report significantly higher level of function. However, the HTRS survey does not use a very intricate, detailed tool to assess function. The above data proposes further investigation of bleeding risk across race/ethnicity in inhibitor vs. non-inhibitor populations. It also prompts us to look at larger databases to assess use and outcome of immune tolerance across races. Thirdly, it poses the question, whether there is a racial/ethnic difference in functional status and whether there could be variation in severity and outcome of bleeds.</jats:p

Association of Intensive vs Standard Blood Pressure Control With Regional Changes in Cerebral Small Vessel Disease Biomarkers

ImportanceLittle is known about the associations of strict blood pressure (BP) control with microstructural changes in small vessel disease markers.ObjectiveTo investigate the regional associations of intensive vs standard BP control with small vessel disease biomarkers, such as white matter lesions (WMLs), fractional anisotropy (FA), mean diffusivity (MD), and cerebral blood flow (CBF).Design, Setting, and ParticipantsThe Systolic Blood Pressure Intervention Trial (SPRINT) is a multicenter randomized clinical trial that compared intensive systolic BP (SBP) control (SBP target &amp;amp;lt;120 mm Hg) vs standard control (SBP target &amp;amp;lt;140 mm Hg) among participants aged 50 years or older with hypertension and without diabetes or a history of stroke. The study began randomization on November 8, 2010, and stopped July 1, 2016, with a follow-up duration of approximately 4 years. A total of 670 and 458 participants completed brain magnetic resonance imaging at baseline and follow-up, respectively, and comprise the cohort for this post hoc analysis. Statistical analyses for this post hoc analysis were performed between August 2020 and October 2022.InterventionsAt baseline, 355 participants received intensive SBP treatment and 315 participants received standard SBP treatment.Main Outcomes and MeasuresThe main outcomes were regional changes in WMLs, FA, MD (in white matter regions of interest), and CBF (in gray matter regions of interest).ResultsAt baseline, 355 participants (mean [SD] age, 67.7 [8.0] years; 200 men [56.3%]) received intensive BP treatment and 315 participants (mean [SD] age, 67.0 [8.4] years; 199 men [63.2%]) received standard BP treatment. Intensive treatment was associated with smaller mean increases in WML volume compared with standard treatment (644.5 mm3 vs 1258.1 mm3). The smaller mean increases were observed specifically in the deep white matter regions of the left anterior corona radiata (intensive treatment, 30.3 mm3 [95% CI, 16.0-44.5 mm3]; standard treatment, 80.5 mm3 [95% CI, 53.8-107.2 mm3]), left tapetum (intensive treatment, 11.8 mm3 [95% CI, 4.4-19.2 mm3]; standard treatment, 27.2 mm3 [95% CI, 19.4-35.0 mm3]), left superior fronto-occipital fasciculus (intensive treatment, 3.2 mm3 [95% CI, 0.7-5.8 mm3]; standard treatment, 9.4 mm3 [95% CI, 5.5-13.4 mm3]), left posterior corona radiata (intensive treatment, 26.0 mm3 [95% CI, 12.9-39.1 mm3]; standard treatment, 52.3 mm3 [95% CI, 34.8-69.8 mm3]), left splenium of the corpus callosum (intensive treatment, 45.4 mm3 [95% CI, 25.1-65.7 mm3]; standard treatment, 83.0 mm3 [95% CI, 58.7-107.2 mm3]), left posterior thalamic radiation (intensive treatment, 53.0 mm3 [95% CI, 29.8-76.2 mm3]; standard treatment, 106.9 mm3 [95% CI, 73.4-140.3 mm3]), and right posterior thalamic radiation (intensive treatment, 49.5 mm3 [95% CI, 24.3-74.7 mm3]; standard treatment, 102.6 mm3 [95% CI, 71.0-134.2 mm3]).Conclusions and RelevanceThis study suggests that intensive BP treatment, compared with standard treatment, was associated with a slower increase of WMLs, improved diffusion tensor imaging, and FA and CBF changes in several brain regions that represent vulnerable areas that may benefit from more strict BP control.Trial RegistrationClinicalTrials.gov Identifier: NCT01206062</jats:sec

Association of Intensive vs Standard Blood Pressure Control With Magnetic Resonance Imaging Biomarkers of Alzheimer Disease: Secondary Analysis of the SPRINT MIND Randomized Trial

Meta-analyses of randomized clinical trials have indicated that improved hypertension control reduces the risk for cognitive impairment and dementia. However, it is unclear to what extent pathways reflective of Alzheimer disease (AD) pathology are affected by hypertension control. To evaluate the association of intensive blood pressure control on AD-related brain biomarkers. This is a substudy of the Systolic Blood Pressure Intervention Trial (SPRINT MIND), a multicenter randomized clinical trial that compared the efficacy of 2 different blood pressure-lowering strategies. Potential participants (n = 1267) 50 years or older with hypertension and without a history of diabetes or stroke were approached for a brain magnetic resonance imaging (MRI) study. Of these, 205 participants were deemed ineligible and 269 did not agree to participate; 673 and 454 participants completed brain MRI at baseline and at 4-year follow-up, respectively; the final follow-up date was July 1, 2016. Analysis began September 2019 and ended November 2020. Participants were randomized to either a systolic blood pressure goal of less than 120 mm Hg (intensive treatment: n = 356) or less than 140 mm Hg (standard treatment: n = 317). Changes in hippocampal volume, measures of AD regional atrophy, posterior cingulate cerebral blood flow, and mean fractional anisotropy in the cingulum bundle. Among 673 recruited patients who had baseline MRI (mean [SD] age, 67.3 [8.2] years; 271 women [40.3%]), 454 completed the follow-up MRI at a median (interquartile range) of 3.98 (3.7-4.1) years after randomization. In the intensive treatment group, mean hippocampal volume decreased from 7.45 cm3 to 7.39 cm3 (difference, -0.06 cm3; 95% CI, -0.08 to -0.04) vs a decrease from 7.48 cm3 to 7.46 cm3 (difference, -0.02 cm3; 95% CI, -0.05 to -0.003) in the standard treatment group (between-group difference in change, -0.033 cm3; 95% CI, -0.062 to -0.003; P = .03). There were no significant treatment group differences for measures of AD regional atrophy, cerebral blood flow, or mean fractional anisotropy. Intensive treatment was associated with a small but statistically significant greater decrease in hippocampal volume compared with standard treatment, consistent with the observation that intensive treatment is associated with greater decreases in total brain volume. However, intensive treatment was not associated with changes in any of the other MRI biomarkers of AD compared with standard treatment. ClinicalTrials.gov Identifier: NCT01206062

Kidney Disease, Hypertension Treatment, and Cerebral Perfusion and Structure

The safety of intensive blood pressure (BP) targets is controversial for persons with chronic kidney disease (CKD). We studied the effects of hypertension treatment on cerebral perfusion and structure in individuals with and without CKD. Neuroimaging substudy of a randomized trial. A subset of participants in the Systolic Blood Pressure Intervention Trial (SPRINT) who underwent brain magnetic resonance imaging studies. Presence of baseline CKD was assessed by estimated glomerular filtration rate (eGFR) and urinary albumin-creatinine ratio (UACR). Participants were randomly assigned to intensive (systolic BP <120 mm Hg) versus standard (systolic BP <140 mm Hg) BP lowering. The magnetic resonance imaging outcome measures were the 4-year change in global cerebral blood flow (CBF), white matter lesion (WML) volume, and total brain volume (TBV). A total of 716 randomized participants with a mean age of 68 years were enrolled; follow-up imaging occurred after a median 3.9 years. Among participants with eGFR <60 mL/min/1.73 m (n = 234), the effects of intensive versus standard BP treatment on change in global CBF, WMLs, and TBV were 3.38 (95% CI, 0.32 to 6.44) mL/100 g/min, -0.06 (95% CI, -0.16 to 0.04) cm (inverse hyperbolic sine-transformed), and -3.8 (95% CI, -8.3 to 0.7) cm , respectively. Among participants with UACR >30 mg/g (n = 151), the effects of intensive versus standard BP treatment on change in global CBF, WMLs, and TBV were 1.91 (95% CI, -3.01 to 6.82) mL/100 g/min, 0.003 (95% CI, -0.13 to 0.13) cm (inverse hyperbolic sine-transformed), and -7.0 (95% CI, -13.3 to -0.3) cm , respectively. The overall treatment effects on CBF and TBV were not modified by baseline eGFR or UACR; however, the effect on WMLs was attenuated in participants with albuminuria (P = 0.04 for interaction). Measurement variability due to multisite design. Among adults with hypertension who have primarily early kidney disease, intensive versus standard BP treatment did not appear to have a detrimental effect on brain perfusion or structure. The findings support the safety of intensive BP treatment targets on brain health in persons with early kidney disease. SPRINT was funded by the National Institutes of Health (including the National Heart, Lung, and Blood Institute; the National Institute of Diabetes and Digestive and Kidney Diseases; the National Institute on Aging; and the National Institute of Neurological Disorders and Stroke), and this substudy was funded by the National Institutes of Diabetes and Digestive and Kidney Diseases. SPRINT was registered at ClinicalTrials.gov with study number NCT01206062

Effects of intensive versus standard blood pressure control on domain-specific cognitive function: a substudy of the SPRINT randomised controlled trial

Results from the Systolic Blood Pressure Intervention Trial (SPRINT) showed that intensive control of systolic blood pressure significantly reduced the occurrence of mild cognitive impairment, but not probable dementia. We investigated the effects of intensive lowering of systolic blood pressure on specific cognitive functions in a preplanned substudy of participants from SPRINT. SPRINT was an open-label, multicentre, randomised controlled trial undertaken at 102 sites, including academic medical centres, Veterans Affairs medical centres, hospitals, and independent clinics, in the USA and Puerto Rico. Participants were adults aged 50 years or older with systolic blood pressure higher than 130 mm Hg, but without diabetes, history of stroke, or dementia. Participants were randomly assigned (1:1) to a systolic blood pressure goal of less than 120 mm Hg (intensive treatment) versus less than 140 mm Hg (standard treatment). All major classes of antihypertensive agents were included. A subgroup of randomly assigned participants including, but not limited to, participants enrolled in an MRI substudy was then selected for a concurrent substudy of cognitive function (target 2800 participants). Each individual was assessed with a screening cognitive test battery and an extended cognitive test battery at baseline and biennially during the planned 4-year follow-up. The primary outcomes for this substudy were standardised composite scores for memory (Logical Memory I and II, Modified Rey-Osterrieth Complex Figure [immediate recall], and Hopkins Verbal Learning Test-Revised [delayed recall]) and processing speed (Trail Making Test and Digit Symbol Coding). SPRINT was registered with ClinicalTrials.gov, NCT01206062. From Nov 23, 2010, to Dec 28, 2012, 2921 participants (mean age 68·4 years [SD 8·6], 1080 [37%] women) who had been randomly assigned in SPRINT were enrolled in the substudy (1448 received intensive treatment and 1473 received standard treatment). SPRINT was terminated early due to benefit observed in the primary outcome (composite of cardiovascular events). After a median follow-up of 4·1 years (IQR 3·7-5·8), there was no between-group difference in memory, with an annual decline in mean standardised domain score of -0·005 (95% CI -0·010 to 0·001) in the intensive treatment group and -0·001 (-0·006 to 0·005) in the standard treatment group (between-group difference -0·004, 95% CI -0·012 to 0·004; p=0·33). Mean standardised processing speed domain scores declined more in the intensive treatment group (between-group difference -0·010, 95% CI -0·017 to -0·002; p=0·02), with an annual decline of -0·025 (-0·030 to -0·019) for the intensive treatment group and -0·015 (-0·021 to 0·009) for the standard treatment group. Intensive treatment to lower systolic blood pressure did not result in a clinically relevant difference compared with standard treatment in memory or processing speed in a subgroup of participants from SPRINT. The effect of blood pressure lowering might not be evident in specific domains of cognitive function, but instead distributed across multiple domains. National Heart, Lung, and Blood Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute on Aging, National Institute of Neurological Disorders and Stroke, and the Alzheimer's Association