Haley, William E.

Background: Ambulatory blood pressure monitoring (ABPM) is important for the diagnosis of hypertension (HTN) as well as variants such as nocturnal HTN (NH), masked HTN and a non-dipping pattern. NH and non-dipping, a failure of the normal circadian drop in blood pressure during sleep, have been associated with all-cause mortality and cardiovascular risk. Obstructive sleep apnea is associated with HTN and a growing body of evidence suggests that limb movement disorders of sleep may also influence cardiovascular morbidity. The present study investigates arousals of sleep disorders, limb movement or respiratory, and their relationship to ABPM measurements. Methods: A retrospective review (January 1, 2010 to December 31, 2014) was performed on patients that underwent both ABPM and polysomnography within a six months of each other. Socio-demographic data, results of 24 hour ABPM and polysomnography, concurrent medication use by class, comorbid conditions and laboratory data were recorded. Patients with incomplete polysomnography or ABPM measurements were excluded. Results: 330 individuals met criterion for inclusion; 59% male, 86% white. 211 (64%) were found to have NH, 106 (32%) had uncontrolled HTN and 202 (61%) had a non-dipping pattern. Patients with NH were more likely to have diabetes, hyperlipidemia and chronic kidney disease. Elevated arousal indices were more prevalent in those with NH, uncontrolled HTN and non-dippers. There was an association of NH with the total number of arousals per hour of sleep (p<0.01), whether related to respiratory disturbances or limb movements. Limb movement index (LMI) was related to age (p<0.0001) and was associated with all type arousals (p<0.0001). Conclusions: ABPM revealed a high prevalence of NH, non-dipping, masked and uncontrolled HTN in patients with sleep disorders. Arousals of all types, whether accompanying respiratory or limb movements, were associated with NH and also with LMI.

Abstract BACKGROUND Adherence to study medications is crucial to evaluating treatment effects in clinical trials. To assess whether in the SPRINT trial, adherence and cardiovascular outcomes are associated regardless of intervention assignment. METHODS This study included 9,361 participants aged ≥50 years, recruited from 102 clinics. Participants were randomized to a Standard Treatment Group (targeted systolic blood pressure [SBP] &lt;140 mm Hg) or an Intensive Treatment Group (targeted SBP &lt;120 mm Hg) and followed for incident cardiovascular events until the study was halted early for benefit. The 8-item Morisky Medication Adherence Scale (MMAS-8) was administered at baseline, and at the 12- and 48-month (or close out) visit. RESULTS Adjusting for covariates, there was no association between the baseline 8-item MMAS-8 and the likelihood of the primary composite endpoint, any of the secondary endpoints, or blood pressure (BP) control. Low adherence was associated with a higher body mass index, SBP, diastolic BP, and Patient Health Questionnaire, and high adherence was associated with a higher Montreal Cognitive Assessment. There was no difference in the MMAS-8 over time by treatment arm assignment. For the primary outcome (a composite of myocardial infarction, other acute coronary syndromes, stroke, heart failure, or death from cardiovascular causes), baseline odds ratios (95% confidence intervals) for the Low vs. Medium and vs. High; and, for Medium vs. High MMAS-8 were 1.02 (0.82–1.28), 1.07 (0.85–1.34), and 1.05 (0.88–1.250). CONCLUSIONS In SPRINT, medication adherence as measured using the MMAS-8 was not associated with outcomes or BP control.

AbstractBackgroundHypertension is a major risk factor for cardiovascular and cerebrovascular disease including stroke, small vessel disease, and dementia. The Systolic blood PRessure INTervention (SPRINT) randomized trial prospectively evaluated the effects of intensive systolic blood pressure (SBP) control (target SBP<120mmHg) versus standard control (SBP<140mmHg) on cardiovascular outcomes in individuals without baseline diabetes or stroke, and included cerebral blood flow (CBF) measurements. Previous studies with much smaller sample sizes and shorter duration suggested stable CBF in response to intensive treatment (SBP<125mmHg) [1], but long term effects are unknown. We evaluated the long‐term effects of intensive blood pressure treatment on CBF.MethodWhole brain CBF was measured at 3T using pseudocontinuous arterial spin labeled (ASL) perfusion MRI at baseline and after 3.9±0.3 years. Total white matter lesion (WML) load was measured from Fluid Attenuated Inversion Recovery T2 MRI. Data from 324 subjects with adequate ASL scan quality acquired from 6 sites were included.ResultDemographics and scanner specific CBF values are provided in Table 1. The intensive treatment group was older (p=0.01), but was otherwise similar to the standard group at baseline. There was a significant effect on the longitudinal CBF change (p=0.006) of the intensive treatment (5.7% increase) compared to the standard treatment (4.0% decrease, Fig 1). Secondary analysis showed a significant increase in age‐adjusted fractional CBF for the intensive treatment group (p<0.001) with no change (p=0.24) in the standard treatment group. Change in CBF was not associated with change in WML.ConclusionSustained intensive antihypertensive treatment does not reduce whole brain CBF, in fact it showed an increase in whole brain CBF relative to standard therapy. While improved CBF might contribute to the reduced WML progression observed in the intensive‐therapy group versus standard therapy in SPRINT[2], we did not observe a direct correlation between CBF changes and WML changes. References: (1) Croall et al. JAMA‐Neurol,2018; (2) Nasrallah et al., JAMA‐Neurol, 2019.

Background and objectives It is unclear whether the presence of albuminuria modifies the effects of intensive systolic BP control on risk of eGFR decline, cardiovascular events, or mortality. Design, setting, participants, & measurements The Systolic Blood Pressure Intervention Trial randomized nondiabetic adults ≥50 years of age at high cardiovascular risk to a systolic BP target of <120 or <140 mm Hg, measured by automated office BP. We compared the absolute risk differences and hazard ratios of ≥40% eGFR decline, the Systolic Blood Pressure Intervention Trial primary cardiovascular composite outcome, and all-cause death in those with or without baseline albuminuria (urine albumin-creatinine ratio ≥30 mg/g). Results Over a median follow-up of 3.1 years, 69 of 1723 (4%) participants with baseline albuminuria developed ≥40% eGFR decline compared with 61 of 7162 (1%) participants without albuminuria. Incidence rates of ≥40% eGFR decline were higher in participants with albuminuria (intensive, 1.74 per 100 person-years; standard, 1.17 per 100 person-years) than in participants without albuminuria (intensive, 0.48 per 100 person-years; standard, 0.11 per 100 person-years). Although effects of intensive BP lowering on ≥40% eGFR decline varied by albuminuria on the relative scale (hazard ratio, 1.48; 95% confidence interval, 0.91 to 2.39 for albumin-creatinine ratio ≥30 mg/g; hazard ratio, 4.55; 95% confidence interval, 2.37 to 8.75 for albumin-creatinine ratio <30 mg/g; P value for interaction <0.001), the absolute increase in ≥40% eGFR decline did not differ by baseline albuminuria (incidence difference, 0.38 events per 100 person-years for albumin-creatinine ratio ≥30 mg/g; incidence difference, 0.58 events per 100 person-years for albumin-creatinine ratio <30 mg/g; P value for interaction =0.60). Albuminuria did not significantly modify the beneficial effects of intensive systolic BP lowering on cardiovascular events or mortality evaluated on relative or absolute scales. Conclusions Albuminuria did not modify the absolute benefits and risks of intensive systolic BP lowering.

Significance Statement Intensive treatment of hypertension is beneficial for cardiovascular disease and cognitive function, but at the short-term expense of reduced kidney function. In a randomized trial of intensive versus standard systolic BP lowering, the authors found an association between a large decline in eGFR and increased incidence of probable dementia and mild cognitive impairment, but no link between urinary albumin-to-creatinine ratio and occurrence of dementia or mild cognitive impairment. Decline in eGFR occurred more frequently in the intensive treatment group, but did not modify the beneficial effect of intensive treatment on cognitive function. Among hypertensive adults, declining eGFR may be a marker for those at higher risk for dementia or mild cognitive impairment, independent of the intensity of hypertension treatment. Background Intensively treating hypertension may benefit cardiovascular disease and cognitive function, but at the short-term expense of reduced kidney function. Methods We investigated markers of kidney function and the effect of intensive hypertension treatment on incidence of dementia and mild cognitive impairment (MCI) in 9361 participants in the randomized Systolic Blood Pressure Intervention Trial, which compared intensive versus standard systolic BP lowering (targeting <120 mm Hg versus <140 mm Hg, respectively). We categorized participants according to baseline and longitudinal changes in eGFR and urinary albumin-to-creatinine ratio. Primary outcomes were occurrence of adjudicated probable dementia and MCI. Results Among 8563 participants who completed at least one cognitive assessment during follow-up (median 5.1 years), probable dementia occurred in 325 (3.8%) and MCI in 640 (7.6%) participants. In multivariable adjusted analyses, there was no significant association between baseline eGFR <60 ml/min per 1.73 m 2 and risk for dementia or MCI. In time-varying analyses, eGFR decline ≥30% was associated with a higher risk for probable dementia. Incident eGFR <60 ml/min per 1.73 m 2 was associated with a higher risk for MCI and a composite of dementia or MCI. Although these kidney events occurred more frequently in the intensive treatment group, there was no evidence that they modified or attenuated the effect of intensive treatment on dementia and MCI incidence. Baseline and incident urinary ACR ≥30 mg/g were not associated with probable dementia or MCI, nor did the urinary ACR modify the effect of intensive treatment on cognitive outcomes. Conclusions Among hypertensive adults, declining kidney function measured by eGFR is associated with increased risk for probable dementia and MCI, independent of the intensity of hypertension treatment.

Background and objectives eGFR and albuminuria primarily reflect glomerular function and injury, whereas tubule cell atrophy and interstitial fibrosis on kidney biopsy are important risk markers for CKD progression. Kidney tubule injury markers have primarily been studied in hospitalized AKI. Here, we examined the association between urinary kidney tubule injury markers at baseline with subsequent loss of kidney function in persons with nondiabetic CKD who participated in the Systolic Blood Pressure Intervention Trial (SPRINT). Design, setting, participants, & measurements Among 2428 SPRINT participants with CKD (eGFR<60 ml/min per 1.73 m 2 ) at baseline, we measured urine markers of tubule injury (IL-18, kidney injury molecule-1 [KIM-1], neutrophil gelatinase-associated lipocalin [NGAL]), inflammation (monocyte chemoattractant protein-1 [MCP-1]), and repair (human cartilage glycoprotein-40 [YKL-40]). Cox proportional hazards models evaluated associations of these markers with the kidney composite outcome of 50% eGFR decline or ESKD requiring dialysis or kidney transplantation, and linear mixed models evaluated annualized change in eGFR. Results Mean participant age was 73±9 (SD) years, 60% were men, 66% were white, and mean baseline eGFR was 46±11 ml/min per 1.73 m 2 . There were 87 kidney composite outcome events during a median follow-up of 3.8 years. Relative to the respective lowest quartiles, the highest quartiles of urinary KIM-1 (hazard ratio, 2.84; 95% confidence interval [95% CI], 1.31 to 6.17), MCP-1 (hazard ratio, 2.43; 95% CI, 1.13 to 5.23), and YKL-40 (hazard ratio, 1.95; 95% CI, 1.08 to 3.51) were associated with higher risk of the kidney composite outcome in fully adjusted models including baseline eGFR and urine albumin. In linear analysis, urinary IL-18 was the only marker associated with eGFR decline (−0.91 ml/min per 1.73 m 2 per year for highest versus lowest quartile; 95% CI, −1.44 to −0.38), a finding that was stronger in the standard arm of SPRINT. Conclusions Urine markers of tubule cell injury provide information about risk of subsequent loss of kidney function, beyond the eGFR and urine albumin.

Orthostatic hypotension (OH) is frequently observed with hypertension treatment, but its contribution to adverse outcomes is unknown. The SPRINT (Systolic Blood Pressure Intervention Trial) was a randomized trial of adults, age ≥50 years at high risk for cardiovascular disease with a seated systolic blood pressure (BP) of 130 to 180 mm Hg and a standing systolic BP ≥110 mm Hg. Participants were randomized to a systolic BP treatment goal of either <120 or <140 mm Hg. OH was defined as a drop in systolic BP ≥20 or diastolic BP ≥10 mm Hg 1 minute after standing from a seated position. We used Cox models to examine the association of OH with cardiovascular disease or adverse study events by randomized BP goal. During the follow-up period (median 3years), there were 1170 (5.7%) instances of OH among those assigned a standard BP goal and 1057 (5.0%) among those assigned the intensive BP goal. OH was not associated with higher risk of cardiovascular disease events (primary outcome: hazard ratio 1.06 [95% CI, 0.78–1.44]). Moreover, OH was not associated with syncope, electrolyte abnormalities, injurious falls, or acute renal failure. OH was associated with hypotension-related hospitalizations or emergency department visits (hazard ratio, 1.77 [95% CI, 1.11–2.82]) and bradycardia (hazard ratio, 1.94 [95% CI, 1.19–3.15]), but these associations did not differ by BP treatment goal. OH was not associated with a higher risk of cardiovascular disease events, and BP treatment goal had no effect on OH’s association with hypotension and bradycardia. Symptomless OH during hypertension treatment should not be viewed as a reason to down-titrate therapy even in the setting of a lower BP goal. Clinical Trial Registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT01206062.

Background Blood pressure ( BP ) varies over time within individual patients and across different BP measurement techniques. The effect of different BP targets on concordance between BP measurements is unknown. The goals of this analysis are to evaluate concordance between (1) clinic and ambulatory BP , (2) clinic visit‐to‐visit variability and ambulatory BP variability, and (3) first and second ambulatory BP and to evaluate whether different clinic targets affect these relationships. Methods and Results The SPRINT (Systolic Blood Pressure Intervention Trial) ambulatory BP monitoring ancillary study obtained ambulatory BP readings in 897 participants at the 27‐month follow‐up visit and obtained a second reading in 203 participants 293±84 days afterward. There was considerable lack of agreement between clinic and daytime ambulatory systolic BP with wide limits of agreement in Bland‐Altman plots of −21 to 34 mm Hg in the intensive‐treatment group and −26 to 32 mm Hg in the standard‐treatment group. Overall, there was poor agreement between clinic visit‐to‐visit variability and ambulatory BP variability with correlation coefficients for systolic and diastolic BP all <0.16. We observed a high correlation between first and second ambulatory BP ; however, the limits of agreement were wide in both the intensive group (−27 to 21 mm Hg) and the standard group (−23 to 20 mm Hg). Conclusions We found low concordance in BP and BP variability between clinic and ambulatory BP and second ambulatory BP . Results did not differ by treatment arm. These results reinforce the need for multiple BP measurements before clinical decision making.

Significance Statement Kidney stone recurrence can manifest with symptoms from stone passage or with asymptomatic changes in kidney stone burden revealed by radiography. In a multicenter, prospective cohort study, the authors demonstrate that substantially more asymptomatic and self-managed symptomatic kidney stone recurrence occur in stone formers than has been appreciated, as many studies consider only symptomatic recurrence that results in clinical care. Among first-time symptomatic stone formers, 54% had an asymptomatic kidney stone; half of those with such a stone passed it within 5 years (but only half who did so experienced symptoms). The findings also show that when a more comprehensive definition of recurrence that includes all symptomatic and radiological manifestations is used, risk factors better predict kidney stone recurrence, thus supporting a comprehensive assessment of recurrence in clinical trials. Background Meaningful interpretation of changes in radiographic kidney stone burden requires understanding how radiographic recurrence relates to symptomatic recurrence and how established risk factors predict these different manifestations of recurrence. Methods We recruited first-time symptomatic stone formers from the general community in Minnesota and Florida. Baseline and 5-year follow-up study visits included computed tomography scans, surveys, and medical record review. We noted symptomatic recurrence detected by clinical care (through chart review) or self-report, and radiographic recurrence of any new stone, stone growth, or stone passage (comparing baseline and follow-up scans). To assess the prediction of different manifestations of recurrence, we used the Recurrence of Kidney Stone (ROKS) score, which sums multiple baseline risk factors. Results Among 175 stone formers, 19% had symptomatic recurrence detected by clinical care and 25% detected by self-report; radiographic recurrence manifested as a new stone in 35%, stone growth in 24%, and stone passage in 27%. Among those with a baseline asymptomatic stone (54%), at 5 years, 51% had radiographic evidence of stone passage (accompanied by symptoms in only 52%). Imaging evidence of a new stone or stone passage more strongly associated with symptomatic recurrence detected by clinical care than by self-report. The ROKS score weakly predicted one manifestation—symptomatic recurrence resulting in clinical care ( c -statistic, 0.63; 95% confidence interval, 0.52 to 0.73)—but strongly predicted any manifestation of symptomatic or radiographic recurrence (5-year rate, 67%; c -statistic, 0.79; 95% confidence interval, 0.72 to 0.86). Conclusions Recurrence after the first stone episode is both more common and more predictable when all manifestations of recurrence (symptomatic and radiographic) are considered.