Patient-Level Pooled Analysis of Endovascular Ultrasound Renal Denervation or a Sham Procedure 6 Months After Medication Escalation: The RADIANCE Clinical Trial Program.

BACKGROUND: The randomized, sham-controlled RADIANCE-HTN (A Study of the Recor Medical Paradise System in Clinical Hypertension) SOLO, RADIANCE-HTN TRIO, and RADIANCE II (A Study of the Recor Medical Paradise System in Stage II Hypertension) trials independently met their primary end point of a greater reduction in daytime ambulatory systolic blood pressure (SBP) 2 months after ultrasound renal denervation (uRDN) in patients with hypertension. To characterize the longer-term effectiveness and safety of uRDN versus sham at 6 months, after the blinded addition of antihypertensive treatments (AHTs), we pooled individual patient data across these 3 similarly designed trials. METHODS: Patients with mild to moderate hypertension who were not on AHT or with hypertension resistant to a standardized combination triple AHT were randomized to uRDN (n=293) versus sham (n=213); they were to remain off of added AHT throughout 2 months of follow-up unless specified blood pressure (BP) criteria were exceeded. In each trial, if monthly home BP was ≥135/85 mm Hg from 2 to 5 months, standardized AHT was sequentially added to target home BP <135/85 mm Hg under blinding to initial treatment assignment. Six-month outcomes included baseline- and AHT-adjusted change in daytime ambulatory, home, and office SBP; change in AHT; and safety. Linear mixed regression models using all BP measurements and change in AHT from baseline through 6 months were used. RESULTS: Patients (70% men) were 54.1±9.3 years of age with a baseline daytime ambulatory/home/office SBP of 150.5±9.8/151.0±12.4/155.5±14.4 mm Hg, respectively. From 2 to 6 months, BP decreased in both groups with AHT titration, but fewer uRDN patients were prescribed AHT (P=0.004), and fewer additional AHT were prescribed to uRDN patients versus sham patients (P=0.001). Whereas the unadjusted between-group difference in daytime ambulatory SBP was similar at 6 months, the baseline and medication-adjusted between-group difference at 6 months was -3.0 mm Hg (95% CI, -5.7, -0.2; P=0.033), in favor of uRDN+AHT. For home and office SBP, the adjusted between-group differences in favor of uRDN+AHT over 6 months were -5.4 mm Hg (-6.8, -4.0; P<0.001) and -5.2 mm Hg (-7.1, -3.3; P<0.001), respectively. There was no heterogeneity between trials. Safety outcomes were few and did not differ between groups. CONCLUSIONS: This individual patient-data analysis of 506 patients included in the RADIANCE trials demonstrates the maintenance of BP-lowering efficacy of uRDN versus sham at 6 months, with fewer added AHTs. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT02649426 and NCT03614260.

Safety and performance of the Clearum™ high flux hemodialyzer.

BACKGROUND: Clearum™ is a high flux steam sterilized dialyzer for patients with hemodialysis or hemodiafiltration. This study evaluated the safety and performance of the Clearum high flux steam sterilized hemodialyzer in the removal of small and middle-sized toxins. METHODS: A prospective, interventional, nonrandomized study enrolled twenty end-stage renal disease patients undergoing hemodialysis. The Clearum high flux steam sterilized dialyzer was compared to Fresenius FX dialyzers for baseline comparison. The duration of the trial was 2 weeks for the FX dialyzer and 6 weeks with the Clearum high flux steam sterilized dialyzer. In vitro studies with dextrans of varying sizes were performed to compare the membrane characteristics and sieving coefficient curves for the two dialyzers. RESULTS: The primary objective of a mean urea reduction ratio >65% was met, with no significant difference in mean urea reduction ratio between the Clearum high flux steam sterilized and Fresenius FX-series of dialyzers (p = 0.86). No dialyzer-related adverse events were reported in the study. ß-2-microglobulin reduction with the Clearum high flux steam sterilized dialyzer was statistically higher than the FX-series dialyzer (66.5% vs. 53.6%; p < 0.0001). Predialysis interleukin-6 and C-reactive protein concentrations, blood-rest scores (residual blood after blood restitution), and thrombin-anti-thrombin values were comparable. Albumin remained stable during the 6 weeks of Clearum high flux steam sterilized dialyzer use, with no appreciable differences compared to the Fresenius FX-series. CONCLUSION: The Clearum high flux steam sterilized dialyzer showed good mid-term effectivity for small and middle molecule removal with no reported dialyzer-related adverse events.

Endovascular Ultrasound Renal Denervation to Treat Hypertension: The RADIANCE II Randomized Clinical Trial.

Importance: Two initial sham-controlled trials demonstrated that ultrasound renal denervation decreases blood pressure (BP) in patients with mild to moderate hypertension and hypertension that is resistant to treatment. Objective: To study the efficacy and safety of ultrasound renal denervation without the confounding influence of antihypertensive medications in patients with hypertension. Design, Setting, and Participants: Sham-controlled, randomized clinical trial with patients and outcome assessors blinded to treatment assignment that was conducted between January 14, 2019, and March 25, 2022, at 37 centers in the US and 24 centers in Europe, with randomization stratified by center. Patients aged 18 years to 75 years with hypertension (seated office systolic BP [SBP] ≥140 mm Hg and diastolic BP [DBP] ≥90 mm Hg despite taking up to 2 antihypertensive medications) were eligible if they had an ambulatory SBP/DBP of 135/85 mm Hg or greater and an SBP/DBP less than 170/105 mm Hg after a 4-week washout of their medications. Patients with an estimated glomerular filtration rate of 40 mL/min/1.73 m2 or greater and with suitable renal artery anatomy were randomized 2:1 to undergo ultrasound renal denervation or a sham procedure. Patients were to abstain from antihypertensive medications until the 2-month follow-up unless prespecified BP criteria were exceeded and were associated with clinical symptoms. Interventions: Ultrasound renal denervation vs a sham procedure. Main Outcomes and Measures: The primary efficacy outcome was the mean change in daytime ambulatory SBP at 2 months. The primary safety composite outcome of major adverse events included death, kidney failure, and major embolic, vascular, cardiovascular, cerebrovascular, and hypertensive events at 30 days and renal artery stenosis greater than 70% detected at 6 months. The secondary outcomes included mean change in 24-hour ambulatory SBP, home SBP, office SBP, and all DBP parameters at 2 months. Results: Among 1038 eligible patients, 150 were randomized to ultrasound renal denervation and 74 to a sham procedure (mean age, 55 years [SD, 9.3 years]; 28.6% female; and 16.1% self-identified as Black or African American). The reduction in daytime ambulatory SBP was greater with ultrasound renal denervation (mean, -7.9 mm Hg [SD, 11.6 mm Hg]) vs the sham procedure (mean, -1.8 mm Hg [SD, 9.5 mm Hg]) (baseline-adjusted between-group difference, -6.3 mm Hg [95% CI, -9.3 to -3.2 mm Hg], P < .001), with a consistent effect of ultrasound renal denervation throughout the 24-hour circadian cycle. Among 7 secondary BP outcomes, 6 were significantly improved with ultrasound renal denervation vs the sham procedure. No major adverse events were reported in either group. Conclusions and Relevance: In patients with hypertension, ultrasound renal denervation reduced daytime ambulatory SBP at 2 months in the absence of antihypertensive medications vs a sham procedure without postprocedural major adverse events. Trial Registration: ClinicalTrials.gov Identifier: NCT03614260.

Ultrasound renal denervation for hypertension resistant to a triple medication pill (RADIANCE-HTN TRIO): a randomised, multicentre, single-blind, sham-controlled trial.

BACKGROUND: Endovascular renal denervation reduces blood pressure in patients with mild-to-moderate hypertension, but its efficacy in patients with true resistant hypertension has not been shown. We aimed to assess the efficacy and safety of endovascular ultrasound renal denervation in patients with hypertension resistant to three or more antihypertensive medications. METHODS: In a randomised, international, multicentre, single-blind, sham-controlled trial done at 28 tertiary centres in the USA and 25 in Europe, we included patients aged 18-75 years with office blood pressure of at least 140/90 mm Hg despite three or more antihypertensive medications including a diuretic. Eligible patients were switched to a once daily, fixed-dose, single-pill combination of a calcium channel blocker, an angiotensin receptor blocker, and a thiazide diuretic. After 4 weeks of standardised therapy, patients with daytime ambulatory blood pressure of at least 135/85 mm Hg were randomly assigned (1:1) by computer (stratified by centres) to ultrasound renal denervation or a sham procedure. Patients and outcome assessors were masked to randomisation. Addition of antihypertensive medications was allowed if specified blood pressure thresholds were exceeded. The primary endpoint was the change in daytime ambulatory systolic blood pressure at 2 months in the intention-to-treat population. Safety was also assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02649426. FINDINGS: Between March 11, 2016, and March 13, 2020, 989 participants were enrolled and 136 were randomly assigned to renal denervation (n=69) or a sham procedure (n=67). Full adherence to the combination medications at 2 months among patients with urine samples was similar in both groups (42 [82%] of 51 in the renal denervation group vs 47 [82%] of 57 in the sham procedure group; p=0·99). Renal denervation reduced daytime ambulatory systolic blood pressure more than the sham procedure (-8·0 mm Hg [IQR -16·4 to 0·0] vs -3·0 mm Hg [-10·3 to 1·8]; median between-group difference -4·5 mm Hg [95% CI -8·5 to -0·3]; adjusted p=0·022); the median between-group difference was -5·8 mm Hg (95% CI -9·7 to -1·6; adjusted p=0·0051) among patients with complete ambulatory blood pressure data. There were no differences in safety outcomes between the two groups. INTERPRETATION: Compared with a sham procedure, ultrasound renal denervation reduced blood pressure at 2 months in patients with hypertension resistant to a standardised triple combination pill. If the blood pressure lowering effect and safety of renal denervation are maintained in the long term, renal denervation might be an alternative to the addition of further antihypertensive medications in patients with resistant hypertension. FUNDING: ReCor Medical.

Non-invasive vagus nerve stimulation for prevention of migraine: The multicenter, randomized, double-blind, sham-controlled PREMIUM II trial.

AIM: Evaluate the efficacy and safety of non-invasive vagus nerve stimulation for migraine prevention. METHODS: After completing a 4-week diary run-in period, adults who had migraine with or without aura were randomly assigned to receive active non-invasive vagus nerve stimulation or sham therapy during a 12-week double-blind period. RESULTS: Of 336 enrolled participants, 113 (active, n = 56; sham, n = 57) completed ≥70 days of the double-blind period and were ≥66% adherent with treatment, comprising the prespecified modified intention-to-treat population. The COVID-19 pandemic led to early trial termination, and the population was ∼60% smaller than the statistical target for full power. Mean reduction in monthly migraine days (primary endpoint) was 3.12 for the active group and 2.29 days for the sham group (difference, -0.83; p = 0.2329). Responder rate (i.e. the percentage of participants with a ≥50% reduction in migraine days) was greater in the active group (44.87%) than the sham group (26.81%; p = 0.0481). Prespecified subgroup analysis suggested that participants with aura responded preferentially. No serious device-related adverse events were reported. CONCLUSIONS: These results suggest clinical utility of non-invasive vagus nerve stimulation for migraine prevention, particularly for patients who have migraine with aura, and reinforce the well-established safety and tolerability profile of this therapy.Trial Registration: ClinicalTrials.gov (NCT03716505).

Six-Month Results of Treatment-Blinded Medication Titration for Hypertension Control After Randomization to Endovascular Ultrasound Renal Denervation or a Sham Procedure in the RADIANCE-HTN SOLO Trial.

BACKGROUND: The multicenter, international, randomized, blinded, sham-controlled RADIANCE-HTN SOLO trial (A Study of the ReCor Medical Paradise System in Clinical Hypertension) demonstrated a 6.3 mm Hg greater reduction in daytime ambulatory systolic blood pressure (BP) at 2 months by endovascular ultrasound renal denervation (RDN) compared with a sham procedure among patients not treated with antihypertensive medications. We report 6-month results after the addition of a recommended standardized stepped-care antihypertensive treatment to the randomized endovascular procedure under continued blinding to initial treatment. METHODS: Patients with a daytime ambulatory BP ≥135/85 mm Hg and <170/105 mm Hg after a 4-week discontinuation of up to 2 antihypertensive medications, and a suitable renal artery anatomy, were randomized to RDN (n=74) or sham (n=72). Patients were to remain off antihypertensive medications throughout the first 2 months of follow-up unless safety BP criteria were exceeded. Between 2 and 5 months, if monthly measured home BP was ≥135/85 mm Hg, a standardized stepped-care antihypertensive treatment was recommended consisting of the sequential addition of amlodipine (5 mg/d), a standard dose of an angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, and hydrochlorothiazide (12.5 mg/d), followed by the sequential uptitration of hydrochlorothiazide (25 mg/d) and amlodipine (10 mg/d). Outcomes included the 6-month (1) change in daytime ambulatory systolic BP adjusted for medications and baseline systolic BP, (2) medication burden, and (3) safety. RESULTS: A total of 69/74 RDN patients and 71/72 sham patients completed the 6-month ambulatory BP measurement. At 6 months, 65.2% of patients in the RDN group were treated with the standardized stepped-care antihypertensive treatment versus 84.5% in the sham group (P=0.008), and the average number of antihypertensive medications and defined daily dose were less in the RDN group than in the sham group (0.9±0.9 versus 1.3±0.9, P=0.010 and 1.4±1.5 versus 2.0±1.8, P=0.018; respectively). Despite less intensive standardized stepped-care antihypertensive treatment, RDN reduced daytime ambulatory systolic BP to a greater extent than sham (-18.1±12.2 versus -15.6±13.2 mm Hg, respectively; difference adjusted for baseline BP and number of medications: -4.3 mm Hg, 95% confidence interval, -7.9 to -0.6, P=0.024). There were no major adverse events in either group through 6 months. CONCLUSIONS: The BP-lowering effect of endovascular ultrasound RDN was maintained at 6 months with less prescribed antihypertensive medications compared with a sham control. CLINICAL TRIAL REGISTRATION: URL: https://www. CLINICALTRIALS: gov. Unique identifier: NCT02649426.

Non-invasive neuromodulation for migraine and cluster headache: a systematic review of clinical trials.

Non-invasive neuromodulation therapies for migraine and cluster headache are a practical and safe alternative to pharmacologics. Comparisons of these therapies are difficult because of the heterogeneity in study designs. In this systematic review of clinical trials, the scientific rigour and clinical relevance of the available data were assessed to inform clinical decisions about non-invasive neuromodulation. PubMed, Cochrane Library and ClinicalTrials.gov databases and the WHO's International Clinical Trials Registry Platform were searched for relevant clinical studies of non-invasive neuromodulation devices for migraine and cluster headache (1 January 1990 to 31 January 2018), and 71 were identified. This analysis compared study designs using recommendations of the International Headache Society for pharmacological clinical trials, the only available guidelines for migraine and cluster headache. Non-invasive vagus nerve stimulation (nVNS), single-transcranial magnetic stimulation and external trigeminal nerve stimulation (all with regulatory clearance) were well studied compared with the other devices, for which studies frequently lacked proper blinding, sham controls and sufficient population sizes. nVNS studies demonstrated the most consistent adherence to available guidelines. Studies of all neuromodulation devices should strive to achieve the same high level of scientific rigour to allow for proper comparison across devices. Device-specific guidelines for migraine and cluster headache will be soon available, but adherence to current guidelines for pharmacological trials will remain a key consideration for investigators and clinicians.

Differential efficacy of non-invasive vagus nerve stimulation for the acute treatment of episodic and chronic cluster headache: A meta-analysis.

BACKGROUND: Two randomized, double-blind, sham-controlled trials (ACT1, ACT2) evaluated non-invasive vagus nerve stimulation (nVNS) as acute treatment for cluster headache. We analyzed pooled ACT1/ACT2 data to increase statistical power and gain insight into the differential efficacy of nVNS in episodic and chronic cluster headache. METHODS: Data extracted from ACT1 and ACT2 were pooled using a fixed-effects model. Main outcome measures were the primary endpoints of each study. This was the proportion of participants whose first treated attack improved from moderate (2), severe (3), or very severe (4) pain intensity to mild (1) or nil (0) for ACT1 and the proportion of treated attacks whose pain intensity improved from 2-4 to 0 for ACT2. RESULTS: The pooled population included 225 participants (episodic: n = 112; chronic: n = 113) from ACT1 (n = 133) and ACT2 (n = 92) in the nVNS (n = 108) and sham (n = 117) groups. Interaction was shown between treatment group and cluster headache subtype (p < 0.05). nVNS was superior to sham in episodic but not chronic cluster headache (both endpoints p < 0.01). Only four patients discontinued the studies due to adverse events. CONCLUSIONS: nVNS is a well-tolerated and effective acute treatment for episodic cluster headache. TRIAL REGISTRATION: The studies were registered at clinicaltrials.gov (ACT1: NCT01792817; ACT2: NCT01958125).

Common carotid artery intima-media thickness increases throughout the pregnancy cycle: a prospective cohort study.

BACKGROUND: High parity is associated with greater cardiovascular disease (CVD) among mid-life and older women. Prospective studies of arterial change throughout pregnancy are needed to provide insight into potential mechanisms. This study assessed vascular adaptation across pregnancy in healthy first-time pregnant women. METHODS: The Maternal Vascular Adaptation to Healthy Pregnancy Study (Pittsburgh, PA, 2010-2015) assessed 37 primigravid women each trimester, 6-8 weeks after delivery and 1-5 years postpartum, with B-mode ultrasound imaging of common carotid artery (CCA) intima-media thickness (IMT) and inter-adventitial diameter (IAD) to assess associations with physical and cardiometabolic measures. RESULTS: Thirty-seven women (age 28.2 ± 4.5 years, pre-pregnant BMI 24.4 ± 3.2 kg/m2) experienced uncomplicated pregnancies. After adjustment for age and pre-pregnancy BMI, mean (SE) IAD (mm) increased each trimester, from 6.38 (0.08) in the 1st trimester to 6.92 (0.09) in the 3rd trimester, and then returned to 1st trimester levels postpartum (6.35 [0.07], P <  0.001). In contrast, mean (SE) CCA IMT (mm) increased from the 2nd trimester (i.e., 0.546 [0.01]) onward, and remained higher at an average of 2.7 years postpartum (0.581 [0.02], P = 0.03). Weight partially explained changes in IAD. CONCLUSIONS: In uncomplicated first pregnancies, IAD increased and returned to 1st trimester levels postpartum. In contrast, CCA IMT remained increased 2 years postpartum. Maternal weight explained vascular changes better than did metabolic changes. Increased postpartum CCA IMT may persist and contribute to long-term CVD risk.

Non-invasive vagus nerve stimulation for treatment of cluster headache: early UK clinical experience.

BACKGROUND: Evidence supports the use of non-invasive vagus nerve stimulation (nVNS; gammaCore®) as a promising therapeutic option for patients with cluster headache (CH). We conducted this audit of real-world data from patients with CH, the majority of whom were treatment refractory, to explore early UK clinical experience with nVNS used acutely, preventively, or both. METHODS: We retrospectively analysed data from 30 patients with CH (29 chronic, 1 episodic) who submitted individual funding requests for nVNS to the National Health Service. All patients had responded to adjunctive nVNS therapy during an evaluation period (typical duration, 3-6 months). Data collected from patient interviews, treatment diaries, and physician notes were summarised with descriptive statistics. Paired t tests were used to examine statistical significance. RESULTS: The mean (SD) CH attack frequency decreased from 26.6 (17.1) attacks/wk. before initiation of nVNS therapy to 9.5 (11.0) attacks/wk. (P < 0.01) afterward. Mean (SD) attack duration decreased from 51.9 (36.7) minutes to 29.4 (28.5) minutes (P < 0.01), and mean (SD) attack severity (rated on a 10-point scale) decreased from 7.8 (2.3) to 6.0 (2.6) (P < 0.01). Use of abortive treatments also decreased. Favourable changes in the use of preventive medication were also observed. No serious device-related adverse events were reported. CONCLUSIONS: Significant decreases in attack frequency, severity, and duration were observed in these patients with CH who did not respond to or were intolerant of multiple preventive and/or acute treatments. These real-world findings complement evidence from clinical trials demonstrating the efficacy and safety of nVNS in CH.

Is self-reported physical functioning associated with incident cardiometabolic abnormalities or the metabolic syndrome?

BACKGROUND: Physical functioning may be an important pre-clinical marker of chronic disease, used as a tool to identify patients at risk for future cardiometabolic abnormalities. This study evaluated if self-reported physical functioning was associated with the development of cardiometabolic abnormalities or their clustering (metabolic syndrome) over time. METHODS: Participants (n = 2,254) from the Study of Women's Health Across the Nation who reported physical functioning on the Short Form health survey and had a metabolic syndrome assessment (elevated fasting glucose, blood pressure, triglycerides and waist circumference; reduced HDL cholesterol) in 2000 were included. Discrete survival analysis was used to assess the 10-year risk of developing metabolic syndrome or a syndrome component through 2010. RESULTS: At baseline, the prevalence of metabolic syndrome was 22.0%. Women with substantial limitations (OR = 1.60; 95% CI: 1.12, 2.29) in physical functioning were significantly more likely to develop the metabolic syndrome compared with women reporting no limitations. Self-reported physical functioning was significantly associated with incident hypertension and increased waist circumference. CONCLUSIONS: Simple screening tools for cardiometabolic risk in clinical settings are needed. Self-reported physical functioning assessments are simple tools that may allow healthcare providers to more accurately predict the course of chronic conditions.

Non-Invasive Vagus Nerve Stimulation for the ACute Treatment of Cluster Headache: Findings From the Randomized, Double-Blind, Sham-Controlled ACT1 Study.

OBJECTIVE: To evaluate non-invasive vagus nerve stimulation (nVNS) as an acute cluster headache (CH) treatment. BACKGROUND: Many patients with CH experience excruciating attacks at a frequency that is not sufficiently addressed by current symptomatic treatments. METHODS: One hundred fifty subjects were enrolled and randomized (1:1) to receive nVNS or sham treatment for ≤1 month during a double-blind phase; completers could enter a 3-month nVNS open-label phase. The primary end point was response rate, defined as the proportion of subjects who achieved pain relief (pain intensity of 0 or 1) at 15 minutes after treatment initiation for the first CH attack without rescue medication use through 60 minutes. Secondary end points included the sustained response rate (15-60 minutes). Subanalyses of episodic cluster headache (eCH) and chronic cluster headache (cCH) cohorts were prespecified. RESULTS: The intent-to-treat population comprised 133 subjects: 60 nVNS-treated (eCH, n = 38; cCH, n = 22) and 73 sham-treated (eCH, n = 47; cCH, n = 26). A response was achieved in 26.7% of nVNS-treated subjects and 15.1% of sham-treated subjects (P = .1). Response rates were significantly higher with nVNS than with sham for the eCH cohort (nVNS, 34.2%; sham, 10.6%; P = .008) but not the cCH cohort (nVNS, 13.6%; sham, 23.1%; P = .48). Sustained response rates were significantly higher with nVNS for the eCH cohort (P = .008) and total population (P = .04). Adverse device effects (ADEs) were reported by 35/150 (nVNS, 11; sham, 24) subjects in the double-blind phase and 18/128 subjects in the open-label phase. No serious ADEs occurred. CONCLUSIONS: In one of the largest randomized sham-controlled studies for acute CH treatment, the response rate was not significantly different (vs sham) for the total population; nVNS provided significant, clinically meaningful, rapid, and sustained benefits for eCH but not for cCH, which affected results in the total population. This safe and well-tolerated treatment represents a novel and promising option for eCH. ClinicalTrials.gov identifier: NCT01792817.

Non-invasive Vagus Nerve Stimulation (nVNS) as mini-prophylaxis for menstrual/menstrually related migraine: an open-label study.

BACKGROUND: Menstrual migraine and menstrually related migraine attacks are typically longer, more disabling, and less responsive to medications than non-menstrual attacks. The aim of this study was to evaluate the efficacy, safety, and tolerability of non-invasive vagus nerve stimulation for the prophylactic treatment of menstrual migraine/menstrually related migraine. METHODS: Fifty-six enrolled subjects (menstrual migraine, 9 %; menstrually related migraine, 91 %), 33 (59 %) of whom were receiving other prophylactic therapies, entered a 12-week baseline period. Fifty-one subjects subsequently entered a 12-week treatment period to receive open-label prophylactic non-invasive vagus nerve stimulation adjunctively (31/51; 61 %) or as monotherapy (20/51; 39 %) on day -3 before estimated onset of menses through day +3 after the end of menses. RESULTS: The number of menstrual migraine/menstrually related migraine days per month was significantly reduced from baseline (mean ± standard error, 7.2 ± 0.7 days) to the end of treatment (mean ± standard error, 4.7 ± 0.5 days; P < 0.001) (primary end point). Of all subjects, 39 % (95 % confidence interval: 26 %, 54 %) (20/51) had a ≥ 50 % reduction (secondary end point). For the other secondary end points, clinically meaningful reductions in analgesic use (mean change ± standard error, -3.3 ± 0.6 times per month; P < 0.001), 6-item Headache Impact Test score (mean change ± standard error, -3.1 ± 0.7; P < 0.001), and Migraine Disability Assessment score (mean change ± standard error, -11.9 ± 3.4; P < 0.001) were observed, along with a modest reduction in pain intensity (mean change ± standard error, -0.5 ± 0.2; P = 0.002). There were no safety/tolerability concerns. CONCLUSIONS: These findings suggest that non-invasive vagus nerve stimulation is an effective treatment that reduces the number of menstrual migraine/menstrually related migraine days and analgesic use without safety/tolerability concerns in subjects with menstrual migraine/menstrually related migraine. Randomised controlled studies are warranted.

Antidiabetogenic effects of hydroxychloroquine on insulin sensitivity and beta cell function: a randomised trial.

AIMS/HYPOTHESIS: Hydroxychloroquine (HCQ), an antimalarial drug with anti-inflammatory properties, is employed in rheumatic diseases. In observational studies, patients with rheumatic diseases treated with HCQ have a lower risk of developing diabetes. However, the physiological mechanisms remain unexplained. We hypothesised that HCQ may have favourable effects on insulin sensitivity and/or beta cell function. METHODS: This was a randomised, double-blind, parallel-arm (placebo vs HCQ 400 mg/day) trial at the University of Pittsburgh. Randomisation was conducted by a computer system with concealment by sealed envelopes. Treatment duration was 13 ± 1 weeks. Randomised participants (HCQ n = 17; placebo n = 15) were non-diabetic volunteers, age >18, overweight or obese, with one or more markers of insulin resistance. All participants were included in intention-to-treat analysis. Outcomes were changes in insulin sensitivity and beta cell function measured by intravenous glucose tolerance tests and minimal model analysis. RESULTS: There was a positive change in insulin sensitivity with HCQ but not placebo (mean ± SEM: +20.0% ± 7.1% vs -18.4% ± 7.9%, respectively; p < 0.01; difference: 38.3% ± 10.6%; 95% CI: 17%, 60%). Improvement in beta cell function was also observed with HCQ but not placebo (+45.4% ± 12.3% vs -19.7% ± 13.6%; p < 0.01; difference: 65% ± 19%; 95% CI: 27%, 103%). There were modest treatment effects on fasting plasma glucose and HbA(1c) (p < 0.05) but circulating markers of inflammation (IL-6, IL-1, TNF-α, soluble intercellular adhesion molecule) were not affected in either group. In contrast, adiponectin levels increased after HCQ treatment but not after placebo (+18.7% vs +0.7%, respectively; p < 0.001). Both low- and high-molecular-weight adiponectin forms accounted for the increase. There were no serious or unexpected adverse effects. CONCLUSIONS/INTERPRETATION: HCQ improves both beta cell function and insulin sensitivity in non-diabetic individuals. These metabolic effects may explain why HCQ treatment is associated with a lower risk of type 2 diabetes. An additional novel observation is that HCQ improves adiponectin levels, possibly being a mediator of the favourable effects on glucose metabolism. Our findings suggest that HCQ is a drug with considerable metabolic effects that warrant further exploration in disorders of glucose metabolism. TRIAL REGISTRATION: Clinicaltrials.gov NCT01326533 FUNDING: This study was funded by National Institutes of Health no. 5R21DK082878, UL1-RR024153 and UL-1TR000005.

Low socioeconomic status over 12 years and subclinical cardiovascular disease: the study of women's health across the nation.

BACKGROUND AND PURPOSE: The inverse relation between socioeconomic status and cardiovascular disease is well established. However, few studies have investigated socioeconomic status assessed repeatedly during adulthood in relation to subclinical atherosclerosis. We aimed to test whether consistently low socioeconomic status, as indexed by education, income, and financial strain, for 12 years of midlife was related to later carotid intima-media thickness and plaque among women. METHODS: The Study of Women's Health Across the Nation is a multisite longitudinal study of midlife women. Education was assessed at the study baseline, income and financial strain were obtained yearly for 12 years, and a carotid ultrasound was obtained at study year 12 among 1402 women. Associations were tested in linear and multinomial logistic regression models adjusted for demographic, biological, and behavioral risk factors. RESULTS: A high school education or less (odds ratio [OR] [95% confidence interval {CI}], 1.72 [1.15-2.59]; P<0.01), some college education (OR [95% CI], 1.65 [1.17-2.32]; P<0.01), consistently low income (OR [95% CI], 1.83 [1.15-2.89]; P<0.05), and consistent financial strain (OR [95% CI], 1.78 [1.21-2.61]; P<0.01) for 12 years were associated with higher carotid plaque, and consistent financial strain was associated with elevated maximal intima-media thickness (ß [SE]=0.02 [0.01]; P<0.05) controlling for standard cardiovascular disease risk factors. When socioeconomic status indices were considered together, financial strain (ß [SE]=0.02 [0.01]; P<0.05) and low education (high school education or less: OR [95% CI], 1.55 [1.01-2.37]; P<0.05; some college: OR [95% CI], 1.56 [1.09-2.21]; P<0.05) were most consistently associated with intima-media thickness and plaque, respectively, controlling for risk factors. CONCLUSIONS: The findings indicate the importance of targeting economically disadvantaged women in efforts to prevent cardiovascular disease among women.

Association of Dialysate Bicarbonate with Arrhythmia in the Monitoring in Dialysis (MiD) Study.

BACKGROUND: Sudden death accounts for ∼25% of deaths among maintenance hemodialysis (HD) patients, occurring more frequently on HD days. Higher dialysate bicarbonate (DBIC) may predispose to alkalemia and arrhythmogenesis. METHODS: We conducted a 12-month analysis of session-level data from 66 patients with implantable loop recorders. We fit logistic regression and negative binomial mixed effects regression models to assess the association of DBIC with clinically significant arrhythmia (CSA - ventricular tachycardia ≥115 beats per minute (BPM) for at least 30 seconds, bradycardia ≤40 BPM for at least 6 seconds, or asystole for at least 3 seconds) and reviewer confirmed arrhythmia (RCA - implantable-loop-recorder-identified or patient-marked event for which a manual review of the stored ECG tracing confirmed the presence of atrial fibrillation, supraventricular tachycardia, sinus tachycardia with rate >130 BPM, ventricular tachycardia, asystole, or bradycardia). Models adjusted for age, sex, race, HD vintage, vascular access, and pre-HD serum bicarbonate and additionally for serum and dialysate potassium levels. RESULTS: Mean age was 56 ± 12 years, 70% were male, 53% were Black, and 35% were Asian. Fewer RCA episodes were associated with DBIC >35 than 35 mEq/L (incidence rate ratio [IRR] 0.45 (0.27, 0.75) and aIRR 0.54 (0.30, 0.97)), but the association was not significant when adjusting for serum and dialysate potassium levels (aIRR 0.60 (0.32, 1.11)). Otherwise, no associations between DBIC and arrhythmia were identified. CONCLUSIONS: We observed a lower frequency of RCA with higher DBIC, compared with DBIC of 35 mEql/L, contrary to our original hypothesis, but this association was attenuated in fully adjusted models. Validation of these findings in larger studies is required, with a further need for interventional studies to explore the optimal DBIC concentration.

Arrhythmia and Time of Day in Maintenance Hemodialysis: Secondary Analysis of the Monitoring in Dialysis Study.

Rationale & Objective: The incidence of arrhythmia varies by time of day. How this affects individuals on maintenance dialysis is uncertain. Our objective was to quantify the relationship of arrhythmia with the time of day and timing of dialysis. Study Design: Secondary analysis of the Monitoring in Dialysis study, a multicenter prospective cohort study. Settings & Participants: Loop recorders were implanted for continuous cardiac monitoring in 66 participants on maintenance dialysis with a follow up of 6 months. Exposure: Time of day based on 6-hour intervals. Outcomes: Event rates of clinically significant arrhythmia. Analytical Approach: Negative binomial mixed effects regression models for repeated measures were used to evaluate data from the Monitoring in Dialysis study for differences in diurnal patterns of clinically significant arrhythmia among those with end-stage kidney disease with heart failure and end-stage kidney disease alone. We additionally analyzed rates according to presence of heart failure, time of dialysis shift, and dialysis versus nondialysis day. Results: Rates of clinically significant arrhythmia peaked between 12:00 AM and 5:59 AM and were more than 1.5-fold as frequent during this interval than the rest of the day. In contrast, variations in atrial fibrillation peaked between 6:00 AM and 11:59 AM, but variations across the day were qualitatively small. Clinically significant arrhythmia occurred at numerically higher rate in individuals with end-stage kidney disease and heart failure (5.9 events/mo; 95% CI, 1.3-26.8) than those without heart failure (4.0 events/mo; 95% CI, 0.9-17.9). Although differences in overall rate were not significant, their periodicity was significantly different (P < 0.001), with a peak between 12:00 AM and 6:00 AM with kidney failure alone and between 6:00 AM and 11:59 AM in those with heart failure. Although the overall clinically significant arrhythmia rate was similar in morning compared with evening dialysis shifts (P = 0.43), their periodicity differed with a peak between 12:00 AM and 5:59 AM in those with AM dialysis and a later peak between 6:00 AM and 11:59 AM in those with PM shifts. Limitations: Post hoc analysis, unable to account for unmeasured confounders. Conclusion: Clinically significant arrhythmias showed strong diurnal patterns with a maximal peak between 12:00 AM and 5:59 AM and noon. Although overall arrhythmia rates were similar, the peak rate occurred overnight in individuals without heart failure and during the morning in individuals with heart failure. Further exploration of the influence of circadian rhythm on arrhythmia in the setting of hemodialysis is needed.

Arrhythmias occur with a high frequency in individuals with kidney failure. We sought to understand whether there were diurnal patterns for common types of arrhythmias in individuals with kidney failure. We used continuous rhythm data from 66 individuals on dialysis with implantable loop recorders. We found that clinically significant arrhythmias including bradycardia primarily occur overnight and in the early morning, whereas atrial fibrillation is more evenly distributed during the day.

Lactation and maternal subclinical cardiovascular disease among premenopausal women.

OBJECTIVE: The objective of the study was to examine the association between lactation and maternal subclinical cardiovascular disease. STUDY DESIGN: The Women and Infants Study of Healthy Hearts enrolled 607 mothers who delivered a singleton between 1997 and 2002. In 2007, participating mothers underwent measurements of carotid intima-media thickness, lumen diameter, adventitial diameter, and carotid-femoral pulse wave velocity. Multivariable linear and logistic regressions were used to estimate the associations between lactation and subclinical cardiovascular disease. RESULTS: Compared with mothers who breastfed for 3 or more months after every birth, mothers who never breastfed exhibited a 0.13 mm larger lumen diameter (95% confidence interval, 0.04-0.22) and a 0.12 mm larger adventitial diameter (95% confidence interval, 0.02-0.22) in models adjusting for age, parity, birth outcome, sociodemographic variables, health-related behaviors, family history, gestational weight gain, early adult body mass index, current body mass index, C-reactive protein, blood pressure, cholesterol, triglyceride, high-density lipoprotein, glucose, and insulin levels. CONCLUSION: Mothers who do not breastfeed have vascular characteristics associated with a greater risk of cardiovascular disease.

Maternal visceral adiposity by consistency of lactation.

The purpose of this study was to examine the assocation between lactation and maternal visceral adiposity among US women who were on average 7 years postpartum. This cross-sectional analysis included 89 women who gave birth between 1997 and 2002, who did not have preeclampsia, prepregnancy hypertension or prepregnancy diabetes, and enrolled in The Women and Infant Study of Healthy Hearts (WISH). Computed tomography was used to assess abdominal adiposity. History of lactation was self-reported. Visceral adiposity was greater by 36.96 cm(2) (95% CI: 20.92,53.01) among mothers who never breastfed than mothers who breastfed for ≥3 months after every birth, even after adjustment for age, parity, years since last birth, site, socioeconomic, lifestyle, psychological, and family history variables, early adult BMI, and current BMI. Similarly, in fully adjusted models, mothers who breastfed any of their children for less than 3 months had 20.38 cm(2) (95% CI: 2.70, 38.06) greater visceral adiposity than mothers who consistently breastfed all their children for 3 or more months. This study found that 7 years postpartum visceral fat depots are significantly greater among mothers who lactated for less than 3 months after the birth of each of their children. These results provide a potential physiologic basis for prior findings that women who do not consistently breastfeed are at an increased risk of diabetes, cardiovascular disease, and the metabolic syndrome.

Association of Bradycardia and Asystole Episodes with Dialytic Parameters: An Analysis of the Monitoring in Dialysis (MiD) Study.

Background: Bradycardia and asystole events are common among patients treated with maintenance hemodialysis. However, triggers of these events in patients on maintenance hemodialysis (HD), particularly during the long interdialytic period when these events cluster, are uncertain. Methods: The Monitoring in Dialysis Study (MiD) enrolled 66 patients on maintenance HD who were implanted with loop recorders and followed for 6 months. We analyzed associations of predialysis laboratory values with clinically significant bradyarrhythmia or asystole (CSBA) during the 12 hours before an HD session. Associations with CSBA were analyzed with mixed-effect models. Adjusted negative binomial mixed-effect regression was used to estimate incidence rate ratios (IRR) for CSBA. We additionally evaluated associations of CSBA at any time during follow-up with time-averaged dialytic and laboratory parameters and associations of peridialytic parameters with occurrence of CSBA from the start of one HD session to the beginning of the next. Results: There were 551 CSBA that occurred in the last 12 hours of the interdialytic interval preceding 100 HD sessions in 12% of patients and 1475 CSBA events in 23% of patients overall. We did not identify significant associations between dialytic parameters or serum electrolytes and CSBA in the last 12 hours of the interdialytic interval in adjusted analyses. Median time-averaged ultrafiltration rate was significantly higher in individuals without CSBA (9.8 versus 8, P=0.04). Use of dialysate sodium concentrations ≤135 (versus 140) mEq/L was associated with a reduced risk of CSBA from the start of one session to the beginning of next. Conclusions: Although a few factors had modest associations with CSBA in some analyses, we did not identify any robust associations of modifiable parameters with CSBA in the MiD Study. Further investigation is needed to understand the high rates of arrhythmia in the hemodialysis population.