Reproducibility of consecutive automated telemetric noctodiurnal IOP profiles as determined by an intraocular implant.

BACKGROUND: Intraocular pressure (IOP) monitoring in glaucoma management is evolving with novel devices. We investigated the reproducibility of 24 hour profiles on two consecutive days and after 30 days of self-measurements via telemetric IOP monitoring. METHODS: Seven primary patients with open-angle glaucoma previously implanted with a telemetric IOP sensor in one eye underwent automatic measurements throughout 24 hours on two consecutive days ('day 1' and 'day 2'). Patients wore an antenna adjacent to the study eye connected to a reader device to record IOP every 5 min. Also, self-measurements in six of seven patients were collected for a period of 30 days. Analysis included calculation of hourly averages to correlate time-pairs of day 1 versus day 2 and the self-measurements vers day 2. RESULTS: The number of IOP measurements per patient ranged between 151 and 268 on day 1, 175 and 268 on day 2 and 19 and 1236 during 30 days of self-measurements. IOP time-pairs of automatic measurements on day 1 and day 2 were significantly correlated at the group level (R=0.83, p<0.001) and in four individual patients (1, 2, 6 and 7). IOP time-pairs of self-measurements and day 2 were significantly correlated at the group level (R=0.4, p<0.001) and in four individual patients (2, 5, 6 and 7). CONCLUSIONS: Twenty-four hour automatic measurements of IOP are correlated on consecutive days and, though to a lesser degree, with self-measurements. Therefore a virtual 24-hour IOP curve might be constructed from self-measurements. Both options provide an alternative to frequent in-office IOP measurements.

Effects of a Polypill, Aspirin, and the Combination of Both on Cognitive and Functional Outcomes: A Randomized Clinical Trial.

Importance: Vascular risk factors are associated with cognitive decline but studies addressing individual risk factors have not demonstrated an effect of risk factor management on the preservation of cognition. Few trials have examined the effect of vascular risk factor management on function. Objective: To determine if a polypill could reduce cognitive and functional decline in people with risk factors but without manifest cardiovascular disease. Design, Setting, and Participants: The International Polycap Study 3 (TIPS-3) was a 2 × 2 × 2 factorial randomized clinical trial. Hospital and community-based centers in 8 countries recruited and followed up participants between July 30, 2012, and September 30, 2020. A total of 5713 individuals were randomly assigned to treatment groups, and 2098 people 65 years or older at intermediate risk of cardiovascular disease completed a cognitive assessment and were included in the analyses. Interventions: Polypill (antihypertensives and a statin), aspirin, or a combination of both treatments. Main Outcomes and Measures: Cognitive and functional assessments completed at baseline, 2 years, and study end. The primary outcome was the effect of a polypill compared with placebo and a polypill plus aspirin compared with double placebo on the composite outcome of the proportion of participants in each group who experienced a substantive decrease (>1.5 SD change) in cognitive or functional abilities. Results: Of the 2389 study participants older than 65 years, a total of 2098 (88%; mean [SD] age, 70.1 [4.5] years; 1266 female individuals [60%]) completed the baseline and follow-up assessment. A total of 1796 participants (86%) had hypertension, and 680 participants (32%) had impaired fasting plasma glucose levels. Mean (SD) baseline systolic blood pressure was 146.1 (17.7) mm Hg, and mean (SD) low-density lipoprotein cholesterol (LDL-C) level was 124.3 (40.7) mg/dL and decreased by 5.7 mm Hg and 24 mg/dL, respectively, among those assigned to the polypill group. During a 5-year follow-up, there were no significant differences between treatment groups in the number of participants who experienced substantive cognitive decline (356 assigned polypill, 328 assigned placebo) or dementia (2 assigned polypill, 4 assigned placebo). Functional decline was reduced during follow-up for those assigned to polypill compared with placebo (mean [SD] country-standardized adjusted follow-up Standard Assessment of Global Everyday Activities [SAGEA] scores, 0.06 [0.03] vs 0.15 [0.03]; P = .01) and polypill plus aspirin compared with double placebo (mean [SD] country-standardized adjusted follow-up SAGEA scores, 0.01 [0.04] vs 0.14 [0.04]; P = .01). Conclusions and Relevance: In this randomized clinical trial of patients 65 years or older with vascular risk factors, a polypill, with or without aspirin, was not associated with reduced cognitive outcomes but was associated with reduced functional decline.

Effect of eyelid muscle action and rubbing on telemetrically obtained intraocular pressure in patients with glaucoma with an IOP sensor implant.

BACKGROUND: Patients with glaucoma on topical glaucoma medication are often affected by dry eye symptoms and thus likely to rub or squeeze their eyelids. Here, we telemetrically measure peak intraocular pressure (IOP) during eyelid manoeuvres and eyelid rubbing. METHODS: Eleven patients with primary open-angle glaucoma (POAG) previously implanted with a telemetric IOP sensor (Eyemate-IO) were instructed to look straight ahead for 1 min as a baseline measurement. Next, 6 repeats of blinking on instruction with 10 s intervals in between were performed. In addition, 5 repeats of eyelid closure (n=9), eyelid squeezing and eyelid rubbing (n=7) were performed with 15 s intervals in between. IOP was recorded via an external antenna placed around the study eye. Average peak IOP increases from baseline were analysed and tested against zero (no change) with one-sample t-tests. RESULTS: For eyelid rubbing, the average peak ∆ IOP increase (mean±SEM) was 59.1±9.6 mm Hg (p<0.001) from baseline. It was 42.2±5.8 mm Hg (p<0.0001) for eyelid squeezing, 3.8±0.6 mm Hg (n=9, p<0.01) for eyelid closure and 11.6±2.4 mm Hg (p<0.001) for voluntary blinking. No IOP change except for a short irregularity in the ocular pulse was observed during involuntary blinking. CONCLUSION: Eyelid manoeuvres in patients with POAG elicited brief increases in IOP that were particularly large with squeezing and rubbing. Further investigation of the potential implications for glaucoma progression is warranted.

Plasma sodium, extracellular fluid volume, and blood pressure in healthy men.

In the general population we recently reported a consistent association between plasma sodium and volume markers, suggesting that individuals with higher plasma sodium have higher extracellular fluid volume (ECFV). To test this hypothesis, we analyzed the association between plasma sodium and directly measured ECFV (iothalamate distribution volume) in healthy men. Second, we studied whether plasma sodium is associated with blood pressure. We analyzed data from 70 men (age 24 ± 7 years) at the end of two 7-day periods on a low-sodium diet (LS, 50 mmol Na/24 h) and a high-sodium diet (HS, 200 mmol Na/24 h), respectively. The association of plasma sodium with blood pressure was assessed in the combined data of the different sodium intakes by linear mixed effects models. A positive univariable association between plasma sodium and ECFV was found during HS (ß = 0.24, p = 0.042) and LS (ß = 0.23, p = 0.058), respectively. Individual values of plasma sodium on LS and HS diet were strongly correlated (ß = 0.68, p < 0.001), as were values for ECFV (ß = 0.54, p < 0.001). In the combined data set plasma sodium level was significantly associated with ECFV (B [SE] = 0.10 [0.04], p = 0.02), and systolic blood pressure (SBP, B [SE] = 0.73 [0.26], p = 0.006), independent of ECFV. In conclusion, plasma sodium concentration is positively associated with ECFV on both LS and HS intake. Our data confirm and extend prior data on individual regulation of plasma sodium and suggest that this is associated with individuality of the regulation of ECFV. Finally, plasma sodium level is associated with SBP, independent of ECFV and diet.

Implanted Microsensor Continuous IOP Telemetry Suggests Gaze and Eyelid Closure Effects on IOP-A Preliminary Study.

Purpose: To explore the effect of gaze direction and eyelid closure on intraocular pressure (IOP). Methods: Eleven patients with primary open-angle glaucoma previously implanted with a telemetric IOP sensor were instructed to view eight equally-spaced fixation targets each at three eccentricities (10°, 20°, and 25°). Nine patients also performed eyelid closure. IOP was recorded via an external antenna placed around the study eye. Differences of mean IOP between consecutive gaze positions were calculated. Furthermore, the effect of eyelid closure on gaze-dependent IOP was assessed. Results: The maximum IOP increase was observed at 25° superior gaze (mean ± SD: 4.4 ± 4.9 mm Hg) and maximum decrease at 25° inferonasal gaze (-1.6 ± 0.8 mm Hg). There was a significant interaction between gaze direction and eccentricity (P = 0.003). Post-hoc tests confirmed significant decreases inferonasally for all eccentricities (mean ± SEM: 10°: -0.7 ± 0.2, P = 0.007; 20°: -1.1 ± 0.2, P = 0.006; and 25°: -1.6 ± 0.2, P = 0.006). Eight of 11 eyes showed significant IOP differences between superior and inferonasal gaze at 25°. IOP decreased during eyelid closure, which was significantly lower than downgaze at 25° (mean ± SEM: -2.1 ± 0.3 mm Hg vs. -0.7 ± 0.2 mm Hg, P = 0.014). Conclusions: Our data suggest that IOP varies reproducibly with gaze direction, albeit with patient variability. IOP generally increased in upgaze but decreased in inferonasal gaze and on eyelid closure. Future studies should investigate the patient variability and IOP dynamics.

Cardiovascular consequences of discontinuing low-dose rivaroxaban in people with chronic coronary or peripheral artery disease.

OBJECTIVE: In patients with chronic coronary or peripheral artery disease enrolled in the Cardiovascular Outcomes for People Using Anticoagulation Strategies trial, randomised antithrombotic treatments were stopped after a median follow-up of 23 months because of benefits of the combination of rivaroxaban 2.5 mg two times per day and aspirin 100 mg once daily compared with aspirin 100 mg once daily. We assessed the effect of switching to non-study aspirin at the time of early stopping. METHODS: Incident composite of myocardial infarction, stroke or cardiovascular death was estimated per 100 person-years (py) during randomised treatment (n=18 278) and after study treatment discontinuation to non-study aspirin (n=14 068). RESULTS: During randomised treatment, the combination compared with aspirin reduced the composite (2.2 vs 2.9/100 py, HR: 0.76, 95% CI 0.66 to 0.86), stroke (0.5 vs 0.8/100 py, HR: 0.58, 95% CI 0.44 to 0.76) and cardiovascular death (0.9 vs 1.2/100 py, HR: 0.78, 95% CI 0.64 to 0.96). During 1.02 years after early stopping, participants originally randomised to the combination compared with those randomised to aspirin had similar rates of the composite (2.1 vs 2.0/100 py, HR: 1.08, 95% CI 0.84 to 1.39) and cardiovascular death (1.0 vs 0.8/100 py, HR: 1.26, 95% CI 0.85 to 1.86) but higher stroke rate (0.7 vs 0.4/100 py, HR: 1.74, 95% CI 1.05 to 2.87) including a significant increase in ischaemic stroke during the first 6 months after switching to non-study aspirin. CONCLUSION: Discontinuing study rivaroxaban and aspirin to non-study aspirin was associated with the loss of cardiovascular benefits and a stroke excess. TRIAL REGISTRATION NUMBER: NCT01776424.

Use of a novel telemetric sensor to study interactions of intraocular pressure and ganglion-cell function in glaucoma.

AIMS: (1) To test the feasibility of simultaneous steady-state pattern electroretinogram (ssPERG) and intraocular pressure (IOP) measurements with an implanted IOP sensor. (2) To explore the scope of this approach for detecting PERG changes during IOP manipulation in a model of lateral decubitus positioning (LDP; lateral position). METHODS: 15 healthy controls and 15 treated glaucoma patients participated in the study. 8 patients had an IOP sensor (Eyemate-IO, Implandata Ophthalmic Products GmbH) in the right eye (GLAIMP) and 7 had no sensor and with glaucoma in the left eye. (1) We compared PERGs with and without simultaneous IOP read-out in GLAIMP. (2) All participants were positioned in the following order: sitting1 (S1), right LDP (LDR), sitting2 (S2), left LDP (LDL) and sitting3 (S3). For each position, PERG amplitudes and IOP were determined with rebound tonometry (Icare TA01i) in all participants without the IOP sensor. RESULTS: Electromagnetic intrusions of IOP sensor read-out onto ssPERG recordings had, due to different frequency ranges, no relevant effect on PERG amplitudes. IOP and PERG measures were affected by LDP, for example, IOP was increased during LDR versus S1 in the lower eyes of GLAIMP and controls (5.1±0.6 mmHg, P0.025=0.00004 and 1.6±0.6 mmHg, P0.025=0.02, respectively) and PERG amplitude was reversibly decreased (-25±10%, P0.025=0.02 and -17±5%, P0.025, respectively). CONCLUSIONS: During LDP, both IOP and PERG changed predominantly in the lower eye. IOP changes induced by LDP may be a model for studying the interaction of IOP and ganglion-cell function.

Major Bleeding in Patients With Coronary or Peripheral Artery Disease Treated With Rivaroxaban Plus Aspirin.

BACKGROUND: In patients with coronary or peripheral artery disease, the combination of rivaroxaban 2.5 mg twice daily and aspirin 100 mg once daily compared with aspirin 100 mg once daily reduced major adverse cardiovascular events and mortality and increased bleeding. OBJECTIVES: This study sought to explore the effects of the combination of rivaroxaban and aspirin compared with aspirin on sites, timing, severity, and management of bleeding in the COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) study. METHODS: This study reports, by treatment group, the number and proportion of patients; hazard rate ratios for bleeding according to site and severity; the timing of bleeding using landmark analyses; and the number and proportion of patients who received blood products and other hemostatic treatments. RESULTS: Of 27,395 patients enrolled (mean age 68 years, 22% women), 18,278 were randomized to the combination of rivaroxaban and aspirin or to aspirin alone and followed for a mean of 23 months. Compared with aspirin alone, the combination increased modified International Society on Thrombosis and Hemostasis major bleeding (288 of 9,152 [3.1%] vs. 170 of 9,126 [1.9%]), (HR: 1.70; 95% CI: 1.40 to 2.05; p < 0.001), International Society on Thrombosis and Hemostasis major bleeding (206 of 9,152 [2.3%] vs. 116 of 9,126 [1.3%]), (HR: 1.78; 95% CI: 1.41 to 2.23; p < 0.0001), and minor bleeding (838 of 9,152 [9.2%] vs. 503 of 9,126 [5.5%]), (HR: 1.70; 95% CI 1.52 to 1.90; p < 0.0001); the combination also increased the need for any red cell transfusion (87 of 9,152 [1.0%] vs. 44 of 9,126 [0.5%]), (HR: 1.97; 95% CI 1.37 to 2.83, p = 0.0002). The gastrointestinal (GI) tract was the most common site of increased major bleeding (140 of 9,152 [1.5%] vs. 65 of 9,126 [0.7%]), (HR: 2.15; 95% CI: 1.60 to 2.89; p < 0.001), and the increase in bleeding was predominantly in the first year after randomization. Approximately one-third of major GI bleeding was gastric or duodenal, one-third was colonic or rectal, and one-third was from an unknown GI site. The study investigators reported that approximately three-quarters of major bleeding episodes were of mild or moderate intensity. A similar proportion of patients in each treatment group who experienced major bleeding received platelets, clotting factors, or other hemostatic agents. CONCLUSIONS: The combination of rivaroxaban and aspirin compared with aspirin alone increased major bleeding, mainly from the GI tract. Most excess bleeding occurred during the first year after randomization, was of mild or moderate intensity, and was managed with conventional supportive therapy. (Rivaroxaban for the Prevention of Major Cardiovascular Events in Coronary or Peripheral Artery Disease [COMPASS]; NCT01776424).

Clinical and neurohumoral associates of variations in plasma Na+ in the PREVEND cohort.

Plasma Na+ concentration is regulated within narrow limits. Yet, substantial interindividual differences exist even in the normal range. The determinants of these differences are not well understood. We therefore investigated the clinical and neurohumoral associates of plasma Na+. We studied 2,364 men (age: 48 ± 12 yr) and 2,710 women (age: 47 ± 12 yr) from the prospective Prevention of Renal and Vascular End-Stage Disease (PREVEND) cohort study. In the present study, we investigated the neurohumoral factors NH2-terminal prohormone of brain natriuretic peptide (NT-proBNP) and aldosterone as volume markers and copeptin as a marker for osmoregulation. Clinical associating variables of plasma Na+ were age, sex, and plasma glucose. Furthermore, plasma Na+ levels were associated with log2 copeptin (men: standardized ß = 0.18, P < 0.001; women: standardized ß = 0.17, P < 0.001), log2 NT-proBNP (men: standardized ß = 0.07, P = 0.008; women: standardized ß = 0.12, P < 0.001), and log2 aldosterone (men: standardized ß = -0.06, P = 0.005; women: standardized ß = -0.09, P < 0.001). Copeptin and NT-proBNP showed an interaction in their association with plasma Na+. Thus, our data 1) support that osmoregulation, as estimated from copeptin levels, is a main associate of plasma Na+; 2) show a consistent association with volume markers, with higher NT-proBNP and lower aldosterone in individuals with higher plasma Na+; and 3) show that the interaction between copeptin and NT-proBNP illustrates that osmoregulation and volume regulation act in concert in the regulation of plasma Na+.

Effects of Dietary Sodium Restriction in Kidney Transplant Recipients Treated With Renin-Angiotensin-Aldosterone System Blockade: A Randomized Clinical Trial.

BACKGROUND: In patients with chronic kidney disease receiving renin-angiotensin-aldosterone system (RAAS) blockade, dietary sodium restriction is an often-used treatment strategy to reduce blood pressure (BP) and albuminuria. Whether these effects extend to kidney transplant recipients is unknown. We therefore studied the effects of dietary sodium restriction on BP and urinary albumin excretion (UAE) in kidney transplant recipients receiving RAAS blockade. STUDY DESIGN: Two-center randomized crossover trial. SETTING & PARTICIPANTS: Stable outpatient kidney transplant recipients with creatinine clearance > 30mL/min, BP ≥120/80mmHg, receiving stable RAAS blockade therapy. INTERVENTION: 6-week regular-sodium diet (target, 150mmol/24 h) and a 6-week low-sodium diet (target, 50mmol/24 h). OUTCOMES & MEASUREMENTS: Main outcome parameters were systolic and diastolic BP, UAE, and estimated glomerular filtration rate (eGFR) at the end of each diet period. Dietary adherence was assessed by 24-hour urinary sodium excretion. RESULTS: We randomly assigned 23 kidney transplant recipients, of whom 22 (mean age, 58±8 [SD] years; 50% men; mean eGFR, 51±21mL/min/1.73m(2)) completed the study. One patient withdrew from the study because of concerns regarding orthostatic hypotension on the low-sodium diet. Sodium excretion decreased from 164±50mmol/24 h during the regular-sodium diet to 87±55mmol/24 h during the low-sodium diet (mean difference, -77 [95% CI, -110 to -44] mmol/24 h; P<0.001). Sodium restriction significantly reduced systolic BP from 140±14 to 129±12mmHg (mean difference, -11 [95% CI, -14 to -7] mmHg; P<0.001), diastolic BP from 86±8 to 79±8mmHg (mean difference, -7 [95% CI, -10 to -5] mmHg; P<0.001). We found no significant effect on natural log (ln)-transformed UAE (mean difference, -0.03 [95% CI, -0.6 to 0.6] ln(mg/24 h); P=0.9) or eGFR. LIMITATIONS: No hard end points; small study; small proportion of patients willing to test the intervention; adherence to sodium diet was achieved in 86% of patients. CONCLUSIONS: In stable kidney transplant recipients receiving RAAS blockade, dietary sodium restriction effectively reduces BP without affecting eGFR. Dietary sodium restriction is relevant to BP management in kidney transplant recipients receiving RAAS blockade.