Association of Sacubitril/Valsartan vs Valsartan With Blood Pressure Changes and Symptomatic Hypotension: the PARAGLIDE-HF Trial.

BACKGROUND: In PARAGLIDE-HF, in patients with ejection fraction (EF) > 40%, stabilized after worsening heart failure (WHF), sacubitril/valsartan led to greater reduction in plasma NT-proBNP levels and was associated with clinical benefit compared to valsartan alone, despite more symptomatic hypotension (SH). Concern about SH may be limiting the use of sacubitril/valsartan in appropriate patients. METHODS: We characterized patients by the occurrence of SH (investigator-reported) after randomization to either sacubitril/valsartan or valsartan. A key trial inclusion criterion was systolic blood pressure (SBP) ≥ 100 mmHg for the preceding 6 hours and no SH. We also compared outcomes based on baseline SBP stratified by the median blood pressure. The primary endpoint was time-averaged proportional change in NT-proBNP levels from baseline through weeks 4 and 8. A secondary hierarchical outcome (win ratio) consisted of: (1) cardiovascular death; (2) hospitalizations due to HF; (3) urgent HF visits; and (4) change in NT-proBNP levels. RESULTS: Among 466 randomized patients, 92 (19.7%) experienced SH (sacubitril/valsartan, n = 56 [24.0%]; valsartan, n = 36 [15.5%]; P = 0.020). The median time to the first SH event was similar between treatment arms (18 days vs 15 days, respectively; P = 0.42) as was the proportion of first SH events classified as serious by investigators. Patients who experienced SH with sacubitril/valsartan were more likely to be white (OR 1.87 [95% CI: 0.31, 11.15]), to have a lower baseline SBP (per 10 mmHg increase, OR 0.68 [95% CI: 0.55, 0.85]), or to have a left ventricular ejection fraction (LVEF) of > 60% (OR 2.21 [95% CI: 1.05, 4.65]). Time-averaged change in NT-proBNP levels did not differ between patients with baseline SBP ≥ 128 mmHg vs SBP < 128 mmHg (interaction, P = 0.43). The composite hierarchical outcome for sacubitril/valsartan in patients with baseline SBP ≥ 128 mmHg had a win ratio of 1.34 ([95% CI: 0.91, 1.99]; P = 0.096) vs SBP < 128 mmHg with a win ratio of 1.09 ([95%CI: 0.73, 1.66]; P = 0 .62; interaction P value = 0.42). CONCLUSION: Among patients with LVEF > 40% stabilized after WHF, incident SH was more common with sacubitril/valsartan compared with valsartan. SH was associated with lower baseline SBP, being white, and having higher LVEF. Treatment benefits with sacubitril/valsartan may be more pronounced in patients with higher baseline SBP and lower LVEF (≤ 60%). (Funded by Novartis Pharmaceutical Corporation; ClinicalTrials.gov number, NCT03988634.).

2.5-Year changes of connectivity dynamism are relevant for physical and cognitive deterioration in multiple sclerosis.

BACKGROUND: In MS, functional connectivity (FC) dynamism may influence disease evolution. OBJECTIVES: The objective is to assess time-varying functional connectivity (TVFC) changes over time at 2.5-year follow-up in MS patients according to physical and cognitive worsening. METHODS: We collected 3T magnetic resonance imaging (MRI) for TVFC assessment (performed using sliding-window analysis of centrality) and clinical evaluations at baseline and 2.5-year follow-up from 28 healthy controls and 129 MS patients. Of these, 79 underwent baseline and follow-up neuropsychological assessment. At 2.5 years, physical/cognitive worsening was defined according to disability/neuropsychological score changes. RESULTS: At follow-up, 25/129 (19.3%) MS patients worsened physically and 14/79 (17.7%) worsened cognitively. At baseline, MS patients showed reduced TVFC versus controls. At 2.5-year follow-up, no TVFC changes were detected in controls. Conversely, TVFC decreased over time in parieto-temporal regions in stable MS patients and in default-mode network in worsened MS. In physically worsened MS, basal ganglia TVFC reductions were also found. Reduced TVFC over time in the putamen in physically worsened and reduced TVFC in the precuneus in cognitively worsened were significant versus stable MS. DISCUSSION: At 2.5-year follow-up, default-mode network TVFC reductions were found in worsening MS. Moreover, reduced deep gray matter TVFC characterized physically worsened patients, whereas precuneus involvement characterized cognitively worsened MS patients.

Association between sun exposure habits and disease progression in multiple sclerosis.

BACKGROUND AND PURPOSE: Higher latitude has been associated with increased occurrence of multiple sclerosis (MS) and with more severe disease. The aim was to study the impact of sun exposure habits on MS disease progression and health-related quality of life. METHODS: Patients from a population-based case-control study were categorized based on sun exposure habits at diagnosis and were followed up to 15 years post-diagnosis through the Swedish MS registry (n = 3314) with regard to changes in Expanded Disability Status Scale (EDSS). Linear mixed models were used to analyse long-term changes, while Cox regression models, with 95% confidence intervals, were used to investigate outcomes, including 24-week confirmed diasability worsening, EDSS3, EDSS4, and physical worsening as measured by the physical component of the Multiple Sclerosis Impact Scale 29. RESULTS: Compared to average sun exposure (median value), low exposure to sunlight was associated with faster EDSS progression, increased risk of confirmed disability worsening (hazard ratio [HR] 1.48, 95% CI 1.21-1.81), increased risk of reaching EDSS 3 (HR 1.35, 95% CI 1.02-1.79), EDSS 4 (HR 1.47, 95% CI 1.01-2.20) and self-reported physical worsening (HR 1.27, 95% CI 1.00-1.62). Significant trends revealed a lower risk of unfavourable outcomes with increasing sun exposure. CONCLUSIONS: Very low levels of sun exposure are associated with worse disease progression and health-related quality of life in patients with MS.

Predicting worsening heart failure hospitalizations in patients with implantable cardioverter defibrillators: is it all about alerts? A pooled analysis of nine trials.

AIMS: To predict worsening heart failure hospitalizations (WHFHs) in patients with implantable defibrillators and remote monitoring, the HeartInsight algorithm (Biotronik, Berlin, Germany) calculates a heart failure (HF) score combining seven physiologic parameters: 24 h heart rate (HR), nocturnal HR, HR variability, atrial tachyarrhythmia, ventricular extrasystoles, patient activity, and thoracic impedance. We compared temporal trends of the HF score and its components 12 weeks before a WHFH with 12-week trends in patients without WHFH, to assess whether trends indicate deteriorating HF regardless of alert status. METHODS AND RESULTS: Data from nine clinical trials were pooled, including 2050 patients with a defibrillator capable of atrial sensing, ejection fraction ≤ 35%, NYHA class II/III, no long-standing atrial fibrillation, and 369 WHFH from 259 patients. The mean HF score was higher in the WHFH group than in the no WHFH group (42.3 ± 26.1 vs. 30.7 ± 20.6, P < 0.001) already at the beginning of 12 weeks. The mean HF score further increased to 51.6 ± 26.8 until WHFH (+22% vs. no WHFH group, P = 0.003). As compared to the no WHFH group, the algorithm components either were already higher 12 weeks before WHFH (24 h HR, HR variability, thoracic impedance) or significantly increased until WHFH (nocturnal HR, atrial tachyarrhythmia, ventricular extrasystoles, patient activity). CONCLUSION: The HF score was significantly higher at, and further increased during 12 weeks before WHFH, as compared to the no WHFH group, with seven components showing different behaviour and contribution. Temporal trends of HF score may serve as a quantitative estimate of HF condition and evolution prior to WHFH.

Timing of Worsening Renal Function in Patients Hospitalized for Heart Failure Exacerbation Who Were Being Treated With Intravenous Diuretic Therapy.

BACKGROUND: This retrospective observational study investigated the incidence of worsening renal function (WRF) in patients hospitalized for heart failure (HF) and treated with intravenous diuretics in Japan.Methods and Results: Associations between WRF at any point and HF treatments, and the effects of WRF on outcomes were evaluated (Diagnosis Procedure Combination database). Of 1,788 patients analyzed (mean [±SD] age 80.5±10.2 years; 54.4% male), 641 (35.9%) had WRF during a course of hospitalization for worsening HF: 208 (32.4%) presented with WRF before admission (BA-WRF; estimated glomerular filtration rate decreased by ≥25% from baseline at least once between 30 days prior to admission and admission); 44 (6.9%) had WRF that persisted before and after admission (P-WRF); and 389 (60.7%) had WRF develop after admission (AA-WRF). Delayed initial diuretic administration, higher maximum doses of intravenous diuretics during hospitalization, and diuretic readministration during hospitalization were associated with a significantly higher incidence of AA-WRF. Patients with WRF at any time point were at higher risk of death during hospitalization compared with patients without WRF, with adjusted hazard ratios of 3.56 (95% confidence interval [CI] 2.23-5.69) for BA-WRF, 3.23 (95% CI 2.21-4.71) for AA-WRF, and 13.16 (95% CI 8.19-21.15) for P-WRF (all P<0.0001). CONCLUSIONS: Forty percent of WRF occurred before admission for acute HF; there was no difference in mortality between patients with BA-WRF and AA-WRF.

Real-world characteristics and use patterns of patients treated with vericiguat: A nationwide longitudinal cohort study in Germany.

PURPOSE: Vericiguat reduced clinical endpoints in patients experiencing worsening heart failure in clinical trials, but its implementation outside trials is unclear. METHODS: This retrospective analysis of longitudinally collected data was based on the IQVIA™ LRx database, which includes ~ 80% of the prescriptions of the 73 million people covered by the German statutory health insurance. RESULTS: Between September 2021 and December 2022, vericiguat was initiated in 2916 adult patients. Their mean age was 73 ± 13 years and 28% were women. While approximately 70% were uptitrated beyond 2.5 mg, only 36% reached 10 mg. Median time to up-titration from 2.5 mg to 5 mg was 17 (quartiles: 11-33) days, and from 2.5 to 10 mg 37 (25-64) days, respectively. In 87% of the patients, adherence to vericiguat was high as indicated by a medication possession ratio of  ≥ 80%, and 67% of the patients persistently used vericiguat during the first year. Women and older patients reached the maximal dose of 10 mg vericiguat less often and received other substance classes of guideline-recommended therapy (GDMT) less frequently. The proportion of patients receiving four pillars of GDMT increased from 29% before vericiguat initiation to 44% afterwards. CONCLUSION: In a real-world setting, despite higher age than in clinical trials, adherence and persistence of vericiguat appeared satisfactory across age categories. Initiation of vericiguat was associated with intensification of concomitant GDMT. Nevertheless, barriers to vericiguat up-titration and implementation of other GDMT, applying in particular to women and elderly patients, need to be investigated further.

The Prognostic Impact of Renal Function Decline during Hospitalization for Heart Failure.

INTRODUCTION: We aimed to evaluate the prognostic impact of renal insufficiency and fluctuation of glomerular filtration observed during hospitalization for heart failure (HF). METHODS: We followed 3,639 patients hospitalized for acute HF and assessed the mortality risk associated with moderate or severe renal insufficiency, either permanent or transient. RESULTS: After adjustment, severe renal failure defined as estimated glomerular filtration (eGFR) <30 mL/min indicates ≈60% increase in 5-year mortality risk. Similar risk also had patients with only transient decline of eGFR to this range. In contrast, we did not observe any apparent mortality risk attributable to mild/moderate renal insufficiency (eGFR 30-59.9 mL/min), regardless of whether it was transient or permanent. CONCLUSION: Even transient severe renal failure during hospitalization indicates poor long-term prognosis of patients with manifested HF. In contrast, only moderate renal insufficiency observed during hospitalization has no additive long-term mortality impact.

Changes in estimated glomerular filtration rate before and after the first visit for atrial fibrillation.

BACKGROUND: Although the development of atrial fibrillation (AF) and the progression of chronic kidney disease are known to be interrelated, it remains unclear when and how renal function changes during the clinical course of AF. METHODS: This study retrospectively enrolled 131 patients who were able to collect data on estimated glomerular filtration rate (eGFR) at least five times during the 500 days before and 500 days after the first visit (baseline) of new-onset AF, respectively. To investigate the temporal relationship between the development of AF and the beginning of worsening renal function (WRF), a piecewise regression model was applied to the eGFR time series data. The time point at which the slopes of the two regression lines changed (inflection -point), the slope before and after the inflection-point (ß1 and ß2, respectively), and the difference in slope (Δß) were estimated. The presence of WRF was defined as having the inflection-point at which both Δß and ß2 were < - 0.0083 mL/min/1.73 m2/day (corresponding to 3.03 mL/min/1.73 m2/year), and the corresponding the inflection-point was defined as the beginning of WRF. RESULTS: WRF was detected in 54 (41.2%) patients. The beginning of WRF were distributed at various times, but most frequently (23 of 54 patients) within 100 days before and after baseline. The presence of WRF was not associated with age, heart failure, or baseline eGFR, but was associated with positive ß1 (odds ratio 30.5, 95% confidence interval 11.1-83.9, P < 0.01). CONCLUSION: In nearly half of AF patients with WRF, the beginning of WRF was observed within a few months before or after the first visit for AF. Patients with a positive eGFR slope before the onset of AF are more likely to develop WRF after the onset of AF, suggesting that potential kidney damage may be underlying.

Impact of COVID-19 Infection and Its Association With Previous Vaccination in Patients With Myasthenia Gravis in Korea: A Multicenter Retrospective Study.

BACKGROUND: During the coronavirus disease 2019 (COVID-19) pandemic, patients with myasthenia gravis (MG) were more susceptible to poor outcomes owing to respiratory muscle weakness and immunotherapy. Several studies conducted in the early stages of the COVID-19 pandemic reported higher mortality in patients with MG compared to the general population. This study aimed to investigate the clinical course and prognosis of COVID-19 in patients with MG and to compare these parameters between vaccinated and unvaccinated patients in South Korea. METHODS: This multicenter, retrospective study, which was conducted at 14 tertiary hospitals in South Korea, reviewed the medical records and identified MG patients who contracted COVID-19 between February 2022 and April 2022. The demographic and clinical characteristics associated with MG and vaccination status were collected. The clinical outcomes of COVID-19 infection and MG were investigated and compared between the vaccinated and unvaccinated patients. RESULTS: Ninety-two patients with MG contracted COVID-19 during the study. Nine (9.8%) patients required hospitalization, 4 (4.3%) of whom were admitted to the intensive care unit. Seventy-five of 92 patients were vaccinated before contracting COVID-19 infection, and 17 were not. During the COVID-19 infection, 6 of 17 (35.3%) unvaccinated patients were hospitalized, whereas 3 of 75 (4.0%) vaccinated patients were hospitalized (P < 0.001). The frequencies of ICU admission and mechanical ventilation were significantly lower in the vaccinated patients than in the unvaccinated patients (P = 0.019 and P = 0.032, respectively). The rate of MG deterioration was significantly lower in the vaccinated patients than in the unvaccinated patients (P = 0.041). Logistic regression after weighting revealed that the risk of hospitalization and MG deterioration after COVID-19 infection was significantly lower in the vaccinated patients than in the unvaccinated patients. CONCLUSION: This study suggests that the clinical course and prognosis of patients with MG who contracted COVID-19 during the dominance of the omicron variant of COVID-19 may be milder than those at the early phase of the COVID-19 pandemic when vaccination was unavailable. Vaccination may reduce the morbidity of COVID-19 in patients with MG and effectively prevent MG deterioration induced by COVID-19 infection.

Renal function and decongestion with acetazolamide in acute decompensated heart failure: the ADVOR trial.

BACKGROUND AND AIMS: In the ADVOR trial, acetazolamide improved decongestion in acute decompensated heart failure (ADHF). Whether the beneficial effects of acetazolamide are consistent across the entire range of renal function remains unclear. METHODS: This is a pre-specified analysis of the ADVOR trial that randomized 519 patients with ADHF to intravenous acetazolamide or matching placebo on top of intravenous loop diuretics. The main endpoints of decongestion, diuresis, natriuresis, and clinical outcomes are assessed according to baseline renal function. Changes in renal function are evaluated between treatment arms. RESULTS: On admission, median estimated glomerular filtration rate (eGFR) was 40 (30-52) mL/min/1.73 m². Acetazolamide consistently increased the likelihood of decongestion across the entire spectrum of eGFR (P-interaction = .977). Overall, natriuresis and diuresis were higher with acetazolamide, with a higher treatment effect for patients with low eGFR (both P-interaction < .007). Acetazolamide was associated with a higher incidence of worsening renal function (WRF; rise in creatinine ≥ 0.3 mg/dL) during the treatment period (40.5% vs. 18.9%; P < .001), but there was no difference in creatinine after 3 months (P = .565). This was not associated with a higher incidence of heart failure hospitalizations and mortality (P-interaction = .467). However, decongestion at discharge was associated with a lower incidence of adverse clinical outcomes irrespective of the onset of WRF (P-interaction = .805). CONCLUSIONS: Acetazolamide is associated with a higher rate of successful decongestion across the entire range of renal function with more pronounced effects regarding natriuresis and diuresis in patients with a lower eGFR. While WRF occurred more frequently with acetazolamide, this was not associated with adverse clinical outcomes. CLINICALTRIALS.GOV IDENTIFIER: NCT03505788.

Urticaria exacerbations and adverse reactions in patients with chronic urticaria receiving COVID-19 vaccination: Results of the UCARE COVAC-CU study.

BACKGROUND: Concern about disease exacerbations and fear of reactions after coronavirus disease 2019 (COVID-19) vaccinations are common in chronic urticaria (CU) patients and may lead to vaccine hesitancy. OBJECTIVE: We assessed the frequency and risk factors of CU exacerbation and adverse reactions in CU patients after COVID-19 vaccination. METHODS: COVAC-CU is an international multicenter study of Urticaria Centers of Reference and Excellence (UCAREs) that retrospectively evaluated the effects of COVID-19 vaccination in CU patients aged ≥18 years and vaccinated with ≥1 dose of any COVID-19 vaccine. We evaluated CU exacerbations and severe allergic reactions as well as other adverse events associated with COVID-19 vaccinations and their association with various CU parameters. RESULTS: Across 2769 COVID-19-vaccinated CU patients, most (90%) received at least 2 COVID-19 vaccine doses, and most patients received CU treatment and had well-controlled disease. The rate of COVID-19 vaccination-induced CU exacerbation was 9%. Of 223 patients with CU exacerbation after the first dose, 53.4% experienced recurrence of CU exacerbation after the second dose. CU exacerbation most often started <48 hours after vaccination (59.2%), lasted for a few weeks or less (70%), and was treated mainly with antihistamines (70.3%). Factors that increased the risk for COVID-19 vaccination-induced CU exacerbation included female sex, disease duration shorter than 24 months, having chronic spontaneous versus inducible urticaria, receipt of adenovirus viral vector vaccine, having nonsteroidal anti-inflammatory drug/aspirin intolerance, and having concerns about getting vaccinated; receiving omalizumab treatment and Latino/Hispanic ethnicity lowered the risk. First-dose vaccine-related adverse effects, most commonly local reactions, fever, fatigue, and muscle pain, were reported by 43.5% of CU patients. Seven patients reported severe allergic reactions. CONCLUSIONS: COVID-19 vaccination leads to disease exacerbation in only a small number of CU patients and is generally well tolerated.

Current Approaches to Worsening Heart Failure: Pathophysiological and Molecular Insights.

Worsening heart failure (WHF) is a severe and dynamic condition characterized by significant clinical and hemodynamic deterioration. It is characterized by worsening HF signs, symptoms and biomarkers, despite the achievement of an optimized medical therapy. It remains a significant challenge in cardiology, as it evolves into advanced and end-stage HF. The hyperactivation of the neurohormonal, adrenergic and renin-angiotensin-aldosterone system are well known pathophysiological pathways involved in HF. Several drugs have been developed to inhibit the latter, resulting in an improvement in life expectancy. Nevertheless, patients are exposed to a residual risk of adverse events, and the exploration of new molecular pathways and therapeutic targets is required. This review explores the current landscape of WHF, highlighting the complexities and factors contributing to this critical condition. Most recent medical advances have introduced cutting-edge pharmacological agents, such as guanylate cyclase stimulators and myosin activators. Regarding device-based therapies, invasive pulmonary pressure measurement and cardiac contractility modulation have emerged as promising tools to increase the quality of life and reduce hospitalizations due to HF exacerbations. Recent innovations in terms of WHF management emphasize the need for a multifaceted and patient-centric approach to address the complex HF syndrome.

Neurological worsening in Wilson disease - clinical classification and outcome.

BACKGROUND & AIMS: Prevention of neurological worsening (NW) under therapy is an unmet need in the management of Wilson disease (WD). In this study, we aimed to characterize the occurrence, associated outcomes and potential reversibility of NW in WD. METHODS: From a total cohort of 457 patients with WD, 128 patients with WD and neurological features at any time point (all Caucasian, 63 females, median age at diagnosis 22 years) were identified by chart review at University Hospital Heidelberg and grouped according to initial presentation. The timing and occurrence of NW was assessed following a structured clinical examination during clinical visits. RESULTS: Early NW (within the first 3 months of therapy) was observed in 30 out of 115 (26.1%) patients with neurological or mixed presentation and never in patients with a purely hepatic or asymptomatic presentation (0%). Late NW (after >12 months) was seen in a further 23 (20%) with neurological or mixed presentation and in 13 out of 294 (4.4%) patients with a hepatic or asymptomatic presentation. The median time from start of treatment to late NW was 20 months. Only three patients experienced NW between 3 and 12 months. NW was observed with D-penicillamine, trientine and zinc therapy and was reversible in 15/30 (50%) with early NW and in 29/36 (81%) with late NW. CONCLUSIONS: In this study, we identified two peaks in NW: an early (≤3 months) treatment-associated peak and a late (>12 months of treatment) adherence-associated peak. Early paradoxical NW was attributed to treatment initiation and pre-existing neurological damage, and was not observed in those with a hepatic or asymptomatic presentation. Late NW is likely to be associated with non-adherence. IMPACT AND IMPLICATIONS: In patients with Wilson disease, defined as an excess accumulation of copper which can damage the liver, brain and other vital organs, neurological worsening can occur despite chelation therapy. The study identifies different patterns of 'early' (<3 months) vs. 'late' (>12 months) neurological worsening in relation to initiation of chelation therapy and establishes possible causes and the potential for reversibility. These data should be useful for counseling patients and for guiding the optimal management of chelation therapy.

Uplifts and hassles are related to worsening in chronic fatigue syndrome: a prospective study.

BACKGROUND: Limited published data suggests that absence of uplifts (minor pleasant events) is associated with clinical worsening in patients with chronic fatigue syndrome (CFS). The current study aimed to assess the relation of illness worsening to the trajectories of social and non-social uplifts and hassles in a six-month prospective study in CFS. METHODS: Participants were primarily in their 40s, female, white, and ill for over a decade. All participants (N = 128) met criteria for CFS. The interview-based global impression of change rating was used to classify individual outcomes as improved, unchanged, or worsened at six- month follow-up. Uplifts and hassles, both social and non-social, were assessed with the Combined Hassles and Uplifts Scale (CHUS). The CHUS was administered weekly in online diaries over six months. Linear mixed effect models were utilized to examine linear trends for hassles and uplifts. RESULTS: No significant differences were found between the three global outcome groups for age, sex, or illness duration; however, work status was significantly lower for the non-improved groups (p < 0.001). Non-social hassles intensity showed an increasing slope for the worsened group (p = 0.03) and a decreasing slope (p = 0.05) for the improved group. For the worsened group, a downward trend was found for frequency of non-social (p = 0.01) uplifts. CONCLUSION: Individuals with worsening as compared to improving illness in CFS show significantly different six-month trajectories for weekly hassles and a deficit in uplifts. This may have clinical implications for behavioral intervention. Trial registration ClinicalTrials.gov ID: NCT02948556.

Long-term Visit-to-Visit Variability in Hemoglobin A1c and Kidney-Related Outcomes in Persons With Diabetes.

RATIONALE & OBJECTIVE: To characterize associations between long-term visit-to-visit variability of hemoglobin A1c (HbA1c) and risk of adverse kidney outcomes in patients with diabetes. STUDY DESIGN: Observational study. SETTING & PARTICIPANTS: 93,598 adults with diabetes undergoing routine care in Stockholm, Sweden. EXPOSURES AND PREDICTORS: Categories of baseline and time-varying HbA1c variability score (HVS, the percentage of total HbA1c measures that vary by>0.5% [5.5mmol/mol] during a 3-year window): 0-20%, 21%-40%, 41%-60%, 61%-80%, and 81%-100%, with 0-20% as the reference group. OUTCOME: Chronic kidney disease (CKD) progression (composite of>50% estimated glomerular filtration rate [eGFR] decline and kidney failure), acute kidney disease (AKI by clinical diagnosis or transient creatinine elevations according to KDIGO criteria), and worsening of albuminuria. ANALYTICAL APPROACH: Multivariable Cox proportional hazards regression. RESULTS: Compared with persons showing low HbA1c variability (HVS 0-20%), any increase in variability was associated with a higher risk of adverse kidney outcomes beyond mean HbA1c. For example, for patients with a baseline HbA1c variability of 81%-100%, the adjusted HR was 1.6 (95% CI, 1.47-1.74) for CKD progression, 1.23 [1.16-1.3] for AKI, and 1.28 [1.21-1.36] for worsening of albuminuria. The results were consistent across subgroups (diabetes subtypes, baseline eGFR, or albuminuria categories), in time-varying analyses and in sensitivity analyses including time-weighted average HbA1c or alternative metrics of variability. LIMITATIONS: Observational study, limitations of claims data, lack of information on diet, body mass index, medication changes, and diabetes duration. CONCLUSIONS: Higher long-term visit-to-visit HbA1c variability is consistently associated with the risks of CKD progression, AKI, and worsening of albuminuria. PLAIN-LANGUAGE SUMMARY: The evidence for current guideline recommendations derives from clinical trials that focus on a single HbA1c as the definitive measure of efficacy of an intervention. However, long-term visit-to-visit fluctuations of HbA1c may provide additional value in the prediction of future kidney complications. We evaluated the long-term fluctuations in glycemic control in almost 100,000 persons with diabetes undergoing routine care in Stockholm, Sweden. We observed that higher long-term HbA1c fluctuation is consistently associated with the risks of chronic kidney disease progression, worsening of albuminuria and acute kidney injury. This finding supports a role for long-term glycemic variability in the development of kidney complications and illustrates the potential usefulness of this metric for risk stratification at the bedside beyond a single HbA1c test.

Comparing the Accuracy of Peripapillary OCT Scans and Visual Fields to Detect Glaucoma Worsening.

PURPOSE: To compare the accuracy of detecting moderate and rapid rates of glaucoma worsening over a 2-year period with different numbers of OCT scans and visual field (VF) tests in a large sample of glaucoma and glaucoma suspect eyes. DESIGN: Descriptive and simulation study. PARTICIPANTS: The OCT sample comprised 12 150 eyes from 7392 adults with glaucoma or glaucoma suspect status followed up at the Wilmer Eye Institute from 2013 through 2021. The VF sample comprised 20 583 eyes from 10 958 adults from the same database. All eyes had undergone at least 5 measurements over follow-up from the Zeiss Cirrus OCT or Humphrey Field Analyzer. METHODS: Within-eye rates of change in retinal nerve fiber layer (RNFL) thickness and mean deviation (MD) were measured using linear regression. For each measured rate, simulated measurements of RNFL thickness and MD were generated using the distributions of residuals. Simulated rates of change for different numbers of OCT scans and VF tests over a 2-year period were used to estimate the accuracy of detecting moderate (75th percentile) and rapid (90th percentile) worsening for OCT and VF. Accuracy was defined as the percentage of simulated eyes in which the true rate of worsening (the rate without measurement error) was at or less than a criterion rate (e.g., 75th or 90th percentile). MAIN OUTCOME MEASURES: The accuracy of diagnosing moderate and rapid rates of glaucoma worsening for different numbers of OCT scans and VF tests over a 2-year period. RESULTS: Accuracy was less than 50% for both OCT and VF when diagnosing worsening after a 2-year period. OCT accuracy was 5 to 10 percentage points higher than VF accuracy at detecting moderate worsening and 10 to 15 percentage points higher for rapid worsening. Accuracy increased by more than 17 percentage points when using both OCT and VF to detect worsening, that is, when relying on either OCT or VF to be accurate. CONCLUSIONS: More frequent OCT scans and VF tests are needed to improve the accuracy of diagnosing glaucoma worsening. Accuracy greatly increases when relying on both OCT and VF to detect worsening. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Practical Patient Care Considerations With Use of Vericiguat After Worsening Heart Failure Events.

Vericiguat is a soluble guanylate cyclase stimulator approved by multiple global regulatory bodies and recommended in recently updated clinical practice guidelines to reduce morbidity and mortality in patients with worsening chronic heart failure (HF) with reduced ejection fraction (HFrEF). Despite the growing armaments of evidence-based medical therapy for HFrEF that have demonstrated clinical outcome benefits, there is a need to address residual risk following worsening HF events. When considering therapies aimed to mitigate postevent cardiovascular risk, potential barriers preventing the prescription of vericiguat in eligible patients may include providers' lack of familiarity with it, clinical inertia, limited knowledge about monitoring response to therapy, and concerns about potential adverse effects as well as integration of its routine use during an era of in-person and telehealth hybrid ambulatory care. This review provides an overview of vericiguat therapy and proposes an evidence-based and practical guidance strategy toward implementing its use in various clinical settings. This review additionally summarizes patient counseling points for its initiation and maintenance.

Association Between Participation in a Heart Failure Telemonitoring Program and Health Care Utilization and Death Within an Integrated Health Care Delivery System.

BACKGROUND: The clinical usefulness of remote telemonitoring to reduce postdischarge health care use and death in adults with heart failure (HF) remains controversial. METHODS AND RESULTS: Within a large integrated health care delivery system, we matched patients enrolled in a postdischarge telemonitoring intervention from 2015 to 2019 to patients not receiving telemonitoring at up to a 1:4 ratio on age, sex, and calipers of a propensity score. Primary outcomes were readmissions for worsening HF and all-cause death within 30, 90, and 365 days of the index discharge; secondary outcomes were all-cause readmissions and any outpatient diuretic dose adjustments. We matched 726 patients receiving telemonitoring to 1985 controls not receiving telemonitoring, with a mean age of 75 ± 11 years and 45% female. Patients receiving telemonitoring did not have a significant reduction in worsening HF hospitalizations (adjusted rate ratio [aRR] 0.95, 95% confidence interval [CI] 0.68-1.33), all-cause death (adjusted hazard ratio 0.60, 95% CI 0.33-1.08), or all-cause hospitalization (aRR 0.82, 95% CI 0.65-1.05) at 30 days, but did have an increase in outpatient diuretic dose adjustments (aRR 1.84, 95% CI 1.44-2.36). All associations were similar at 90 and 365 days postdischarge. CONCLUSIONS: A postdischarge HF telemonitoring intervention was associated with more diuretic dose adjustments but was not significantly associated with HF-related morbidity and mortality.

Association of Prolonged Nocturnal Hypoxemia with Clinical Worsening in Patients with Chronic Thromboembolic Pulmonary Hypertension Undergoing Pulmonary Endarterectomy.

Background: Obstructive sleep apnea (OSA) is common in patients with chronic thromboembolic pulmonary hypertension (CTEPH), but the pathological determinants of adverse outcomes remain unknown. This study aimed to investigate the prognostic significance of various sleep parameters in patients with CTEPH undergoing pulmonary endarterectomy. Methods: Consecutive patients diagnosed with CTEPH who underwent overnight cardiorespiratory polygraphy for the assessment of OSA were enrolled. Time-to-event analysis was performed investigating cardiorespiratory indices (e.g., apnea-hypopnea index [AHI], time percentage with oxygen saturation below < 90% [T90]) and clinical worsening using the log-rank test, and multivariable Cox proportional hazard models adjusted for multiple confounders. Results: Of the 71 patients with operable CTEPH who underwent overnight cardiorespiratory polygraphy, 36 (50.7%) had OSA (AHI of ≥ 5) and 32 (45.1%) had nocturnal hypoxemia (T90 of ≥ 30%). A 10% increase in T90 was associated with a 27% greater risk of worse hemodynamics, as quantified by mean pulmonary artery pressure of ≥ 46 mmHg (odds ratio: 1.27, 95% confidence interval [CI]: 1.07-1.50, p = 0.006). Clinical worsening (CW) was experienced by 19 (26.8%) patients over a median follow-up of 26.8 months. AHI did not predict a higher risk of CW (hazard ratio [HR]: 1.00, 95% CI: 0.93-1.06, p = 0.906). A higher cumulative incidence of CW was seen in patients with nocturnal hypoxemia than in those with normoxemia (43.8% vs. 12.8%, log-rank p = 0.017). Cox regression analysis revealed the association between nocturnal hypoxemia and an increased risk of CW (HR: 3.27, 95% CI: 1.17-9.13, p = 0.024), and these associations persisted after covariate adjustment. Conclusions: Nocturnal hypoxemia quantified by T90 was a risk predictor of short- and long-term CW events among patients with operable CTEPH.

Diabetes-associated thigh muscle degeneration mediates knee osteoarthritis-related outcomes: results from a longitudinal cohort study.

OBJECTIVES: We examined the association between diabetes mellitus (DM) and longitudinal MRI biomarkers for thigh muscle degeneration in patients with knee osteoarthritis (KOA) and their mediatory role in worsening KOA-related symptoms. METHODS: The Osteoarthritis Initiative (OAI) participants with radiographic KOA (Kellgren-Lawrence grade ≥ 2) were included. Thighs and corresponding knees of KOA patients with versus without self-reported DM were matched for potential confounders using propensity score (PS) matching. We developed and used a validated deep learning method for longitudinal thigh segmentation. We assessed the association of DM with 4-year longitudinal muscle degeneration in biomarkers of muscle cross-sectional area (CSA) and contractile percentage (non-fat CSA/total CSA). We further investigated whether DM is associated with 9-year risk of KOA radiographic progression, knee replacement (KR), and symptoms worsening. Finally, we evaluated whether the DM-KOA worsening association is mediated through preceding muscle degeneration. RESULTS: After PS matching, 698 thighs/knees were included (185:513 with:without DM; average ± SD age:64 ± 8-years; female/male:1.4). Baseline DM was associated with a decreased contractile percent of total thigh muscles and quadriceps (mean difference, 95%CI -0.16%/year, -0.25 to -0.07, and -0.21%/year, -0.33 to -0.08). DM was also associated with an increased risk of worsening KOA-related symptoms (hazard ratio, 95%CI 1.70, 1.18-2.46) but not radiographic progression or KR. The decrease in quadriceps contractile percent partially mediated the increased risk of symptoms worsening in patients with DM. CONCLUSIONS: Baseline DM is associated with thigh muscle degeneration and KOA-related symptoms worsening. As a potentially modifiable risk factor, DM-associated longitudinal thigh muscle degeneration may partially mediate the symptoms worsening in patients with DM and coexisting KOA. KEY POINTS: • Diabetes mellitus (DM) is associated with worsening knee osteoarthritis (KOA)-related symptoms. • As a potentially modifiable factor, DM-associated thigh muscle (quadriceps) degeneration partially mediates the worsening of KOA-related symptoms.