Absence of Pericarditis Recurrence in Rilonacept-Treated Patients With COVID-19 and SARS-CoV-2 Vaccination: Results From the RHAPSODY Long-term Extension

Background: Rilonacept inhibits the interleukin-1 pathway, and extended treatment in patients with recurrent pericarditis (RP) reduced recurrence risk by 98% in the phase 3 trial, RHAPSODY long-term extension (LTE). Severe acute respiratory syndrome (SARS)-CoV-2 vaccination and/or infection may trigger pericarditis recurrence, and in clinical practice, it is unknown whether to continue rilonacept during SARS-CoV-2 infection. This post-hoc analysis of the RHAPSODY LTE aimed to inform rilonacept management in RP patients vaccinated against SARS-CoV-2 or who contract COVID-19. Methods: Analysis was conducted from May 2020 to June 2022. The LTE portion of RHAPSODY LTE enabled up to 24 months of additional open-label rilonacept treatment beyond the pivotal study. Rilonacept efficacy data in preventing pericarditis recurrence were assessed, and concomitant SARS-CoV-2 vaccination and COVID-19 adverse event data were evaluated. Results: No pericarditis recurrences were temporally associated with vaccination. Sixteen COVID-19 cases were reported; 10 in 30 unvaccinated or partially vaccinated patients (33%) vs 6 of 44 fully vaccinated patients (14%; P = 0.04). Twelve of 16 patients (75%) were receiving rilonacept at the time of infection, and none experienced pericarditis recurrence. One pericarditis recurrence occurred in the peri-COVID-19 period in 1 of 4 patients who had stopped rilonacept treatment > 4.5 months prior. COVID-19 severity was mild in 13 patients, moderate in 2, and severe in 1. Conclusions: Full vaccination effectively reduced COVID-19 events in patients treated with rilonacept. Vaccination or COVID-19 during rilonacept treatment did not increase pericarditis recurrence. Continued rilonacept treatment in patients contracting COVID-19 did not worsen disease severity, whereas rilonacept interruption increased pericarditis recurrence, supporting a recommendation for continued rilonacept treatment for RP during vaccination or COVID-19. ClinicalTrials.gov identifier: NCT0373711

Transition to rilonacept monotherapy from oral therapies in patients with recurrent pericarditis

Objective Polypharmacy management of recurrent pericarditis (RP) often involves long-term therapies, often with negative effects. Slow tapering of oral therapies is often required to avoid recurrence. A post hoc analysis of the phase III trial Rilonacept inHibition of interleukin-1 Alpha and beta for recurrent Pericarditis: a pivotal Symptomatology and Outcomes Study (RHAPSODY) evaluated investigator approaches to transitioning to IL-1 blockade monotherapy with rilonacept, which was hypothesised to allow accelerated withdrawal of common multidrug pericarditis regimens.Methods RHAPSODY was a multicentre (Australia, Israel, Italy, USA), double-blind, placebo-controlled, randomised-withdrawal trial in adults and adolescents with RP. Investigators initiated rilonacept at the labelled dose level and discontinued oral pericarditis therapies during the 12-week run-in; randomised patients received study drug as monotherapy. Time to rilonacept monotherapy was quantified in patients receiving multidrug regimens at baseline who achieved rilonacept monotherapy during run-in.Results In 86 enrolled patients, mean time to rilonacept monotherapy was 7.9 weeks, with no recurrences. Of these, 64% (n=55) entered on multidrug regimens: non-steroidal anti-inflammatory drugs (NSAIDs) plus colchicine (44% (24/55)), colchicine plus glucocorticoids (24% (13/55)), or NSAIDs, colchicine, plus glucocorticoids (33% (18/55)). Investigators transitioned patients receiving colchicine and glucocorticoids at baseline to rilonacept monotherapy without recurrence regardless of taper approach: sequential (n=14; median, 7.7 weeks) or concurrent (n=17; median, 8.0 weeks). Median time to rilonacept monotherapy was similar regardless of glucocorticoid dose and duration: <= 15 mg/day (n=21): 7.3 weeks; >15 mg/day (n=18): 8.0 weeks; long-term (>= 28 days): 7.6 weeks.Conclusions Rapid discontinuation of oral RP therapies while transitioning to rilonacept monotherapy was feasible without triggering pericarditis recurrence

Sustained Pericarditis Recurrence Risk Reduction With Long-Term Rilonacept

BACKGROUND: Rilonacept, a once-weekly interleukin-1 alpha and beta cytokine trap, reduced pericarditis recurrence in the phase 3 study, RHAPSODY (Rilonacept Inhibition of Interleukin-1 Alpha and Beta for Recurrent Pericarditis: A Pivotal Symptomatology and Outcomes Study). The RHAPSODY long-term extension further explored recurrent pericarditis natural history and treatment duration decision-making during 24 additional months of open-label rilonacept treatment. METHODS AND RESULTS: Seventy-four patients commenced the long-term extension, with a median (maximum) total rilonacept duration of 22 (35) months. Individually, 18 months after the most proximal pericarditis recurrence, investigators decided to continue rilonacept on study, suspend rilonacept for off-treatment observation (rescue allowed), or discontinue the study. The annualized incidence of pericarditis recurrence on rilonacept up to the 18-month decision milestone was 0.04 events/patient-year versus 4.4 events/patient-year prestudy while on oral therapies. At the 18-month decision milestone, 64% (33/52) continued rilonacept, 15% (8/52) suspended rilonacept for observation, and 21% (11/52) discontinued the study. Among the 33 patients (1/33; 3.0%) continuing rilonacept (median time to recurrence could not be estimated due to too few events), a single recurrence occurred 4 weeks after a treatment interruption. Among patients suspending rilonacept, 75% (6/8) experienced recurrence (median time to recurrence, 11.8 weeks [95% CI, 3.7 weeks to not estimable]). There was a 98% reduction in risk of pericarditis recurrence among patients continuing rilonacept treatment after the 18-month decision milestone versus those suspending treatment for observation (hazard ratio, 0.02; P<0.0001). CONCLUSIONS: In the RHAPSODY long-term extension, continued rilonacept treatment resulted in continued response; treatment suspension at the 18-month decision milestone was associated with pericarditis recurrence. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03737110

New proglacial meteorology and river stage observations from Inglefield Land and Pituffik, NW Greenland

Meltwater runoff from the Greenland ice sheet (GrIS) is an important contributor to global sea level rise, but substantial uncertainty exists in its measurement and prediction. Common approaches for estimating ice sheet runoff are in situ gauging of proglacial rivers draining the ice sheet and surface mass balance (SMB) modeling. To obtain hydrological and meteorological data sets suitable for both runoff stage characterization and, pending the establishment of stage–discharge curves, SMB model evaluation, we established an automated weather station (AWS) and a cluster of traditional and experimental river stage sensors on the Minturn River, the largest proglacial river draining Inglefield Land, NW Greenland. Secondary installations measuring river stage were installed in the Fox Canyon River and North River at Pituffik Space Base, NW Greenland. Proglacial runoff at these sites is dominated by supraglacial processes only, uniquely advantaging them for SMB studies. The three installations provide rare hydrological time series and an opportunity to evaluate experimental measurements of river stage from a harsh, little-studied polar region. The installed instruments include submerged vented and non-vented pressure transducers, a bubbler sensor, experimental bank-mounted laser rangefinders, and time-lapse cameras. The first 3 years of observations (2019 to 2021) from these stations indicate (a) a meltwater runoff season from late June to late August/early September that is roughly synchronous throughout the region; (b) the early onset (∼ 23 June to 8 July) of a strong diurnal runoff signal in 2019 and 2020, suggesting minimal meltwater storage in snow and/or firn; (c) 1 d lagged air temperature that displays the strongest correlation with river stage; (d) river stage that correlates more strongly with ablation zone albedo than with net radiation; and (e) the late-summer rain-on-ice events appear to trigger the region's sharpest and largest floods. The new gauging stations provide valuable in situ hydrological observations that are freely available through the PROMICE network (https://promice.org/weather-stations/, last access: 14 September 2023).</p

Acceptability, Feasibility and Preliminary Evaluation of a Novel, Personalised, Home based Physical Activity Intervention for Chronic Heart Failure (Active-at-Home-HF)::A Pilot Study

Purpose: Less than 10% of heart failure patients in the UK participate in cardiac rehabilitation programmes. The present pilot study evaluated feasibility, acceptability and physiological effects of a novel, personalised, home-based physical activity intervention in chronic heart failure. Methods: Twenty patients (68±7 years old, 20% females) with stable chronic heart failure due to reduced left ventricular ejection fraction (31±8 %) participated in a single group, pilot study assessing the feasibility and acceptability of a 12-week personalised home-based physical activity intervention aiming to increase daily number of steps by 2000 from baseline (Active-at-Home-HF). Patients completed cardiopulmonary exercise testing with non-invasive gas exchange and haemodynamic measurements and quality of life questionnaire pre- and post-intervention. Patients were supported weekly via telephone and average weekly step count data collected using pedometers. Results: 43 patients were screened and 20 recruited into the study. Seventeen patients (85%) completed the intervention, and 15 (75%) achieved the target step count. Average step count per day increased significantly from baseline to 3 weeks by 2546 (5108±3064 to 7654±3849 P=0.03, n=17), and was maintained until week 12 (9022±3942). Following completion of the intervention, no adverse events were recorded, quality of life improved by 4 points (26±18 vs. 22±19). Peak exercise stroke volume increased by 19% (127±34 vs 151±34 m/beat, P=0.05), while cardiac index increased by 12% (6.8±1.5 vs. 7.6±2.0 L/min/m2, P=0.19). Workload and oxygen consumption at anaerobic threshold also increased by 16% (49±16 vs. 59±14 watts, P=0.01) and 10% (11.5±2.9 vs. 12.8±2.2 ml/kg/min, P=0.39). Conclusion: The Active-at-Home-HF intervention is feasible, acceptable and effective for increasing physical activity in CHF. It may lead to improvements in quality of life, exercise tolerance and haemodynamic function

Recent in vitro findings of negative inotropy of pantoprazole did not translate into clinically relevant effects on left ventricular function in healthy volunteers

Reports on cardiac problems with oral proton pump inhibitors have caused extensive safety reviews by the US Food and Drug Administration. We provide additional data on acute cardiac effects of an intravenous application. Echocardiography was performed in 18 healthy volunteers after administration of a common high-dose regimen of pantoprazole (80 mg i.v. bolus followed by 8 mg/h for 1 h) or placebo. The design included a randomized, double-blind, placebo-controlled cross-over trial. Ejection fraction (%, mean +/- A SE) in the treatment group (placebo group) was 60.7 +/- A 1.1 (61.2 +/- A 1.7) at baseline, and 62.6 +/- A 1.1 (62.1 +/- A 1.9), 64.7 +/- A 1.6 (63.5 +/- A 1.3), 62.6 +/- A 1.6 (61.0 +/- A 1.6) and 63.0 +/- A 1.4 (61.8 +/- A 1.5) at 7.5, 15, 30 and 60 min after bolus application, respectively (p = n.s.). Similarly, no significant changes were found for cardiac output, cardiac index, blood pressure and heart rate. In contrast, gastric pH that was used as a treatment control was significantly increased 60 min after the application of pantoprazole as compared to baseline and to placebo. Pantoprazole as injection is safe in healthy subjects with respect to cardiac contractile function. However, in view of recent reports of negative inotropy of the drug, further studies in heart failure patients are required