Cremer, Paul

Abstract Background Recurrent pericarditis (RP) is a chronic autoinflammatory disease mediated by IL-1 that requires long-term treatment. While the 2015 European Society of Cardiology Guidelines position IL-1 pathway inhibition only after corticosteroids, complications associated with long-term steroid use underscore the importance of steroid-sparing strategies. Rilonacept, an IL-1α and IL-1β cytokine trap, is the only FDA-approved treatment for RP (available since April 2021). RESONANCE, an ongoing 5-year non-interventional US registry of patients (pts) with RP, has collected real-world data from pts cared for by cardiologists with a focus on pericardial disease, with a goal of informing contemporary RP clinical management. Purpose Analysis of temporal trends in RP management from RESONANCE. Methods From a database cut-off (DCO) on 21 December 2023, patient demographics and disease characteristics are reported for 242 active RP pts (excluding RHAPSODY prior participants) at 20 US sites (median [Q1:Q3] 2.1 [1.5:2.6] years and 556 patient-years [PY] of observation). Complete medication class use data were available for 239 pts (total 546 PY). Proportional medication class use prior to initiating rilonacept was analyzed annually across the observation period. Results Mean (standard deviation) age at DCO was 50.2 (16.6) years; 58.1% were female. Median [Q1:Q3] disease duration at DCO from index pericarditis episode was 3.1 [2.2:5] years. Median [Q1:Q3] number of prior recurrences at enrollment was 3 [2:5]. Prior to rilonacept availability, NSAIDs/Colchicine/Aspirin represented the highest proportion of treatment (73% of PY); steroid use was 9% of PY, IL-1 pathway inhibition (anakinra) was 13% of PY, and conventional synthetic disease modifying antirheumatic drugs (csDMARDs) were 0.46% PY (no RP-specific treatment was 5% of PY) (Fig 1). In the years since rilonacept availability, proportional IL-1 pathway inhibition use has increased, from 13% of PY in 2020-21 to 26% of PY in 2023, driven by an increase in rilonacept use (6%, 13%, 16% of PY in 2021, 2022, and 2023, respectively). Over that same period, proportional NSAIDs/Colchicine/Aspirin use (57%-63% of PY) has been consistently 6-times more than proportional steroid use (10%-11% of PY). Among pts who initiated rilonacept (n=81), similar proportions transitioned from NSAIDs/Colchicine/Aspirin as from corticosteroids (Fig 2), a robust trend observed each year. Of those pts transitioning from corticosteroids, 1/3 had used corticosteroids for <30 days and 1/3 for >6 months. Conclusions Real-world data from the RESONANCE registry reveal a temporal shift in RP management in US centers with RP-focused cardiologists, with increased proportional IL-1 pathway inhibition use since rilonacept availability in 2021. Advancing beyond 2015 guideline recommendations, IL-1 pathway inhibition is often being used as steroid-sparing treatment, i.e., after colchicine instead of chronic corticosteroids.

Abstract Background In severely symptomatic patients with obstructive hypertrophic cardiomyopathy (HCM), the VALOR-HCM phase 3 randomized, double-blind, placebo-controlled clinical trial demonstrated that mavacamten, a cardiac myosin inhibitor, reduces the eligibility for septal reduction therapy with sustained improvement in left ventricular (LV) outflow tract gradients and symptoms. Mavacamten also resulted in favorable cardiac remodeling, including improvement in left atrial volume index (LAVI), LV diastolic function, and biomarkers (NT-proBNP and troponin T). However, the impact of mavacamten on LA function is not known. Objective We sought to assess serial changes in LA strain measures in patients enrolled in the VALOR-HCM trial. Methods VALOR-HCM included 112 symptomatic obstructive HCM patients (mean age 60 years, 51% male). Patients assigned to mavacamten at baseline (n=56) continued therapy for 56 weeks and those assigned to placebo crossed over to mavacamten (n=52) from week 16-56 (40-week exposure). Echocardiographic LA strain assessment was performed according to the current American and European guideline recommendations, using a vendor-neutral post processing software. For assessment of LA strain components (reservoir, conduit, and contraction), the non-foreshortened apical 4-chamber view was utilized. The zero reference was set at end-diastole. Results Serial changes in LAVI and all components of mean LA strain from baseline to week 56 are shown in the Figure. At baseline, LAVI and all mean LA strain values were worse than reported normal mean thresholds. There was a continued and significant improvement in all 3 LA strain values, from baseline to week 56, along with a significant reduction in LAVI. Improvement in LAVI was seen earlier than improvements in LA strain. There was a significant inverse correlation between change in mean LAVI and LA reservoir strain from baseline to week 56 (r= -0.42, p<0.001). Conclusions In the VALOR-HCM trial, average LAVI and baseline LA strain values were significantly worse than reported normal thresholds. Treatment with mavacamten resulted in an improvement in LAVI and LA strain values from baseline through week 56 suggesting a sustained favorable impact on cardiac remodeling. The advantageous cardiac remodeling associated with long-term treatment with mavacamten may in turn have a favorable impact on the observed high burden of atrial tachyarrhythmias in HCM.Serial changes in LA strain in VALOR-HCM

BACKGROUND: In severely symptomatic patients with obstructive hypertrophic cardiomyopathy, VALOR-HCM (A Study to Evaluate Mavacamten in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy Who Are Eligible for Septal Reduction Therapy) demonstrated that mavacamten reduces the need for septal reduction therapy with sustained improvement in left ventricular (LV) outflow tract gradients and symptoms. Global longitudinal strain (GLS), a measure of regional myocardial function, is a more sensitive marker of systolic function. In VALOR-HCM, we assessed serial changes in LV and right ventricular (RV) strain. METHODS: VALOR-HCM included 112 patients with symptomatic obstructive hypertrophic cardiomyopathy (mean, 60 years; 51% male; LV ejection fraction, 68%). Patients assigned to mavacamten at baseline continued the drug for 56 weeks (n=56) and those assigned to placebo (n=52) transitioned to mavacamten from weeks 16 to 56 (40-week exposure). LV-GLS and RV-GLS assessment was performed using a vendor-neutral software. Non-foreshortened apical (4-, 3-, and 2-chamber) views were used to obtain peak LV-GLS. RV focused 4-chamber view was used to calculate RV 4-chamber and free wall strain. A more negative strain value is favorable. RESULTS: At baseline, the mean LV-GLS, RV 4-chamber, and free wall strain values were −14.7%, −22.2%, and −16.8%, respectively (all worse than reported normal means). In the total study sample, LV-GLS significantly improved from baseline to week 56 ( P =0.02). Twelve patients had transient reduction in LV ejection fraction (<50%) requiring temporary drug interruption (including 3 permanent discontinuations). The LV-GLS in this subgroup was worse at baseline versus total study population (−11.4%), with no significant worsening from baseline through week 56 ( P =0.64). Both free wall and 4-chamber RV-GLS remained unchanged from baseline to week 56 ( P =0.62 and P =0.56, respectively). CONCLUSIONS: In VALOR-HCM, treatment with mavacamten improved LV-GLS from baseline through week 56 (with no significant worsening of LV-GLS in patients with a reduction in LV ejection fraction ≤50%), suggesting a favorable long-term impact on regional LV systolic function. Additionally, there was no detrimental impact on RV systolic function. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04349072.

Abstract Aims In the Phase 3 trial, RHAPSODY, rilonacept effectively resolved active pericarditis recurrences, and long-term treatment led to sustained pericarditis recurrence risk reduction. Prior analysis suggested association between higher late gadolinium enhancement (LGE) at baseline and more rapid recurrence upon rilonacept suspension after 12 weeks of treatment. This subgroup analysis assessed the utility of longitudinal serial cardiac magnetic resonance (CMR) imaging for tracking clinical improvement and predicting post-treatment cessation outcomes to help guide clinical decision-making. Methods and results At an 18-month decision milestone (18MDM) in the RHAPSODY long-term extension, investigators decided if patients would continue rilonacept, suspend rilonacept for off-treatment observation, or discontinue the study. Pericardial thickness, pericardial oedema (T2-short tau inversion recovery, T2-STIR), and LGE were determined at baseline and 18MDM by an imaging core lab blinded to clinical data, and pericarditis recurrence was investigator-assessed. CMR results in patients with data at both baseline and 18MDM (n = 13) showed that pericardial thickness, T2-STIR, and LGE were reduced during rilonacept treatment. Among patients with CMR data who suspended rilonacept at the 18MDM (n = 7), five (71%) had a pericarditis recurrence within 1–4 months of rilonacept suspension, despite all having had none/trace LGE (n = 7) and negative T2-STIR (n = 7) at the 18MDM and two having received prophylactic colchicine. Conclusion Continued clinical improvement during prolonged rilonacept treatment corresponded with improvement on CMR, including reduced pericardial thickness, resolution of pericardial oedema, and resolution of LGE. However, none/trace LGE at 18MDM while on treatment did not predict absence of pericarditis recurrence upon subsequent rilonacept suspension in this size-limited subgroup.

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.

Introduction: The performance of automated left ventricular ejection fraction (LVEF) assessment in patients with altered cardiac chamber geometry, such as those with obstructive hypertrophic cardiomyopathy (HCM), is not well described. Aims: Accurate assessment of LVEF is required for dose titration and continuation of myosin inhibitors in obstructive HCM. From the VALOR-HCM trial (NCT04349072), the agreement of two commercially available software packages was compared with blinded core lab assessment of LVEF. Methods: From baseline and week 16, among 112 patients randomized to either mavacamten or placebo, 178 echocardiograms were analyzed. Representative clips were manually selected, and automated LVEFs were calculated. Comparisons of LVEFs were made using Pearson’s correlation coefficients and Bland-Altman analysis. Results: With core lab assessment, the overall median LVEF was 68% (Q1 66%, Q3 70%). The correlation with vendor 1 was moderate (r = 0.47, 95% CI 0.35-0.58, p <0.001) and weak with vendor 2 (r =0.21, 95% CI 0.07-0.35, p =0.004). Correlation was also weak between vendor 1 and 2 (r = 0.14, 95% CI 0.00-0.28, p = 0.06). Vendors 1 and 2 had an underestimation bias of LVEF of 8% (95% CI 6-9%) and 8% (95% CI 7-9%), respectively, compared to core lab LVEF (Figure 1). Conclusions: In VALOR-HCM, the concordance of LVEF between different commercially available software packages with each other and with a core lab assessment was limited. Further study is needed to evaluate and improve the performance of automated LVEF tools in obstructive HCM patients who have altered cardiac chamber geometry.

Introduction: Rilonacept treatment in RHAPSODY resolved active pericarditis recurrences, and long-term treatment led to sustained risk reduction. Prior analysis linked greater baseline Late Gadolinium Enhancement (LGE), with more rapid recurrence upon rilonacept suspension after 12 weeks of treatment. Serial cardiac magnetic resonance (CMR) imaging (T2-STIR, LGE) enabled longitudinal assessment for tracking clinical improvement, guiding decision-making, and predicting patient outcomes after treatment cessation. Methods: At the long-term extension (LTE) 18-month decision milestone (18MDM), investigators chose, based on clinical status, to continue rilonacept, suspend rilonacept/observe, or discontinue the LTE. An imaging core lab blinded to clinical data measured pericardial thickness and graded pericardial edema (T2-STIR) and LGE at baseline and 18MDM. Pericarditis recurrence was assessed clinically following rilonacept suspension. Results: Baseline and 18MDM CMRs were available for 13 patients. Reductions in pericardial thickness, T2-STIR, and LGE from baseline to 18MDM while on treatment are provided in Figure . CMRs were obtained in 7/8 patients suspending rilonacept at 18MDM: LGE was none/trace, and T2-STIR was negative; yet, 5/7 (71%) had pericarditis recurrence within 1-4 months of rilonacept suspension despite prophylactic colchicine (n=2). Conclusions: Continued clinical improvement during prolonged rilonacept treatment corresponded with improvement on CMR, including reduced pericardial thickness, resolution of pericardial edema on T2-STIR, and resolution of LGE. Negative/trace LGE at 18MDM while on treatment did not predict absence of pericarditis recurrence upon subsequent rilonacept suspension in this size-limited subgroup. Larger prospective studies examining CMR parameters in guiding RP treatment duration decisions and informing associated clinical outcomes are warranted.

Importance There is an unmet need for novel medical therapies before recommending invasive therapies for patients with severely symptomatic obstructive hypertrophic cardiomyopathy (HCM). Mavacamten has been shown to improve left ventricular outflow tract (LVOT) gradient and symptoms and may thus reduce the short-term need for septal reduction therapy (SRT). Objective To examine the cumulative longer-term effect of mavacamten on the need for SRT through week 56. Design, Setting, and Participants This was a double-blind, placebo-controlled, multicenter, randomized clinical trial with placebo crossover at 16 weeks, conducted from July 2020 to November 2022. Participants were recruited from 19 US HCM centers. Included in the trial were patients with obstructive HCM (New York Heart Association class III/IV) referred for SRT. Study data were analyzed April to August 2023. Interventions Patients initially assigned to mavacamten at baseline continued the drug for 56 weeks, and patients taking placebo crossed over to mavacamten from week 16 to week 56 (40-week exposure). Dose titrations were performed using echocardiographic LVOT gradient and LV ejection fraction (LVEF) measurements. Main Outcome and Measure Proportion of patients undergoing SRT, remaining guideline eligible or unevaluable SRT status at week 56. Results Of 112 patients with highly symptomatic obstructive HCM, 108 (mean [SD] age, 60.3 [12.5] years; 54 male [50.0%]) qualified for the week 56 evaluation. At week 56, 5 of 56 patients (8.9%) in the original mavacamten group (3 underwent SRT, 1 was SRT eligible, and 1 was not SRT evaluable) and 10 of 52 patients (19.2%) in the placebo crossover group (3 underwent SRT, 4 were SRT eligible, and 3 were not SRT evaluable) met the composite end point. A total of 96 of 108 patients (89%) continued mavacamten long term. Between the mavacamten and placebo-to-mavacamten groups, respectively, after 56 weeks, there was a sustained reduction in resting (mean difference, −34.0 mm Hg; 95% CI, −43.5 to −24.5 mm Hg and −33.2 mm Hg; 95% CI, −41.9 to −24.5 mm Hg) and Valsalva (mean difference, −45.6 mm Hg; 95% CI, −56.5 to −34.6 mm Hg and −54.6 mm Hg; 95% CI, −66.0 to −43.3 mm Hg) LVOT gradients. Similarly, there was an improvement in NYHA class of 1 or higher in 51 of 55 patients (93%) in the original mavacamten group and in 37 of 51 patients (73%) in the placebo crossover group. Overall, 12 of 108 patients (11.1%; 95% CI, 5.87%-18.60%), which represents 7 of 56 patients (12.5%) in the original mavacamten group and 5 of 52 patients (9.6%) in the placebo crossover group, had an LVEF less than 50% (2 with LVEF ≤30%, one of whom died), and 9 of 12 patients (75%) continued treatment. Conclusions and Relevance Results of this randomized clinical trial showed that in patients with symptomatic obstructive HCM, mavacamten reduced the need for SRT at week 56, with sustained improvements in LVOT gradients and symptoms. Although this represents a useful therapeutic option, given the potential risk of LV systolic dysfunction, there is a continued need for close monitoring. Trial Registration ClinicalTrials.gov Identifier: NCT04349072

Introduction: In the randomized VALOR-HCM study of symptomatic patients with obstructive hypertrophic cardiomyopathy (oHCM), mavacamten reduced the need for septal reduction therapy at 16 weeks. The current sub-study sought to assess the impact of mavacamten on systolic anterior motion (SAM) of the mitral valve and associated mitral regurgitation (MR). Methods: Patients on maximally-tolerated medical therapy referred for septal reduction therapy were randomized 1:1 to mavacamten or placebo. Echocardiographic assessment was performed by an independent, blinded core laboratory. SAM was assessed as none, mild (anterior leaflet >/= 1 cm from the septum), moderate (anterior leaflets <1cm from the septum), and severe (anterior leaflet in contact with septum). MR was assessed according to ASE guidelines. Results: Among 112 enrolled patients, 23.2% (n=27) had at least moderate (2+) MR. Most (92.9%, n=104) had at least moderate resting SAM, of whom 55.4% (n = 62) had severe SAM. At 16 weeks, 53.7% of patients treated with mavacamten had at least one level improvement in resting SAM compared to 21.6% of patients treated with placebo ( p = 0.001), and 35.2% had at least a two level improvement in SAM compared with 11.8% of placebo patients ( p = 0.007)(Figure 1A). Similarly, patients treated with mavacamten had an improvement of -36.0 + 28.8 mmHg in resting left ventricular outflow tract gradient at week 16 compared to -1.5 + 26.5 mmHg with placebo (<0.001). At week 16, 48.1% of patients treated with mavacamten had at least a one grade improvement in MR, and 23.1% had at least a two grade improvement compared to 12.2% and 6.1% of patients treated with placebo ( p <0.001 and 0.025, respectively)(Figure 1B). Conclusions: In highly symptomatic patients with oHCM, treatment with mavacamten reduced resting SAM with an improvement in associated MR.

Introduction: In the randomized VALOR-HCM study of symptomatic patients with obstructive hypertrophic cardiomyopathy (oHCM), mavacamten reduced the need for septal reduction therapy at 16 weeks. Because mavacamten is a cardiac myosin inhibitor that may improve ventricular compliance, this sub-study hypothesized that mavacamten would favorably impact diastolic function. Methods: Symptomatic patients on maximally-tolerated medical therapy referred for septal reduction therapy were randomized 1:1 to mavacamten or placebo. Echocardiographic assessment was performed by an independent, blinded core laboratory. Diastolic grade was determined according to ASE guidelines. Between-group comparisons were made from baseline to week 16. Results: Among 112 enrolled patients, baseline left atrial volume index (LAVi) was similar (Table). At 16 weeks, mavacamten treatment resulted in a significant reduction in LAVi (-5.2 vs -0.5 with placebo, p = .003). Similarly, although lateral E/e’ and septal E/e’ were comparable at baseline, patients treated with mavacamten demonstrated a significant reduction at week 16 (lateral E/e’: -3.5 vs 0.7, p <0.001; septal E/e’: -3.3 vs 0.7, p < 0.001)(Table). Patients treated with mavacamten were also more likely to improve their diastolic dysfunction grade (31.4% vs 12.8%, p = 0.032) (Figure). Conclusions: After only 16 weeks of therapy, in a highly symptomatic oHCM population with echocardiographic-guided drug titration, mavacamten improved measures of diastolic function.