Cappelli, Francesco

Abstract Background In patients with suspected amyloid cardiomyopathy (CM) and a monoclonal protein, tissue biopsy is mandatory to exclude amyloid light-chain CM (AL-CM), the subtype requiring urgent therapy. We aimed to develop a pragmatic approach to estimate the most likely final diagnosis before biopsy. Methods We studied a multicenter cohort of adults referred for biopsy because of suspected amyloid CM. Clinical, laboratory, ECG/echocardiographic and bone-tracer scintigraphy data were collected at initial suspicion. In patients with a monoclonal protein, we derived age cut-offs overall and by carpal tunnel syndrome (CTS), defined an age-based "gray zone" (74–83 years), and evaluated risk modifiers for AL-CM and transthyretin CM (ATTR-CM). We built a points-based algorithm for "gray-zone" patients. Clinical utility was assessed using decision-curve analysis. Results Among 602 patients (median age 76 years; 81% male), 524 (87%) had a monoclonal protein. In the monoclonal-protein subgroup, ATTR-CM accounted for 49%, AL-CM for 30%, and neither ATTR- nor AL-CM for 21%. Age ≤73 years was the Youden-optimal threshold favoring AL-CM (sensitivity 66%, specificity 78%), whereas age >84 years made AL-CM unlikely (sensitivity 98%, negative predictive value 94%), defining a "gray zone" (n=261; ATTR-CM 63%, AL-CM 18%, no amyloid CM 20%). Within the gray zone, abnormal free light-chain ratio, positive urine immunofixation, proteinuria, and higher troponin T and N-terminal pro-B-type natriuretic peptide (NT-proBNP) favored AL-CM, while higher Perugini grade, male sex, greater interventricular septal thickness, and higher NT-proBNP favored ATTR-CM. Penalized models achieved cross-validated area under the curves of 0.87 (AL-CM) and 0.94 (ATTR-CM). A two-score algorithm identified small gray-zone subsets enriched for AL-CM (positive predictive value 81.5%, specificity 98%) or ATTR-CM (positive predictive value 95.2%, specificity 94%). DCA showed higher net benefit for score- and model-based strategies versus treat-all/treat-none across clinically relevant threshold probabilities, with consistent patterns across regions. Conclusions In patients with suspected amyloid CM and a monoclonal protein, age- and CTS-anchored stratification refined by a compact set of routine laboratory and imaging features provides actionable pre-biopsy probabilities and may help prioritize urgent biopsy and AL-directed work-up while definitive tissue typing is pursued.For image description, please refer to the figure legend and surrounding text.

BACKGROUND: Transthyretin amyloidosis with cardiomyopathy is a progressive, fatal disease characterized by deposition of extracellular misfolded transthyretin (TTR) in the myocardium. Eplontersen is an N-acetylgalactosamine ligand–conjugated antisense oligonucleotide targeting hepatocyte TTR messenger RNA to reduce the production of circulating TTR. METHODS: CARDIO-TTRansform is a Phase 3, randomized, double-blind, placebo-controlled trial to assess the efficacy and safety of eplontersen in transthyretin amyloidosis with cardiomyopathy. Key inclusion criteria include histological evidence of amyloid deposits or grade 2 to 3 cardiac uptake on cardiac scintigraphy in the absence of plasma cell dyscrasia, New York Heart Association class I–III, and end-diastolic interventricular septum thickness >12 millimeters. Participants were randomized 1:1 to receive eplontersen 45 mg or placebo, administered subcutaneously every 4 weeks for up to 140 weeks, followed by a 20-week post-treatment evaluation period or open-label extension. Participants received locally available standard of care, including unrestricted use of TTR stabilizers. The primary end point is a composite of cardiovascular mortality and recurrent clinical cardiovascular events through 140 weeks. Secondary end points, in order of testing hierarchy, include changes from baseline in 6-minute walk distance and Kansas City Cardiomyopathy Questionnaire overall summary score, recurrent cardiovascular events, all-cause mortality, the primary end point in the patient subgroup receiving stabilizers at baseline, and cardiovascular mortality. Echocardiography was performed in all participants, with cardiovascular magnetic resonance imaging and technetium scintigraphy in a subset. CONCLUSIONS: CARDIO-TTRansform is fully enrolled, with 1432 randomized participants who were dosed with study drug or placebo. As the largest transthyretin amyloidosis with cardiomyopathy study to date, it will evaluate whether eplontersen improves cardiovascular outcomes in patients receiving locally available standard of care, including TTR stabilizers. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04136171. URL: http://ClinicalTrialsRegister.eu ; Unique identifier: EudraCT number 2019-002835-27.

Abstract Background The clinical efficacy of tafamidis in patients with transthyretin amyloid cardiomyopathy (ATTR-CM) was demonstrated during the phase 3, multinational, randomised, placebo-controlled Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT).(1) In ATTR-ACT, the risk of any cardiovascular (CV)-related hospitalisation was significantly reduced among patients who received tafamidis meglumine 80 mg (the approved dose) vs placebo (relative risk ratio 0.70 [95% CI 0.57, 0.85]; P=0.0005).(2) The benefit of tafamidis treatment was largest among patients with New York Heart Association (NYHA) class I/II vs III symptoms at baseline.(1,3,4) Purpose ATTR-CM is a progressive disease with a natural history that typically includes an increasing frequency of CV-related hospitalisation as the condition worsens. This post hoc analysis adds to current knowledge by evaluating the risk of recurrent (≥1) CV-related hospitalisation by baseline NYHA class in ATTR-ACT patients taking the approved dose of tafamidis or placebo. Methods Patients aged 18 to 90 years with biopsy-confirmed wild-type or variant ATTR-CM and NYHA class I-III symptoms took part in ATTR-ACT between 2013 and 2018. During the trial, the cause of hospitalisation was adjudicated by an independent committee. The hazard ratio (HR) for first CV-related hospitalisation was calculated using a Cox proportional hazards model. The HR for recurrent CV-related hospitalisation was calculated using the Liu-Wei-Yang-Ying (LWYY; also known as the modified Anderson-Gill) model. Models compared tafamidis meglumine 80 mg vs placebo and adjusted for transthyretin genotype (wild-type or variant). In the overall population, the LWYY model was also adjusted for baseline NYHA class. Results The frequency of adjudicated CV-related hospitalisations during ATTR-ACT by NYHA class are shown in the Figure. Across patients who were NYHA class I-III at baseline, the risk of recurrent CV-related hospitalisation was 37% lower in those who received tafamidis vs placebo treatment (HR 0.627 [95% CI 0.463, 0.848]; P=0.0025; Table). Among those who were NYHA class I/II at baseline, a lower proportion of tafamidis- vs placebo-treated patients (44% vs 61%) had ≥1 CV-related hospitalisation. The risks of first and recurrent CV-related hospitalisation were 40% (HR 0.601 [95% CI 0.420, 0.861]; P=0.0055) and 55% (HR 0.449 [95% CI 0.305, 0.661]; P<0.0001) lower with tafamidis vs placebo treatment. Consistent with the survivor bias previously observed in ATTR-ACT,(1-4) the risk of recurrent CV-related hospitalisation was statistically similar in tafamidis- and placebo-treated patients who were NYHA class III at baseline (HR 1.113 [95% CI 0.688, 1.799]; P=0.6624). Conclusions Building on previous findings, this analysis found the risk of recurrent CV-related hospitalisation to be reduced by tafamidis meglumine 80 mg treatment in patients with early stage ATTR-CM.

Background Transthyretin amyloid cardiomyopathy (ATTR‐CM) has a specific pathophysiology, with myocardial stiffening and systolic dysfunction only in advanced stages. We aimed to investigate the response to cardiac resynchronization therapy (CRT) in ATTR‐CM compared with heart failure. Methods In this multicenter, observational study, patients with ATTR‐CM receiving CRT (n=101) were matched to patients without amyloid cardiomyopathy by sex, age, and implantation type (CRT with versus without defibrillator versus conduction system pacing, upgrade versus first implant). We evaluated changes in QRS duration and echocardiographic parameters following CRT implantation and at the most recent available assessments. The study end points were all‐cause death alone or combined with heart failure hospitalization. Results Patients with ATTR‐CM (median age, 76 [interquartile range, 72–83] years, 98% men, left ventricular (LV) ejection fraction 30% [26–33]) showed greater QRS shortening after CRT implantation ( P =0.012), but not after a median of around 1 year ( P =0.152). There were no significant differences in the absolute LV ejection fraction changes immediately after implantation (+7 [+2/+10] versus +3 [0/+9] units; P =0.124), or to the last echo ( P =0.796), which was performed after 1.3 years in patients with ATTR‐CM and 2.9 years in patients without amyloid cardiomyopathy. Patients with ATTR‐CM had a shorter survival than controls ( P <0.001 for both end points). Patients with ATTR‐CM experiencing an early improvement in LV ejection fraction had a longer survival (log‐rank, 4.3; P =0.038). Conclusions Following CRT implantation, patients with ATTR‐CM show QRS narrowing and improvement in LV ejection fraction, not different from patients without amyloid cardiomyopathy. Early favorable LV remodeling seems to be associated with a lower risk of all‐cause death.

Background: Atrial fibrillation (AF) significantly impacts quality of life (QoL) and is often observed in patients with transthyretin amyloid cardiomyopathy (ATTR-CM). Acoramidis achieves near-complete (≥90%) transthyretin (TTR) stabilization and is approved in the USA, the UK, Europe and Japan for the treatment of ATTR-CM in adults. In the phase 3 ATTRibute-CM study (NCT03860935), acoramidis treatment significantly reduced the time to all-cause mortality (ACM) or first cardiovascular-related hospitalization (CVH) at Month 30, and resulted in improved 6-minute walk distance (6MWD), Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS) scores and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels relative to placebo. The clinical efficacy of acoramidis has not yet been reported in patients with ATTR-CM and with an AF or atrial flutter (AFL) diagnosis at baseline. Research Question: How does acoramidis treatment affect ACM or first CVH, 6MWD, KCCQ-OS scores, and NT-proBNP levels at Month 30 in participants with ATTR-CM with or without AF/AFL diagnosis at baseline? Methods: The ATTRibute-CM study design has been previously published. This post hoc analysis included participants in the modified intention-to-treat population (N=611) grouped by AF/AFL diagnosis at baseline (defined as recorded AF medical history or the presence of AF or AFL on an ECG at enrollment). The rate of ACM or first CVH at Month 30 was compared between groups using a stratified Cox proportional hazards model. Changes from baseline to Month 30 in 6MWD, KCCQ-OS scores and NT-proBNP levels were summarized descriptively. Results: Overall, 62.8% (384/611) of participants had an AF/AFL diagnosis at baseline (acoramidis: 255/409, placebo: 129/202). These participants had lower mean 6MWD and KCCQ-OS scores and higher median NT-proBNP levels than those without AF/AFL diagnosis at baseline. Treatment with acoramidis reduced ACM or first CVH, slowed the decline in 6MWD and KCCQ-OS scores and blunted the rise in NT-proBNP compared with placebo, regardless of AF/AFL diagnosis at baseline ( Table ). Conclusions: Acoramidis improved clinical outcomes (ACM, CVH), functional status, QoL and NT-proBNP levels relative to placebo in participants with ATTR-CM, regardless of AF/AFL diagnosis at baseline.

Introduction: Patients with variant transthyretin (TTR) amyloid cardiomyopathy (ATTRv-CM) experience early onset disease, rapid progression, and poor outcomes due to amyloid aggregated from destabilized tetrameric TTR. Acoramidis, a highly selective, oral TTR stabilizer, achieves ≥90% TTR stabilization and is approved in the USA, EU, Japan, and UK for adults with wild-type (ATTRwt-CM) or ATTRv-CM. In the phase 3 ATTRibute-CM study and its open-label extension (OLE), acoramidis reduced both the risk of all-cause mortality (ACM) or first cardiovascular-related hospitalization (CVH) through Month 30 and risk of ACM through Month 42 by 36%. Research Question: Is acoramidis efficacy in ATTRv-CM consistent with that observed in the overall ATTRibute-CM population? Methods: In ATTRibute-CM, participants with ATTR-CM were randomized 2:1 to acoramidis HCl 800 mg or PBO, twice daily (BID) for 30 months. After Month 30, all participants enrolled in the OLE received acoramidis HCl 800 mg BID. Genotype (ATTRwt-CM or ATTRv-CM) was captured at randomization; efficacy was analyzed separately in ATTRv-CM. Time-to-event analyses used a stratified Cox model with terms for treatment, baseline 6MWT, genotype, genotype×treatment interaction, stratified by randomization NT-proBNP and eGFR levels. ACM was analyzed at Month 42 (ATTRibute-CM 30 months + OLE 12 months). Results: The ATTRv-CM group comprised 59 patients (39 acoramidis, 20 PBO). Baseline characteristics were mostly similar in both groups ( Table ). The three most common variants reported were p.V142I (n=35), p.I88L (n=7), and p.T80A (n=5). Compared with PBO, acoramidis reduced the risk of ACM/first CVH through Month 30 by 59% (acoramidis, 46.2%; PBO, 75.0%; HR 0.41; 95% CI 0.21–0.81; P =0.011; Fig 1 ) and ACM through Month 42 by 59% (continuous acoramidis, 30.8%; PBO to acoramidis, 60.0%; HR 0.41; 95% CI 0.19–0.93; P =0.032; Fig 2 ) , with Kaplan–Meier curves separating at Months 5 and 10, respectively. Conclusions: In ATTRibute-CM, acoramidis use was associated with clinical benefit in the ATTRv-CM group as demonstrated by a 59% risk reduction in both ACM/first CVH at Month 30, and ACM at Month 42 compared to PBO. These previously unreported findings support the hypothesis that near complete TTR stabilization observed experimentally with acoramidis across multiple TTR mutations translates into improvement in long-term outcomes. Further validation by individual TTR variant is warranted.

BACKGROUND: Thresholds to define prognosis with hs-cTnI (high-sensitivity cardiac troponin I) have not been systematically addressed in wild-type transthyretin amyloid cardiomyopathy, in part because of the multiplicity of hs-cTnI assays. The aims of this study were: first, to assess the prognostic performance of hs-cTnI measured with different assays in patients with wild-type transthyretin amyloid cardiomyopathy and, second, to identify assay-specific hs-cTnI thresholds for prognosis that could be integrated into staging systems for risk stratification. METHODS: Observational multicenter study of stable wild-type transthyretin amyloid cardiomyopathy patients from different cohorts using the Abbott Architect Stat hs-cTnI assay and the Beckman Coulter Access hs-cTnI assay (testing cohorts) and the Siemens Centaur XPT hs-cTnI assay (validation cohort). Outcome was all-cause mortality. RESULTS: In the Abbott cohort (n=136; median follow-up 22 [13–41] months; 31 [23%] deaths) and Beckman cohort (n=98; median follow-up 19 [12–28] months; 16 [16%] deaths), natural log-transformed hs-cTnI was an independent predictor of mortality (age- and sex-adjusted hazard ratio, 1.62 [95% CI, 1.11–2.35]; P =0.012 and 2.47 [95% CI, 1.48–4.14]; P <0.001, respectively). The best hs-cTnI threshold for 18-month mortality of the combined Abbott/Beckman cohorts (n=234) was 81 ng/L, rounded to 80 ng/L for simplicity of clinical use. A 2-variable staging system (based on the Mayo Clinic system) using hs-cTnI (>80 ng/L) and NPs (natriuretic peptides; NT-proBNP [N-terminal pro-B-type natriuretic peptide] >3000 ng/L or BNP [B-type natriuretic peptide] >250 ng/L) identified 3 groups with progressively worse prognosis. The staging system (using hs-cTnI >80 ng/L and NT-proBNP>3000 ng/L) was then applied to an independent cohort evaluated with the hs-cTnI Siemens assay (n=345, median follow-up 32 [24-42] months, 119 [34%] deaths). The significant differences between the groups were maintained. CONCLUSIONS: In patients with wild-type transthyretin amyloid cardiomyopathy, hs-cTnI is a strong and independent predictor of mortality. A threshold of hs-cTnI of 80 ng/L for these 3 assays provides effective risk stratification alone and in a staging system with NP.

BACKGROUND: In the phase 3 randomized controlled study ATTRibute-CM (Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy), acoramidis, a transthyretin stabilizer, demonstrated significant efficacy on the primary end point. Participants with transthyretin amyloid cardiomyopathy who completed ATTRibute-CM were invited to enroll in an open-label extension study (OLE). We report the efficacy and safety data of acoramidis in participants who completed ATTRibute-CM and enrolled in the ongoing OLE. METHODS: Participants who previously received acoramidis through month 30 in ATTRibute-CM continued to receive it (continuous acoramidis), and those who received placebo through month 30 were switched to acoramidis (placebo to acoramidis). Participants who received concomitant tafamidis in ATTRibute-CM were required to discontinue it to be eligible to enroll in the OLE. Clinical efficacy outcomes analyzed through month 42 included time to event for all-cause mortality (ACM) or first cardiovascular-related hospitalization (CVH), ACM alone, first CVH alone, ACM or recurrent CVH, change from baseline in NT-proBNP (N-terminal pro-B-type natriuretic peptide), 6-minute walk distance, serum transthyretin, and Kansas City Cardiomyopathy Questionnaire Overall Summary score. Safety outcomes were analyzed through month 42. RESULTS: Overall, 438 of 632 participants in ATTRibute-CM completed treatment, and 389 enrolled in the ongoing OLE (263 continuous acoramidis and 126 placebo to acoramidis). The hazard ratio for ACM or first CVH was 0.57 (95% CI, 0.46–0.72) at month 42 based on a stratified Cox proportional hazards model ( P <0.0001) favoring continuous acoramidis. Similar analyses were performed on ACM alone and first CVH alone, with hazard ratios of 0.64 (95% CI, 0.47–0.88) and 0.53 (95% CI, 0.41–0.69), respectively, at month 42. Treatment effects for NT-proBNP and 6-minute walk distance also favored continuous acoramidis. On initiation of open-label acoramidis in the placebo-to-acoramidis arm, there was a prompt increase in serum transthyretin. Quality of life assessed by Kansas City Cardiomyopathy Questionnaire Overall Summary score was well preserved in continuous-acoramidis participants compared with the placebo-to-acoramidis participants. No new clinically important safety issues were identified in this long-term evaluation. CONCLUSIONS: Early initiation and continuous use of acoramidis in the ATTRibute-CM study through month 42 of the ongoing OLE study were associated with sustained clinical benefits in a contemporary transthyretin amyloid cardiomyopathy cohort, with no clinically important safety issues newly identified. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04988386.

Abstract Background/Introduction Patients with ATTR-CM can have lower circulating TTR levels, which is associated with worsening of cardiac function and increased risk of cardiovascular mortality.[1] Acoramidis has been shown to reduce cardiovascular mortality and hospitalization, while increasing circulating TTR levels, in the ATTRibute-CM phase 3 study.[2] Purpose I. Evaluate serum TTR levels in participants (pts) receiving acoramidis vs those who received tafamidis in the placebo group in ATTRibute-CM at Month 30. II. Evaluate serum TTR levels in pts who transitioned from placebo+tafamidis to acoramidis in the open-label long term extension (OLE) study. Methods ATTRibute-CM study: Eligible pts with ATTR-CM were randomized in a 2:1 ratio to receive acoramidis or placebo for 30 months. Pts in both groups had the option of initiating open-label, commercially available tafamidis after 12 months in the study. Upon completion of Month 30, pts were invited to participate in the OLE study. In OLE, pts who had previously received acoramidis continued acoramidis, and those who had previously received placebo+tafamidis were switched to acoramidis-only treatment. All pts in the OLE study received acoramidis only. Change in serum TTR levels in ATTRibute-CM and OLE at data cutoff (Oct 9, 2023) are summarised using descriptive statistics. Results In the phase 3 study, efficacy analyses were performed in 611 pts, of which 61 of 409 (14.9%) and 46 of 202 (22.8%) received tafamidis in acoramidis and placebo groups, respectively. The median time until tafamidis initiation was 17.8 and 16.1 months, respectively; median exposure duration was 11.6 and 10.5 months, for acoramidis and placebo groups, respectively.[3] Change from baseline (CFB) in serum TTR levels remained unchanged at Month 30 in the placebo-only group (mean [SD] = –0.4 [4.92] mg/dL). Characteristics of pts analysed are described in Fig. 1. A total of 380/611 pts (62.2%) entered the OLE study (229 pts continued acoramidis only, and 23 switched from placebo+tafamidis to acoramidis). At the time of data cutoff, 214 pts who had received acoramidis only completed Month 6 in OLE versus 18 who switched from placebo+tafamidis to acoramidis. At Month 30 in ATTRibute-CM, CFB in serum TTR levels were higher for patients who received acoramidis only than those receiving placebo+tafamidis (Fig 2A). Serum TTR levels increased further in pts who switched from placebo+tafamidis to acoramidis in OLE (Fig. 2B). The OLE study is ongoing, and this analysis includes pts who completed the Month 6 visit at time of data-cut. Conclusion(s) CFB in serum TTR levels were higher in pts receiving acoramidis only than those receiving placebo+tafamidis at Month 30 in the double-blind study. A further significant increase in serum TTR levels was observed in those who received placebo+tafamidis and switched to acoramidis in OLE.