Contemporary rates of disease progression in tafamidis-treated patients with wild-type ATTR-CM: a real-world single-centre study

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Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive and life-threatening disease whose natural history has been substantially modified by tafamidis.1 Real-world studies have confirmed these benefits; however, mortality and clinical progression remain clinically relevant despite treatment.2 Several parameters tracking disease progression have prognostic value in ATTR-CM; however, whether their predictive value is robust in contemporary populations of ATTR-CM patients treated with tafamidis is largely unknown.3,4 We conducted a single-centre observational study of consecutive patients diagnosed with wild-type ATTR-CM who initiated tafamidis between 11 November 2020 and 19 November 2024, at the ATTR-CM outpatient clinic of the Cardiomyopathy Centre, Azienda Ospedaliero-Universitaria delle Marche, Ancona, Italy. ATTR-CM diagnosis was confirmed by endomyocardial biopsy or a non-invasive pathway consistent with European consensus recommendations, with TTR genetic testing performed in all patients. Exclusion criteria included baseline New York Heart Association (NYHA) functional class > II, premature tafamidis discontinuation unrelated to clinical events, and incomplete 12-month follow-up. Clinical data were collected at tafamidis initiation, at the following 12 months, and at the last available follow-up, and comprised medical history, laboratory tests, and echocardiography. The primary endpoint was a composite of all-cause mortality, hospitalization for heart failure requiring intravenous diuretic therapy, and hospitalization for other cardiovascular causes. Disease progression at 12 months from tafamidis initiation was defined according to the following validated consensus criteria: (i) worsening by at least one NYHA functional class; (ii) worsening of NAC stage; (iii) increase in NT-proBNP defined as an absolute rise >700 ng/L and a relative increase >30%; (iv) deterioration in renal function defined as a >20% reduction in estimated glomerular filtration rate (eGFR), expressed as mL/min/1.73 m2 and calculated using the CKD-EPI equation); (v) outpatient diuretic intensification (ODI), defined as any initiation or dose increase of loop diuretics in the outpatient setting; (vi) increase in left ventricular wall thickness (LVWT) ≥ 2 mm; (vii) increase in the E/e′ ratio ≥2; (viii) reduction in left ventricular ejection fraction (LVEF) ≥ 5%; (ix) reduction in 6-min walk test distance (6MWTD) > 35 m; (x) and (xi) progression of mitral (MR) and tricuspid regurgitation (TR), graded on a six-level scale (0–5) and defined as a ≥ 1-grade increase.3,4–6 Statistical analysis comprised: (i) a baseline time-to-event analysis with censoring at last follow-up for event-free patients; and (ii) a 12-month landmark analysis, excluding events occurring before 12 months to minimize intervention-related bias, in which the prognostic value of progression markers between baseline and 12 months was assessed in a tafamidis-treated population. The study population comprised 88 patients with wild-type ATTR-CM: 84% males, median age 78 years (Q1–Q3: 75–81 years). The median time from diagnosis to tafamidis initiation was 3.7 months (Q1–Q3: 1.2–7.9). At baseline, most patients were NYHA class II (92%) and NAC stage I (65.9%). Median NT-proBNP was 1517 pg/ml, eGFR was 64 ml/min/1.73 m2, and 6MWTD was 365 m. Beta-blockers were used in 52% of patients; angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, or angiotensin receptor–neprilysin inhibitors in 53%; mineralocorticoid receptor antagonists in 48%; and sodium–glucose cotransporter 2 inhibitors in 12%. Loop diuretics were prescribed in 70%, with a mean daily dose of 36 ± 42 mg (furosemide equivalent). Over a median follow-up period of 26 months (Q1-Q3: 14–34 months) after tafamidis initiation, the primary endpoint occurred in 25 patients (28.4%), including 5 deaths (5.7%). The cumulative incidence of the primary endpoint was 8.0%, 16.2%, 21.0%, and 26.7% at 6, 12, 18, and 30 months (Figure 1A), respectively. Cumulative mortality incidence was 1.1%, 2.3%, 5.3%, and 8.7% at the same timepoints. Panel A: Cumulative incidence of the primary endpoint in the study population over time during follow-up; Panel B: Distribution of disease progression during follow-up. Bars show the proportion of patients meeting the progression criteria between baseline and 12 months; Panel C: Distribution of patients according to progression criteria. Patients were classified according to the absence of progression criteria, progression of either NT-proBNP or ODI, or progression of both parameters during follow-up; Panel D: Cumulative incidence of the primary endpoint according to NT-proBNP and outpatient diuretic intensification progression In baseline time-to-event analyses, higher loop diuretic dose and lower LVEF were independently associated with the primary endpoint (HR 1.01, 95% CI 1.00–1.001; P = .043 and HR 0.957, 95% CI 0.918–0.997; P = .035, respectively). The relationship between loop diuretic dose and risk was non-linear, with a marked increase beyond 100 mg/day (HR 2.91, 95% CI 1.14–7.47; P = .0026). Criteria of disease progression were fulfilled in 13 patients (14.9%) for NT-proBNP, 23 (26.7%) for eGFR decline, and 31 (36%) for ODI. Additional changes across functional, laboratory, and imaging domains included: worsening NYHA class (5.8%), NAC stage progression (20.5%), reduced 6MWTD (31.6%), increased LVWT (24.4%), reduced LVEF (25%), worsened E/e′ (18.5%), and progression of MR and TR in 8.1% and 10.5% of patients, respectively (Figure 1B and C). In 12-month landmark analysis, the presence of a single progression marker (NT-proBNP or ODI) had a clear trend towards an increased risk of the primary endpoint (HR 2.47, 95% CI 0.99–6.27; P = .058), while the concomitant presence of both markers conferred a substantially higher risk (HR 4.40, 95% CI 1.32–14.70; P = .016). No other progression markers were significantly associated with the primary endpoint. Cumulative incidence curves are shown in Figure 1D. The event rate observed in our cohort was lower than that reported in ATTR-ACT trial,1 and this difference may be largely explained by the different clinical profile of the two study populations (we excluded patients with NYHA class >II because tafamidis reimbursement in Italy is currently restricted to NYHA class I–II). Despite favourable survival, disease progression remains common in patients with wild-type ATTR-CM treated with tafamidis. NT-proBNP and ODI were the only markers of disease progression associated with outcomes in our cohorts. Previous studies have highlighted the prognostic value of these parameters. Ioannou and colleagues showed that a combined increase in NT-proBNP (>700 ng/l and >30% from baseline) and ODI was independently associated with disease progression and mortality in patients with ATTR-CM not treated with disease-modifying therapies.3 Our findings are consistent with these data and extend their relevance to tafamidis-treated patients in a real-world setting. Similarly, Sinigiani et al., in a large real-world cohort of NYHA class I–II patients treated with tafamidis, reported disease progression within 12 months in nearly one-third of patients. In that study, worsening NT-proBNP, renal function decline, and diuretic intensification were associated with adverse outcomes, whereas echocardiographic parameters appeared less sensitive to early disease changes.4 The absence of a control group should be considered a limitation when interpreting these findings. In conclusion, our study shows a favourable outcome in terms of all-cause mortality in a contemporary, real-world, single-centre population of patients with wild-type ATTR-CM treated with tafamidis. However, a significant rate of disease progression was observed in our cohort; NT-proBNP changes and ODI may represent simple and readily available parameters in routine clinical practice to help identify disease progression in patients

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.