In a retrospective, longitudinal study among >2000 patients with transthyretin-mediated amyloid cardiomyopathy (ATTR-CM), NT-proBNP increase and outpatient diuretic intensification were associated with increased mortality after the first year.

This summary is based on the publication of Ioannou A, Cappelli F, Emdin M, et al. - Stratifying Disease Progression in Patients With Cardiac ATTR Amyloidosis. J Am Coll Cardiol. 2024 Mar 1;83(14):1276-1291. doi: 10.1016/j.jacc.2023.12.036

Introduction and methods

Background

Transthyretin-mediated amyloid cardiomyopathy (ATTR-CM) is a progressive and fatal disease characterized by the deposition of amyloid fibrils, which consist of misfolded TTR aggregates, in the myocardium. To guide treatment decisions, there is an urgent need for widely applicable markers of disease progression.

Recently, an increase in NT-proBNP level was identified as a marker of disease progression in a small cohort of patients with noninherited (wild-type) ATTR-CM [1], but this still awaits validation in patients with the hereditary form and those prescribed disease-modifying therapy. Outpatient diuretic intensification (ODI) directly influences NT-proBNP levels and is a strong independent predictor of prognosis in patients with HF [2-4], similar to NT-proBNP elevation [5].

Aim of the study

The authors assessed the prognostic importance of an NT-proBNP increase and ODI as markers of disease progression in a large cohort of ATTR-CM patients.

Methods

This was a retrospective, multinational, longitudinal study of 2275 patients diagnosed with ATTR-CM at 7 specialist referral centers from 2005 through 2022. The study population was divided into a development cohort, which consisted of patients from the National Amyloidosis Centre (NAC) cohort in London, the UK (n=1598), and an external validation cohort, comprising patients from the remaining 6 centers (USA (1), Austria (1), and Italy (4); n=677). In the NAC cohort, 1110 patients (68.8%) had wild-type ATTR-CM (wtATTR-CM), 252 patients (15.8%) had p.(V142I) hATTR-CM, and 236 patients (14.8%) had non-p.(V142I) hATTR-CM. ODI was defined as any postdiagnosis initiation of loop diuretics or increase of the dose (furosemide equivalent).

Outcomes

In landmark survival analyses, the relationship of NT-proBNP progression (defined as NT-proBNP increase >700 ng/L and >30%) or ODI at 1 year with all-cause mortality from the 1-year follow-up assessment onward was investigated.

Main results

NT-proBNP progression

• Between the day their diagnosis was made and the 1-year follow-up visit, 551 NAC patients (34.5%) and 204 patients (30.1%) in the external validation cohort experienced NT-proBNP progression.
• In the NAC cohort (median follow-up duration from 1-year time point: 32.7 months), patients with NT-proBNP progression had a higher mortality rate (25.0 deaths per 100 patient-years; 95%CI: 22.4–27.8) than patients with no progression (14.0 deaths per 100 patient-years; 95%CI: 12.8–15.4; HR: 1.82; 95%CI: 1.57–2.10; P<0.001). A similar association was found in across ATTR-CM subtypes (HR: 1.62; 95%CI: 1.40–2.00 in wtATTR-CM; HR: 1.72; 95%CI: 1.27–2.32 in p.(V142I) hATTR-CM; and HR: 2.33; 95%CI: 1.52–3.57 in non-p.(V142I) hATTR-CM).
• In the external validation cohort (median follow-up duration from 1-year time point: 22.6 months), NT-proBNP progression was also associated with increased mortality (18.4 deaths per 100 patient-years; 95%CI: 14.8–22.9 vs. 10.6 deaths per 100 patient-years; 95%CI: 8.8–12.8; HR: 1.75; 95%CI: 1.32–2.33; P<0.001).
• In the subgroup of patients who were prescribed disease-modifying therapy or enrolled in clinical trials (n=515), 131 (25.4%) showed NT-proBNP progression, which was associated with an increased risk of mortality (HR: 3.02; 95%CI: 1.87–4.87; P<0.001).

Outpatient diuretic intensification

• At 1 year, ODI was reported for 451 NAC patients (28.2%) and 301 patients (44.5%) in the external validation cohort.
• In the NAC cohort, patients with ODI had a higher mortality rate than those with no ODI (26.5 deaths per 100 patient-years; 95%CI: 23.6–29.7 vs. 14.3 deaths per 100 patient-years; 95%CI: 13.1–15.7; HR: 1.88; 95%CI: 1.62–2.18; P<0.001). ODI was associated with increased mortality risk across ATTR-CM-subtypes (in patients with wtATTR-CM [HR: 1.76; 95%CI: 1.48–2.11], p.(V142I) hATTR-CM [HR: 1.47; 95%CI: 1.08–2.01] and non p.(V142I) hATTR-CM [HR: 3.65; 95%CI: 2.29–5.81]).
• In the external validation cohort, the mortality rates were 18.0 deaths per 100 patient-years (95%CI: 15.1–21.7) in patients with ODI and 8.8 deaths per 100 patient-years in patients with no ODI (95%CI: 7.0–11.1) (HR: 2.05; 95%CI: 1.53–2.74; P<0.001).
• In the subgroup of patients prescribed disease-modifying therapy or enrolled in clinical trials, 143 (27.7%) experienced ODI, which was also associated with a higher mortality risk (HR: 2.77; 95%CI: 1.72–4.45; P<0.001).

Combined NT-proBNP progression and outpatient diuretic intensification

• In the NAC cohort, patients with either NT-proBNP progression or ODI at 1 year had an increased mortality risk compared with those with a stable NT-proBNP level and stable diuretic dose (HR: 1.93; 95%CI: 1.65–2.27; P<0.001), as did patients with patients with both NT-proBNP progression and ODI (HR: 2.98; 95%CI: 2.42–3.67; P<0.001).
• In the external validation cohort, patients with either NT-proBNP progression or ODI at 1 year (HR: 1.94; 95%CI: 1.36–2.77; P<0.001) and patients with both NT-proBNP progression and ODI (HR: 3.23; 95%CI: 2.17–4.79; P<0.001) showed higher mortality risks compared with those with a stable NT-proBNP level and stable diuretic dose.

Conclusion

This retrospective, multinational, longitudinal study showed that approximately 1 in 3 patients with ATTR-CM experienced NT-proBNP progression (i.e., NT-proBNP increase >700 ng/L and >30%) or ODI in the first year after diagnosis. Both NT-proBNP progression and ODI, and especially their combination, were associated with an increased mortality risk after the first year. The authors believe “[c]ombining both variables produces a simple, universally applicable model that detects disease progression” in ATTR-CM.

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References

1. Law S, Petrie A, Chacko L, et al. Change in N-terminal pro-B-type natriuretic peptide at 1 year predicts mortality in wild-type transthyretin amyloid cardiomyopathy. Heart. 2022;108:474–478.
2. Ferreira JP, Liu J, Claggett BL, et al. Outpatient diuretic intensification as endpoint in heart failure with preserved ejection fraction trials: an analysis from TOPCAT. Eur J Heart Fail. 2022;24:378–384.
3. Chatur S, Vaduganathan M, Claggett BL, et al. Outpatient worsening among patients with mildly reduced and preserved ejection fraction heart failure in the DELIVER trial. Circulation. 2023;148:1735–1745.
4. Mullens W, Damman K, Harjola VP, et al. The use of diuretics in heart failure with congestion—a position statement from the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail. 2019;21:137–155.
5. Masson S, Latini R, Anand IS, et al. Prognostic value of changes in N-terminal pro-brain natriuretic peptide in Val-HeFT (Valsartan Heart Failure Trial). J Am Coll Cardiol. 2008;52:997–1003.