Cardiac findings and events observed in an open-label clinical trial of tafamidis in patients with non-Val30Met and non-Val122Ile hereditary transthyretin amyloidosis

Abstract

A phase 2, open-label study in 21 patients with non-Val30Met and non-Val122Ile hereditary transthyretin amyloidosis showed that tafamidis (20 mg daily for 12 months) stabilized these transthyretin variants. We assessed cardiac amyloid infiltration and cardiac abnormalities in this same study population. At baseline, median age was 64.3 years, 11 patients were in NYHA class II, 13 had conduction abnormalities, 14 N-terminal pro-hormone brain natriuretic peptide concentrations >300 pg/ml, and 17 interventricular septal thickness >12 mm. Mean (SD) left ventricular ejection fraction was 60.3% (9.96). Patients with normal heart rate variability increased from 4/19 at baseline to 8/19 at month 12 (p < 0.05). Cardiac biomarkers remained stable. Although four patients had increases in interventricular septal thickness ≥ 2 mm, the remainder had stable septal wall thickness. There were no clinically relevant changes in mean echocardiographic/electrocardiographic variables and no safety concerns.

Fig. 1

Holter monitoring HRV values in the safety population showed that mean and median values for the percentage of successive RR intervals with >50 mg difference between normal beats (pNN50) (a), the root mean square of successive differences of the RR intervals between normal beats (RMS-SD) (b), the Magid SD (c), and the Kleiger SD of all RR intervals (d) did not deteriorate over the study period. Bars indicate the range of values observed, boxes span from the 25th to the 75th percentiles, horizontal lines within the boxes indicate median change, and plus sign indicates mean changes. HRV heart rate variability, SD standard deviation

Fig. 2

The proportion of patients with normal HRV in the safety population increased from 4/19 at baseline to 8/19 at month 12 (p < 0.05). p values are based on two-sided McNemar’s tests. HRV heart rate variability, ns non-significant

Fig. 3

NT-proBNP concentrations in individual patients with baseline concentrations <300 pg/ml (a) or >300 pg/ml (b). No consistent, clinically meaningful increases in NT-proBNP were detected during 12 months of tafamidis treatment, with the exception of a steady rise from 2603 to 7902 pg/ml in patient 10. NT-proBNP N-terminal pro-hormone brain natriuretic peptide. a Patients had missing baseline data, and the last pre-treatment assessment during screening is depicted. b Patient discontinued tafamidis on day 31 following a transient ischemic attack. c Patient discontinued tafamidis prior to month 12 to undergo combined liver/heart transplant. d Patient discontinued tafamidis prior to month 3 to undergo a liver transplant

Fig. 4

Changes in cardiac amyloid infiltration, systolic function, and LV filling pressure from baseline within individual patients. a LV mass, as a measure of cardiac amyloid infiltration, was maintained or improved (<10 % increase) in 8/14 (57.1 %) from baseline to month 12. b LVEF as a measure of systolic function was maintained or improved (<10 % decrease) in 16/18 (88.9 %) from baseline to month 12. c Lateral E/e′ as an estimate of LV filling pressure was normal (E/e′ <8), undetermined (8 ≤ E/e′ ≤ 15), or elevated (E/e′ > 15) in 6/16 (37.5 %), 5/16 (31.3 %), and 5/16 (31.3 %) at baseline and in 3/11 (27.3 %), 5/11 (45.5 %), and 3/11 (27.3 %) at month 12, respectively. LV left ventricular, LVEF LV ejection fraction, E/e′ ratio of peak mitral inflow velocity of early filling to early diastolic mitral annular velocity