Mechanistic insights into effects of siRNA targeting transthyretin on LV function
Effect of patisiran on stroke volume in hereditary transthyretin-mediated amyloidosis: insights from pressure–volume analysis of the APOLLO studyLiterature - Rosenblum HR, Griffin JM, Minamisawa M, et al. - Eur J Heart Fail. 2023 Jan 24 [Online ahead of print]. doi: 10.1002/ejhf.2783
Introduction and methods
Transthyretin-mediated (ATTR) amyloidosis is characterized by extracellular deposition of amyloid fibrils composed of TTR protein in the heart, nerves, and other organs. In the heart, this leads to increased ventricular wall thickness, progressive diastolic dysfunction, and restrictive cardiomyopathy. Patisiran, a small interfering RNA therapeutic agent that inhibits hepatic synthesis of TTR, was approved for the treatment of hereditary ATTR amyloidosis with polyneuropathy based on the results of the APOLLO study. Besides showing beneficial effects on neuropathy and quality of life , this trial also suggested patisiran can improve LV mechanics after 18 months of therapy compared with placebo [2,3].
Aim of the study
The study aim was to determine the mechanisms underlying stabilization of LV mechanics with patisiran by quantifying overall LV function using LV stroke volume and noninvasive pressure–volume techniques in a prespecified cardiac subpopulation of the APOLLO trial.
The APOLLO study was an international, randomized, double-blind, placebo-controlled, phase 3 study in which 225 patients with hereditary ATTR amyloidosis with polyneuropathy were randomized in a 2:1 ratio to patisiran (0.3 mg/kg intravenously) or placebo once every 3 weeks for 18 months. The prespecified cardiac subpopulation for the current secondary analysis comprised 126 patients (56%) with evidence of cardiac involvement at study entry, defined as a baseline LV wall thickness ≥13 mm and no history of aortic valve disease or hypertension. Exclusion criteria were, amongst others, NYHA class >II HF symptoms, ACS within previous 3 months, uncontrolled cardiac arrhythmia, and unstable angina. No patients had relevant mitral or aortic regurgitation.
Exploratory endpoints of the APOLLO study included LV wall thickness, LV mass, and LV end-diastolic and end-systolic volumes assessed with transthoracic echocardiography at baseline, 9 months, and 18 months. LV stroke volume and LVEF were calculated from 2D volumes. Noninvasive pressure–volume parameters, including end-systolic pressure–volume relationship (ESPVR) and end-diastolic pressure–volume relation (EDPVR), were estimated using single-beat techniques.
- In the cardiac subpopulation, mean (± SD) LV stroke volume at baseline was 51 ± 14 mL. At 9 months, the least-squares (LS) mean (± SEM) change in LV stroke volume was –0.3 ± 1.2 mL in patients treated with patisiran and –5.4 ± 1.9 mL in the group treated with placebo (P=0.021), while this was –1.7 ± 1.3 mL and – 8.1 ± 2.3 mL, respectively, at 18 months (P=0.016).
- The myocardial contraction fraction was stable for patients receiving patisiran and declined for those on placebo (LS mean ± SEM change: 0.5% ± 0.6% vs. −2.6% ± 1.0%; P=0.014 at 9 months; 1.4% ± 0.8% vs. −3.4% ± 1.4%; P=0.004 at 18 months).
- Patients on patisiran showed a smaller decrease in LV end-diastolic volume compared with placebo-treated patients at 9 months (LS mean ± SEM change: –2.5 ± 1.7 mL vs. –10.3 ± 2.8 mL; P=0.017) and 18 months (LS mean change: –5.0 ± 1.9 mL vs. –14.2 ± 3.5 mL; P=0.023).
- At 18 months only, the patisiran group showed larger decreases in interventricular septal thickness (LS mean ± SEM change: –0.110 ± 0.022 cm vs. –0.010 ± 0.039 cm; P=0.029) and relative wall thickness (LS mean change: –0.072 ± 0.014 cm vs. –0.006 ± 0.025 cm; P=0.023) compared with the placebo group, whereas there was a trend towards significance for LV mass index (LS mean change: –9.05 ± 3.25 g/m² vs. 4.02 ± 5.83 g/m² ; P=0.053).
- There was no difference in change in LVEF or LV end-systolic volume between the groups over the study period.
- From baseline to 9 months, there was an upward and leftward shift of the EDPVR in the placebo group compared with the patisiran group as marked by a decline in the estimated LV volume at a pressure of 30 mmHg (V30)—which is an index of ventricular capacitance—(LS mean change ± SEM: −12.4 ± 3.5 mL vs. −2.1 ± 2.0 mL; P=0.012 ). At 18 months, both groups displayed an upward and leftward shift of the EDPVR as indicated by a decline in V30, but this was more pronounced in patients on placebo compared with those taking patisiran (LS mean change in V30:–11.9 ± 4.3 mL vs. −5.1 ± 2.1 mL; P=0.161).
- No changes in contractility were observed, despite a reduction in LV end-systolic pressure in the placebo group compared with the patisiran group (LS mean change ± SEM: −7.1 ± 2.5 mmHg vs. −1.0 ± 1.5 mmHg; P=0.043 at 9 months; −11.0 ± 3.1 vs. −3.3 ± 1.7 mmHg; P=0.033 at 18 months).
- There was no difference in change in ESPVR or LV end-diastolic pressure (LVEDP) between the groups over the study period.
- At 9 months, the isovolumetric pressure–volume area indexed to an LVEDP of 30 mmHg (PVAiso30) showed a decline at 9 months in the placebo group (LS mean change ± SEM: − 1978 ± 599 mmHg × mL) and was stable in the patisiran group (LS mean change: 18 ± 341 mmHg × mL; P=0.005). At 18 months, the decline in PVAiso30 was greater in the placebo group than in the patisiran group (LS mean change: −3143 ± 747 mmHg × mL vs. −375 ± 393 mmHg × mL; P=0.002).
- Change in V30 was moderately correlated with change in left atrial volume index from baseline to 9 months (r=0.38; P<0.001) and from baseline to 18 months (R=0.19; P=0.066). Change in V30 was also moderately correlated with change in septal thickness at 9 months (r=−0.32; P=0.001) but not at 18 months (r=−0.05; P=0.67). Change in V30 was not significantly correlated with the change in NT-proBNP level at 9 or 18 months.
This secondary analysis of the APOLLO trial showed that patisiran attenuated the progression of LV dysfunction seen with placebo in patients with hereditary ATTR amyloidosis with polyneuropathy and evidence of cardiac involvement. Patisiran’s effects were observed starting at 9 months of therapy and continued throughout the 18-month study period. The decline in LV function in placebo-treated patients was associated with a reduction in LV capacitance rather than a change in chamber contractility. The authors note that further studies, such as the ongoing phase 3 APOLLO-B study, are needed to confirm the current results and “elucidate the mechanisms by which TTR reduction with [RNA interference therapeutics] modulates progression of cardiac disease.”