Physicians' Academy for Cardiovascular Education

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 study

Literature - 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

Background

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 [1], 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.

Methods

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.

Outcomes

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.

Main results

Echocardiographic parameters

Pressure–volume parameters

Conclusion

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.”

References

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Find this article online at Eur J Heart Fail.

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