Association of Patisiran, an RNA Interference Therapeutic, With Regional Left Ventricular Myocardial Strain in Hereditary Transthyretin Amyloidosis: The APOLLO Study

Abstract

Importance: Patients with cardiac amyloidosis demonstrate reduced myocardial strain with associated sparing of the cardiac apex. In the APOLLO randomized clinical trial, patisiran, an RNA interference therapeutic that inhibits transthyretin synthesis, improved left ventricular (LV) global longitudinal strain (LV GLS) compared with placebo in patients with hereditary transthyretin-mediated (hATTR) amyloidosis with polyneuropathy and evidence of cardiac involvement.

Objective: To evaluate the treatment association of patisiran with regional LV myocardial strain in cardiac manifestation in hATTR amyloidosis.

Design, setting, and participants: This exploratory analysis of APOLLO, a randomized, double-blind, placebo-controlled, phase 3, multicenter international clinical trial that was conducted from December 2013 to January 2016, included patients with hATTR amyloidosis with polyneuropathy who were randomized 2:1 to receive patisiran or placebo. The prespecified cardiac subpopulation (126 of 225 [56%]) comprised patients with a baseline LV wall thickness of 13 mm or more and no history of hypertension or aortic valve disease. This post hoc data analysis was performed between September 2018 and January 2019.

Intervention: Placebo or patisiran, 0.3 mg/kg, via intravenous infusion once every 3 weeks for 18 months.

Main outcomes and measures: The association of patisiran with LV regional longitudinal strain at 18 months.

Results: Of the 126 patients included in the prespecified cardiac subpopulation, 36 patients (28.6%) received placebo (median [interquartile range] age, 62 [57-72] years) and 90 patients (71.4%) received patisiran (median [interquartile range] age, 60 [54-66] years); 98 (77.8%) were men, 28 (22.2%) were from North America, and 43 (34.1%) were from Western Europe. At baseline, LV GLS was impaired and regional longitudinal strains were lowest in the basal segments with apical sparing. There were no differences in regional longitudinal strains between the treatment groups at baseline. Patisiran improved the absolute GLS (least-squares mean [SE] difference, 1.4% [0.6%]; 95% CI, 0.3%-2.5%; P = .02) compared with placebo at 18 months, with the greatest differential increase observed in the basal region (overall least-squares mean [SE] difference, 2.1% [0.8%]; 95% CI, 0.6%-3.6%; P = .006) and no significant differences in the mid and apical regions among groups.

Conclusions and relevance: Patisiran prevented the deterioration of LV GLS over 18 months, driven primarily by attenuating disease progression in the basal region, suggesting that basal longitudinal strain may be a more sensitive marker of treatment associations with the cardiac manifestation in hATTR amyloidosis and that basal region may be influenced by disease-modifying therapies more than other ventricular regions.

Trial registration: ClinicalTrials.gov identifier: NCT01960348.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Minamisawa reported receiving support from the Japanese Circulation Society, the Japanese Society of Echocardiography, and the Uehara Memorial Foundation Overseas Research Fellowship. Dr Adams reported personal fees from Alnylam outside the submitted work. Dr Slama reported personal fees from Alnylam during the conduct of the study and personal fees from Pfizer and grants from Ionis outside the submitted work. Dr Dispenzieri reported grants from Alnylam and Pfizer during the conduct of the study and grants from Celgene, Takeda, and Prothena outside the submitted work and serves on the advisory board for Janssen. Dr Shah reported research support from Alnylam during the conduct of the study and personal fees from Philips Ultrasound and Bellerophon and research support from Novartis outside the submitted work. Dr Falk reported personal fees from Alnylam and grants and personal fees from Akcea outside the submitted work. Dr Sweetser reported being an employee of Alnylam and owning stock and stock options. Drs Chen, Karsten, Vest, and Riese reported being employees of Alnylam. Dr Solomon reported grants from Alnylam during the conduct of the study and grants from Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, BMS, Celladon, Cytokinetics, Eidos, Gilead, GSK, Ionis, Lone Star Heart, Mesoblast, MyoKardia, National Institutes of Health/National Heart, Lung, and Blood Institute, Novartis, Sanofi Pasteur, and Theracos and personal fees from Akros, Alnylam, Amgen, AstraZeneca, Bayer, BMS, Cardior, Corvia, Cytokinetics, Gilead, GSK, Ironwood, Merck, Myokardia, Novartis, Roche, Takeda, Theracos, Quantum Genetics, Cardurion, AoBiome, Janssen, Cardiac Dimensions, and Tenaya outside the submitted work. No other disclosures were reported.

Figures

Figure.. Absolute Left Ventricular Longitudinal Strain Modified Bull’s-eye Plot in a Patient Taking Patisiran Who Had Improvement in the Basal Longitudinal Strain

A, A man in his early 60s was assigned to receive patisiran in the cardiac subpopulation at baseline, showing apical sparing; his left ventricular (LV) mean wall thickness was 13.3 mm, his LV ejection fraction (LVEF) was 62.4%, and his absolute LV global longitudinal strain was 12.3%. B, A modified bull’s-eye plot in the same patient at 18 months in which the LV mean wall thickness was 13.4 mm, LVEF was 62.5%, and absolute LV global longitudinal strain was 14.1%. The changes in absolute LV global, basal, mid, and apical longitudinal strain values were 1.8%, 4.1%, 0.1%, and 1.0%, respectively. C, Absolute LV regional median longitudinal strain values at baseline for overall patients in the cardiac subpopulation. D, Least squares mean change difference from baseline at 18 months (patisiran − placebo) and percentage change. The percentage change represents the magnitude of the estimated treatment effect compared with the cardiac subpopulation regional median longitudinal strain value at baseline. The whiskers indicate 95% CIs. The absolute increase in longitudinal strain indicates improvement in systolic function. aSignificant difference of change in the absolute regional longitudinal strain from baseline at 18 months between the patisiran and placebo groups.