Association of Patisiran, an RNA Interference Therapeutic, with Regional Left Ventricular Myocardial Strain in Hereditary Transthyretin Amyloidosis

The APOLLO Study

Masatoshi Minamisawa, Brian Claggett, David Adams, Arnt V. Kristen, Giampaolo Merlini, Michel S. Slama, Angela Dispenzieri, Amil M. Shah, Rodney H. Falk, Verena Karsten, Marianne T. Sweetser, Jihong Chen, Richard Riese, John Vest, Scott D. Solomon

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish (US)
JournalJAMA cardiology
DOIs
StatePublished - Jan 1 2019

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Familial Amyloidosis
RNA Interference
Placebos
Polyneuropathies
Therapeutics
Least-Squares Analysis
Aortic Diseases
Prealbumin
patisiran
Amyloidosis, Hereditary, Transthyretin-Related
Amyloidosis
North America
Aortic Valve
Intravenous Infusions
Disease Progression
Randomized Controlled Trials
Outcome Assessment (Health Care)
Clinical Trials
Hypertension

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Association of Patisiran, an RNA Interference Therapeutic, with Regional Left Ventricular Myocardial Strain in Hereditary Transthyretin Amyloidosis : The APOLLO Study. / Minamisawa, Masatoshi; Claggett, Brian; Adams, David; Kristen, Arnt V.; Merlini, Giampaolo; Slama, Michel S.; Dispenzieri, Angela; Shah, Amil M.; Falk, Rodney H.; Karsten, Verena; Sweetser, Marianne T.; Chen, Jihong; Riese, Richard; Vest, John; Solomon, Scott D.

In: JAMA cardiology, 01.01.2019.

Research output: Contribution to journalArticle

Minamisawa, M, Claggett, B, Adams, D, Kristen, AV, Merlini, G, Slama, MS, Dispenzieri, A, Shah, AM, Falk, RH, Karsten, V, Sweetser, MT, Chen, J, Riese, R, Vest, J & Solomon, SD 2019, 'Association of Patisiran, an RNA Interference Therapeutic, with Regional Left Ventricular Myocardial Strain in Hereditary Transthyretin Amyloidosis: The APOLLO Study', JAMA cardiology. https://doi.org/10.1001/jamacardio.2019.0849
Minamisawa, Masatoshi ; Claggett, Brian ; Adams, David ; Kristen, Arnt V. ; Merlini, Giampaolo ; Slama, Michel S. ; Dispenzieri, Angela ; Shah, Amil M. ; Falk, Rodney H. ; Karsten, Verena ; Sweetser, Marianne T. ; Chen, Jihong ; Riese, Richard ; Vest, John ; Solomon, Scott D. / Association of Patisiran, an RNA Interference Therapeutic, with Regional Left Ventricular Myocardial Strain in Hereditary Transthyretin Amyloidosis : The APOLLO Study. In: JAMA cardiology. 2019.
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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.",
author = "Masatoshi Minamisawa and Brian Claggett and David Adams and Kristen, {Arnt V.} and Giampaolo Merlini and Slama, {Michel S.} and Angela Dispenzieri and Shah, {Amil M.} and Falk, {Rodney H.} and Verena Karsten and Sweetser, {Marianne T.} and Jihong Chen and Richard Riese and John Vest and Solomon, {Scott D.}",
year = "2019",
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day = "1",
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TY - JOUR

T1 - Association of Patisiran, an RNA Interference Therapeutic, with Regional Left Ventricular Myocardial Strain in Hereditary Transthyretin Amyloidosis

T2 - The APOLLO Study

AU - Minamisawa, Masatoshi

AU - Claggett, Brian

AU - Adams, David

AU - Kristen, Arnt V.

AU - Merlini, Giampaolo

AU - Slama, Michel S.

AU - Dispenzieri, Angela

AU - Shah, Amil M.

AU - Falk, Rodney H.

AU - Karsten, Verena

AU - Sweetser, Marianne T.

AU - Chen, Jihong

AU - Riese, Richard

AU - Vest, John

AU - Solomon, Scott D.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

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