Lead Investigator: Joel Skaistis, Corewell Health East
Title of Proposal Research: Effect of Tafamidis Across the Range of Systolic Function: A Post-Hoc Analysis of the ATTR-ACT Trial
Vivli Data Request: 9102
Funding Source: None
Potential Conflicts of Interest: None
Summary of the Proposed Research:
Transthyretin (TTR) is a protein which is made by the liver and circulates in the blood, transporting substances such as vitamin A and a thyroid hormone, thyroxine, around the body. Mutations in this protein can cause it to misfold or change shape, and to form into clumps called amyloids. A buildup of these abnormal proteins in the body’s organs is called amyloidosis. Cardiac transthyretin amyloidosis (ATTR) is a progressive, life-threatening disease where abnormal TTR is deposited in various organs, particularly the heart. This affects the heart’s ability to function properly, and can cause heart failure and an enlarged heart which leads to significant morbidity and mortality.
ATTR is common in certain populations and found in up to 20% of individuals over 60 with heart failure, aortic stenosis (thickening and narrowing of the valve between the heart’s main pumping chamber and the body’s main artery (the aorta)) or who have a pacemaker implanted (a small device that’s implanted in the chest to help control the heartrate).1 Tafamidis is a medication used to delay disease progression in adults with ATTR by inhibiting the formation of amyloids. This medication was shown to improve survival and control heart failure in a clinical trial, the ATTR-ACT trial. This trial was pivotal in the history of cardiovascular medicine because it was the first trial to demonstrate a medication improving survival in heart failure regardless of what the underlying heart function was. Specifically, heart failure is typically divided into two groups according to ejection fraction, which is parameter derived from cardiac imaging that measures the reduction in cardiac volume with each beat. Normal ejection fraction is over 55%. Patients with heart failure and an ejection fraction greater than 55% are considered to have heart failure with preserved ejection fraction (HFpEF) and patients with an ejection fraction below 55% are identified as having heart failure with reduced ejection fraction (HFrEF). Several medications have demonstrated a survival benefit in HFrEF but not HFpEF. Tafamidis was the first drug to demonstrate improved survival in both conditions. The aim of this current work is to test for an interaction between ejection fraction and treatment benefit with tafamidis. Furthermore, we will test for an interaction between tafamidis treatment and another measure of cardiac function, global longitudinal strain (GLS). GLS measures the shortening of the heart chamber as it pumps blood and has been demonstrated to be a much more accurate marker for heart failure disease severity than ejection fraction.2 Global longitudinal strain has not been previously tested as a parameter for identifying populations with improved response to heart failure medication. We will perform a post hoc analysis of the ATTR-ACT trial and measure the association between measures of heart function, ejection fraction and global longitudinal strain and the treatment benefit of tafamidis. We will compare the strength of association between these parameters and outcomes. The result of this work will offer insight for future heart failure drug trial design. By establishing which parameter, GLS or ejection fraction, more strongly associates with treatment benefit, we can better select patients for future clinical trials.
Requested Studies:
TTRACT trial. A phase 3 randomized trial of tafamidis in TTR cardiac amyloidosis
Data Contributor: Pfizer Inc.
Study ID: NCT01994889