Background: Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive, fatal condition characterized by worsening heart failure (HF), exercise intolerance, cardiac arrhythmias, aortic stenosis, and orthopedic manifestations. Recent analyses have shown ATTR-CM presents a significant burden to the healthcare system, but data on healthcare resource utilization (HCRU) comparing ATTR-CM to non-ATTR HF in the US are lacking. Aim: To compare HCRU and costs in patients (pts) with ATTR-CM to that of pts with non-ATTR HF using medical and pharmacy claims. Methods: Using the Optum Clinformatics Data Mart (Jan 2016-Sep 2023), pts with ATTR-CM were identified based on presence of HF and/or cardiomyopathy (CM) occurring within 2 years of first amyloidosis diagnosis (excluding light-chain amyloidosis) and followed for at least 12 months after first HF/CM diagnosis. ATTR-CM pts were matched 1:1 to non-ATTR HF pts using propensity score matching. After index diagnosis, both groups were assessed for HCRU, including inpatient acute cardiovascular (CV) hospitalizations (CVH), length of stay, and cost. Hospitalizations were considered CV if a pt received a CV diagnosis during the hospitalization period. Results: There were 4581 pts with ATTR-CM (mean [±SD] age: 76 [9.13] years; 56.2% male) who met inclusion criteria and were matched to 4581 non-ATTR HF pts (mean [±SD] age: 76 [8.86] years; 56.0% male) for comparison (Table). ATTR-CM pts had a higher trend of CVH and a higher number of total CVHs and mean hospitalizations per pt compared to non-ATTR HF pts (p<0.001). The mean cost per hospitalization (p=0.00463) and mean cost per annual hospitalizations per pt (p<0.001) were higher for ATTR-CM compared to non-ATTR HF. ATTR-CM pts were also hospitalized for more mean days annually for CV-related reasons compared to non-ATTR HF pts (p<0.001). On average, pts with ATTR-CM spent 2.3 days more than matched non-ATTR HF pts in the hospital each year. Conclusion: Compared to non-ATTR HF, ATTR-CM is associated with a greater burden on the healthcare system as evaluated by hospitalization rate, costs per hospitalization, annual hospitalization costs, and days hospitalized annually.
Objectives: Acoramidis (AG10) is a novel investigational stabilizer of transthyretin (TTR or prealbumin) that achieves ≥ 90% TTR stabilization, in development for the treatment of TTR amyloid cardiomyopathy (ATTR-CM), a progressive, fatal disease in which the deposition of amyloid resultant of dissociation of either variant or wild-type TTR causes progressive heart failure. The Phase 3, 30-month ATTRibute-CM study showed a 25% risk reduction in all-cause mortality (ACM) with acoramidis relative to placebo. The objective was to evaluate exposure-efficacy relationships based on this study and two Phase 2 studies. Too few serious adverse events (SAE) occurred to establish an exposure-response model between acoramidis exposure and incidence of any particular SAE. Cardiovascular (CV)-related SAEs were excluded from the analysis since ATTR-CM patients are inclined to experience CV-related AEs and acoramidis exposure decreased the expected number of hospitalizations due to CV AEs. Methods: Using individual-subject steady-state exposure measures (plasma AUC, Cmax, and Cmin) estimated with a population pharmacokinetic model based on 8 clinical studies (Phase 1-3), exposure-efficacy relationships were modeled for cumulative CV-related hospitalization (CVH) counts using Poisson regression. Other efficacy measures could not be related directly to exposure but were related to change in serum TTR, an in vivo measure of TTR stabilization that increased with plasma exposure and served as an indirect exposure measure. ACM was modeled with logistic regression, and over time with Cox proportional hazards (CPH), while percent change from baseline (%CfB) in the Six Minute Walk Test (6MWT) at Month 30 was modeled as linear. Results: Change in serum TTR was predictive of ACM risk (p=0.00539) when adjusting for baseline demographic variables, diuretics, New York Heart Association (NYHA) class, baseline serum TTR, TTR variant vs wild-type and National Amyloidosis Centre (NAC) stage. For every 5 mg/dL increase in serum TTR from baseline to Day 28, the models predicted a 26.1% decrease in instantaneous mortality risk (CPH model) and a 30.9% (logistic model) decrease in the odds of mortality by Month 30, and the linear 6MWT model predicted an increase of 8.9 meters in the CfB 6MWT at Month 30. For every 1000 ng/mL increase in acoramidis steady-state Cmax, the Poisson model for CVH predicted a 2.7% decrease in the expected number of cumulative CVH events. Conclusions: Acoramidis exposure was found to directly predict cardiovascular hospitalizations, but change in serum TTR, which increases with acoramidis exposure, was needed to predict improved survival and 6MWT performance in ATTR-CM patients. The need for this indirect exposure measure could be due to limited and sparse concentration data at a single dose.Citations: .
Following acute coronary syndrome (ACS), the risk for future cardiovascular events is high and is related to levels of low-density lipoprotein cholesterol (LDL-C) even within the setting of intensive statin treatment. Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates LDL receptor expression and circulating levels of LDL-C. Antibodies to PCSK9 can produce substantial and sustained reductions of LDL-C. The ODYSSEY Outcomes trial tests the hypothesis that treatment with alirocumab, a fully human monoclonal antibody to PCSK9, improves cardiovascular outcomes after ACS.This Phase 3 study will randomize approximately 18,000 patients to receive biweekly injections of alirocumab (75-150 mg) or matching placebo beginning 1 to 12 months after an index hospitalization for acute myocardial infarction or unstable angina. Qualifying patients are treated with atorvastatin 40 or 80 mg daily, rosuvastatin 20 or 40 mg daily, or the maximum tolerated and approved dose of one of these agents and fulfill one of the following criteria: LDL-C ≥ 70 mg/dL, non-high-density lipoprotein cholesterol ≥ 100 mg/dL, or apolipoprotein B ≥ 80 mg/dL. The primary efficacy measure is time to first occurrence of coronary heart disease death, acute myocardial infarction, hospitalization for unstable angina, or ischemic stroke. The trial is expected to continue until 1613 primary end point events have occurred with minimum follow-up of at least 2 years, providing 90% power to detect a 15% hazard reduction. Adverse events of special interest include allergic events and injection site reactions. Interim analyses are planned when approximately 50% and 75% of the targeted number of primary end points have occurred.ODYSSEY Outcomes will determine whether the addition of the PCSK9 antibody alirocumab to intensive statin therapy reduces cardiovascular morbidity and mortality after ACS.
Background: In the phase 3 randomized controlled study, ATTRibute-CM, acoramidis, a transthyretin (TTR) stabilizer, demonstrated significant efficacy on the primary endpoint. Participants with transthyretin amyloid cardiomyopathy (ATTR-CM) who completed ATTRibute-CM were invited to enroll in an open-label extension study (OLE). We report efficacy and safety data of acoramidis in participants who completed ATTRibute-CM and enrolled in the ongoing OLE. Methods: Participants who previously received acoramidis through Month 30 (M30) in ATTRibute-CM continued to receive it (continuous acoramidis), and those who received placebo through M30 were switched to acoramidis (placebo to acoramidis). Participants who received concomitant tafamidis in ATTRibute-CM were required to discontinue it to be eligible to enroll in the OLE. Clinical efficacy outcomes analyzed through Month 42 (M42) included time to event for all-cause mortality (ACM) or first cardiovascular-related hospitalization (CVH), ACM alone, first CVH alone, ACM or recurrent CVH, change from baseline in N-terminal pro-B-type natriuretic peptide (NT-proBNP), 6-minute walk distance (6MWD), serum TTR, and the Kansas City Cardiomyopathy Questionnaire Overall Summary score (KCCQ-OS). Safety outcomes were analyzed through M42. Results: Overall, 438 of 632 participants in ATTRibute-CM completed treatment and 389 enrolled in the ongoing OLE (263 continuous acoramidis, 126 placebo to acoramidis). The hazard ratio (HR) (95% CI) for ACM or first CVH was 0.57 (0.46, 0.72) at M42 based on a stratified Cox proportional hazards model ( P -value < 0.0001) favoring continuous acoramidis. Similar analyses were performed on ACM alone and first CVH alone, with HRs (95% CI) of 0.64 (0.47, 0.88) and 0.53 (0.41, 0.69), respectively, at M42. Treatment effects for NT-proBNP and 6MWD also favored continuous acoramidis. Upon initiation of open-label acoramidis in the placebo-to-acoramidis arm there was a prompt increase in serum TTR. Quality of life assessed by KCCQ-OS was well preserved in continuous acoramidis participants compared with the placebo to acoramidis participants. No new clinically important safety issues were identified in this long-term evaluation. Conclusions: Early initiation and continuous use of acoramidis in the ATTRibute-CM study through M42 of the ongoing OLE study was associated with sustained clinical benefits in a contemporary ATTR-CM cohort, with no clinically important safety issues newly identified.
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