Do Heart Failure Therapies Contribute to Survival in ATTR-CM Cases?

To date, there remains a lack of data supporting the widespread belief that heart failure treatments are ineffective in patients with transthyretin amyloid cardiomyopathy (ATTR-CM). Recognizing that ATTR-CM is increasingly being diagnosed, Cheng and colleagues evaluated whether neurohormonal blockade, particularly focusing on beta-blockers, has the potential for decreasing cardiac output. Specifically, they evaluated whether there was a connection between survival and treatment with mineralocorticoid receptor antagonists (MRAs), beta-blockers, or angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blockade (ARB), in 309 ATTR-CM patients enrolled in a registry at Columbia University between February 2002 and November 2018.

At baseline and subsequent visits, medication inventory was recorded. The medication inventory was manually adjudicated at baseline, at each study visit, and at study termination. Each heart failure medication class was considered as exposure. All-cause mortality was the primary outcome. The investigators adjusted for age, gender, systolic blood pressure, hereditary versus wild-type ATTR status and evaluated the interaction of beta-blocker use by left-ventricular ejection fraction (LVEF) and an ATTR-CM risk model. Time-varying exposure to beta-blockers was tested as a secondary analysis. The investigators also performed during prespecified exploratory analyses, stratifying exposure by TTR risk score, stopping or continuing medications during follow-up, and ejection fraction cutoff of ≥50%. The primary end point was all-cause mortality. During follow-up, the impact of beta-blocker cessation was examined.

Although patients with ATTR-CM are traditionally thought of as having preserved ejection fraction, a surprising number of patients had reduced ejection fraction; in the cohorts, the distribution of ejection fraction was described; approximately one-third (34%) of patients had preserved LVEF, 47% had reduced LVEF, and 19% had mid-range LVEF. Patients with lower ejection fraction were more likely to be receiving these medications at baseline.

In this study, the majority (84.1%) of patients were male, 17.2% had atrial fibrillation/flutter, and the median age was 75 years. At baseline, nearly half (49.8%) of patients were receiving beta-blocker therapy, more than one-third (35%) were receiving treatment with ACE inhibitors/ARBs, and 23.9% were receiving MRA treatment; at last treatment follow-up, beta-blocker treatment decreased to 17.3%, with ACE inhibitor/ARB decreased slightly to 29.7%, and MRA treatment increased significantly to 43%.

Patients who received beta-blocker therapy were more likely to be older, have a lower heart rate, and be New York Heart Association functional class II or III; they were more likely to have atrial fibrillation or flutter, higher B-type natriuretic peptide, lower ejection fraction, and were more likely to be receiving treatment concurrently with ACE inhibitors/ARBs.

The TTR risk model that was used in the study was a modified Mayo or UK Risk Model that was published in 2020.1 When stratified by this risk model into 3 groups, the investigators found no difference in baseline beta-blocker use. Patients in the intermediate-risk group had a higher mean dose of beta-blockers at baseline, compared with the other cohorts.

There was no association of beta-blocker use and mortality when stratified by ejection fraction or risk score. For ACE inhibitor/ARB use, there was no difference in total cohorts in all-cause mortality; when stratified by ejection fraction, there was a trend toward benefit in those patients with ejection fraction less than 50%. Finally, for MRA use and all-cause mortality, there was no significant association after adjusting for diuretics, highlighting the role that diuretics potentially play.

The researchers noted that the study limitations included a mixed population of both wild-type ATTR and hereditary ATTR, and it was a single-center study. In addition, there may have been a bias of baseline medications over time, and varying exposure to medications since it was not a randomized trial. Finally, there may have been residual confounding factors despite efforts to adjust. The authors concluded that there were no survival benefits of traditional heart failure medications. For the total cohort, the cessation of beta-blocker treatment was associated with improved survival, and future studies are warranted.

Reference

  1. Cheng RK, Levy WC, Vasbinder A, et al. Diuretic dose and NYHA functional class are independent predictors of mortality in patients with transthyretin cardiac amyloidosis. JACC Cardio Oncol. 2020;2:414-424.

Source: Cheng RK, Vasbinder A, Levy WC, et al. Association of traditional heart failure therapies with survival in transthyretin cardiac amyloidosis. Presented at: ACC.21, American College of Cardiology 70th Annual Scientific Session & Expo, May 15-17, 2021. Poster 1032-07.

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