Prevalence and Prognostic Significance of Frailty Among Patients With Transthyretin Amyloidosis Cardiomyopathy.

Abstract

HomeCirculation: Heart FailureVol. 14, No. 6Prevalence and Prognostic Significance of Frailty Among Patients With Transthyretin Amyloidosis Cardiomyopathy Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessLetterPDF/EPUBPrevalence and Prognostic Significance of Frailty Among Patients With Transthyretin Amyloidosis Cardiomyopathy Nowell M. Fine, MD, SM and Jacqueline M. McMillan, MD Nowell M. FineNowell M. Fine Correspondence to: Nowell M. Fine, MD, SM, S Health Campus, 4448 Front St Southeast, Calgary Alberta, T3M 1M4, Canada. Email E-mail Address: [email protected] https://orcid.org/0000-0002-6546-6587 Division of Cardiology, Department of Cardiac Sciences, Medicine, and Community Health Sciences, Libin CardiovascularInstitute, Cumming School of Medicine, University of Calgary, Calgary Alberta Canada (N.M.F.). Search for more papers by this author and Jacqueline M. McMillanJacqueline M. McMillan https://orcid.org/0000-0002-7090-9485 Division of Geriatrics, Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada (J.M.M.). Search for more papers by this author Originally published26 May 2021https://doi.org/10.1161/CIRCHEARTFAILURE.120.008105Circulation: Heart Failure. 2021;14:e008105Transthyretin amyloidosis cardiomyopathy (ATTR-CM) represents an underrecognized cause of heart failure that is caused either by a gene mutation of the transthyretin protein (hereditary transthyretin amyloidosis) or an age-related disorder (wild-type transthyretin amyloidosis) occurring in the absence of a transthyretin gene mutation.1 Wild-type transthyretin amyloidosis occurs predominantly in older men, with a reported median age of onset >70 years of age. Hereditary transthyretin amyloidosis has a more variable demographic distribution as a result of multiple genotypes; however, in North America is also predominantly diagnosed in older patients. The approval of tafamidis, a transthyretin-stabilizer, for the treatment of ATTR-CM has increased the importance of accurate prognostic assessment. This need is compounded by the high cost of tafamidis, whose list price is the highest ever in the United States for a cardiovascular medication.2 Although different disease staging systems have been developed, to date, none have achieved widespread consensus adoption. Frailty is defined as impaired ability to recover from pathological or iatrogenic stressors due to aging-related impairments3 and has demonstrated prognostic importance for multiple cardiovascular diseases.4 Given the older age demographic of ATTR-CM patients, measures of frailty may demonstrate prognostic importance in this population, however to date this has yet to be examined. The purpose of this analysis was to determine the prevalence, severity, and prognostic significance of frailty assessment in patients with ATTR-CM.The data that support the findings of this study are available from the corresponding author upon reasonable request. Patients diagnosed with ATTR-CM followed at our center’s dedicated cardiac amyloidosis clinic between January 2014 and December 2019 were included if they were ≥65 years of age at the time of diagnosis. Standard criteria for ATTR-CM diagnosis were used as follows: (1) exclusion of AL (light chain)amyloidosis by the absence of serum and urine monoclonal protein and (2) evidence of ATTR-CM by either endomyocardial biopsy with confirmation of subtype by proteomic analysis using mass spectrometry or positive technetium-99 m–pyrophosphate nuclear scintigraphy, defined as grade 2 to 3 myocardial uptake or heart-to-contralateral lung ratio >1.5.1 Genetic sequencing was performed on all patients, and patients with hereditary transthyretin amyloidosis with non-pV142I mutation were excluded. Frailty was assessed at the time of ATTR-CM diagnosis by a single observer using the Clinical Frailty Scale (CFS), a validated tool that stages frailty according to a 9-point scale (with higher values indicating greater frailty) based upon semiquantitative clinical evaluation.3 Following comprehensive clinical assessment, a CFS score is assigned based upon a patient’s baseline mobility, energy, physical activity, and functional abilities using the descriptive information provided on the tool.3 Frailty was defined as a CFS ≥5.4 The primary end point was all-cause mortality. This study was approved by the institutional Research Ethics Board.Out of 182 ATTR-CM patients followed during the study period, 19 (10%) were excluded because of age <65 years, 7 (4%) were excluded due to non-pV142I mutations, and 11 (6%) did not have a frailty assessment performed at the time of diagnosis, for a final study population of 145. Baseline characteristics for the full study population and categorized by CFS tertile are presented in the Table. There were 9 (6%) patients with pV142I mutation. The median CFS was 4 (3–6), and there were 57 (39%) patients who met criteria for frailty (CFS ≥5). Between CFS tertiles, there were significant differences in age, body mass index, hemoglobin, albumin, estimated glomerular filtration rate, and NTproBNP (N-terminal pro-B-type natriuretic peptide; Table). There were 16 (11%) patients included who were treated with tafamidis, and the proportion of patients receiving tafamidis therapy was not significantly different between CFS tertiles (P=0.84). There were no patients treated with other types of ATTR therapy. The median follow-up duration was 2.6 years (interquartile range, 1.2–3.6), during which time there were 36 (25%) deaths, including 3 (7%), 19 (25%), and 14 (61%) for ATTR patients with CFS scores 1 to 3, 4 to 6, and 7 to 9, respectively (P=0.010). Using Cox regression modeling, CFS tertile was significantly associated with mortality (hazard ratio, 1.97 [95% CI, 1.68–2.41], P<0.001) by univariable analysis. When adjusted for ATTR-CM disease stage (as described by Gillmore et al,1Table), New York Heart Association Functional class and treatment with tafamidis, CFS tertile remained significantly associated with mortality (hazard ratio, 1.49 [95% CI, 1.28–1.83], P<0.001).Table. Baseline Characteristics of ATTR-CM Patients for the Total Study Population and Stratified by CFS TertileParameterStudy population (N=145)CFS 1–3 (n=46)CFS 4–6 (n=76)CFS 7–9 (n=23)P valueDemographic and clinical Age, y78 (73–84)75 (69–83)78 (71–85)86 (81–89)<0.001 Sex (male)132 (91)41 (89)69 (91)22 (96)0.67 Body mass index, kg/m222.9 (19.8–26.1)24.3 (21.6–27.7)22.5 (20.6–26.2)21.1 (18.3–24.1)0.009 NYHA class III/IV78 (54)22 (48)42 (55)15 (65)0.38Laboratory Hemoglobin, g/dL10.8 (9.3–12.4)11.5 (10.0–12.9)10.7 (10.2–12.4)9.8 (8.5–10.9)0.011 Albumin, mg/dL3.64 (3.07–4.15)3.91 (3.43–4.38)3.60 (3.09–4.16)3.24 (2.76–3.81)0.027 Prealbumin, mg/dL21 (16–25)22 (16–27)21 (14–25)18 (13–22)0.21 eGFR, mL/(min·1.73 m2)50 (35–64)55 (39–67)49 (34–61)43 (28–57)0.033 NT-proBNP1604 (1152–2107)1256 (869–1683)1647 (1061–2143)2283 (1716–2847)<0.001 Troponin-T, ng/L45 (27–71)38 (21–70)46 (24–73)58 (35–89)0.014Echocardiographic LV ejection fraction, %50 (34–62)51 (36–63)51 (35–61)48 (33–59)0.39ATTR-CM ATTR subtype ATTRh9 (6)4 (9)4 (5)1 (4)0.69 ATTRwt136 (94)42 (91)72 (95)22 (96) Tafamidis therapy16 (11)6 (13)8 (11)2 (9)0.84 ATTR-CM stage* Stage I45 (31)18 (39)26 (34)4 (17)0.22 Stage II76 (52)23 (50)35 (46)12 (52) Stage III24 (17)5 (11)15 (20)7 (31)Values are presented as the median (interquartile range) for continuous variables or frequency (percentage of total) for categorical variables. ATTR-CM indicates transthyretin amyloidosis cardiomyopathy; ATTRh, hereditary transthyretin amyloidosis; ATTRwt, wild-type transthyretin amyloidosis; CFS, clinical frailty scale; eGFR, estimated glomerular filtration rate; NT-proBNP, N-terminal pro-B-type natriuretic peptide; and NYHA, New York Heart Association.* ATTR-CM staging system developed by Gillmore et al.1Among patients with ATTR-CM, frailty was highly prevalent and an important risk factor for mortality. As assessed by the CFS, frailty was independently associated with mortality and may be a valuable component of routine clinical assessment. Important limitations of our analysis include its single-center design and that other objective and validated frailty scales were not assessed for direct comparison. The CFS is a semi-quantitative and subjective tool for frailty assessment, and our study did not assess intraobserver or interobserver reliability. The CFS was selected because it is easy to perform and incorporate into routine clinical assessment, is well validated with a high interobserver reliability,3 and can be performed by nongeriatricians without the need for special equipment. The CFS has previously demonstrated a significant association with late mortality among older patients undergoing transcatheter aortic valve replacement.5 However, other frailty assessment tools are more objective and may demonstrate superior prognostic significance in patients with ATTR-CM. Another limitation is that the impact of tafamidis therapy on prognosis in patients according to their frailty stage could not be rigorously evaluated due to the small number of patients on treatment and the observational design of this study. Further research is warranted to determine whether other frailty indices can better predict outcome in patients with ATTR-CM and, importantly, whether frailty assessment can improve selection criteria for novel disease-modifying therapies such as tafamidis.AcknowledgmentsWe acknowledge the nursing staff of the Cardio-Oncology Clinic at South Health Campus hospital (Alberta Health Services, Calgary, Alberta, Canada) for their support and dedication to patient care.Sources of FundingNone.Disclosures Dr Fine has received research support and consulting honoraria from Pfizer, Akcea, and Alnylam. The other author reports no conflicts.FootnotesFor Sources of Funding and Disclosures, see page 724.Correspondence to: Nowell M. Fine, MD, SM, S Health Campus, 4448 Front St Southeast, Calgary Alberta, T3M 1M4, Canada. Email [email protected]ca