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Outcome in Cardiac Transthyretin Amyloidosis
Study Questions:
What is the natural history of, and how do the outcomes and quality of life compare among patients with acquired and hereditary forms of transthyretin amyloidosis cardiomyopathy (ATTR-CM)?
Methods:
The study cohort was comprised of 1,034 patients, of whom 69% (n = 711) had wild-type ATTR-CM (ATTRwt-CM), 20% (n = 205) had V1221 variant (V122I-hATTRCM), and 11% (n = 118) had non–V122I-hATTR-CM, comprising 80% of all referrals who were diagnosed with ATTR-CM. Of the study patients with non–V122I-hATTRCM, the majority (n = 97, 83%) had the T60A variant, although other pathogenic variants were represented; 96% of patients with non–V122I-hATTR-CM had coexistent, symptomatic amyloid polyneuropathy at the time of diagnosis as opposed to <5% of patients within the other genotypic subgroups. Patients underwent prospective evaluations comprising assessment of cardiac parameters, functional status by 6-minute walk test (6MWT), quality of life according to the Kansas City Cardiomyopathy Questionnaire, and survival. Centralized health records were utilized to determine hospital service usage pre- and post-diagnosis.
Results:
Male gender dominated in all three subgroups: 94%, 71%, and 69%, respectively, although the proportion of males was significantly higher in ATTRwt-CM than hATTR-CM (p < 0.001). There was no association between gender and survival, and there were no significant differences in baseline disease characteristics between males and females. Median age at diagnosis was significantly higher in ATTRwt-CM (79 years) and V122I-hATTR-CM (77 years) than in non–V122I-hATTR-CM (67 years) (p < 0.001). Median patient survival from diagnosis by Kaplan-Meier analysis was 31 months in patients with V122I-hATTRCM in comparison to 57 months among patients with ATTRwt-CM (p < 0.0001) and 69 months in non–V122IhATTR-CM (p < 0.0001).
A multivariable model combining age, UK National Amyloidosis Center (NAC) ATTR Disease Stage, left ventricular ejection fraction (LVEF), genotypic subgroup, and 6MWT distance at the time of diagnosis revealed that age (hazard ratio [HR], 1.037 per year; 95% confidence interval [CI], 1.008–1.067; p < 0.011), NAC ATTR Disease Stage (HR, 2.049; 95% CI, 1.352–3.104; p = 0.001 for stage II and HR, 3.705; 95% CI, 2.313–5.933; p < 0.001 for stage III in comparison to stage I), LVEF (HR, 0.978 per 1% increase; 95% CI, 0.963–0.993; p = 0.003), genotypic subgroup (HR, 2.071; 95% CI, 1.415–3.031; p < 0.001 for V122I-hATTR-CM and HR, 2.727; 95% CI, 1.458–5.098; p = 0.002 for non–V122I-hATTR-CM in comparison to ATTRwt-CM), and 6MWT distance (HR, 0.881 per 50-m increase; 95% CI, 0.832–0.933; p < 0.001) were independently associated with patient survival.
There was substantial diagnostic delay, with patients using hospital services a median (interquartile range) of 17 (9–27) times during the 3 years before diagnosis, by which time quality of life was poor; diagnosis of ATTRwt-CM was delayed >4 years after presentation with cardiac symptoms in 42% of cases. Patients with V122I-hATTR-CM were more impaired functionally (p < 0.001) and had worse measures of cardiac disease (p < 0.001) at the time of diagnosis, a greater decline in quality of life, and poorer survival (p < 0.001) in comparison with the other subgroups.
Conclusions:
The authors concluded that ATTR-CM is an inexorably progressive and eventually fatal cardiomyopathy associated with poor quality of life. Diagnosis is often delayed for many years after symptoms develop.
Perspective:
This is an important study because it shows that ATTR-CM is not benign. For many years, liver or combined cardiac and liver transplantation have been the only available therapies for patients with mutations causing ATTR, including those with ATTR-CM. A phase 3 clinical trial showed that tafamidis was associated with reductions in all-cause mortality and cardiovascular-related hospitalizations and reduced the decline in functional capacity and quality of life as compared with placebo (ATTR-ACT study: N Engl J Med 2018;379:1007-16). Because of these findings, the Food and Drug Administration has now approved tafamidis for treatment of ATTR-CM; and therefore, it is important that there is a high-index of suspicion for this condition, particularly in those with African ancestry (of whom ~4% possess the disease-associated transthyretin V1221 variant), so that this new live-saving pharmacologic therapy can be initiated in a timely manner.
Clinical Topics: Cardio-Oncology, Cardiovascular Care Team, Geriatric Cardiology, Heart Failure and Cardiomyopathies, Acute Heart Failure
Keywords: Amyloid Neuropathies, Amyloid Neuropathies, Familial, Cardiomyopathies, Cardiotoxicity, Genotype, Geriatrics, Heart Failure, Liver Transplantation, Mutation, Prealbumin, Quality of Life, Stroke Volume
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