BACKGROUND:Transthyretin amyloidosis cardiomyopathy (ATTR-CM) is an increasingly recognized cause of heart failure in older individuals. We sought to characterize the natural history of ATTR-CM and ...compare outcomes and quality of life among patients with acquired and hereditary forms of the disease.
METHODS:We studied 711 patients with wild-type ATTR-CM, 205 with hereditary ATTR-CM associated with the V1221 variant (V122I-hATTR-CM), and 118 with non-V122I-hATTR-CM at the UK National Amyloidosis Center between 2000 and 2017. Patients underwent prospective protocolized evaluations comprising assessment of cardiac parameters, functional status by 6-minute walk test, quality of life according to the Kansas City Cardiomyopathy Questionnaire, and survival. Hospital service usage pre- and postdiagnosis was established using English central health records in a subset of patients.
RESULTS: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 wild-type ATTR-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: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. Improved awareness and wider use of recently validated diagnostic imaging methods are urgently required for patients to benefit from recent therapeutic developments.
The purpose of this study was to determine the effect of patisiran on the cardiac amyloid load as measured by cardiac magnetic resonance and extracellular volume (ECV) mapping in cases of ...transthyretin cardiomyopathy (ATTR-CM).
Administration of patisiran, a TTR-specific small interfering RNA (siRNA), has been shown to benefit neuropathy in patients with hereditary ATTR amyloidosis, but its effect on ATTR-CM remains uncertain.
Patisiran was administered to 16 patients with hereditary ATTR-CM who underwent assessment protocols at the UK National Amyloidosis Centre. Twelve of those patients concomitantly received diflunisal as a “TTR-stabilizing” drug. Patients underwent serial monitoring using cardiac magnetic resonance, echocardiography, cardiac biomarkers, bone scintigraphy, and 6-min walk tests (6MWTs). Findings of amyloid types and extracellular volumes were compared with those of 16 patients who were retrospectively matched based on cardiac magnetic resonance results.
Patisiran was well tolerated. Median serum TTR knockdown among treated patients was 86% (interquartile range IQR: 82% to 90%). A total of 82% of cases showed >80% knockdown. Patisiran therapy was typically associated with a reduction in ECV (adjusted mean difference between groups: −6.2% 95% confidence interval CI: −9.5% to −3.0%; p = 0.001) accompanied by a fall in N-terminal pro–B-type natriuretic peptide concentrations (adjusted mean difference between groups: −1,342 ng/l 95% CI: −2,364 to −322; p = 0.012); an increase in 6MWT distances (adjusted mean differences between groups: 169 m 95% CI: 57 to 2,80; p = 0.004) after 12 months of therapy; and a median reduction in cardiac uptake by bone scintigraphy of 19.6% (IQR: 9.8% to 27.1%).
Reductions in ECV by cardiac magnetic resonance provided evidence for ATTR cardiac amyloid regression in a proportion of patients receiving patisiran.
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Hereditary transthyretin‐mediated (hATTR) amyloidosis, or ATTRv amyloidosis, is a progressive disease, for which liver transplantation (LT) has been a long‐standing treatment. However, disease ...progression continues post‐LT. This Phase 3b, open‐label trial evaluated efficacy and safety of patisiran in patients with ATTRv amyloidosis with polyneuropathy progression post‐LT. Primary endpoint was median transthyretin (TTR) reduction from baseline. Twenty‐three patients received patisiran for 12 months alongside immunosuppression regimens. Patisiran elicited a rapid, sustained TTR reduction (median reduction Months 6 and 12 average, 91.0%; 95% CI: 86.1%–92.3%); improved neuropathy, quality of life, and autonomic symptoms from baseline to Month 12 (mean change SEM, Neuropathy Impairment Score, −3.7 2.7; Norfolk Quality of Life‐Diabetic Neuropathy questionnaire, −6.5 4.9; least‐squares mean SEM, Composite Autonomic Symptom Score‐31, −5.0 2.6); and stabilized disability (Rasch‐built Overall Disability Scale) and nutritional status (modified body mass index). Adverse events were mild or moderate; five patients experienced ≥1 serious adverse event. Most patients had normal liver function tests. One patient experienced transplant rejection consistent with inadequate immunosuppression, remained on patisiran, and completed the study. In conclusion, patisiran reduced serum TTR, was well tolerated, and improved or stabilized key disease impairment measures in patients with ATTRv amyloidosis with polyneuropathy progression post‐LT (www.clinicaltrials.gov NCT03862807).
Patisiran, a small‐interfering RNA therapeutic, is well‐tolerated and stabilizes or improves multiple disease symptoms for patients with hereditary transthyretin‐mediated amyloidosis with polyneuropathy who experience disease progression after liver transplantation.
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