gms | German Medical Science

Background: Amyloidosis involves deposition of misfolded proteins that builds up in organs resulting in dysfunctions. Amyloidosis is classified based on the proteins involved. Transthyretin-related amyloidosis (ATTR) is caused by deposits of TTR, a transport protein for thyroxine and vitamin A produced by the liver. Depositions in the heart results in ATTR cardiomyopathy (ATTR-CM), a rare and progressive disease. The average survival time after diagnosis on symptomatic treatment, which was the only available option until market authorization of Tafamidis in the indication ATTR-CM in February 2020, is estimated to be 2–5 years [1]. A systematic literature review revealed the absence of information on the overall epidemiology of this condition in Germany.

Materials and methods: A retrospective cohort study using anonymized German healthcare claims data on a representative sample of 4 million patients over 6 years from the Institute for Applied Health Research Berlin GmbH (InGef) database was performed to assess incidence and prevalence of diagnosed ATTR-CM. Analyses of individual patient data were performed by the InGef. Since there is currently no code in the International Classification of Diseases 10^th Revision (ICD-10) for ATTR-CM in Germany, a proxy was created: a combination of ICD-10 for Amyloidosis and CM, considered in a time-dependent fashion. An inpatient Operation and Procedure (OPS) code was also required to exclude suspicious cases. Two alternative case definitions were explored in sensitivity analyses: (i) using German physician fee schedule (EBM) codes for outpatient diagnostic measures in addition to OPS codes and (ii) using ICD-10 codes only. Four study years were examined separately, including a baseline period of two years. The representativity of the database to the German population enabled us to simply use the proportion of cases in the database to extrapolate the results to the entire adult German population. Prevalent cases were simulated using a multistate model with two possible states: “diagnosed” and “dead”. Entry data for the simulation were (i) the number of incident cases from the claim analysis and (ii) the mortality hazard rate per year of the placebo arm of the ATTR-ACT study [2] as the transition probability between states. The Markov property was assumed: survival times were constant and independent from the past. Every year, survival times were simulated for each incident patient. New and alive prevalent cases were summed up to assess yearly prevalence. The simulation was run over 50 years and repeated 500 times to get bootstrapped confidence intervals.

Results: Estimated incidence of ATTR-CM for the adult German population for 2014 to 2017 was 372 [212; 603], 442 [266; 691], 282 [146; 493] and 328 [180; 551] cases respectively. When EBM codes were added, incidence increased by 37.7% and prevalence by 22.7%. When only ICD-10 Codes were considered in the case definition, incidence increased 2.49-fold and prevalence 2.04-fold compared to the primary analysis including OPS codes. It took 27 simulation years to stabilize around 1920 patients in Germany before the authorization of Tafamidis.

Conclusion: Even if the lack of proper IDC-10 for ATTR-CM adds uncertainty to the definition of cases, we were able to retrieve realistic estimates of incident cases. The additional cases identified in sensitivity analyses might be false-positive, because of (i) nonspecific EBM codes and (ii) unreliable identification of cases in the absence of appropriate diagnostic procedures. Furthermore, medical experts regard the outpatient sector as irrelevant for the diagnosis of ATTR-CM. The methodology remained challenging for prevalence estimates: with no treatment option, rare specialized cardiologists and older age at diagnosis, prevalent patients are unlikely to consult on a regular basis for this indication and might remain uncaptured by a design that requires a repeated diagnosis at least once a year. Plausible results were retrieved by simulation, in line with the perception of medical experts. However, diagnosis of ATTR-CM is known to be difficult and often mixed up with other forms of cardiomyopathy. The true number of cases in the population is likely to be much higher than the number of diagnosed patients.