Participant characteristics

There were 1022 responses to the online survey, 802 of which met the survey inclusion criteria. After further screening, 47 respondents were determined to be ASG members: 20 had ATTRv amyloidosis, and 27 had ATTRwt amyloidosis. People with ATTRwt amyloidosis were invited for interviews, and a total of 14 people with ATTRwt amyloidosis agreed to be interviewed (Fig. 2). Participant characteristics for survey respondents and interview participants are presented in Tables 1 and 2, respectively.

Fig. 2

Flow chart illustrating the recruitment process. ASG, Amyloidosis Support Groups; ATTRv, Hereditary transthyretin; ATTRwt, Wild-type transthyretin

Table 1 Survey respondent characteristicsTable 2 Interview participant characteristicsSurvey resultsJourney to diagnosis

According to survey results, the mean age of diagnosis was 60.1 years (median: 60 years; range: 42–79 years) for respondents with ATTRv amyloidosis and 69.5 years (median: 70 years; range: 46–82) for survey respondents with ATTRwt amyloidosis. To estimate the journey length of patients and consider the potential delay to diagnosis, we used the time between: (1) the age at which participants reported to have experienced their first symptom suspected to be related to amyloidosis or procedure relating to this potential symptom; and (2) the year of their formal ATTR amyloidosis diagnosis. For the former value, participants were presented with a list of symptoms and procedures to select from and report the age at which they had experienced the symptom or undergone the procedure (see Additional file 4 for the predefined list of symptoms and procedures). Based on this approach, participants with ATTRv amyloidosis were diagnosed with a potential median delay of 13 years (range: 0–35). Participants with ATTRwt amyloidosis had a potential median delay of 16 years (range: 2–32 years; one participant's result was omitted as an outlier, as it was reported to be 58 years due to a shoulder dislocation at 20 years old).

The initial number of signs and symptoms differed between respondents with ATTRv and ATTRwt amyloidosis. However, both conditions demonstrated progressive disease burden over time. Fifteen percent and 63% of respondents with ATTRv and ATTRwt amyloidosis, respectively, reported experiencing at least 4–6 symptoms in the period before ATTR amyloidosis diagnosis. However, people with ATTRv amyloidosis experienced a greater number of symptoms, with 35% of people with ATTRv amyloidosis reporting more than 10 signs or symptoms. Figure 3a, b present the number of signs and symptoms experienced by amyloidosis type.

Fig. 3

Percentage of survey respondents who experienced 0–10 + signs or symptoms before diagnosis. ATTRv, hereditary transthyretin; ATTRwt, wild-type transthyretin. Notes: Percentage of survey respondents who experienced 0–10 + signs or symptoms before diagnosis with a ATTRwt amyloidosis (n = 27) and b ATTRv amyloidosis (n = 20)

Prior to diagnosis, the most prevalent respondent-reported symptom in people with ATTRwt amyloidosis was shortness of breath (63%) (Fig. 4a). Numbness (55%) and/or tingling-like pins and needles in hands (50%) and feet (60%) were the most common signs/symptoms reported in people with ATTRv amyloidosis (Fig. 4b). Fatigue was frequently reported as a symptom associated with their condition by both groups of respondents. When considering signs or symptoms more than 10 years before diagnosis, erectile dysfunction was the only symptom reported in 10% or more of male respondents with ATTRwt amyloidosis.

Fig. 4

Prevalence of signs or symptoms before diagnosis. ATTRv, Hereditary transthyretin; ATTRwt, Wild-type transthyretin. Notes: Prevalence of signs or symptoms before diagnosis with a ATTRwt amyloidosis (n = 27) and b ATTRv amyloidosis (n = 20). When analysing the prevalence of ‘Erectile dysfunction’ and ‘Sexual dysfunction’, we have used the denominator of male respondents (ATTRwt, n = 24; ATTRv, n = 9) and female respondents (ATTRwt, n = 3; ATTRv, n = 0), respectively

People with both ATTRv and ATTRwt amyloidosis experienced severe to very severe impact on their daily lives due to their symptoms (Fig. 5a, d), most of which occurred between 0 and 4 years before their diagnosis. Shortness of breath was the most burdensome of the most prevalent cardiovascular symptoms in people with ATTRwt amyloidosis, followed by fatigue. Erectile dysfunction (among men), difficulty walking and muscle weakness were the most burdensome non-cardiovascular-related signs or symptoms. Respectively, 22%, 19% and 15% of respondents with these symptoms experienced a severe to very severe impact on their daily life.

Fig. 5

Impact of prevalent signs or symptoms (≥ 20%) in survey participants. ATTRv, Hereditary transthyretin; ATTRwt, Wild-type transthyretin. Notes: Impact of prevalent signs or symptoms (≥ 20%) in survey participants: a ATTRwt (n = 26), cardiovascular-related; b ATTRwt (n = 26), other, non-cardiovascular-related signs and symptoms; c ATTRv (n = 20), cardiovascular-related; d ATTRv (n = 20), other, non-cardiovascular-related signs and symptoms. The graph reports impact of cardiovascular-related and other, non-cardiovascular-related signs and symptoms that were prevalent in 20% or more of the population. One male respondent in the ATTRwt group skipped the question. For the other symptoms, when analysing the prevalence of erectile dysfunction/sexual dysfunction, the denominator used was out of either male respondents only (for erectile dysfunction; n = 23 for ATTRwt and 9 for ATTRv) or female respondents only (for sexual dysfunction; n = 3 for ATTRwt and 0 for ATTRv)

Burdensome cardiovascular-related signs or symptoms present in 20% or more of ATTRv amyloidosis respondents were fatigue (20%), followed by swelling in lower legs/feet (10% and dizziness/light-headedness (10%). For each of these, respondents reported being severely to very severely impacted by these symptoms. The most prevalent symptoms categorized as non-cardiovascular for the purpose of this study were as follows: erectile dysfunction (22%) (among men) was the most burdensome, followed by numbness in hands (20%), alternating constipation and diarrhoea (20%), difficulty walking (20%), and tingling pins and needles in the hands (20%). Respondents reported being severely to very severely impacted by these signs and symptoms.

Other diagnoses

Many survey respondents reported being diagnosed with other diseases prior to their ATTR amyloidosis diagnosis. Those with ATTRwt amyloidosis experienced a greater number of other diagnoses than those with ATTRv amyloidosis (Fig. 6a, b). The most common other diagnosis for both amyloidosis groups was bilateral carpal tunnel syndrome (ATTRwt amyloidosis: 56%; ATTRv amyloidosis: 30%). Respondents with ATTRwt amyloidosis most commonly reported being diagnosed with thickened left ventricular heart wall (70%), followed by atrial fibrillation (48%) and sleep apnoea (44%), prior to formal diagnosis. For those with ATTRv amyloidosis, common diagnoses prior to diagnosis with amyloidosis included thickened left ventricular wall, rotator cuff tendon tear, trigger finger and irritable bowel syndrome (20% for each).

Fig. 6

Prevalence of other diagnoses received by survey respondents. ATTRv, Hereditary transthyretin; ATTRwt, Wild-type transthyretin; AV, Atrioventricular; MGUS, Monoclonal gammopathy of undetermined significance. Notes: Prevalence of other diagnoses received by survey respondents with a ATTRwt (n = 27) and b ATTRv (n = 20)

Procedures during journey to diagnosis

Survey respondents with ATTRwt amyloidosis underwent substantially more procedures to manage their symptoms and reach a correct final diagnosis, compared with patients with ATTRv amyloidosis (31% of patients with ATTRwt reported experiencing ≥ 4 procedures prior to diagnosis of wtATTR amyloidosis versus 5% patients with ATTRv). Orthopaedic procedures were the most prevalent across both amyloidosis types. Over 50% of respondents with ATTRwt amyloidosis required carpal tunnel release surgery in both wrists, typically 4 or more years before diagnosis. Respondents with ATTRv amyloidosis frequently underwent carpal tunnel release surgery in one wrist (20%), with it being performed most often either more than 10 years before or 0–3 years before diagnosis. Shoulder repair surgery was also a common procedure (10%) occurring 0–3 years before diagnosis.

HCP interactions

Survey respondents with either type of amyloidosis reported seeing a mix of HCPs during their journey to diagnosis. These were mainly primary care physicians, neurologists, cardiologists, and orthopaedists, owing to the variety of symptoms they experienced (Fig. 7a, b). Before their ATTR amyloidosis diagnosis, survey respondents with ATTRv and ATTRwt amyloidosis primarily visited cardiologists, followed by orthopaedists. Cardiac signs and symptoms reported by respondents with ATTRwt amyloidosis were atrial fibrillation, atrial flutter, or atrial tachycardia and thickened left ventricular wall. Cardiac signs and symptoms reported by respondents with ATTRv amyloidosis were thickened left ventricular heart wall and atrioventricular block. Orthopaedic signs and symptoms reported by respondents with ATTRwt amyloidosis were bilateral carpal tunnel syndrome and biceps tendon rupture. Orthopaedic signs and symptoms reported by respondents with ATTRv amyloidosis were rotator cuff tendon tear and bilateral carpal tunnel syndrome in both wrists.

Fig. 7

Healthcare practitioners consulted for signs and symptoms by survey respondents. ATTRv, Hereditary transthyretin; ATTRwt, Wild-type transthyretin; HCP, Healthcare practitioner. Notes: Healthcare practitioners consulted for signs and symptoms by survey respondents with a ATTRwt amyloidosis (n = 26) and b ATTRv amyloidosis (n = 18)

Respondents with ATTRwt amyloidosis primarily received other diagnoses from orthopaedists and underwent a greater number of procedures (mainly orthopaedic) compared with respondents with ATTRv amyloidosis. The latter respondents most often received other diagnoses from cardiologists and underwent fewer procedures before formal diagnosis. The second-most-common type of HCP to whom respondents reported their signs and symptoms differed between the two subgroups. While a large proportion of respondents with ATTRwt amyloidosis reported their signs and symptoms (e.g., shortness of breath, heart palpitations/heart fluttering and swelling in lower legs/feet) to a cardiologist, those with ATTRv amyloidosis often reported their signs and symptoms (e.g., fatigue, tingling in feet and numbness in feet) to a neurologist.

Interview results

Out of the 14 participants with ATTRwt interviewed, the diagnostic journey spanned a median of 16 years. Some participants were diagnosed within 3 years of experiencing their first suspected amyloidosis-related symptom, while one participant reported their first suspected amyloidosis-related symptom 32 years prior to their diagnosis. Irrespective of the length of the diagnostic journey, participants reported that the process was physically burdensome, frustrating, and emotionally taxing.

Experience of symptoms of ATTRwt amyloidosis

Participants consistently reiterated that ATTRwt amyloidosis is a multisystem, heterogeneous disease with wide-ranging impacts on all aspects of their lives. The most prevalent symptoms reported by interview participants mirrored those found in the survey. During the early phase of the diagnostic journey, steadily worsening physical health was the most reported sign of disease progression. Twelve out of 14 participants noted being unable to physically exert themselves in the same way as previously, or having a decline in their ability to perform tasks (see participant quotes in Table 3).

Table 3 Incremental changes reported during participant interviews

Manageable, incremental changes in health status were followed by more impactful manifestations, the effects of which were felt in various spheres of participants’ daily lives. Palpitations, shortness of breath, and fatigue were some of the most prevalent participant-reported symptoms. These had a substantial effect on participants’ mobility and physical health, and severely affected their ability to conduct daily activities (Table 3).

Among orthopaedic manifestations, carpal tunnel syndrome was the most reported sign in the population of interviewees with ATTRwt amyloidosis (n = 9 of 14), followed by trigger finger (n = 4 of 14). The associated pain led to significant sleep disturbances, which itself impacted physical and mental functioning during the day (Table 3).

Pain and erectile dysfunction were also commonly reported signs. As outlined in the Methods section, manifestations were pre-categorized into three categories—orthopaedic, cardiovascular, and other (not cardiovascular or orthopaedic)—to provide an analysis scheme for the report (note that these categories are not clinically validated aetiological groups, and certain symptoms are multifactorial). Pain and sleep apnoea had the largest impact on participants’ physical functioning, while erectile dysfunction had the largest impact on the participants’ relationships as it affected their intimacy with their partners (Table 3).

Sleep apnoea and musculoskeletal pain, which were previously discussed in the survey, were also reported by participants as having a large impact on their physical functioning and daily lives. The cumulative effect of all manifestations presented an important burden and impediment on the participants to live their lives (Table 3).

Journey towards diagnosis of ATTRwt amyloidosis

Owing to the length of the journey and the multiplicity of manifestations experienced by participants, most reported being referred to a range of different clinical specialists and undergoing numerous tests and procedures before being diagnosed (see selection of participant quotes in Table 4).

Table 4 Participant journey toward diagnosis of ATTRwt amyloidosis reported during participant interviews

Participants reported that they felt that the many different physicians and the high number of procedures resulted in a high burden of manifestations, symptom progression, and misdiagnoses (theme: feeling like ‘a lab rat’). Participant 3 described the process as “this never-ending situation of more doctors’ appointments, changes in medication, a-fib, sinus rhythm”. They kept a record of their journey and, during the interview, referred to their notes pointing to a “four-page document of every doctor’s appointment I had going back to when I first started noticing heart issues, shortness of breath, dizziness. So, it’s just a chronological record of all the people that I saw, all the different medications they put me on, all the ablations, all the cardioversions, before they finally recognized what was going on and sent me to (centre with experience managing amyloidosis redacted) critical heart care specialist and I got this thing all figured out”. Participant 12, who saw approximately eight different doctors before diagnosis, described the situation succinctly: “It was frustrating. I did feel a little bit maybe like a volleyball being bounced over from one to another to another.”

A key issue was that the medical specialists that participants saw often worked in unintegrated silos, and participants felt that they were burdened with the responsibility of communicating across an array of HCPs (Table 4).

On top of navigating various medical specialists, participants reported that coordinating care was also particularly challenging from a health insurance perspective. While most participants interviewed felt they had good coverage, this may not be representative of the wider population with ATTR amyloidosis (Table 4).

Examples of insurance implications for participants included navigating: coverage for out-of-network ATTR amyloidosis specialists; changes in coverage after reaching retirement age; and eligibility for Medicare. Participant 9, for example, mentioned that transitioning to Medicare involved a “whole new learning curve”; however, this was manageable and had little impact on the participant’s life. In contrast, out-of-pocket costs for certain participants were significant. Participants 7 and 11 reported having to travel out of state to access specialist care before their diagnosis (Table 4).

Key indicators of ATTRwt amyloidosis

Interview participants were typically diagnosed only after the disease had progressed to include severe cardiac symptoms such as atrial fibrillation and severe shortness of breath. Atrial fibrillation and other cardiovascular-related events (e.g., thickened left-ventricular wall) were important triggers that brought participants closer to a formal diagnosis. However, musculoskeletal symptoms (particularly carpal tunnel syndrome and trigger finger) were very prevalent. Participants believed these musculoskeletal symptoms were often overlooked and could be considered missed opportunities for diagnosis by HCPs. Specifically, just over half of participants singled out carpal tunnel syndrome as a key missed opportunity for an earlier diagnosis (Table 5).

Table 5 Key indicators of ATTRwt amyloidosis reported during participant interviews