Key Data

Reasons for Delays in Cardiac Amyloidosis Diagnosis

USA

A robust survey of US cardiologists* showed that >99% believe that patients with cardiac amyloidosis (CA) experience delays in diagnosis;
they cite misdiagnosis, low awareness of CA and diagnostic algorithm / tests as top reasons for why

Respondents

505 US cardiologists
Age (mean): 51 years
Male: 87%
Clinical exp. (mean): 20 years

Note: as of 2019, 45% of cardiologists noted an increased number of patients with CA in their practice compared to 5 years ago

ESTIMATED SPLIT OF CA PATIENTS

CARDIOLOGIST-CITED REASONS FOR DELAYS IN DIAGNOSIS OF CA

Notes: * Cardiologists (mean age 51.3 y; male, 87%; city/suburban practice, 87%; mean clinical experience, 20.2 y) saw an average of 433 patients with HF and 14.5 patients with CA in the last year. Cardiologists estimated that 41%, 28%, and 31% of their patients with CA had AL, hereditary, and wild-type disease, respectively. Nearly half of cardiologists (45%) noted an increased number of patients with CA managed in their practice compared to 5 years ago. Nearly all cardiologists (>99%) believed patients with CA experience delays in diagnosis; the most common reasons were misdiagnosis and low awareness of CA and diagnostic tests. Most cardiologists (96%) requested additional education on CA.

Castano, et al. Cardiac Amyloidosis: Current Insights from Patients and Cardiologists Journeying Together. J. Card Fai. 2019. Vol. 25, No. 8S

Delayed Diagnosis Specifically with Respect to ATTRwt-CM

Data demonstrate huge delays in establishing the diagnosis of ATTRwt-CM following presentation with cardiac symptoms [1]

In a large study at the UK National Amyloidosis Center (NAC) between 2000 and 2017, ATTR-CM patients overall used hospital services a median of 17 times during the 3 years before diagnosis, by which time quality of life was poor
For ATTRwt-CM patients, the median diagnostic delay from first presentation with cardiac symptoms was 39 months;
- Just over 1/3 were diagnosed within 6 months
- 23% waited between 6 months and 4 years before receiving an ATTR diagnosis
- 42% waited >4 years [1]

In a targeted literature review (n=23 articles), weighted means of reported mean and median diagnostic delays were 6.1 and 3.4 years for wild-type (ATTRwt-CM) and 5.7 and 2.6 years for hereditary (ATTRv-CM) [4]

Notes: * Study of 711 patients with wild-type ATTR-CM, 205 with V122I-ATTRv-CM, and 118 with non-V122I-ATTRv-CM at the UK National Amyloidosis Center between 2000 and 2017. only patients in whom there was a complete 3-year observation window across all 3 care settings prediagnosis of ATTR-CM (n=534, diagnosed April 2010 through August 2016) and a complete 3-year observation window across all 3 care settings postdiagnosis of ATTR-CM (n=364, diagnosed April 2007 through August 2013) were included in analyses of hospital service usage.1

Notes: ** Survival of patients diagnosed with ATTRwt-CM from 2012, the year that 99mTc-DPD scintigraphy was routinely introduced into the diagnostic algorithm for ATTR-CM at NAC, and after which 75% of patients were diagnosed noninvasively, was significantly better (median 60.2 months) than among patients diagnosed with ATTRwt-CM pre-2012 (median 46.3 months) when histology was usually required to establish the diagnosis (63% diagnosed via biopsy, usually endomyocardial biopsy)1

Notes: *** Consecutive patients (78.5 ± 6.4 years old at diagnosis) with ATTRwt‐CM diagnosed at Kumamoto University Hospital between December 2002 and December 2019 were retrospectively reviewed. Of 129 patients included in this study, 110 patients (85%) were male. The median period from initial symptom onset to diagnosis was 15.5 (2–75) months.3

Lane, T, et al. May 21, 2019. Natural History, Quality of Life, and Outcome in Cardiac Transthyretin Amyloidosis. https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.118.038169.
Dang D, et al. Gateway and journey of patients with cardiac amyloidosis. ESC Heart Failure. Volume: 7, Issue: 5, Pages: 2418-2430, First published: 26 June 2020, DOI: (10.1002/ehf2.12793).
Yamada T, Takashio S, Arima Y, et al. Clinical characteristics and natural history of wild-type transthyretin amyloid cardiomyopathy in Japan. ESC Heart Fail. 2020;7(5):2829-2837. doi:10.1002/ehf2.12884.
Rozenbaum MH, Large S, Bhambri R, et al. Impact of Delayed Diagnosis and Misdiagnosis for Patients with Transthyretin Amyloid Cardiomyopathy (ATTR-CM): A Targeted Literature Review. Cardiol Ther. 2021;10(1):141-159. doi:10.1007/s40119-021-00219-5

New and Improved Testing Methods Are Increasing Diagnoses

ATTR-CM—and ATTRwt-CM in particular—is being increasingly recognized, although much work remains to establish the diagnosis earlier in the course of the disease [1]

ATTRwt-CM is now diagnosed more than twice as frequently as hereditary ATTR-CM [1]

Presumably reflecting the remarkable sensitivity and increasingly widespread use of CMR imaging and bone scintigraphy, which in turn have fueled increased awareness of the condition among cardiologists
Nonetheless, historical autopsy evidence showed ATTR amyloid deposits in ≤25% of elderly male hearts, suggesting many are currently not being diagnosed during their lifetimes** [1]

# of New Diagnoses of ATTR-CM by Year per Genotypic Subgroup [1]*

(n=1034 total)
UK NAC, 2000-2017

However, recent THAOS data shows that median time from symptom onset to ATTRwt diagnosis did not change over the past 5 years (>60 months from 2015-2019)*** [3]

Number of Newly Diagnosed Patients by Year [3]

For comparison: a smaller study (n=122 ATTRwt patients) in France found significantly shorter delays after 2012, averaging ~5-12 months between when cardiac amyloidosis was first suspected and diagnosis [2]

Notes: CMR = cardiac magnetic resonance; NAC = National Amyloidosis Center; THAOS = Transthyretin Amyloidosis Outcomes Survey

Notes: * Study of 711 patients with wild-type ATTR-CM, 205 with V122I-ATTRv-CM, and 118 with non-V122I-ATTRv-CM at the UK National Amyloidosis Center between 2000 and 2017

Notes: ** Encouragingly, evidence suggests that survival among ATTRwt-CM patients has also improved since 2012 due to patients being diagnosed earlier in the disease course than pre-2012. Survival of patients diagnosed with ATTRwt-CM from 2012, the year that 99mTc-DPD scintigraphy was routinely introduced into the diagnostic algorithm for ATTR-CM at NAC, and after which 75% of patients were diagnosed noninvasively, was significantly better (median 60.2 months) than among patients diagnosed with ATTRwt-CM pre-2012 (median 46.3 months) when histology was usually required to establish the diagnosis (63% diagnosed via biopsy, usually endomyocardial biopsy)1

Notes: *** Using THAOS (Transthyretin Amyloidosis Outcomes Survey) data from December 2007 to January 2020, the median time from symptom onset to ATTRwt amyloidosis diagnosis did not change over the past 5 years (>60 months from 2015–2019). ATTRwt amyloidosis diagnoses increased from 2 in 2005 to >100 per year from 2016, with a more pronounced increase in the United States compared with the rest of the world. Diagnoses of ATTRwt amyloidosis by tissue biopsy increased yearly and peaked in 2014 before declining, whereas diagnoses by bone scintigraphy increased markedly since 2011.

Notes: Despite the increase in the number of patients with ATTRwt amyloidosis in THAOS, including those diagnosed in NYHA functional class I or II, and the increase in use of bone scintigraphy, there remains an unmet clinical need, with patients waiting for several years (on average) from the onset of symptoms until diagnosis. The diagnostic delay observed here may even underestimate the real-world experience of patients with ATTRwt amyloidosis. By nature of the registry, THAOS patients are in a catchment area for specialized centers with a focus and interest in this disease, whereas many patients in the real world are not and may experience greater barriers to diagnosis. Overall, the observed discrepancy between increased use of bone scintigraphy and continued prolonged time to diagnosis highlights the need for improved education on the early symptoms of ATTR amyloidosis.

Lane, T, et al. May 21, 2019. Natural History, Quality of Life, and Outcome in Cardiac Transthyretin Amyloidosis. https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.118.038169.
Dang D, et al. Gateway and journey of patients with cardiac amyloidosis. ESC Heart Failure. Volume: 7, Issue: 5, Pages: 2418-2430, First published: 26 June 2020, DOI: (10.1002/ehf2.12793).
Nativi-Nicolau J, et al. Temporal Trends of Wild-Type Transthyretin Amyloid Cardiomyopathy in the Transthyretin Amyloidosis Outcomes Survey. J Am Coll Cardiol CardioOnc. 2021 Oct, 3 (4) 537–546. DOI: https://www.jacc.org/doi/10.1016/j.jaccao.2021.08.009.

Cardiac Amyloidosis Patients are Frequently Misdiagnosed

Misdiagnoses are very common and made by a wide range of specialists but most commonly cardiologists, GPs, or internists—with conditions including unspecified heart failure or heart disease; most misdiagnosed patients receive treatment for their misdiagnosed condition(s)—some of which may be counter-indicated for ATTR

% MISDIAGNOSED [1]

ATTR patients with cardiac amyloidosis (CA)

Misdiagnosed ATTR patients reported receiving:

Surgery
Medications: beta-blockers, calcium channel blockers, angiotensin-converting enzyme inhibitors

Note some of these Txs are counter-indicated and/or poorly tolerated in ATTR [1]

MISDIAGNOSING PHYSICIAN(S) [1]

% of CA patients who received a misdiagnosis

Which type of doctor told you that you had something other than amyloidosis?

ATTRwt patients with CA most commonly report misdiagnosis by a cardiologist, general practitioner, or internist

Notes: * other includes dermatologists, endocrinologists, gastroenterologists, infectious disease specialists, oncologists, oral surgeons, otolaryngologists, pulmonologists, podiatrists, rheumatologists, surgeons, and urologists

Notes: At the time of this analysis, there were 589 total responders, 445 (233 patients, 212 caregivers) for AL amyloidosis and 144 (79 patients, 65 caregivers) for ATTR amyloidosis (89 ATTRv, 55 ATTRwt).1

Lousada, et al. Amyloidosis Research Consortium Cardiac Amyloidosis Survey: Results from Patients with AL and ATTR Amyloidosis and Their Caregivers. Poster presented at the XVIth International Symposium on Amyloidosis; March 26-29, 2018; Kumamoto, Japan.
- “Overall 294 (45%) patients (42% in AL, 39% in wtATTR, 44% in hATTR) received ≥1 misdiagnoses before being correctly diagnosed with amyloidosis.”
- “Unspecified heart failure or heart disease was a common misdiagnosis across all types (24%) and most common in ATTRwt patients (33%).”
- “The next most common misdiagnoses were all cardiac related: hypertrophic cardiomyopathy (11%), high blood pressure (5%), and heart arrhythmias (5%).”
Lousada, et al. Amyloidosis Research Consortium Cardiac Amyloidosis Survey: Results from Patients with AL and ATTR Amyloidosis and Their Caregivers. Poster presented at the 23rd annual Heart Failure Society of America; September 13-16, 2019; Philadelphia, PA.
- “A majority of patients (75%) received treatment for their misdiagnosis.”
- “Treatment with beta blockers and/or ace inhibitors, which are poorly tolerated in amyloidosis, was common in all patients (35%) and most common in wtATTR (51%).”

Overall, the road to an ATTRwt-CM diagnosis can be complex and frustrating-–awareness among patients—and even physicians—remains low, with delay in the diagnosis and even misdiagnosis of the disease being relatively common [1, 2]

CA is a “great mimicker,” and the diagnosis is delayed due to both physician and disease-related factors [3]

Misdiagnosed Conditions

Amyloidosis (of all types) patients with CA [4]

Unspecified HF was a common misdiagnosis across all types—and most common in ATTRwt patients (33%) [4]

ATTRwt-CM

For example, although a nationwide survey in Japan identified 51 patients with ATTRwt-CM between 2012 and 2014, a diagnosis was only made in 11 of 2341 departments that responded to the survey [1]
Moreover, 29% and 26% of participants of an online survey by the Amyloidosis Research Consortium (patients with ATTRwt-CM or their caregivers, n = 55) reported missed diagnoses and misdiagnoses, respectively, and 65% of patients had to see 2 cardiologists before diagnosis [1]
In Europe, among 100 ATTRwt-CM patients diagnosed at 2 centers, 34% had been previously misdiagnosed; most commonly with:
- Hypertensive cardiomyopathy (12 patients)
- Hypertrophic cardiomyopathy (8 patients) [1]
Misdiagnosis of cardiac AL amyloidosis is also a common pitfall as up to 10% of misdiagnoses occur even in referral centers [1]
- Differentiation is crucial, as untreated cardiac AL amyloidosis has a poor prognosis (<1 year)
- And requires a completely different treatment strategy—high-dose chemotherapy with stem cell transplant

# of Different Cardiologists Seen

(n=89 ATTRwt patients, %)

Likewise, in a larger US cohort (n=89), 63% reported seeing 2 or more cardiologists [6]

Notes: CM = cardiomyopathy; HF = heart failure; * other includes dermatologists, endocrinologists, gastroenterologists, infectious disease specialists, oncologists, oral surgeons, otolaryngologists, pulmonologists, podiatrists, rheumatologists, surgeons, and urologists

Notes: A multidisciplinary amyloid team of cardiologists, neurologists, nephrologists, and hematologists is optimal for diagnosis and management, but such teams are rare and isolated to a few academic medical centers.3

Inomata, T, et al. Diagnosis of wild-type transthyretin amyloid cardiomyopathy in Japan: red-flag symptom clusters and diagnostic algorithm. ESC Heart Failure. 2021. DOI: 10.1002/ehf2.13473.
https://www.yourheartsmessage.com/attr-cm-diagnosis.
Thoracic Key: Cardiac Amyloidosis. https://thoracickey.com/cardiac-amyloidosis-4/. Accessed November 3, 2021.
Lousada, et al. Amyloidosis Research Consortium Cardiac Amyloidosis Survey: Results from Patients with AL and ATTR Amyloidosis and Their Caregivers. Poster presented at the XVIth International Symposium on Amyloidosis; March 26-29, 2018; Kumamoto, Japan.
- “Overall 294 (45%) patients (42% in AL, 39% in wtATTR, 44% in hATTR) received ≥1 misdiagnoses before being correctly diagnosed with amyloidosis.”
- “Unspecified heart failure or heart disease was a common misdiagnosis across all types (24%) and most common in wtATTRpatients (33%).”
- “The next most common misdiagnoses were all cardiac related: hypertrophic cardiomyopathy (11%), high blood pressure (5%), and heart arrhythmias (5%).”
Cleveland Clinic: Hypertrophic Cardiomyopathy (https://my.clevelandclinic.org/health/diseases/17116-hypertrophic-cardiomyopathy: accessed 1/12/20)
- “Hypertrophic cardiomyopathy (HCM) is a complex type of heart disease that affects the heart muscle. It causes thickening of the heart muscle (especially the ventricles, or lower heart chambers), left ventricular stiffness, mitral valve changes and cellular changes.”
Rozenbaum MH, Large S, Bhambri R, et al. Impact of Delayed Diagnosis and Misdiagnosis for Patients with Transthyretin Amyloid Cardiomyopathy (ATTR-CM): A Targeted Literature Review. Cardiol Ther. 2021;10(1):141-159. doi:10.1007/s40119-021-00219-5.

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