Clinical Geriatrics - Original Investigations
Published: 2021-06-15

Cardiac amyloidosis awareness among residents/specialists in Geriatrics: an Italian national survey

Unit of Geriatrics, Campus Bio-Medico University of Rome, Rome, Italy
Unit of Geriatrics, Campus Bio-Medico University of Rome, Rome, Italy
Department of Translationl Medical Sciences, University of Naples “Federico II”, Naples, Italy
for the Società Italiana di Gerontologia e Geriatria; Unit of Geriatrics, Campus Bio-Medico University of Rome, Rome, Italy
Cardiovascular

Abstract

Objective. Cardiac amyloidosis (CA) among older adults is less infrequent than usually considered, and often underdiagnosed. Geriatricians’ awareness and knowledge of CA is unknown. Objectives of the study are to assess actual CA knowledge among residents/specialists in Geriatrics, and their usual clinical practice in managing suspected CA.
Methods. In this Nation-wide survey carried out by the Italian Society of Gerontology and Geriatrics in April-August 2020, we administered to residents/specialists in Geriatrics a questionnaire divided in three sections: socio-demographical, procedural and knowledge. Results were stratified by qualification (resident/specialist) and by performance (best/worst performers).
Results. 289 residents and 104 specialists participated. The overall proportion of correct answers was 57.9% (58.4% residents, 56.1% specialists); knowledge about clinical (89% of correct answers, 91% residents and 84% specialists, P = 0.062), ECG (72% of correct answers, no differences between groups), and echocardiographic (86% of correct answers, no differences between groups) signs of CA was good. However, only 8% participants knew how to diagnose ATTRwt CA (no differences between groups), and 19% which diuretic is indicated in CA (22% residents, 13% specialists, P = 0.069). Only 25% of the participants knew the natural history of ATTRwt (19% residents, 41% specialists, P < 0.001), and 37% was aware of the target of the ATTR treatment. Prevalence of CA was underestimated by 57% specialists and 37% residents (P = 0.001).
Conclusions. Knowledge of CA among residents/specialists in Geriatrics is uncomplete. Education campaigns on this topic are desirable, to improve physicians’ awareness of CA, thus reducing the number of potential misdiagnosis/delay in correct diagnoses.

INTRODUCTION

Amyloidosis is a systemic chronic and progressive disease characterized by extracellular deposition of amyloid, a fibrillar material derived from various precursor proteins, that leads to organ failure 1. Although there are more than 30 different precursor proteins implicated in various amyloid diseases, only 2 types account for over 95% of all cardiac amyloidosis (CA), characterized by diffuse amyloid fibril deposition in the heart causing thickening of both ventricles and appearing phenotypically as hypertrophic cardiomyopathy: immunoglobulin light chain amyloidosis (AL) and transthyretin amyloidosis (ATTR) 2. AL is a rare disease characterized by a clonal plasma cell disorder due to the overproduction and misfolding of antibody light chain fragments, while ATTR is due to misfolding of the liver-derived precursor protein transthyretin (TTR), either as a hereditary mutant (ATTRm) or as an acquired wild-type variant (ATTRwt) 3. The latter is the most common and typically has its clinical onset in advanced age, with clinical signs of heart failure 4.

Although CA has been considered a rare disease for a long time, recent evidence show that its prevalence has been largely underestimated. In the US, both incidence and prevalence increased over the years, up to a prevalence of about 55 cases per 100,000 persons/year in 2012 5. In older people, the prevalence is probably higher, as reported by several autopsy studies indicating the presence of ATTRwt myocardial deposits in 20-25% of octogenarians 6, and up to 37% in patients older than > 95 years 5.

Being a relatively rarely diagnosed syndrome, the underdiagnosis may be related to the poor awareness of this disease among physicians, bringing to late or no diagnosis. However, little is known about the real knowledge of CA among physicians: a survey on physicians’ attitudes in amyloidosis treatment has been recently performed 7, while only one study assessed knowledge among cardiologists 8.

Given the late clinical manifestations of ATTRwt CA and its common presentation as heart failure, a clinical condition frequently treated by geriatricians 9, it is pivotal for these specialists to suspect this disease when indicated. Therefore, assessing the knowledge about CA among specialists and trainees in Geriatrics, would allow to identify the educational needs in all the phases of these physicians’ training.

The aim of this nationwide Italian survey was to assess the actual knowledge about CA among residents and specialists in Geriatrics, in order to plan instructional programs on this topic, if needed. Secondary aim was to evaluate usual clinical practice in managing suspected CA by these physicians.

METHODS

This National survey was ideated and carried out in Italy from April to August 2020 by the Italian Society of Gerontology and Geriatrics (Società Italiana di Gerontologia e Geriatria, SIGG).

The study questionnaire was developed by a consensus group including three Geriatricians expert in CA. It included three sections, using clinical vignettes and multiple-choice answers: the first section collected demographic data, information on working geographical data and setting; the second section included procedural information, exploring education on amyloidosis and clinical attitudes in the management of patients with suspected or diagnosed CA; the third section explored the knowledge about the epidemiology, clinical features, diagnosis, and management of CA according to the most recent evidences available on this topic. In the design of the latest section, a particular interest was given to the most common types of CA, especially to the ATTRwt, the most widespread in older adults (Supplemental text 1).

This kind of questionnaire proved useful to interpret current practice on the basis of individual experience and culture in previous surveys on geriatric competences among Nephrologists 10, nephrological competences among Geriatricians 11, vaccines and vaccination in older people 12, and heart failure 9.

The secretary of the Society sent an email with an electronic copy of the survey to all the Italian Directors of Internship Programs in Geriatrics who were registered in the membership list of the Society, and to all the members of the National and Regional Governing Councils of the Society. They were invited to participate to the survey and to share the e-mail with the attached survey to all their colleagues being specialists or fellows in Geriatrics.

STATISTICAL ANALYSIS

Quantitative variables were reported using mean and standard deviation, while categorical ones were reported using proportions. All the analyses were performed on the whole sample and stratified according to qualification (specialist vs. resident). Comparison between groups were performed using the t-test for continuous variables and the chi-squared test for proportions.

In the third section, we calculated the proportion of correct answers for each question (only one possible correct answer), and a pooled proportion of correct answers.

In order to identify the characteristics of participants needing more educational support, we performed a comparison between participant in the highest (best performers) and lowest (worst performers) quartile of percentage of correct answers.

All the analyses were performed using R software, version 3.6.1 (Vienna, Austria).

RESULTS

GENERAL CHARACTERISTICS OF THE POPULATION

A total of 393 physicians, 289 residents and 104 specialists, participated to the survey. Mean age of the study population was 34.5 years (SD 9.2); 35% were male. With respect to specialists, residents were younger (45.3 years, SD 11.1 vs 30.6 years, SD 3.6) and less frequently male (42.3 vs 32.3%, P = 0.008), more frequently working in acute care ward (58.7 vs 90.3%), and less frequently in nursing home (13.5 vs 0%), or in outpatient clinic (14.4 vs 5.2%) (P < 0.001) (Tab. I). The distribution of specialists participating to the survey across National macro-areas is reported in Figure 1. Forty-five percent of participants worked in Southern Italy, while 32.8% in Central and 22.1% in Northern Italy, with a higher prevalence of residents in Northern (25.3 vs 13.5%) Italy, and a slight lower prevalence in Central and Southern Italy (P = 0.046) (Tab. I).

EDUCATION AND CLINICAL ATTITUDES FOR CA OF THE POPULATION

Most of the participants obtained information on CA from Pubmed (78.1%, with no differences between residents and specialists), or by individual web search (54.2%; residents 58.8 vs specialists 41.3%, P = 0.003); specialists more frequently studied using material provided by pharmaceutical company representatives (21.2 vs 5.2%, P < 0.001), and using International scientific journals (44.2 vs 30.8%, P = 0.019). Globally, 38.7% of the participants had previously managed patients with CA (60.6% among specialists and 30.1% among residents), 20.6% of which were patients visited for symptoms of heart failure, and 20.1% visited for other diseases, and in 13% of cases it was a first diagnosis of CA. About 68% of participants (74.8% of the specialists and 65% of the residents, P = 0.191) prescribed second level exams with suspected CA regardless of age and comorbidities.

In case of CA with cardiologic symptoms, 59% preferred to manage personally older patients with multimorbidity (no differences between groups), and 41.2% asked for a cardiologic visit to all patients, independently from age or other characteristics (residents 40.1 vs specialists 44.2, P = 0.543).

When visiting patients with features suggestive for CA, screening exams for amyloidosis were prescribed by only 55.1% of the participants, while 26.5% of physicians preferred to firstly treat heart failure symptoms, and prescribed a screening for CA only in case of treatment failure (no differences between groups).

Only 50.9% of participants reported that amyloidosis was included in teaching activities during medical school, and 12% reported that it was never included in their training (8.3 among residents and 22.3% among specialists) (P < 0.001) (Supplemental Table I).

KNOWLEDGE ABOUT CA OF THE STUDY SAMPLE

Overall, the rate of correct answers was 57.9% (58.4% among residents and 56.1% among specialists). However, this result stems from a sharp difference between general knowledge of CA, fair, and that of the diagnostic pathway, such as diagnostic criteria of amyloidosis or scintigraphy interpretation, which was poor. Indeed, the knowledge about clinical (89% of correct answers, 91% among residents and 84% among specialists, P = 0.062), ECG (72% of correct answers, with no differences between groups), and echocardiographic (86% of correct answers, 84% among residents and 91% among specialists, P = 0.091) signs of CA was good. Comparable figures were obtained for the knowledge of the clinical history leading to suspect CA (90% of correct answers, 96% among residents and 75% among specialists), and the diagnostic role of immunofixation in suspected CA (87% of correct answers, no differences between groups). On the other hand, very poor was the knowledge about how to diagnose ATTRwt CA (8% of correct answers, no differences between groups), or about diuretic treatment in patients with CA (19% of correct answers, 22% among residents and 13% among specialists, P = 0.069). Furthermore, only 25% of the participants knew the natural history of ATTRwt (19% among residents and 41% among specialists, P < 0.001), and only 38% how to perform differential diagnosis of CA using bone scintigraphy (30% among specialists and 41% among residents, P = 0.065), and only 37% of participants was aware of the target of the ATTR treatment. Finally, the prevalence of CA was underestimated by 57% specialists and 37% residents (P = 0.001) (Tab. II).

Comparing “best” with “worst” performers, there were no differences in age, sex, and status, despite the former group was slightly younger and included a majority of residents. Best performers worked more frequently in Southern Italy (59 vs 33%, P < 0.001) and in acute care wards (90 vs 81%, P = 0.028), and used more frequently Pubmed to study CA (84.5 vs 73.3%, P = 0.068). There were no differences in clinical experience of CA, while best performers more frequently prescribed second level exams in the case of suspected CA, independently from age and comorbidities (75.3 vs 60.7%, P = 0.048). Finally, best performers more frequently had studied amyloidosis both during medical school and the internship program (30.5 vs 16.7%, P = 0.045).

DISCUSSION

Overall, the participants in this Italian National survey had an uncomplete knowledge of CA, independently from their status of specialist or resident in Geriatrics: despite the good theoretical education on clinical features of this disease, they lacked information on how to diagnose it, especially the ATTRwt, that is the most common form of CA in older adults.

Our data are in line with the results reported by Mircsof et al among 72 Cardiologists working in Switzerland, that showed a wide variation in knowledge and in diagnostic tests used during differential diagnosis of ATTR CA, and concluded that Cardiologists in that country would benefit from information on the latest advances in ATTR 8.

A key result of our survey is the evidence that most physician, independently from their status of resident or specialist, underestimate the prevalence of CA. This indicates that improving the awareness of the physician about the frequency of this disease is pivotal: other studies have shown that there is a delay of up to 39 months from first presentation of cardiac symptoms to CA diagnosis and over 4 years if considering ATTRwt 13.

Furthermore, there is inadequate knowledge on how to diagnose CA and to interpret bone scintigraphy results. This non-invasive diagnostic technique, easy to perform also among older adults 14, has 99% sensitivity and 86% specificity for cardiac ATTR 15 and has been included as a screening tool for ATTR-CA in the 2016 European Society of Cardiology guidelines for the treatment of heart failure 16.

Worthy of note also are the really poor physicians’ awareness of how to diagnose ATTRwt, the most common form of CA among older adults 4, and the relatively low number of patients sent for specific treatments (already documented among Cardiologists 8), probably due to the poor knowledge of which is the target for ATTRwt treatment.

All these issues are pivotal considering that new and effective treatments for CA have become available in the latest years. For example, Tafamidis, a tetramer stabilizer that binds with high affinity and selectivity to the thyroxine site of TTR slowing dissociation of TTR tetramers into monomers and preventing aggregation in amyloid fibrils, has been shown to be effective in reducing cardiovascular-related hospitalizations and all-cause mortality; it also improves physical performance and quality of life of patients affected by TTR CA 17, and has been approved for treatment of both wild-type and mutated TTR CA 18. Other molecules, such as AG10, another transthyretin tetramer stabilizer, and Patisiran, a transthyretin synthesis inhibitor, have shown promising results, and, currently, are under investigation in phase III trials 18. Furthermore, it should be considered that awareness on CA could help, if diagnosed or even only suspected, in revising carefully the cardiologic drugs used to treat symptoms of heart failure. Indeed, selected drugs, such as non-dihydropyridine calcium channel-blockers and digoxin, could have important adverse effects when used in patients affected by CA 3.

Interestingly, our survey documented that participants having the best performance were slightly younger and more frequently resident, and that there were no differences with respect to worst performers in their personal experience of CA, and best performers more frequently studied CA both during their MD and fellowship. These physicians were also those that more frequently prescribed second level exams for suspected amyloidosis. Thus, our findings once more highlight the importance of an adequate education in CA to improve physicians’ awareness of this disease and, thus, to suspect CA and prescribe second levels exams.

Our study has some weaknesses: firstly, the sampling of the study population mostly included physicians working in University settings, thus leading to a plausible overestimation of the guidelines’ knowledge from the whole cohort of the Italian Geriatricians 19. Nevertheless, this was an obvious selection condition to focus on residents in Geriatrics. Second, it was a questionnaire developed ad hoc for the purpose of this survey, and its clinimetric properties were not evaluated. However, previous experience is consistent with this kind of questionnaire having classificatory properties able to gain insight into the dynamic underlying physician’s awareness of and practice with selected different conditions 9,12. Furthermore, the main aim of the survey was to have an overview of the approach to CA and not a punctual assessment of this disease.

CONCLUSIONS

This Italian National survey highlighted that the knowledge of CA among both residents and specialists in Geriatrics is uncomplete, and, thus, education campaigns on this topic are desirable, with the aim of improving physicians’ awareness of CA, thus reducing the number of potential misdiagnosis or delay in correct diagnoses, and improving quality of life and prognosis of these patients.

Ethical consideration

This research complies with the ethical rules for human experimentation stated in the Declaration of Helsinki.

Acknowledgement

We would like to acknowledge all the Directors of the Italian Internship programs in Geriatrics for their participation to the Survey.

We would like to acknowledge also Gilda Borselli and Letizia Scarpelli for their support for data management. The corresponding author has listed everyone who contributed significantly to the work and has obtained written consent from all contributors who are not authors and are named in the Acknowledgment section.

Conflict of interest

The authors have no conflicts of interest to disclose.

Author contributions

Diana Lelli, Claudio Pedone, Dario Leosco, and Raffaele Antonelli Incalzi contributed to the study conception and design and to the acquisition of data. Data analysis were performed by Diana Lelli, and were interpreted by all the authors. The first draft of the manuscript was written by Diana Lelli, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Funding sources and sponsors’ role

This study was supported by a liberal, non-conditioning, educational grant by Pfizer Italia.

Figures and tables

Figure 1.Participation to the survey. Distribution of specialists participating to the survey across National macro-areas. Grey areas indicate regions without participants to the survey.

Residents | N: 289 Specialists | N: 104 All | N: 393 P
Age, years, mean (SD) 30.6 (3.6) 45.3 (11.1) 34.5 (9.2) < 0.001
Male sex N (%) 93 (32.3) 44 (42.3) 137 (34.9) 0.008
Type of practice, N (%)
  Outpatient clinic 15 (5.2) 15 (14.4) 30 (7.6) < 0.001
  Acute care ward 261 (90.3) 61 (58.7) 322 (81.9)
  Rehabilitation 3(1) 2 (1.9) 5 (1.3)
  Nursing home 0 (0) 14 (13.5) 14 (3.6)
  Other 7 (2.5) 9 (8.6) 16 (3.1)
  No answer 3(1) 3 (2.9) 6 (1.5)
Geographical area, N (%)
  North 73 (25.3) 14 (13.5) 87 (22.1) 0.046
  Center 91 (31.5) 38 (36.5) 129 (32.8)
  South 125 (43.3) 52(50) 177(45)
Table I.General characteristics of the population.
Questions Residents (%) Specialists (%) All (%) P
Clinical signs of CA among older adults 91 84 89 0.062
ECG typical signs of CA 72 69 72 0.616
Echocardiographic typical signs of CA 84 91 86 0.091
Prevalence of CA 37 57 43 0.001
Common arrhythmic/conduction system defects in CA 69 60 67 0.146
Common features of amyloidosis 70 65 69 0.487
Amyloidosis AL 61 46 57 0.011
Amyloidosis ATTR 65 62 64 0.656
Amyloidosis ATTRwt 19 41 25 < 0.001
Role of serum and urinary immunofixation in suspected CA 86 89 87 0.423
Instrumental diagnosis of amyloidosis 58 54 57 0.570
Management of older patient with atrial fibrillation and new onset of heart failure with history of carpal tunnel 96 75 90 < 0.001
Diagnosis of amyloidosis ATTRwt 9 6 8 0.403
Diuretic treatment in CA 22 13 19 0.069
Drugs not recommended in CA 67 75 69 0.210
The target of amyloidosis ATTR treatment 40 30 37 0.100
Clinical classification of amyloidosis ATTR 41 53 45 0.050
Prevalence of association between aortic valve stenosis and CA 56 42 52 0.024
Differential diagnosis of CA from myocardial uptake in bone scintigraphy 41 30 38 0.065
Tafamidis mechanism of action 85 80 84 0.330
Abbreviations: AL: light chain; ATTRwt: transthyretin wild type; CA: cardiac amyloidosis; ECG: electrocardiogram
Table II.Summary of correct answers per issue.
Worst performers Best performers P
Age, years, mean (SD) 35.6 (10.2) 33.4 (7.3) 0.071
Male sex, % 41 33 0.295
Resident, % 70 81 0.075
Region of working, % < 0.001
                     Center 24 27
                     North 42 14
                     South 33 59
Type of practice, % 0.028
                     Outpatient clinic 9 2
                     Acute care ward 81 90
                     Rehabilitation 2 1
                     Nursing home 2 0
                     No answer 0 4
Where do you study clinical features, diagnosis and treatment of cardiac amyloidosis (more than one answer possible)?
PubMed 73.3 84.5 0.068
Web pages and publications of the Ministry of Health 10.8 19.6 0.106
Congresses and training courses 25 16 0.120
International Scientific journals 28 33 0.466
Individual web search 53 61 0.275
If you suspect cardiac amyloidosis:
You always prescribe second level exams, independently of age and comorbidities, with the exception of terminal patients 60.7 75.3 0.048
You prescribe second level exams only for younger patients 1.7 0
You prescribe second level exams only for patients with good performance status and few comorbidities 37.6 24.7
In your training, amyloidosis was studied:
During the MD 55.8 43.2 0.045
During the fellowship 12.5 7.4
Both during the MD and the fellowship 16.7 30.5
Never, only occasional information during congresses 15 18.9
In your clinical practice, heart failure is:
Very common (> 30% of cases) 71.7 66 0.781
Common (10-30% of cases) 19.2 22.7
Uncommon (< 10% of cases) 7.5 8.2
Very uncommon 16.7 3.1
No significant differences were reported in experience with patients with cardiac amyloidosis, nor for their clinical management.
Table III.Main characteristics of the participants according to their performance.

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Affiliations

Diana Lelli

Unit of Geriatrics, Campus Bio-Medico University of Rome, Rome, Italy

Claudio Pedone

Unit of Geriatrics, Campus Bio-Medico University of Rome, Rome, Italy

Dario Leosco

Department of Translationl Medical Sciences, University of Naples “Federico II”, Naples, Italy

Raffaele Antonelli Incalzi

for the Società Italiana di Gerontologia e Geriatria; Unit of Geriatrics, Campus Bio-Medico University of Rome, Rome, Italy

Copyright

© JOURNAL OF GERONTOLOGY AND GERIATRICS , 2021

How to Cite

[1]
Lelli, D., Pedone, C., Leosco, D. and Antonelli Incalzi, R. 2021. Cardiac amyloidosis awareness among residents/specialists in Geriatrics: an Italian national survey. JOURNAL OF GERONTOLOGY AND GERIATRICS. 69, 3 (Jun. 2021), 177-187. DOI:https://doi.org/10.36150/2499-6564-N374.
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