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Temporal Trends in Diagnostic Testing Patterns for Wild-Type Transthyretin Amyloid Cardiomyopathy in the Medicare Fee-for-Service Population

Open AccessPublished:January 09, 2022DOI:https://doi.org/10.1016/j.amjcard.2021.11.048
      Wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM) is frequently misdiagnosed or diagnosed late in the disease course. ATTRwt-CM can be diagnosed invasively through tissue biopsy, but current diagnostic recommendations indicate technetium-99m pyrophosphate (99mTc-PYP) bone scintigraphy is an acceptable noninvasive alternative. The relative use of these confirmatory diagnostic tests in routine clinical practice is unknown. A retrospective observational study assessed temporal trends in biopsy and 99mTc-PYP scintigraphy and differences in patient characteristics using in/outpatient claims data from the US Medicare fee-for-service database. Claims prevalence for biopsy alone (≥1 claim for cardiac/extracardiac biopsy), imaging alone (≥1 claim for 99mTc-PYP scintigraphy), and both tests and patient demographic, geographic, and clinical characteristics were examined. Of patients (n = 1226) receiving an ATTRwt-CM diagnostic code, 29%, 47%, and 24% were diagnosed by biopsy alone, 99mTc-PYP scintigraphy alone, and both tests, respectively. Patients with claims for 99mTc-PYP scintigraphy alone were older than those with claims for biopsy alone (79.9 vs 76.5; p <0.001). Fewer patients in the southern United States and more patients in the northeastern United States had claims for 99mTc-PYP scintigraphy alone than biopsy alone (p <0.001). There was a temporal trend toward more claims for 99mTc-PYP scintigraphy alone (odds ratio 1.21; p <0.001) and both tests (odds ratio 1.10; p = 0.008) versus biopsy alone. From 2017 to 2019, claims increased for 99mTc-PYP scintigraphy alone. In conclusion, these data suggest a growing preference for the noninvasive imaging technique, which has high sensitivity/specificity, usability, and accessibility and may help facilitate earlier disease diagnosis. United States regional differences in the use of 99mTc-PYP scintigraphy highlight the need for education initiatives.
      Transthyretin amyloid cardiomyopathy (ATTR-CM) is often misdiagnosed or diagnosed late in the disease course, resulting in a poorer prognosis.
      • Witteles RM
      • Bokhari S
      • Damy T
      • Elliott PM
      • Falk RH
      • Fine NM
      • Gospodinova M
      • Obici L
      • Rapezzi C
      • Garcia-Pavia P.
      Screening for transthyretin amyloid cardiomyopathy in everyday practice.
      With the advent of disease-modifying therapies,
      • Maurer MS
      • Sultan MB
      • Rapezzi C.
      Tafamidis for transthyretin amyloid cardiomyopathy.
      more rapid diagnosis, and treatment of ATTR-CM has become a critical unmet need.
      • Rozenbaum MH
      • Large S
      • Bhambri R
      • Stewart M
      • Whelan J
      • van Doornewaard A
      • Dasgupta N
      • Masri A
      • Nativi-Nicolau J.
      Impact of delayed diagnosis and misdiagnosis for patients with transthyretin amyloid cardiomyopathy (ATTR-CM): a targeted literature review.
      Although endomyocardial biopsy remains the gold standard for the definitive diagnosis of ATTR-CM, broader use of contemporary technetium-99m pyrophosphate (99mTc-PYP) bone scintigraphy is recommended to diagnose ATTR-CM, based on its high sensitivity and specificity, in appropriate clinical scenarios (e.g., in patients for whom a diagnosis of light-chain amyloidosis has been ruled out), to facilitate early diagnosis with minimal risk to and easier access for patients with suspected disease.
      • Maurer MS
      • Bokhari S
      • Damy T
      • Dorbala S
      • Drachman BM
      • Fontana M
      • Grogan M
      • Kristen AV
      • Lousada I
      • Nativi-Nicolau J
      • Cristina Quarta C
      • Rapezzi C
      • Ruberg FL
      • Witteles R
      • Merlini G
      Expert consensus recommendations for the suspicion and diagnosis of transthyretin cardiac amyloidosis.
      • Dorbala S
      • Ando Y
      • Bokhari S
      • Dispenzieri A
      • Falk RH
      • Ferrari VA
      • Fontana M
      • Gheysens O
      • Gillmore JD
      • Glaudemans AWJM
      • Hanna MA
      • Hazenberg BPC
      • Kristen AV
      • Kwong RY
      • Maurer MS
      • Merlini G
      • Miller EJ
      • Moon JC
      • Murthy VL
      • Quarta CC
      • Rapezzi C
      • Ruberg FL
      • Shah SJ
      • Slart RHJA
      • Verberne HJ
      • Bourque JM.
      ASNC/AHA/ASE/EANM/HFSA/ISA/SCMR/SNMMI expert consensus recommendations for multimodality imaging in cardiac amyloidosis: part 1 of 2-evidence base and standardized methods of imaging.
      • Dorbala S
      • Ando Y
      • Bokhari S
      • Dispenzieri A
      • Falk RH
      • Ferrari VA
      • Fontana M
      • Gheysens O
      • Gillmore JD
      • Glaudemans AWJM
      • Hanna MA
      • Hazenberg BPC
      • Kristen AV
      • Kwong RY
      • Maurer MS
      • Merlini G
      • Miller EJ
      • Moon JC
      • Murthy VL
      • Quarta CC
      • Rapezzi C
      • Ruberg FL
      • Shah SJ
      • Slart RHJA
      • Verberne HJ
      • Bourque JM
      ASNC/AHA/ASE/EANM/HFSA/ISA/SCMR/SNMMI expert consensus recommendations for multimodality imaging in cardiac amyloidosis: part 2 of 2-diagnostic criteria and appropriate utilization.
      The importance of both tissue biopsy and myocardial scintigraphy for the diagnosis of wild-type ATTR-CM (ATTRwt-CM) has been increasingly recognized,
      • Maurer MS
      • Bokhari S
      • Damy T
      • Dorbala S
      • Drachman BM
      • Fontana M
      • Grogan M
      • Kristen AV
      • Lousada I
      • Nativi-Nicolau J
      • Cristina Quarta C
      • Rapezzi C
      • Ruberg FL
      • Witteles R
      • Merlini G
      Expert consensus recommendations for the suspicion and diagnosis of transthyretin cardiac amyloidosis.
      ,
      • Dorbala S
      • Ando Y
      • Bokhari S
      • Dispenzieri A
      • Falk RH
      • Ferrari VA
      • Fontana M
      • Gheysens O
      • Gillmore JD
      • Glaudemans AWJM
      • Hanna MA
      • Hazenberg BPC
      • Kristen AV
      • Kwong RY
      • Maurer MS
      • Merlini G
      • Miller EJ
      • Moon JC
      • Murthy VL
      • Quarta CC
      • Rapezzi C
      • Ruberg FL
      • Shah SJ
      • Slart RHJA
      • Verberne HJ
      • Bourque JM.
      ASNC/AHA/ASE/EANM/HFSA/ISA/SCMR/SNMMI expert consensus recommendations for multimodality imaging in cardiac amyloidosis: part 1 of 2-evidence base and standardized methods of imaging.
      ,
      • Gillmore JD
      • Maurer MS
      • Falk RH
      • Merlini G
      • Damy T
      • Dispenzieri A
      • Wechalekar AD
      • Berk JL
      • Quarta CC
      • Grogan M
      • Lachmann HJ
      • Bokhari S
      • Castano A
      • Dorbala S
      • Johnson GB
      • Glaudemans AW
      • Rezk T
      • Fontana M
      • Palladini G
      • Milani P
      • Guidalotti PL
      • Flatman K
      • Lane T
      • Vonberg FW
      • Whelan CJ
      • Moon JC
      • Ruberg FL
      • Miller EJ
      • Hutt DF
      • Hazenberg BP
      • Rapezzi C
      • Hawkins PN.
      Nonbiopsy diagnosis of cardiac transthyretin amyloidosis.
      but the frequency of their use in clinical practice has not been well established. In this study, we evaluated patterns of diagnostic testing with these techniques for ATTRwt-CM in a Medicare fee-for-service population and potential differences in demographic and other clinical characteristics of patients with ATTRwt-CM confirmed with the techniques.

      Methods

      A detailed description of the study methodology is available in Supplementary Table 1. In brief, this retrospective observational study was conducted using administrative claims data from the Medicare fee-for-service database. Claims data were analyzed from patients with ≥1 inpatient or outpatient claim for ATTRwt-CM International Classification of Diseases, Tenth Revision, Clinical Modification Code E85.82 during the 2-year identification period of October 1, 2017 to December 31, 2019. Continuous enrollment in Medicare Parts A or B was required from ≥6 months before to ≥3 months after the date of first use of the ATTRwt-CM diagnosis code (that is, the index diagnosis date); this period was selected based on sensitivity analyses conducted to determine the most robust output.
      The prevalence of ≥1 claim for the following diagnostic tests was analyzed: (1) cardiac or extracardiac biopsy alone; (2) 99mTc-PYP bone scintigraphy alone; and (3) both biopsy and 99mTc-PYP scintigraphy. Changes in the frequency of claims for these diagnostic tests over the study period were examined.
      In all, 3 cohorts of patients with the ATTRwt-CM diagnostic code were created based on their diagnostic test claims (that is, biopsy alone, 99mTc-PYP scintigraphy alone, and both diagnostic tests) during the study period. Demographic characteristics of patients, United States geographic locations (regions and states), comorbidities, and clinical characteristics potentially associated with ATTRwt-CM at the index diagnosis date were derived from the claims data. Comorbidities were assessed using the Quan-Charlson comorbidity index for 6 months before the index date.
      • Quan H
      • Li B
      • Couris CM
      • Fushimi K
      • Graham P
      • Hider P
      • Januel JM
      • Sundararajan V.
      Updating and validating the Charlson comorbidity index and score for risk adjustment in hospital discharge abstracts using data from 6 countries.
      For patient characteristics, continuous variables were analyzed using analysis of variance; categorical variables were analyzed using chi-square test/Fisher's exact test. Two-sided p values <0.05 were considered statistically significant. The choice of diagnostic test was modeled using multinomial logistic regression (that is, a generalized logit model) with aggregate data on 3 months (that is, quarter [Q]) level. Time was modeled as a continuous variable to test for a trend.

      Results

      Of 1,226 patients with ATTRwt-CM diagnostic codes on claims included in this analysis, 354 (29%), 582 (47%), and 290 (24%) had claims for biopsy alone, 99mTc-PYP scintigraphy alone, and both biopsy and 99mTc-PYP scintigraphy, respectively (Figure 1). Patients with claims for 99mTc-PYP scintigraphy alone were statistically significantly older than patients with claims for biopsy alone, less likely to be male, and more likely to be White (Table 1).
      Figure 1
      Figure 1Flowchart of patient disposition. aIndex date is the date of first use of the ATTRwt-CM diagnostic code.
      Table 1Demographic and clinical characteristics of Medicare-enrolled patients with confirmed ATTRwt-CM by diagnostic test
      CharacteristicsBiopsy Alone (n = 354)99mTc-PYP Scintigraphy Alone (n = 582)Both Biopsy and 99mTc-PYP Scintigraphy (n = 290)p Value
      Age, mean (SD), (years)76.5 (8.0)79.9 (7.4)77.5 (7.2)<0.001
      Age range<0.001
       <6512 (3%)0 to 11 (0% to 2%)0 to 11 (0% to 4%)
       65–74119 (34%)118 (20%)96 (33%)
       75–84172 (49%)300 (52%)148 (51%)
       >8551 (14%)150 to 160 (26% to 28%)40 to 50 (14% to 17%)
      Men299 (84%)462 (79%)252 (87%)0.01
      White259 (73%)461 (79%)242 (83%)0.04
      Black75 (21%)95 (16%)35 to 45 (12 to 16%)
      Other (race)20 (6%)26 (5%)0 to 11 (0% to 4%)
      Charlson comorbidity index, mean (SD)8.7 (3.4)8.3 (2.7)8.7 (3.2)0.07
      Hypertension307 (87%)527 (91%)253 (87%)0.14
      Atrial fibrillation/flutter261 (74%)436 (75%)227 (78%)0.39
      Heart failure with preserved ejection fraction273 (77%)418 (72%)209 (72%)0.17
      Permanent pacemaker and/or implantable cardioverter-defibrillator91 (26%)152 (26%)75 (26%)0.98
      Conduction disease
      Heart block and/or bundle branch block.
      73 (21%)126 (22%)66 (23%)0.81
      Pericardial effusion65 (18%)93 (16%)45 (16%)0.55
      Aortic stenosis42 (12%)106 (18%)47 (16%)0.04
      Left ventricular hypertrophy
      Or increased wall thickness.
      46 (13%)56 (10%)37 (13%)0.20
      Chronic kidney disease190 (54%)291 (50%)151 (52%)0.54
      Cataracts171 (48%)278 (48%)144 (50%)0.87
      Glaucoma151 (26%)72 (25%)69 (24%)0.07
      Lumbar spinal stenosis75 (21%)110 (19%)89 (31%)<0.001
      Carpal tunnel syndrome74 (21%)103 (18%)75 (26%)0.02
      Monoclonal gammopathy69 (19%)52 (9%)48 (17%)<0.001
      Peripheral neuropathy44 (12%)59 (10%)41 (14%)0.20
      Erectile dysfunction42 (12%)52 (9%)34 (12%)0.26
      99mTc-PYP = technetium-99m pyrophosphate; ATTRwt-CM = wild-type transthyretin amyloid cardiomyopathy; CMS = Centers for Medicare & Medicaid Services.
      Statistical data are for comparison in the 3 diagnostic test cohorts.
      Ranges are displayed for values <11 as required by the CMS for privacy protection.
      ATTR-CM–related medical history was extrapolated from claims for a 2-year period preceding the index date.
      Clinical cardiac and noncardiac characteristics occurring in >5% of all patients are shown, ranked by frequency in all patients.
      low asterisk Heart block and/or bundle branch block.
      Or increased wall thickness.
      Based on claims data, across all diagnostic test cohorts, cardiac conditions most commonly present in patients with ATTRwt-CM were hypertension, atrial fibrillation, and heart failure with preserved ejection fraction, whereas the most common noncardiac conditions were chronic kidney disease and cataracts (Table 1). The comorbidity index and the frequency of claims for most potentially ATTRwt-CM–associated conditions were comparable in the diagnostic test cohorts. Significant differences were observed in claims frequency for biopsy alone, scintigraphy alone, and both biopsy and scintigraphy for aortic stenosis, lumbar spinal stenosis, carpal tunnel syndrome, and monoclonal gammopathy.
      Statistically significant United States regional differences were observed in the diagnostic test cohorts (Figure 2). Significantly fewer patients in the South had claims for 99mTc-PYP scintigraphy alone than biopsy alone, and significantly more patients in the Northeast had claims for the imaging test alone than biopsy alone. These regional trends were also observed with claims for both biopsy and 99mTc-PYP scintigraphy compared with biopsy alone. Claims frequency for the imaging test alone and biopsy alone were similar in the Midwest and West. Differences in claims for these diagnostic tests at the state level are shown in Supplementary Table 2. United States states with the highest frequencies of claims for 99mTc-PYP scintigraphy alone in the Northeast, South, Midwest, and West, respectively, were Massachusetts, Florida, Ohio, and California.
      Figure 2
      Figure 2Proportions of patients with ATTRwt-CM by diagnostic test and United States region. Bars show % of patients. p <0.001 for comparison in the 3 diagnostic test cohorts.
      The frequency of claims for 99mTc-PYP scintigraphy alone increased by 42% over the study period, from 38% of patients in Q4 2017 to 54% in Q3 2019 (Figure 3). During this period, claims frequency for biopsy alone decreased by 38%, from 34% of patients in Q4 2017 to 21% in Q3 2019. The frequency of claims for both biopsy and 99mTc-PYP scintigraphy remained stable during the study period, as frequency of use decreased minimally from 28% of patients in Q4 2017 to 26% in Q3 2019. Over the study period, patients with confirmed ATTRwt-CM in this analysis had significantly greater odds of having a claim for 99mTc-PYP scintigraphy alone or both biopsy and 99mTc-PYP scintigraphy versus biopsy alone.
      Figure 3
      Figure 3Proportion of patients with ATTRwt-CM by diagnostic test(s) based on Medicare claims (October 2017 to December 2019). aConfirmed with associated diagnostic code, ICD-10-CM Code E85.82. bStatistical data are for comparison of 99mTc-PYP scintigraphy alone or both biopsy and 99mTc-PYP scintigraphy versus biopsy alone. CI = confidence interval; ICD-10-CM = International Classification of Diseases, Tenth Revision, Clinical Modification; OR = odds ratio.

      Discussion

      In this retrospective observational study, we found that tissue biopsy continued to be a commonly used test from 2017 to 2019, both with and without radionuclide imaging, for the definitive diagnosis of ATTRwt-CM. However, during the study period, claims increased for 99mTc-PYP scintigraphy alone, in parallel with declining claims for biopsy alone, suggesting a growing preference for noninvasive imaging testing with 99mTc-PYP scintigraphy for the diagnosis of ATTRwt-CM.
      We observed significant differences in diagnostic test cohorts in some patient characteristics, but their clinical relevance is unclear. Claims for 99mTc-PYP scintigraphy alone were less common in younger patients (that is, 65 to 75 years old) and more common in older patients (that is, >85 years old) than claims for biopsy alone. This finding may reflect the preference of clinicians for the imaging technique over invasive (and thereby riskier) tissue biopsy in patients of advancing age who have suspected ATTR-CM disease. Importantly, the highest frequency of claims for 99mTc-PYP scintigraphy was observed in the northeastern United States, whereas claims rates for the imaging technique were lower in other regions, suggesting the need for further education to support broader adoption of 99mTc-PYP scintigraphy when appropriate.
      Additional clinical implications can be garnered from this study's findings. Increasing awareness and use of 99mTc-PYP scintigraphy for the diagnosis of ATTRwt-CM may help address important challenges associated with disease recognition and treatment. For example, it may hasten and facilitate clinicians’ suspicion and identification of ATTRwt-CM, which is frequently overlooked or misidentified as other, more common, causes of heart failure.
      • Witteles RM
      • Bokhari S
      • Damy T
      • Elliott PM
      • Falk RH
      • Fine NM
      • Gospodinova M
      • Obici L
      • Rapezzi C
      • Garcia-Pavia P.
      Screening for transthyretin amyloid cardiomyopathy in everyday practice.
      ,
      • Ruberg FL
      • Grogan M
      • Hanna M
      • Kelly JW
      • Maurer MS.
      Transthyretin amyloid cardiomyopathy: JACC state-of-the-art review.
      More frequent use of bone scintigraphy highlights the accessibility of the test in the clinical practice setting, not only in academic or amyloidosis specialty centers. Although broader guidance on scintigraphy performance and interpretation is needed, many health care providers in the community currently consider this noninvasive diagnostic test to be a viable option for patients with suspected amyloidosis.
      With the earlier diagnosis of ATTR-CM, patients will also likely benefit from a shortened pathway to currently available and future disease-modifying treatments. At present, tafamidis is the only agent approved by the US Food and Drug Administration for the treatment of ATTR-CM. Tafamidis was shown to reduce all-cause mortality and cardiovascular-related hospitalizations in patients with hereditary or wild-type disease and provided the greatest benefits when administered early in the disease course.
      • Maurer MS
      • Sultan MB
      • Rapezzi C.
      Tafamidis for transthyretin amyloid cardiomyopathy.
      Clinical trials are also ongoing for investigational therapies for ATTR-CM, including the transthyretin stabilizer acoramidis, which may also prove to be beneficial against this progressive multisystem disease.
      • Judge DP
      • Heitner SB
      • Falk RH
      • Maurer MS
      • Shah SJ
      • Witteles RM
      • Grogan M
      • Selby VN
      • Jacoby D
      • Hanna M
      • Nativi-Nicolau J
      • Patel J
      • Rao S
      • Sinha U
      • Turtle CW
      • Fox JC.
      Transthyretin stabilization by AG10 in symptomatic transthyretin amyloid cardiomyopathy.
      ,
      • Benbrahim M
      • Norman K
      • Sanchorawala V
      • Siddiqi OK
      • Hughes D.
      A review of novel agents and clinical considerations in patients with ATTR cardiac amyloidosis.
      The growing preference for 99mTc-PYP bone scintigraphy observed in this study is consistent with recent advances in diagnostic strategies
      • Witteles RM
      • Bokhari S
      • Damy T
      • Elliott PM
      • Falk RH
      • Fine NM
      • Gospodinova M
      • Obici L
      • Rapezzi C
      • Garcia-Pavia P.
      Screening for transthyretin amyloid cardiomyopathy in everyday practice.
      ,
      • Ruberg FL
      • Grogan M
      • Hanna M
      • Kelly JW
      • Maurer MS.
      Transthyretin amyloid cardiomyopathy: JACC state-of-the-art review.
      and expert consensus recommendations.
      • Maurer MS
      • Bokhari S
      • Damy T
      • Dorbala S
      • Drachman BM
      • Fontana M
      • Grogan M
      • Kristen AV
      • Lousada I
      • Nativi-Nicolau J
      • Cristina Quarta C
      • Rapezzi C
      • Ruberg FL
      • Witteles R
      • Merlini G
      Expert consensus recommendations for the suspicion and diagnosis of transthyretin cardiac amyloidosis.
      • Dorbala S
      • Ando Y
      • Bokhari S
      • Dispenzieri A
      • Falk RH
      • Ferrari VA
      • Fontana M
      • Gheysens O
      • Gillmore JD
      • Glaudemans AWJM
      • Hanna MA
      • Hazenberg BPC
      • Kristen AV
      • Kwong RY
      • Maurer MS
      • Merlini G
      • Miller EJ
      • Moon JC
      • Murthy VL
      • Quarta CC
      • Rapezzi C
      • Ruberg FL
      • Shah SJ
      • Slart RHJA
      • Verberne HJ
      • Bourque JM.
      ASNC/AHA/ASE/EANM/HFSA/ISA/SCMR/SNMMI expert consensus recommendations for multimodality imaging in cardiac amyloidosis: part 1 of 2-evidence base and standardized methods of imaging.
      • Dorbala S
      • Ando Y
      • Bokhari S
      • Dispenzieri A
      • Falk RH
      • Ferrari VA
      • Fontana M
      • Gheysens O
      • Gillmore JD
      • Glaudemans AWJM
      • Hanna MA
      • Hazenberg BPC
      • Kristen AV
      • Kwong RY
      • Maurer MS
      • Merlini G
      • Miller EJ
      • Moon JC
      • Murthy VL
      • Quarta CC
      • Rapezzi C
      • Ruberg FL
      • Shah SJ
      • Slart RHJA
      • Verberne HJ
      • Bourque JM
      ASNC/AHA/ASE/EANM/HFSA/ISA/SCMR/SNMMI expert consensus recommendations for multimodality imaging in cardiac amyloidosis: part 2 of 2-diagnostic criteria and appropriate utilization.
      Increased recognition of the importance of this diagnostic tool has been accompanied by a raised awareness of ‘red flag’ sign/symptom patterns, such as heart failure with preserved ejection fraction, carpal tunnel syndrome, lumbar spinal stenosis, and spontaneous biceps tendon rupture, that may be early manifestations of ATTR-CM.
      • Maurer MS
      • Bokhari S
      • Damy T
      • Dorbala S
      • Drachman BM
      • Fontana M
      • Grogan M
      • Kristen AV
      • Lousada I
      • Nativi-Nicolau J
      • Cristina Quarta C
      • Rapezzi C
      • Ruberg FL
      • Witteles R
      • Merlini G
      Expert consensus recommendations for the suspicion and diagnosis of transthyretin cardiac amyloidosis.
      • Dorbala S
      • Ando Y
      • Bokhari S
      • Dispenzieri A
      • Falk RH
      • Ferrari VA
      • Fontana M
      • Gheysens O
      • Gillmore JD
      • Glaudemans AWJM
      • Hanna MA
      • Hazenberg BPC
      • Kristen AV
      • Kwong RY
      • Maurer MS
      • Merlini G
      • Miller EJ
      • Moon JC
      • Murthy VL
      • Quarta CC
      • Rapezzi C
      • Ruberg FL
      • Shah SJ
      • Slart RHJA
      • Verberne HJ
      • Bourque JM.
      ASNC/AHA/ASE/EANM/HFSA/ISA/SCMR/SNMMI expert consensus recommendations for multimodality imaging in cardiac amyloidosis: part 1 of 2-evidence base and standardized methods of imaging.
      • Dorbala S
      • Ando Y
      • Bokhari S
      • Dispenzieri A
      • Falk RH
      • Ferrari VA
      • Fontana M
      • Gheysens O
      • Gillmore JD
      • Glaudemans AWJM
      • Hanna MA
      • Hazenberg BPC
      • Kristen AV
      • Kwong RY
      • Maurer MS
      • Merlini G
      • Miller EJ
      • Moon JC
      • Murthy VL
      • Quarta CC
      • Rapezzi C
      • Ruberg FL
      • Shah SJ
      • Slart RHJA
      • Verberne HJ
      • Bourque JM
      ASNC/AHA/ASE/EANM/HFSA/ISA/SCMR/SNMMI expert consensus recommendations for multimodality imaging in cardiac amyloidosis: part 2 of 2-diagnostic criteria and appropriate utilization.
      The central role of radionuclide imaging in the noninvasive diagnosis of ATTR-CM is supported by evidence of its high sensitivity and specificity in select patients,
      • Gillmore JD
      • Maurer MS
      • Falk RH
      • Merlini G
      • Damy T
      • Dispenzieri A
      • Wechalekar AD
      • Berk JL
      • Quarta CC
      • Grogan M
      • Lachmann HJ
      • Bokhari S
      • Castano A
      • Dorbala S
      • Johnson GB
      • Glaudemans AW
      • Rezk T
      • Fontana M
      • Palladini G
      • Milani P
      • Guidalotti PL
      • Flatman K
      • Lane T
      • Vonberg FW
      • Whelan CJ
      • Moon JC
      • Ruberg FL
      • Miller EJ
      • Hutt DF
      • Hazenberg BP
      • Rapezzi C
      • Hawkins PN.
      Nonbiopsy diagnosis of cardiac transthyretin amyloidosis.
      and its accuracy has been confirmed in a bivariate meta-analysis.
      • Treglia G
      • Glaudemans AWJM
      • Bertagna F
      • Hazenberg BPC
      • Erba PA
      • Giubbini R
      • Ceriani L
      • Prior JO
      • Giovanella L
      • Slart RHJA.
      Diagnostic accuracy of bone scintigraphy in the assessment of cardiac transthyretin-related amyloidosis: a bivariate meta-analysis.
      Other substantial benefits of radionuclide imaging of ATTR-CM include the potential to assess multi-organ amyloid involvement by performing concurrent whole-body imaging and to reliably differentiate cardiac amyloidosis from other conditions with similar characteristics, such as, hypertrophic cardiomyopathy.
      • Dorbala S
      • Ando Y
      • Bokhari S
      • Dispenzieri A
      • Falk RH
      • Ferrari VA
      • Fontana M
      • Gheysens O
      • Gillmore JD
      • Glaudemans AWJM
      • Hanna MA
      • Hazenberg BPC
      • Kristen AV
      • Kwong RY
      • Maurer MS
      • Merlini G
      • Miller EJ
      • Moon JC
      • Murthy VL
      • Quarta CC
      • Rapezzi C
      • Ruberg FL
      • Shah SJ
      • Slart RHJA
      • Verberne HJ
      • Bourque JM.
      ASNC/AHA/ASE/EANM/HFSA/ISA/SCMR/SNMMI expert consensus recommendations for multimodality imaging in cardiac amyloidosis: part 1 of 2-evidence base and standardized methods of imaging.
      However, 99mTc-PYP bone scintigraphy also has several noteworthy limitations, including the potential for false positives in patients with previous myocardial infarction or cardiac contusions and false negatives in patients with early ATTR-CM or light-chain cardiac amyloidosis in whom a definitive diagnosis of amyloidosis has not been established.
      • Hanna M
      • Ruberg FL
      • Maurer MS
      • Dispenzieri A
      • Dorbala S
      • Falk RH
      • Hoffman J
      • Jaber W
      • Soman P
      • Witteles RM
      • Grogan M.
      Cardiac scintigraphy with technetium-99m-labeled bone-seeking tracers for suspected amyloidosis: JACC review topic of the week.
      In addition, because the high sensitivity and specificity of 99mTC-PYP scintigraphy have been documented in patients in advanced stages of the disease in centers that specialize in ATTR-CM, the findings require confirmation in patients in earlier disease stages.
      • Dorbala S
      • Ando Y
      • Bokhari S
      • Dispenzieri A
      • Falk RH
      • Ferrari VA
      • Fontana M
      • Gheysens O
      • Gillmore JD
      • Glaudemans AWJM
      • Hanna MA
      • Hazenberg BPC
      • Kristen AV
      • Kwong RY
      • Maurer MS
      • Merlini G
      • Miller EJ
      • Moon JC
      • Murthy VL
      • Quarta CC
      • Rapezzi C
      • Ruberg FL
      • Shah SJ
      • Slart RHJA
      • Verberne HJ
      • Bourque JM.
      ASNC/AHA/ASE/EANM/HFSA/ISA/SCMR/SNMMI expert consensus recommendations for multimodality imaging in cardiac amyloidosis: part 1 of 2-evidence base and standardized methods of imaging.
      This study used national claims-based data derived from the Medicare fee-for-service population. With any claims-based analysis, there are inherent limitations to the conclusions drawn, as the data are intended for billing and administrative purposes, not for clinical or research purposes. Other limitations include changes in the availability and specificity of diagnosis codes related to ATTRwt-CM and changes in coding practices over time, which potentially explain the variability of patients and comorbidities seen during the study period. The specific time frame for diagnostic testing searches (that is, 6 months before and 3 months after the index diagnosis date) was selected at the discretion of the researchers to allow a sufficiently robust yield of claims; it is not known how other time frames, if selected, would have affected outcomes.
      In conclusion, the findings of this retrospective, observational study indicate that claims to diagnose ATTRwt-CM increased for 99mTc-PYP scintigraphy use alone from 2017 to 2019. Growing use of this radionuclide imaging technique, supported by its high sensitivity and specificity, usability, and accessibility, may help facilitate earlier diagnosis of patients with the disease. Findings of differences in scintigraphy use in United States regions and states suggest that education initiatives may be needed to reinforce its important role in ATTR-CM diagnosis.

      Author Contributions

      Authors employed by Pfizer, along with all other authors, were involved in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and in the preparation, review, approval, and decision to submit the manuscript.

      Disclosures

      Dr. Schepart, Dr. Bhambri, Dr. Roy, and Dr. Chen are full-time employees of Pfizer and hold stock and/or stock options. Dr. Castaño was a full-time employee of Pfizer at the time that this research was conceived and conducted. Dr. O'Brien and Dr. Prasad are employees of Clarify Health Solutions, which received financial support from Pfizer for use of the Medicare claims database, consultation on study decisions, and data analysis. Dr. Bourque receives consulting fees from Pfizer and GE Healthcare. Dr. Grodin has research support from the Texas Health Resources Clinical Scholarship and Eidos, and receives consulting fees from Pfizer, Alnylam, Eidos, and Sarepta. The other authors have no conflicts of interest to declare.

      Appendix. Supplementary materials

      References

        • Witteles RM
        • Bokhari S
        • Damy T
        • Elliott PM
        • Falk RH
        • Fine NM
        • Gospodinova M
        • Obici L
        • Rapezzi C
        • Garcia-Pavia P.
        Screening for transthyretin amyloid cardiomyopathy in everyday practice.
        JACC Heart Fail. 2019; 7: 709-716
        • Maurer MS
        • Sultan MB
        • Rapezzi C.
        Tafamidis for transthyretin amyloid cardiomyopathy.
        N Engl J Med. 2019; 380: 196-197
        • Rozenbaum MH
        • Large S
        • Bhambri R
        • Stewart M
        • Whelan J
        • van Doornewaard A
        • Dasgupta N
        • Masri A
        • Nativi-Nicolau J.
        Impact of delayed diagnosis and misdiagnosis for patients with transthyretin amyloid cardiomyopathy (ATTR-CM): a targeted literature review.
        Cardiol Ther. 2021; 10: 141-159
        • Maurer MS
        • Bokhari S
        • Damy T
        • Dorbala S
        • Drachman BM
        • Fontana M
        • Grogan M
        • Kristen AV
        • Lousada I
        • Nativi-Nicolau J
        • Cristina Quarta C
        • Rapezzi C
        • Ruberg FL
        • Witteles R
        • Merlini G
        Expert consensus recommendations for the suspicion and diagnosis of transthyretin cardiac amyloidosis.
        Circ Heart Fail. 2019; 12e006075
        • Dorbala S
        • Ando Y
        • Bokhari S
        • Dispenzieri A
        • Falk RH
        • Ferrari VA
        • Fontana M
        • Gheysens O
        • Gillmore JD
        • Glaudemans AWJM
        • Hanna MA
        • Hazenberg BPC
        • Kristen AV
        • Kwong RY
        • Maurer MS
        • Merlini G
        • Miller EJ
        • Moon JC
        • Murthy VL
        • Quarta CC
        • Rapezzi C
        • Ruberg FL
        • Shah SJ
        • Slart RHJA
        • Verberne HJ
        • Bourque JM.
        ASNC/AHA/ASE/EANM/HFSA/ISA/SCMR/SNMMI expert consensus recommendations for multimodality imaging in cardiac amyloidosis: part 1 of 2-evidence base and standardized methods of imaging.
        J Card Fail. 2019; 25: e1-e39
        • Dorbala S
        • Ando Y
        • Bokhari S
        • Dispenzieri A
        • Falk RH
        • Ferrari VA
        • Fontana M
        • Gheysens O
        • Gillmore JD
        • Glaudemans AWJM
        • Hanna MA
        • Hazenberg BPC
        • Kristen AV
        • Kwong RY
        • Maurer MS
        • Merlini G
        • Miller EJ
        • Moon JC
        • Murthy VL
        • Quarta CC
        • Rapezzi C
        • Ruberg FL
        • Shah SJ
        • Slart RHJA
        • Verberne HJ
        • Bourque JM
        ASNC/AHA/ASE/EANM/HFSA/ISA/SCMR/SNMMI expert consensus recommendations for multimodality imaging in cardiac amyloidosis: part 2 of 2-diagnostic criteria and appropriate utilization.
        J Nucl Cardiol. 2020; 27: 659-673
        • Gillmore JD
        • Maurer MS
        • Falk RH
        • Merlini G
        • Damy T
        • Dispenzieri A
        • Wechalekar AD
        • Berk JL
        • Quarta CC
        • Grogan M
        • Lachmann HJ
        • Bokhari S
        • Castano A
        • Dorbala S
        • Johnson GB
        • Glaudemans AW
        • Rezk T
        • Fontana M
        • Palladini G
        • Milani P
        • Guidalotti PL
        • Flatman K
        • Lane T
        • Vonberg FW
        • Whelan CJ
        • Moon JC
        • Ruberg FL
        • Miller EJ
        • Hutt DF
        • Hazenberg BP
        • Rapezzi C
        • Hawkins PN.
        Nonbiopsy diagnosis of cardiac transthyretin amyloidosis.
        Circulation. 2016; 133: 2404-2412
        • Quan H
        • Li B
        • Couris CM
        • Fushimi K
        • Graham P
        • Hider P
        • Januel JM
        • Sundararajan V.
        Updating and validating the Charlson comorbidity index and score for risk adjustment in hospital discharge abstracts using data from 6 countries.
        Am J Epidemiol. 2011; 173: 676-682
        • Ruberg FL
        • Grogan M
        • Hanna M
        • Kelly JW
        • Maurer MS.
        Transthyretin amyloid cardiomyopathy: JACC state-of-the-art review.
        J Am Coll Cardiol. 2019; 73: 2872-2891
        • Judge DP
        • Heitner SB
        • Falk RH
        • Maurer MS
        • Shah SJ
        • Witteles RM
        • Grogan M
        • Selby VN
        • Jacoby D
        • Hanna M
        • Nativi-Nicolau J
        • Patel J
        • Rao S
        • Sinha U
        • Turtle CW
        • Fox JC.
        Transthyretin stabilization by AG10 in symptomatic transthyretin amyloid cardiomyopathy.
        J Am Coll Cardiol. 2019; 74: 285-295
        • Benbrahim M
        • Norman K
        • Sanchorawala V
        • Siddiqi OK
        • Hughes D.
        A review of novel agents and clinical considerations in patients with ATTR cardiac amyloidosis.
        J Cardiovasc Pharmacol. 2021; 77: 544-548
        • Treglia G
        • Glaudemans AWJM
        • Bertagna F
        • Hazenberg BPC
        • Erba PA
        • Giubbini R
        • Ceriani L
        • Prior JO
        • Giovanella L
        • Slart RHJA.
        Diagnostic accuracy of bone scintigraphy in the assessment of cardiac transthyretin-related amyloidosis: a bivariate meta-analysis.
        Eur J Nucl Med Mol Imaging. 2018; 45: 1945-1955
        • Hanna M
        • Ruberg FL
        • Maurer MS
        • Dispenzieri A
        • Dorbala S
        • Falk RH
        • Hoffman J
        • Jaber W
        • Soman P
        • Witteles RM
        • Grogan M.
        Cardiac scintigraphy with technetium-99m-labeled bone-seeking tracers for suspected amyloidosis: JACC review topic of the week.
        J Am Coll Cardiol. 2020; 75: 2851-2862