Transthyretin Cardiac Amyloidosis: A treatable form of heart failure with a preserved ejection fraction

Abstract

Cardiac amyloidosis (CA) is considered a rare disease with poor prognosis and limited therapeutic options. However, non-biopsy diagnostic modalities as well as emerging therapies are challenging this long-held belief. Radionuclide bone scintigraphy is increasingly being used in the diagnosis of transthyretin amyloid cardiomyopathy (ATTR-CA). As such, it is expected that the number of patients diagnosed with ATTR-CA will continue to rise. Emerging therapies decrease the progressive morbidity and mortality associated with ATTR-CA. The importance of early recognition of ATTR-CA is imperative as prompt initiation of these novel agents is essential to maximize their therapeutic potential. Herein, we outline the current approach to diagnosis of ATTR-CA and review the therapeutic management of the disease.

Introduction

Transthyretin cardiac amyloidosis (ATTR-CA) is considered a rare disease with poor prognosis, though improvements in diagnostic modalities as well as emerging therapies are challenging this long-held belief. There are over 30 proteins capable of forming amyloid fibrils in vivo. In the heart, two amyloidotic proteins account for >95% of all CA – immunoglobulin light-chain (AL) which is derived from monoclonal light chains and transthyretin (TTR), on which this review will focus [1]. ATTR-CA is further classified as wild-type (formerly senile systemic amyloidosis, ATTRwt) or variant (familial, hereditary, mutant, ATTRv) depending on whether a mutation is present in the TTR gene. TTR (formerly known as prealbumin) is composed of 4 monomeric proteins, covalently bonded to form a tetramer. It is produced predominantly in hepatocytes and functions as a carrier for thyroxine and retinol-binding protein. The prevailing pathophysiologic paradigm is that mutations in the TTR protein (ATTRv) or changes with aging (ATTRwt) result in instability of the homotetrameric protein with resulting misfolding and aggregation of the monomers or oligomers forming amyloid fibrils [2]. These rigid, insoluble TTR amyloid fibrils deposit in the extracellular space of the myocardium causing a restrictive cardiomyopathy with heart failure and arrhythmias.

Clinical Features and Prognosis

The prevalence of ATTR-CA has not been well elucidated. It is often misdiagnosed as hypertensive heart failure or hypertrophic cardiomyopathy (HCM). One study found that 13% of hospitalized HFpEF patients over 60 years of age with an interventricular septal thickness >12mm were diagnosed with ATTR-CA on nuclear scintigraphy [3]. Among patients over the age of 80 with presumed HCM, >25% are misdiagnosed, having CA and not HCM [4]. Interestingly, 1–3% of patients over 75 years of age undergoing whole body scintigraphy showed cardiac uptake of a radiolabeled bone tracer, 3,3-diphosphono-1,2-propanodicarboxylic acid (DPD), consistent with ATTRwt-CA [5]. The most common variant in TTR in the US is p.Val142Ile, traditionally known as Val122Ile. The early nomenclature was based on analysis of the mature protein, lacking the initial 20 amino acids from the N-terminus of the pro-protein. It is found in 3–4% of African-Americans [6], though penetrance is unknown. ATTRwt has been described in mainly white males and presents at an older age than p.Val142Ile (76 years vs 69 years), the latter of which is found almost exclusively in the black population [7]. Data from the THAOS (Transthyretin Amyloid Outcomes Survey) registry showed that ATTRwt is the most common form of ATTR-CA followed by the p.Val142Ile mutation in the US [7]. ATTRwt typically presents with heart failure, though syncope, arrhythmias and conduction abnormalities are not uncommon. The phenotype of ATTRv is more varied with presentations including a predominant neuropathic phenotype (familial amyloid polyneuropathy, FAP), cardiac phenotype (familial amyloid cardiomyopathy, FAC) or mixed phenotype (Figure 1). p.Val142Ile presents with a predominantly cardiac phenotype similar to that of ATTRwt, while the second most common variant in the US, p.Thr80Ala which originates in Northwest Ireland presents with a mixed phenotype. p.Val50Met, the most common mutation worldwide is endemic to Japan, Sweden and Portugal. Early onset disease (<50 years) typically presents with a neuropathic phenotype while late onset presents with a mixed phenotype.

Figure 1:

Phenotypic Heterogeneity of Hereditary ATTR Amyloidosis (nomenclature includes mature protein (italics) and pro-protein).

N-terminal pro-B-type natriuretic peptide (NT-proBNP) is useful in the diagnosis of ATTR-CA as a marker of the severity of cardiac amyloid infiltration, reflecting not only elevated left ventricular filling pressures but also direct myocyte damage from the amyloid fibrils. BNP elevations have been shown to highly correlate with interventricular septal thickness and basal septal strain pattern in ATTR-CA [8]. Cardiac troponin, NT-proBNP and eGFR can be used to prognosticate. A staging system for ATTRwt-CA has been developed in which patients are stratified into 1 of 3 groups [9]. Using a threshold troponin T of 0.05ng/ml and NT-proBNP of 3000pg/ml, Grogan et al. estimated 4-year overall survival as 57% for stage I (both values below cutoff), 42% for stage II (one value above cutoff) and 18% for stage III (both values above cutoff). More recently, a staging system has been proposed using NT-proBNP (>3000pg/ml) and eGFR (<45ml/min/1.73m2), which can be applied to both ATTRwt and ATTRv [10]. In those with stage II disease, median survival was 49months in ATTRwt compared to 29months in p.Val142Ile, underlining the poor prognosis in this patient population particularly in those who have ATTRv or advanced disease at diagnosis.

Diagnostic Approach (Figure 2)

Figure 2:

Diagnostic approach to ATTR-CA. Adapted from Ruberg FL, et al. Transthyretin Amyloid Cardiomyopathy. J Am Coll Cardiol. 2019;73:2872–91. Figure 6, Diagnostic algorithm for evaluation of suspected ATTR-CM; p. 2883. AL-CA, immunoglobulin light chain cardiac amyloidosis; ATTRwt, wild type transthyretin amyloid; ATTRv, variant transthyretin amyloid; ATTR-CA, transthyretin cardiac amyloid; AV, atrioventricular; CTS, carpal tunnel syndrome; DPD, 3,3-diphosphono-1,2-propanodicarboxylic acid; eGFR, estimated glomerular filtrate rate; FLC, free light chains; GI, gastrointestinal; HMDP, 99^mTc-labeled hydroxymethylene diphosphonate; LVWT, left ventricular wall thickness; LVM, LV mass; NT-proBNP, N-terminal pro-B-type natriuretic peptide; PYP, 99^mTc pyrophosphate; STE, speckle tracking echocardiography; Tn, troponin. *If biopsy of the affected organ is negative and there is high clinical suspicion for CA, endomyocardial biopsy should be pursued.

Raising Suspicion:

There are several ‘red flags’ that should alert the clinician to a possible diagnosis of CA aside from the cardiac manifestations of the disease, including neurologic, orthopedic and gastrointestinal manifestations. Figure 2 outlines an approach to the clinical evaluation of a patient with suspected CA. Atrial fibrillation (AF) is present in more than half of patients with ATTRwt-CA [9, 11] and to a lesser extent in ATTRv. Low voltage may be seen on ECG though is a relatively late finding and indicative of advanced disease, so integration of the ECG voltage to LV mass ratio is critical in facilitating early recognition of CA [12, 13]. LV ejection fraction (EF) by 2-D echocardiography is usually slightly reduced [14]. Speckle-tracking echocardiography (STE), is used to assess myocardial deformation patterns. A basal-to-apical gradient in longitudinal strain (LS) is seen in patients with CA, such that degree of impairment in LS correlates with cardiac amyloid infiltration burden [15]. In approximately 50% of cases, LS can demonstrate ‘apical sparing’. A cut-off value of 1 for the relative apical LS, (defined as average apical LS/[average basal LS + average midcavity LS]), is highly sensitive and specific in differentiating CA from HCM, left ventricular hypertrophy and aortic stenosis [15, 16]. A notable orthopedic manifestation of amyloidosis is carpal tunnel syndrome. In a study of 98 patients undergoing carpal tunnel release surgery, 10 (10.2%) were diagnosed with amyloidosis (8 with ATTR) and of these one person was found to have cardiac involvement diagnosed by examination and advanced cardiac imaging [17].

Evaluate for AL–CA:

Serum kappa/lambda free light chain assay in addition to serum and urine immunofixation (more sensitive than electrophoresis) should be performed to rule out AL-CA. It is possible that a monoclonal protein may be detected, however, this does not ensure the patient has AL-CA, rather it is often indicative of a monoclonal gammopathy of undetermined significance [11] which may be present with concomitant ATTR-CA. In such cases, if there is suspicion for ATTR-CA an endomyocardial biopsy must be performed to unequivocally identify the amyloidogenic protein.

Non-biopsy diagnosis:

Radionuclide bone scintigraphy with DPD, 99^mTc pyrophosphate (PYP) or 99^mTc-labeled hydroxymethylene diphosphonate (HMDP) can differentiate ATTR-CA from AL-CA and be used for non-biopsy diagnosis. Cardiac retention is assessed using both a semiquantitative visual score (0 = no cardiac uptake; 3 = uptake greater than bone) and quantitative analysis (heart-to-contralateral ratio). A heart-to-contralateral ratio of >1.5 has a 97% sensitivity and 100% specificity for distinguishing ATTR-CA from AL-CA [18]. A multicenter study of biopsy proven cases of ATTR-CA demonstrated that bone avid radiotracers have 100% specificity and 100% positive predictive value for ATTR-CA in the absence of a monoclonal protein in serum or urine [19].

Biopsy:

The gold standard for the diagnosis of ATTR-CA is endomyocardial biopsy, which is ~100% sensitive to detect ATTR-CA, though requires specialist expertise and is associated with a small risk of serious complication. In order to circumvent such risk, extracardiac biopsy of an affected organ may be pursued which, if positive in the presence of typical echocardiographic findings is sufficient for diagnosis. The least invasive method, fat pad fine needle aspiration, yields a positive result in ~15% of those with ATTRwt, due to the often localized nature of the disease [20]. By virtue of the more extensive extracardiac deposition of amyloid protein in ATTRv, up to 70% of fat aspiration samples return positive for amyloid and over 80% in AL-CA depending on the whole body amyloid burden [20, 21]. As such, a negative result is insufficient to exclude CA, particularly in ATTRwt and biopsy of the clinically affected organ should be pursued.

Genetic Testing:

Once the diagnosis of ATTR-CA is made, TTR gene sequencing must be performed to elucidate whether a mutation is present and if so, the exact variant. If a mutation is found, screening of first-degree relatives of the proband and referral to genetic counseling should be offered [22]. There are currently no guidelines or recommendations regarding initiation of screening in gene mutation carriers. A suggested approach is to screen with nuclear scintigraphy in allele carriers between 5 and 10 years prior to the mutation becoming penetrant.

Treatment

Medical management of heart failure

Historically, treatment of CA has focused on symptom management, specifically relieving congestion with salt restriction (<2g/day) and loop diuretics. Bumetanide and torsemide are preferred over furosemide due to their greater bioavailability. Spironolactone works synergistically with bioavailable loop diuretics in maintaining euvolemia, especially in the setting of right heart failure that is common in CA and reduces the chance of hypokalemia. Other guideline directed heart failure therapies tend to be poorly tolerated in patients with CA. Angiotensin converting enzyme inhibitors and angiotensin receptor blockers may cause hypotension especially in ATTRv patients with concomitant autonomic dysfunction. Since cardiac output is dependent on stroke volume and heart rate, beta blockers may worsen cardiac output in patients with CA and restrictive cardiomyopathies who rely on the ability to increase heart rates in the setting of a fixed stroke volume. Agents with alpha blocking properties, such as carvedilol, should be avoided due to the propensity to exacerbate hypotension. Non-dihydropyridine calcium channel blockers, such as verapamil, are contraindicated due to the risk of high-degree heart block and significant negative inotropic effect. As ATTR-CA progresses, patients become intolerant of medications with blood pressure lowering effect and may require the addition of midodrine for symptomatic hypotension.

Managing Arrhythmias and Anticoagulation

AF is more prevalent in patients with CA than in age matched cohorts. It may be poorly tolerated since rapid heart rates limit ventricular filling time which further decreases stroke volume and therefore reduces cardiac output. Conversely, owing to the presence of amyloid infiltration affecting the conduction system, many patients with ATTR-CA and concomitant AF may be naturally rate controlled. The use of digoxin is controversial, though previously thought to be harmful in ATTR-CA due to its propensity to bind to amyloid fibrils and thus increase risk of drug toxicity, it may be used for rate control provided it is carefully monitored [23]. Amiodarone is the most commonly used antiarrhythmic particularly for maintenance of sinus rhythm following cardioversion.

The presence of amyloidosis increases the risk of thromboembolism, even in sinus rhythm. In one autopsy series, 33% of patients with CA (AL and ATTR) were found to have intracardiac thrombosis despite a low proportion of these (37%) having a known history of AF [24]. In a recent study of CA patients with AF almost 50% of those with intracardiac thrombosis on transesophageal echocardiogram (TEE) at the time of scheduled direct current cardioversion (DCCV) either had therapeutic levels of anticoagulation for >3 weeks or had arrhythmia onset <48 hours before the planned DCCV, in which case TEE would not be indicated under current guidelines [25, 26]. As a result of this increased incidence of atrial thrombosis, complication rates following DCCV appear to be higher in the CA population, though success and recurrence rates are similar to those without CA [25]. Thus, consideration should be given to preprocedural TEE to rule out atrial thrombus even in patients for whom there is low suspicion and anticoagulation should be initiated at the first sign of AF, regardless of the CHADs-VASc score. Choice of agent (warfarin or DOAC) should be individualized based on patient factors, with recent retrospective data suggesting no difference in thrombotic or major bleeding events between the agents in TTR amyloid patients with AF [27]. Data on the use of catheter ablation is limited, but less effective than in the non-amyloid infiltrated atrium.

Emerging therapies

There are several novel agents emerging on the market or under investigation for the treatment of ATTR-CA (Table 1). Many have already been approved for use in patients with ATTR-FAP. However, for patients with ATTR-CA without a concomitant neuropathy, only tafamidis to date has been approved by the US Food and Drug Administration (FDA). These agents act as 1) stabilizers of the TTR homotetramer, addressing the rate limiting step in amyloid formation, or 2) silencers of the TTR gene thus limiting TTR production by the liver (Figure 3).

Table 1:

Approved and investigational therapeutic agents for ATTR-CA

	Drug (Brand)	Trial	Population Studied	Dose	Primary Outcome	Monitoring	Adverse Events	Concomitant Medications	Indication	Annual Cost (List price)
	APPROVED
STABILIZERS	Diflunisal	NCT00294671	130 ATTR-FAP, Excluded NYHA IV & ATTRwt	250mg or placebo BID PO × 2 years	1)Difference in polyneuropathy progression favored diflunisal. 2)Neurological stability exhibited in 29.7% of diflunisal group vs 9.4% of placebo.	CBC, BMP q 3–6 months	Bleeding, hypertension, fluid retention, renal dysfunction. Adverse events did not differ between diflunisal vs placebo groups.	Proton pump inhibitor	ATTR-CA & FAP Off-label use	$720
	Tafamidis meglumine (Vyndaqel)	ATTR-ACT Phase III NCT01994889	441 ATTR-CA, Excluded NYHA IV	20mg, 80mg or placebo QD PO × 30 months	1)All-cause mortality lower with tafamidis (29.5% vs 42.9%) 2)Frequency of CV related hospitalizations lower with tafamidis (RRR 0.68)	None	No safety signals of potential clinical concern.	None	ATTR-CA ATTR-FAP outside US	$225,000
	Tafamidis free salt (Vyndamax)	ATTR-ACT Extended Access Protocol (EAP)	ATTR-ACT OLE and expanded access programs	61mg PO daily	Safety, tolerability and efficacy	None	No safety signals of potential clinical concern	None	ATTR-CA	$225,000
SILENCERS	Patisiran (Onpattro)	APOLLO Phase III NCT01960348	225 ATTR-FAP; Excluded NYHA III-IV	0.3mg/kg IV q 3 weeks or placebo × 18 months	Change in mNIS + 7 favored Patisiran	None	20% infusion reactions. Vitamin A deficiency	Steroid IV, APAP, H1 & H2 blocker IV & Vitamin A Supplement	ATTR-FAP +/− ATTR-CA	$450,000
	Inotersen (Tegsedi)	NEURO-TTR Phase II/III NCT01737398	172 ATTR-FAP +/− ATTR-CA, Excluded NYHA III-IV	300mg SC per week or placebo × 64 weeks	Change in mNIS + 7 and Norfolk QOL-DN favored Inotersen	Plt count weekly; BMP, UA, UPCR q 2 weeks; LFTs q 4 weeks	Glomerulonephritis (3%) & thrombocytopenia (3%) with one death due to thrombocytopenia Vitamin A deficiency	Vitamin A supplement	ATTR-FAP +/− ATTR-CA	$450,000
	INVESTIGATIONAL
STABILIZERS	AG10	Phase II NCT03458130 Recruitment complete	49 ATTR-CA, Excluded NYHA IV	400mg, 800mg or placebo BID PO × 28 days	Safety and tolerability demonstrated at 28 days	None	No safety signals of potential clinical concern	None	ATTRv and ATTRwt CA	Unknown
		ATTRibute-CM Phase III NCT03860935 Enrolling	Estimated 510 ATTR-CA, Excluded NYHA IV	800mg or placebo BID PO × 30 months	1)Change in 6MWT at 12 months 2)All-cause mortality and CV-related hospitalizations at 30 months	None	Unknown	None	ATTRv and ATTRwt CA	Unknown
SILENCERS	Patisiran	APOLLO - B Phase III NCT03997383 Plannedinitiation 2019	Estimated 300 ATTR-CA, Excluded NYHA III-IV	IV infusion	Change in 6MWT at 12 months	None	Unknown	Steroid IV, APAP, H1 & H2 blocker IV & Vitamin A	ATTRv and ATTRwt CA	Unknown
	Inotersen	Single center, Phase II NCT03702829 Enrolling	Estimated 50 ATTR-CA; Excluded NYHA IV	300mg SC per week × 24 months	LVLS on echo compared to baseline	CBC, BMP, UPCR q 2 weeks	Unknown	Vitamin A supplement	ATTRv and ATTRwt CA	Unknown
		Single center, Phase II Enrolling	Estimated 30 ATTR-CA	300mg SC per week × 3 years	Safety and tolerability	CBC, BMP, UA & UPCR	Localized injection site reactions	Vitamin A supplement	ATTRv and ATTRwt CA	Unknown
	Vutrisiran	HELIOS-A Phase III NCT03759379 Enrolling	Estimated 160 ATTRv; Excluded NYHA III-IV	Vutrisiran SC vs Patisir an IV	Change in mNIS + 7 & Norfolk QOL-DN at 9 months	Unknown	Unknown	Vitamin A supplement	ATTR-FAP	Unknown
		HELIOS-B Phase III Planned late 2019	ATTR-CA	Vutrisiran SC vs Patisiran IV	Unknown	Unknown	Unknown	Vitamin A supplement	ATTRv and ATTRwt CA	Unknown
	ION-682884	Phase I/II NCT03728634 Enrolling	Estimated 56 ATTR-FAP; Excluded NYHA III-IV	SC	Safety and tolerability	Unknown	Unknown	Vitamin A supplement	ATTR-FAP	Unknown
EXTRACTORS	PRX004	Phase I NCT03336580 Enrolling	Estimated 36 ATTRv	IV q 28 days	Maximum tolerated dose	Unknown	Unknown	None anticipated	ATTRv and ATTRwt CA	Unknown

6MWT, 6-minute walk test; APAP, acetaminophen; ATTR-CA, transthyretin cardiac amyloidosis; ATTR-FAP, transthyretin familial amyloid polyneuropathy; BMP, basic metabolic panel; CBC, complete blood count; CV, cardiovascular; EAP, extended access protocol; LFT, liver function tests; LVLS, left ventricular longitudinal strain; NIS+7, Neuropathy Impairment Score plus 7 nerve tests; Norfolk QOL-DN, Norfolk quality of life – diabetic neuropathy questionnaire; NYHA, New York Heart Association class; QoL, quality of life; RRR, relative risk ratio; SC, subcutaneous; TTE, transthoracic echocardiography; UA, urinalysis; UPCR, urinary protein-creatinine ratio.

Figure 3:

Target Sites of Therapy in ATTR-CA

Stabilizers:

Diflunisal, a non-steroidal anti-inflammatory agent, has been shown to stabilize TTR in patients with FAP and slow progression of neuropathy. In a study of 130 patients with FAP, diflunisal reduced the rate of progression of neurological impairment and preserved quality of life compared to placebo [28]. Although half of the patients in this trial had evidence of cardiac involvement, there has been no large-scale clinical trial investigating the use of diflunisal in ATTR-CA. As a NSAID, diflunisal is associated with side effects including gastrointestinal bleeding, acute kidney injury, hypertension and worsening heart failure. However, the dose of diflunisal for ATTR-CA is below the recommended anti-inflammatory dose and thus NSAID related side effects may be less. In 2 small studies of patients with FAC, diflunisal was shown to be well tolerated with the main reasons cited for discontinuation being due to the development of volume overload (1 of 13) or gastrointestinal complaints (3 of 23) [29, 30]. As such, diflunisal may be considered for the treatment of ATTR-CA, though with careful monitoring of renal function and discontinuation at the first sign of worsening heart failure.

Tafamidis (Pfizer Inc, New York, NY, USA) binds to the thyroxine binding site of TTR, stabilizing the molecule and inhibiting the dissociation of TTR homotetramers into monomers and thus amyloid fibril formation. It is formulated as tafamidis meglumine (20mg tablets) and as tafamidis free salt (61mg tablets), which are not substitutable on a per mg basis. The cardiac phenotype of the disease was investigated in the ATTR-ACT trial [31]. This was a multicenter randomized controlled trial of 441 patients with NYHA I-III heart failure, assigned to tafamidis 20mg or 80mg daily vs placebo for 30 months. All-cause mortality was lower with tafamidis than with placebo (29.5% vs 42.9%) and the tafamidis group had a lower rate of cardiovascular-related hospitalizations. However, it was noted that those with NYHA class III, had a higher rate of cardiovascular-related hospitalizations compared to NYHA I-II, which highlights the necessity of early identification and treatment. There was also a reduced decline in the secondary endpoints of functional capacity and quality of life. It has recently been approved by the FDA for the treatment of ATTR-CA.

AG10 mimics the stabilizing properties of a TTR variant p.Thr139Met, which acts by forming hydrogen bonds between the serine residues at position 117 on the TTR monomers. Patients with this variant have 20% higher TTR concentrations compared to the general population and are protected from the development of FAP in heterozygous patients carrying the p.Val50Met mutation [32]. In a Phase II clinical trial, 49 participants with NYHA class II-III ATTR-CA (hereditary or wild-type) were randomized to AG10 400mg, 800mg or placebo twice daily for 28 days [33]. Treatment with AG10 was shown to be well-tolerated with near complete stabilization of TTR. ATTRibute-CM, a phase III trial in ATTR-CA is currently enrolling.

Silencers:

Patisiran is a small interfering RNA (siRNA) molecule which targets the 3′ untranslated region of transthyretin mRNA thus reducing TTR production in the liver. In the APOLLO trial, 225 patients with ATTR-FAP were randomized 2:1 to patisiran 0.3mg/kg once every 3 weeks or placebo [34]. Patients with NYHA III-IV HF were excluded. There was a significant reduction in serum TTR levels (median reduction of 81%) in the patisiran group, which was sustained at 18 months. In the cardiac subpopulation (n=126), patisiran decreased mean LV wall thickness by ~1mm compared to placebo, global LS by −1.4% and lowered NT-proBNP by ~55% compared to placebo. In a post hoc analysis, there was a reduction of ~45% in the event rate for cardiac hospitalizations and all-cause mortality, suggesting that patisiran also improves the cardiac manifestations of the disease [35]. Deterioration of regional LV myocardial strain in this group was shown to be attenuated by the use of patisiran, particularly in the basal segments [36]. The greatest effect was noted in patients who had larger absolute basal LS values at baseline (better systolic function), thus supporting the role of novel agents at an early stage in the disease process. The efficacy of intravenous patisiran in ATTR-CA will be evaluated in the APOLLO-B trial, with initiation planned in late 2019.

Vutrisiran (ALN-TTRSC02), is currently being studied in patients with ATTRv in the HELIOS-A trial. It is a subcutaneous formulation, dosed every 3 months. Participants receive vutrisiran or the reference comparator, patisiran, during the treatment period. This is followed by an extension period during which all participants in the patisiran group will switch to vutrisiran. This study will use the placebo arm of the APOLLO study as an external comparator for the co-primary endpoint. The HELIOS-B trial, a phase III study in ATTR-CA, is planned for late 2019.

Inotersen (formerly IONIS-TTR) is a single-stranded antisense oligonucleotide that lowers the production of TTR in the liver. The NEURO-TTR trial randomized 172 patients with ATTR-FAP, with or without ATTR-CA (NYHA I-II) in a 2:1 ratio to inotersen 300mg weekly or placebo, by subcutaneous injection for 64 weeks [37]. Inotersen demonstrated a favorable effect on progression of neuropathy and quality of life, however, adverse events including glomerulonephritis (3%) and thrombocytopenia (3%) although rare, occurred more frequently than with placebo. Inotersen is currently being investigated in 2 single-center phase II studies of patients with ATTR-CA (Table 1). Preliminary results at 1 year from Benson et al. have shown stabilization of disease as measured by LV wall thickness, LV mass, 6-minute walk test and echocardiographic global systolic strain indicating efficacy in the cardiac phenotype and no major adverse effects [38].

AKCEA-TTR-LRx (ION-682884), a ligand conjugated antisense oligonucleotide (LICA), is currently in phase I/II study in patients with ATTR-FAP. Phase III trials in ATTR-FAP and ATTR-CA are planned for late 2019.

Extractors:

PRX004 (Prothena Biosciences Limited) is an investigational monoclonal antibody designed to specifically target and clear TTR amyloid protein. It is currently in a phase I study in patients with TTR amyloidosis.

Future Directions

Despite advances in diagnosis and treatment of ATTR-CA, several questions remain. Firstly, the prevalence of ATTR-CA is likely more common than current data suggest. An analysis of Centers for Medicare and Medicaid Services data found that the prevalence of CA increased from 18 to 55 per 100,000 between 2000 and 2012 [36], likely due to increasing awareness and improved diagnostic methods, rather than an actual increase in prevalence. As such, it is expected that the number of patients diagnosed with ATTR-CA will continue to rise. Secondly, with the emergence of these novel agents, the appropriate time to start treatment for ATTR-CA remains unclear. Significant myocardial infiltration of amyloid occurs prior to deterioration in systolic function or elevation in cardiac biomarkers (Figure 4) [39]. Patients who present with NYHA stage III disease, typically have had a long latency period prior to developing acute decompensated heart failure with declining functional status and end organ function. In the ATTR-ACT trial, survival benefit was shown to be greater in patients with an earlier stage of disease indicating that earlier diagnosis and treatment is imperative for a beneficial therapeutic effect [31]. But, how early should treatment be initiated and at what cost? Tafamidis, the only agent that is currently approved by the FDA for the treatment of ATTR-CA comes at an annual cost of approximately $225,000 and agents currently under investigation are likely to be similar. Finally, how will the clinical outcomes of emerging agents compare in the longer term, and what will be the role of combination therapy going forward?

Figure 4:

Model for Progression of ATTR-CA. Grodin JL, Maurer MS. The Truth is Unfolding About Transthyretin Cardiac Amyloidosis. Circulation. 2019;140:27–30. Figure, Conceptual model of ATTR-CA progression over time; p.28.

Conclusion

Advances in non-invasive imaging techniques have contributed to earlier recognition of ATTR-CA, which has translated into a growing number of people being diagnosed with the disease. With the emergence of novel therapies to target the TTR amyloid protein, this once terminal illness is being transformed into a treatable disease, however, early diagnosis is essential in order to obtain maximum therapeutic benefit.