Not So Rare After All: Pharmacists Weigh In on Diagnosing and Managing ATTR-CM

Transthyretin amyloid cardiomyopathy (ATTR-CM) has moved from what some consider an obscure diagnosis to a growing focus in cardiology, as increased awareness, improved imaging, and a maturing pipeline of disease-modifying therapies (DMTs) have made earlier identification and treatment more achievable. Despite this progress, the condition remains widely underdiagnosed, with many patients cycling through years of unexplained symptoms before a health care professional can diagnose them based on their heart failure and the extracardiac clues that so often precede it.

In a recent virtual Pharmacy Times Clinical Forum, moderator Craig Beavers, PharmD, FACC, FAHA, FCCP, BCCP, BCPS-AQ Cardiology, CACP, a cardiovascular clinical pharmacist and vice president of operations at Baptist Health, was joined by a panel of cardiology pharmacists who discussed the current state of ATTR-CM care, from recognizing red-flag symptoms and navigating an evolving treatment landscape to the practical realities of insurance coverage and treatment access. The panelists also examined data supporting current and emerging therapies, including a discussion of tafamidis (Vyndamax; Pfizer) and the role of sodium-glucose cotransporter-2 (SGLT2) inhibitors in combination with DMTs.

Throughout the conversation, the pharmacists returned to a recurring message: the pharmacist’s expanding role as clinician, educator, and key player in identifying and managing a disease that is not as rare as health care professionals may think.

What Is ATTR-CM?

ATTR-CM is a condition that is characterized by the stiffening of the heart muscle and preload dependence resulting from the accumulation of amyloid fibrils in the heart. Although often discussed as a rare disease, it is more accurately described as “a condition that is rarely identified,” according to panelist Ralph Riello, PharmD, BCPS, clinical pharmacy specialist, clinical and translational research at Yale School of Medicine.

The condition is caused by the misfolding of the transthyretin (TTR) protein, which is produced in the liver. When these proteins misfold, they form amyloid fibrils that deposit in the heart tissue. There are 2 primary types: hereditary (variant), caused by genetic mutations such as the V122I mutation, which may lead to more severe symptoms and heart failure with reduced ejection fraction (HFrEF); and wild-type, which is typically associated with aging and more commonly presents as heart failure with preserved ejection fraction (HFpEF).

Patients often present with standard heart failure symptoms, but certain “extracardiac red flags,” as Beavers described, are considered hallmark indicators of the disease.

“[As far as] extracardiac red flags, [we are] obviously thinking about the things you traditionally think about, [such as bilateral carpal] tunnel syndrome, spinal stenosis, biceps tendon rupture…patients may have neuropathy or gastrointestinal [adverse] effects or other things that can be contributory toward thinking about an overall broad amyloid picture,” Beavers explained. “That should ring bells, thinking about these patients having potentially amyloid in conjunction with their heart failure symptoms, and we really know that some of those may actually come up before the cardiomyopathy-based symptoms.”

Catching and treating ATTR-CM early is critical for improving patient trajectories and preventing irreversible physical decline. The panelists also cautioned against the consequences of delayed diagnosis, noting that patients who go unidentified for too long risk reaching a state of “burned-out” amyloid, often only recognized once they are critically ill in an intensive care unit. At that stage, treatment options become far more limited, with care frequently shifting toward palliative measures rather than DMT.

“The earlier we can identify these patients and get them treated, the less damage over time occurs, and the better outcomes these patients end up having from that aspect,” Beavers emphasized.

One significant indicator outlined by Beavers is an intolerance to standard heart failure medications, as patients often cannot tolerate even low doses of β-blockers or angiotensin-converting enzyme (ACE) inhibitors due to hypotension caused by their restrictive physiology.

Further, the panelists identified several major hurdles that make diagnosing ATTR-CM difficult. Riello explained that, because many patients with wild-type disease have a preserved ejection fraction, they are often diagnosed with HFpEF first, which can delay the identification of the underlying amyloidosis. Many primary care providers and even some cardiologists do not proactively look for the disease or recognize the connection between cardiac symptoms and extracardiac markers. Additionally, patients often do not mention certain symptoms (eg, neuropathy, back pain) to their cardiologists because they do not believe those issues are related to their heart health.

“[At my institution,] we’ve had a bunch of patients that we’ve recently recognized ATTR-CM in and diagnosed them finally after years of jumping around health systems [and] never getting answers,” Ami Patel, PharmD, BCCP, cardiology clinical pharmacist at HonorHealth Scottsdale Shea Medical Center, told her fellow panelists. “We’ve really found that, in those patients that never seem to believe in medical care and just have never gotten an answer and still are having heart failure symptoms and a lot of those things that we already mentioned, these are the people that are actually having undiagnosed ATTR well into their 80s and 90s [who] just were never diagnosed.”

What Is the Current Treatment and What Factors Lead to Treatment Selection?

The current treatment landscape for ATTR-CM centers on a dual approach of DMTs and tailored heart failure management; however, the field is rapidly evolving with new data and emerging therapies.

Typically, pharmacological treatment for ATTR-CM is divided into DMTs and symptom management. Within DMTs, tafamidis and acoramidis (Attruby; BridgeBio Pharma) stabilize the TTR protein and prevent misfolding, whereas silencers such as vutrisiran (Amvuttra; Alnylam Pharmaceuticals) work by reducing TTR production in the liver. Regarding combination therapy, the panelists noted there is insufficient evidence to support combining a silencer and a stabilizer, and clinical guidelines do not yet recommend it; however, some practitioners use dual therapy in specific cases, such as patients with certain variants or those whose treatment predated newer data.

On the heart failure and symptom management side, SGLT2 inhibitors and mineralocorticoid receptor antagonists (MRAs) are standard pillars, widely used and generally well tolerated in these patients. By contrast, standard heart failure treatments like ACE inhibitors, angiotensin receptor-neprilysin inhibitors, and β-blockers are often poorly tolerated due to the patients’ restrictive physiology and reliance on heart rate for cardiac output, which can frequently cause hypotension when these drugs are used. For atrial fibrillation (Afib), anticoagulation is recommended for all patients with ATTR-CM and Afib regardless of their CHA²DS²-VASc score, because of high thrombosis risk. Digoxin, although historically avoided, is used by some specialists at low doses for rate control.

It is important for health care professionals to consider several critical factors when suggesting or prescribing treatments. For example, patients with the hereditary variant often present with more severe symptoms and HFrEF compared with patients who have wild-type disease, who more commonly present with HFpEF. Additionally, financial access and payer coverage play a significant role, as high annual costs and insurance requirements (eg, specific diagnostic confirmation) significantly influence therapy selection.

“One of the things that I’ve noticed from when I first started working with [these] patients now is the new Medicare rules. They’re not perfect, but [they have] really changed the game of who we are able to offer therapies to. Before, when tafamidis was our only medication, [it] would be about $2000 every month, rather than the $2000 per year,” Lauren Kemp, PharmD, BCCP, BCPS, CPP, cardiology clinical pharmacist at the Advanced Heart Failure Clinic at Moses H. Cone Memorial Hospital in Greensboro, North Carolina, explained. “…[The whole process] was extremely manual, extremely difficult to do, and patients were worried that they would have treatment gaps, and I definitely feel like having the cap has really helped with that. It also means that there are more funds for everyone because we are not taking multiple grants up for 1 person, and you only have to cover the [initial amount].”

Shared decision-making remains central, with clinicians discussing the route of administration, frequency, safety profile, and potential functional impact with the patient to reach a tailored treatment plan. Clinical staging and prognosis are other considerations: Tools such as the Mayo Clinic score or the UK National Amyloidosis Centre staging help clinicians determine the risk trajectory and median survival, which informs the urgency and type of intervention. Treatment may be withheld if a patient's life expectancy is less than 1 year (eg, New York Heart Association [NYHA] class IV). Biomarkers and monitoring also factor in, the panelists explained.

“...If [a patient] doesn’t have that expected response, then some of our [doctors] are using that as a justification to switch to a silencer,” said Dan Landup, PharmD, HF-Cert, a clinical pharmacist in heart failure, cardiology, and anticoagulation at Advocate Medical Group in Chicago.

The Use of SGLT2 Inhibitors and DMTs in ATTR-CM

One specific piece of trial data mentioned during the panel is an analysis in the Journal of the American College of Cardiology that demonstrated decreased mortality with SGLT2 inhibitors, which the panelists used to justify their use in patients with ATTR-CM alongside DMTs, including tafamidis. The study determined that SGLT2 inhibitors are well tolerated and associated with significant clinical and survival benefits for patients with ATTR-CM. Because patients with ATTR-CM were excluded from previous landmark SGLT2 inhibitor trials, this study used a multicenter, propensity-matched analysis of 440 patients—of whom 220 were treated with SGLT2 inhibitors and DMTs, and the remaining 220 were matched controls—to assess effectiveness and safety.¹

Generally, the study determined that treatment was well tolerated, with a low discontinuation rate of approximately 4.5% over a median follow-up of 28 months. Importantly, SGLT2 inhibitor use was not associated with significant changes in systolic blood pressure, which is critical for patients with ATTR-CM who are often prone to hypotension. At the 12-month mark, patients who were treated with SGLT2 inhibitors showed several favorable effects compared with their control counterparts. SGLT2 inhibitor therapy reduced new initiations of loop diuretic agents by 86% among previously diuretic-naive patients. Treated patients also had an approximately 53% lower probability of their NYHA functional class deteriorating, and the increase in N-terminal pro–brain natriuretic peptide (NT-proBNP) was significantly slower, with a slower rate of decline in renal function (measured by estimated glomerular filtration rate).

Over the follow-up period, SGLT2 inhibitor therapy with DMTs was also associated with a reduced risk across all major clinical end points, including an approximate 43% reduced risk of all-cause mortality (HR, 0.57), a 59% reduced risk of cardiovascular mortality (HR, 0.41), a 43% reduced risk of hospitalizations related to heart failure (HR, 0.57), and a 43% reduced risk of the composite outcome combining cardiovascular-related mortality and heart failure hospitalization.¹

These benefits were consistent across the spectrum of left ventricular ejection fraction, transthyretin genotype, and the presence or absence of diabetes. Although the study authors noted that their findings are “hypothesis-generating” and that the effect size is likely overestimated given the study’s observational design, the results still provide strong evidence for the use of SGLT2 inhibitors alongside DMT in ATTR-CM clinical practice in the absence of randomized controlled trials.¹

What Is the Pharmacist’s Role in the ATTR-CM Space?

Pharmacists play a multifaceted role in the management of ATTR-CM. The panelists emphasized that pharmacists are often the ones acting as clinicians, educators, and navigators who help bridge the gap between ATTR-CM diagnosis and sustainable treatment. According to the panelists, their responsibilities extend from early patient identification to managing complex financial access and long-term clinical monitoring.

Specifically, one of several core areas where pharmacists are essential to the care team is early detection and screening. By utilizing electronic health record (EHR) “sniffers” and phenotyping tools, pharmacists are able to identify high-risk patients who may have been misdiagnosed with general HFpEF, and they also screen for red flags in those who fail to tolerate standard heart failure medications. Through multidisciplinary collaboration, pharmacists establish themselves as trusted clinical partners by providing evidence-based recommendations and facilitating appropriate referral pathways to amyloid or advanced heart failure clinics.

On the education front, they bridge gaps by teaching fellows, primary care providers, and patients about disease progression and the nuances of therapy. In clinical management, under collaborative practice agreements (CPAs), pharmacists can independently order diagnostic labs (like monoclonal protein screens), refer for imaging, initiate therapies, and titrate heart failure medications.

“[Currently,] I practice under a CPA with advanced heart failure and all cardiology as well. I would say a lot of my role is kind of getting tagged in to counsel patients or talk with the provider through if we are selecting a silencer or a stabilizer, all those access issues that go along with it, [and then communicate with] specialty pharmacy as well,” Kelly Nguyen, PharmD, BCPS, BCCP, cardiology clinical pharmacist at Tufts Medical Center in Boston, Massachusetts, explained. “I would say previously in my inpatient role, it definitely was when patients got admitted to the hospital, and there was suspicion, I was one to help educate new fellows or residents on what labs to order [as well as] what things to rule in [and] rule out.”

To effectively manage ATTR-CM, the panelists emphasized that pharmacists must be experts in several areas. Recognizing and acknowledging the extracardiac red flag hallmark indicators (eg, bilateral carpal tunnel syndrome, lumbar spinal stenosis, biceps tendon rupture, neuropathy) is critical, as these often predate cardiac symptoms. Pharmacists must also understand diagnostic markers and staging, including the significance of NT-proBNP, troponin, and prealbumin levels, as well as staging systems, such as the Mayo Clinic score and National Amyloidosis Centre staging, to assess the risk trajectory.

Tailored heart failure management is another key area of expertise. Pharmacists must know that patients with ATTR-CM have restrictive physiology and are preload dependent, requiring caution with β-blockers, ACE inhibitors, and vasodilators, which are often poorly tolerated, whereas SGLT2 inhibitors and MRAs are generally better tolerated and recommended.

A deep understanding of DMTs—including stabilizers (eg, tafamidis, acoramidis) and silencers (eg, vutrisiran)—as well as the current lack of evidence for combination therapy is also necessary.

Pharmacists are also uniquely positioned to help patients overcome the significant logistical and financial hurdles that are often associated with ATTR-CM. In securing financial access, pharmacists find the “holes” in diagnostic documentation to successfully appeal insurance denials, and they manually navigate complex grant systems and manufacturer assistance programs to ensure patients do not face treatment gaps due to high out-of-pocket costs. In managing administration logistics for injectable silencers, pharmacists are often the ones coordinating clinic administration or working toward establishing home injection programs to help reduce the burden that comes with frequent clinic visits.

Additionally, they play a role in setting treatment expectations, providing crucial counseling that explains that DMTs are often intended to prevent future decline rather than provide immediate symptomatic relief, which helps improve long-term adherence. Pharmacists can also assist with clinical trial enrollment, helping identify candidates for upcoming trials—such as those studying combination therapy or newer depleter agents—and offering patients access to cutting-edge care. Above all, the panelists emphasized the importance of finding tools to help them—as well as patients with ATTR-CM—maneuver the obstacles that come with the treatment journey.

“Nobody has to reinvent the wheel [when figuring out what works], and the same thing goes for CPAs…. These things are scalable, and I know the legislation for pharmacists [and] what [working at] the top of their license [looks like] varies state by state, but the EHR is definitely a universal tool, love it or hate it. Pharmacists are here to stay, and I think [we are] well positioned to be the conduit that can capture these patients sooner in disease progression and get them to the next step in care far faster than they ever would have prior,” Riello explained. “And I think linking that step to the access to the specialty precision medications—especially in view of what’s coming down the pipeline—for ATTR-CM [is important]. This is not a rare disease; it is rarely identified, and we can use the EHR to find these patients sooner, and we should share that technology with everybody who wants to have it.”

REFERENCES

1. Porcari A, Cappelli F, Nitsche C, et al. SGLT2 inhibitor therapy in patients with transthyretin amyloid cardiomyopathy. J Am Coll Cardiol. 2024;83(24):2411-2422. doi:10.1016/j.jacc.2024.03.429

2. CARDIO-TTRansform: a study to evaluate the efficacy and safety of eplontersen (formerly known as ION-682884, IONIS-TTR-LRx and AKCEA-TTR-LRx) in participants with transthyretin-mediated amyloid cardiomyopathy (ATTR CM). ClinicalTrials.gov. Updated August 8, 2025. Accessed July 29, 2026. https://clinicaltrials.gov/study/NCT04136171

3. HELIOS-B: a study to evaluate vutrisiran in patients with transthyretin amyloidosis with cardiomyopathy. ClinicalTrials.gov. Updated January 12, 2026. Accessed July 29, 2026. https://clinicaltrials.gov/study/NCT04153149