Fellows in training (FITs) and early career cardiologists (ECs) are often eager to make an impact, especially when joining a new team. There is a perception that it's difficult to make a significant contribution in established fields as the team is saturated with senior experts and it may seem insurmountable to start a new service. And care models have shifted from lone practitioner to a team sport. Thus, FITs and ECs often seek novel opportunities to start a niche program and partner with colleagues across several disciplines to provide a comprehensive approach to clinical care and research. Such approaches include the pulmonary embolism response team and the shock team, as well as cardio-obstetrics and amyloidosis programs.

We recognized, in 2020, the lack of a structured pathway for screening, workup or initiation of therapy for patients we were starting to encounter with suspected amyloidosis. Often this led to confusion on which tests to order, who to consult, what therapies are available and how to prescribe them. This in turn led to delay in care of this deadly disease. Therefore, we met with representatives from cardiology, neurology and hematology/oncology to discuss forming a cohesive collaborative effort to address this unmet need in a pragmatic fashion.

The challenges we encountered as ECs when developing the program at Thomas Jefferson University Hospital are likely germane to cardiologists starting many such programs. Here we review six challenges and proposed solutions for others leading an effort to establish a program.

Challenge #1: Starting without prior experience.

Proposed Solution: When forming a new program, it is difficult to anticipate problems which may arise along the way. Form a close relationship with an established amyloidosis center to ask for guidance and troubleshoot problems as they arise. We partnered with two centers, one where we had a close mentor relationship developed during training and another local center nearby. The mentoring relationship was a safe environment to ask questions about patient cases and seek advice and support for broader programmatic decisions. The local center allowed us an opportunity for patient referral for services we did not yet provide, such as ongoing clinical trial enrollment or financial assistance for out-of-pocket costs, which may be more readily available at an established center. This nurturing environment creates an ongoing relationship which benefits patients, established centers, and up-and-coming programs.

Challenge #2: Amyloidosis is a team sport. How do we build the team?

Proposed Solution: We identified key members of the team with a specific interest and expertise to diagnose cardiomyopathy, polyneuropathy and plasma cell dyscrasias, and familiarity with approved therapies. As our program grew, we developed an in-person multidisciplinary clinic with cardiology and neurology. We are now adding hematology/oncology representation to the multidisciplinary clinic. This will be helpful for patients with light-chain amyloidosis (AL) and substantial cardiac involvement. These patients need to be seen frequently for chemotherapy infusions and their volume management is often challenging, requiring frequent adjustment of diuretics.

The multispecialty in-person clinic is more reasonable once the patient volume grows to justify regularly scheduled clinic sessions. The process for setting up an in-person clinic is challenging. It requires working closely with administrative teams to build clinic templates for providers to schedule patients and bill properly within another department. We also had to obtain approval from Pennsylvania's Department of Health as we were providing a new service, which took several months.

While an in-person multidisciplinary clinic is not strictly necessary, we found it beneficial, as it allowed us to offer patients same-day appointments with two specialists, particularly helpful for new patients with hereditary transthyretin amyloidosis (ATTR). These patients can have cardiac and neuropathic manifestations and there are two classes of medications with cardiac and neuropathic indications.^1-3

The optimal composition of an amyloidosis program remains unknown and individual members will vary by institution. The composition will depend on the resources of the institution, the interests of its members, and the clinical demands of the community.

Challenge #3: Amyloidosis is a heterogeneous disorder requiring expedited workup.

Proposed Solution: We developed a standardized approach to screening at-risk populations and developed protocols to exclude AL, which is associated with a substantially worse prognosis and requires urgent initiation of targeted chemotherapy. Moreover, due to the high cost of current medical therapy and associated poor outcomes when diagnosed with late-stage disease, it's of interest to establish the correct diagnosis in a timely fashion and institute appropriate care.⁴

Testing often starts with echocardiography which can identify suggestive features of underlying AL-cardiomyopathy (CM) and ATTR-CM. Noninvasive testing with technetium-99m pyrophosphate scintigraphy (PYP) imaging can establish the diagnosis in 80% to 90% of patients with suspected AL in the absence of plasma cell dyscrasia.⁵ However, PYP scan requires expertise with proper acquisition and interpretation of data, including mandatory SPECT imaging to confirm myocardial uptake and exclude blood pool.

Improper testing may lead to substantial risk of false positive results.⁶ Noninvasive testing with serum and urine protein electrophoresis with immunofixation and serum and urine free light chains is associated with high sensitivity and negative predictive value for excluding AL and therefore allow excluding a diagnosis without requiring a biopsy. Confirmatory testing with endomyocardial biopsy may be required in selected cases where AL cannot be ruled out noninvasively or ATTR suspected clinically but PYP is not diagnostic (Grade 1).

To ensure results were available for real-time discussion during a clinic visit, we organized laboratory evaluation to be completed before the visit and PYP testing to be done the same day.

Electromyography nerve conduction studies (EMG/NCS), and sometimes skin biopsy, are done expeditiously to confirm clinical suspicion of large or small fiber neuropathy. This model allowed us to quickly evaluate the patient, establish the diagnosis, either rule in or rule out multiorgan involvement, and implement appropriate therapy.

Challenge #4: Nurses are vital to patient care. How to justify the cost?

Proposed Solution: Nursing coordinators and advanced practice providers (APPs) provide key roles within a multidisciplinary amyloidosis program. They ensure streamlined care across subspecialties by coordinating appointments and appropriate diagnostic testing. They can also screen at-risk populations for increased referrals, such as patients undergoing TAVR, carpal tunnel release surgery or admission for heart failure with preserved ejection fraction, among others.

APPs also play an important role in patient education and family support, and can provide independent patient follow-up, freeing up physicians to take on new patients. However, obtaining nursing support requires either hiring new staff or redistributing limited nursing resources from other services. We justified the need for additional resources by demonstrating growth: from no patients at the start to >100 by year four. We also projected growth over the next year and how the addition of a dedicated nurse can further invigorate that growth. In a multidisciplinary model it may be a challenge to decide which department will provide funding for the nurse or APP. In our institution, cardiology provided the necessary resources, but this is likely to vary among institutions.

Challenge #5: Amyloidosis is often missed due to lack of disease awareness. How do we gain institutional reputation and build a referral network?

Proposed Solution: We started an education campaign to promote the program and increase awareness of amyloidosis. Our campaign involved lectures to residents, fellows, primary care physicians and hospitalists, who often encounter the patient before any specialists. We partnered with our marketing department to develop educational materials for patients, caregivers and physicians.

For systems where such resources may be scarce, it is helpful to partner with an outside support network such as the Amyloidosis Research Consortium, which has dedicated substantial resources to develop unbranded education resources that are free of charge.⁷

We created the "Cardiac Amyloidosis Response Team" (CART) to promote our program, create a sense of urgency in establishing the diagnosis and encourage early referral of patients with suspected cardiac amyloidosis. Knowing this would generate substantial referral of patients with and without cardiac amyloidosis, we implemented CART after our clinic was up and running and some of the initial obstacles were overcome.

We also developed the Best Practice Advisory (BPA) within our electronic medical record to simplify the referral process for patients being worked up for amyloidosis. Other institutions have developed machine-learning algorithms to identify patients at risk of amyloidosis who may have echocardiographic, ECG and other clinical features suspicious for amyloidosis. We thought it would be critical to build our infrastructure and develop diagnostic and therapeutic pathways before implementing machine-learning algorithms, which could generate an overwhelming number of referrals, quickly overpower the system and create a substantial delay in patient care.

As we scaled up our clinical bandwidth, we formed a collaborative network within our health care enterprise. We identified experts across the different hospitals in our network to share resources we developed and established pathways for patient referral if advanced diagnostics or therapies are needed, as well allowed for close follow-up local to the patient.

Challenge #6: Establishing quality metrics and targets to improve care.

Proposed Solution: Initially we focused on several key metrics, including time to diagnosis and time delay from diagnosis to implementing treatment. We started the program in 2020 with a handful of patients with confirmed amyloidosis. As we implemented the program and the education campaign, we saw about a 40% increase per year of referrals for PYP scans and a substantial increase in confirmed diagnosis, to a current clinic volume of >100 patients with ATTR.

We partnered with a specialty pharmacy that handles prior authorization for therapy and secures external funding when necessary. Overall, our model allows for rapid diagnosis and a very short delay between diagnosis and implementation of therapy.

Other metrics we will track are the numbers of referrals and from where, patients referred for advanced therapies and patients diagnosed from at-risk populations, and others. The metrics will change over time in concert with the needs of the institution.

Future Perspective

As we identify more patients with amyloidosis, more centers equipped to handle an influx of patients with suspected and confirmed cases will be needed. After the diagnosis is established and treatment is initiated, the follow up care can be done locally with a shared-care model with an expert center. We propose a multilevel collaboration between centers caring for patients with amyloidosis (Figure).

The recent advances in systemic amyloidosis and emergence of several approved therapies, along with more under investigation, sets the stage for cardiologists to develop a multidisciplinary team to manage this complex patient population. FITs and ECs can gain a highly valuable skillset as more institutions recognize the need for expertise in managing systemic amyloidosis.

References

1. Maurer MS, Schwartz JH, Gundapaneni B, et al. Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy. N Engl J Med. 2018;379(11):1007-1016. doi:10.1056/NEJMOA1805689/SUPPL_FILE/NEJMOA1805689_DATA-SHARING.PDF
2. Benson MD, Waddington-Cruz M, Berk JL, et al. Inotersen treatment for patients with hereditary transthyretin amyloidosis. N Engl J Med. 2018;379(1):22-31.
3. Adams D, Tournev IL, Taylor MS, et al. Efficacy and safety of vutrisiran for patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy: A randomized clinical trial. Amyloid. 2023;30(1):18-26.
4. Kumar S, Dispenzieri A, Lacy MQ, et al. Revised prognostic staging system for light chain amyloidosis incorporating cardiac biomarkers and serum free light chain measurements. J Clin Oncol. 2012;30(9):989-995.
5. Gillmore JD, Maurer MS, Falk RH, et al. Nonbiopsy diagnosis of cardiac transthyretin amyloidosis. Circulation. 2016;133(24):2404-2412.
6. Poterucha TJ, Elias P, Bokhari S, et al. Diagnosing transthyretin cardiac amyloidosis by technetium tc 99m pyrophosphate: A test in evolution. JACC Cardiovasc Imaging. 2021;14(6):1221-1231.
7. Amyloidosis Research Consortium (ARC). Accessed Nov. 29, 2023. Available here.

Clinical Topics: Cardiovascular Care Team, Heart Failure and Cardiomyopathies

Keywords: Cardiology Magazine, ACC Publications, Immunoglobulin Light-chain Amyloidosis, Amyloidosis, Hematology