Ahmad Masri, MD, MS, is the director of the Hypertrophic Cardiomyopathy Center at Oregon Health and Science University. 

Ahmad Masri, MD, MS

A Look Into the Future of ATTR-CM Clinical Trials

Summary for Physicians: Designing Future Trials in ATTR-CM

 (transthyretin amyloid cardiomyopathy) should focus not only on evaluating the efficacy of 

, including amyloid depleters, but also on enhancing our understanding of the mechanisms driving 

 to current treatments. Key considerations for trial design include:

 Trials should incorporate biomarkers (eg, NT-proBNP, troponin, TTR, amyloid-related markers) to assess how therapies impact both amyloid burden and cardiac dysfunction. This will help define the relationship between amyloid deposition and heart failure progression.

 mutations) and advanced techniques such as 

 could help identify specific molecular mechanisms underlying disease progression, particularly in wild-type ATTR-CM and in nonresponders.

 with advanced imaging techniques could provide insights into amyloid infiltration, inflammation, and fibrosis, allowing for a deeper understanding of the pathological changes in the heart.

 Trials should stratify patients into distinct groups (eg, wild-type vs hereditary ATTR, responders vs nonresponders) to assess differential responses to therapies. This approach can identify factors that contribute to lack of response in certain patients and guide more personalized treatment strategies.

 Include long-term follow-up data to capture how treatments impact disease progression over time, particularly for patients with wild-type disease, who may have a slower progression.

 In addition to traditional clinical outcomes such as mortality or hospitalization, surrogate end points (eg, improvement in biomarkers, cardiac imaging findings, or exercise capacity) should be included to more quickly evaluate therapeutic effects.

 should be incorporated to assess the broader impact of therapy on daily functioning and patient well-being.

Trials should explicitly include patients who have shown little to no benefit from current therapies (eg, tafamidis, diflunisal) to better understand the reasons behind therapy resistance. This can help identify potential new therapeutic targets or biomarkers associated with nonresponsiveness.

 Investigating combination therapies, including amyloid depleters and other novel agents targeting different pathways involved in cardiac dysfunction (eg, inflammation, fibrosis), may provide insights into better treatment strategies for nonresponders.

 collection and collaboration across centers to enhance the diversity of the patient population and improve generalizability. Multicenter collaborations, including registries and biobanks, could facilitate a deeper understanding of disease variability and therapeutic outcomes.

In conclusion, future clinical trials for ATTR-CM should integrate 

 to better understand and address the underlying causes of cardiac dysfunction, leading to more effective, personalized treatment strategies.

Videos

Panelists discuss how future clinical trials in transthyretin amyloid cardiomyopathy (ATTR-CM) should focus on incorporating mechanistic research, patient stratification, and diverse end points, while also including nonresponders to current therapies to better understand cardiac dysfunction and develop more personalized treatment strategies.

Prognostic Indicators of Disease Progression in ATTR-CM

Summary for Physicians: Prognostic Indicators and Detection of Progression in ATTR-CM

 (transthyretin amyloid cardiomyopathy), identifying and monitoring progression is crucial for optimal patient management. Several 

 and methods for detecting progression include:

 Increasing shortness of breath, fatigue, and edema suggest cardiac deterioration.

 New-onset atrial fibrillation, sustained ventricular arrhythmias, or worsening arrhythmias signal disease progression.

 A reduction in exercise tolerance or worsening ability to perform daily activities.

 Progression can be indicated by worsening left ventricular ejection fraction, increased wall thickness, or diastolic dysfunction.

 Increased gadolinium retention (suggesting amyloid deposition) or worsening myocardial edema may indicate progression.

 In patients with bone tracer uptake, an increase in uptake may reflect more extensive amyloid deposition.

 An increase in NT-proBNP levels indicates worsening heart failure and may suggest progression.

 Continuous or rising levels of cardiac troponin reflect myocardial injury and may signal disease progression.

 Changes in these biomarkers may indicate disease progression or response to treatment.

 A decline in the distance walked may reflect worsening functional status.

 Tools assessing functional capacity and patient-reported symptoms, such as the Kansas City Cardiomyopathy Questionnaire, can provide insight into disease progression.

 Lack of response or disease stabilization despite treatment may signal progression.

 Worsening symptoms of other organ involvement (eg, neuropathy, carpal tunnel syndrome) may also be indicative of disease progression.

 in ATTR-CM is defined by a combination of clinical, imaging, biomarker, and functional assessments. Monitoring these factors regularly helps physicians detect progression early, enabling timely interventions to manage the disease effectively.

Panelists discuss how monitoring clinical indicators, cardiac imaging, biomarkers, and functional assessments—such as NT-proBNP, troponin, and the 6-minute walk test—helps detect progression in transthyretin amyloid cardiomyopathy (ATTR-CM), allowing for early intervention and optimal disease management.

Using Biomarkers to Monitor ATTR-CM

Summary for Physicians: Long-Term Monitoring in ATTR-CM and Biomarkers Used

 (transthyretin amyloid cardiomyopathy) involves regular clinical assessments, imaging studies, and biomarker evaluations to track disease progression and manage complications. Key aspects of monitoring include:

Regular assessment of cardiac symptoms such as heart failure, arrhythmias, and functional status

Monitoring for signs of organ involvement beyond the heart, as ATTR-CM can affect other organs, such as the liver and nervous system

 to assess left ventricular function and wall thickness

 to evaluate myocardial involvement and amyloid deposits

 to detect amyloid deposition in the heart

N-terminal pro B-type natriuretic peptide (NT-proBNP):

 A marker for heart failure, often elevated in ATTR-CM

 Can indicate myocardial injury or stress, which may be elevated in patients with ATTR-CM

 Helpful in distinguishing ATTR-CM from other forms of amyloidosis, such as light chain amyloidosis

 Can be elevated in systemic inflammation associated with amyloidosis

TTR genetic testing and serum TTR concentration

 may help to confirm the diagnosis and assess familial risk.

, including exercise tolerance and quality of life (using tools such as the 6-minute walk test and patient-reported outcome measures).

Monitoring these biomarkers, alongside clinical and imaging evaluations, helps physicians track the progression of ATTR-CM, adjust therapies, and intervene early in cases of disease progression or complications. Regular follow-up is essential for optimizing management and improving patient outcomes.

Panelists discuss how long-term monitoring in transthyretin amyloid cardiomyopathy (ATTR-CM) involves regular clinical assessments, imaging studies, and biomarker evaluations—such as NT-proBNP, troponin, and TTR testing—to track disease progression, manage complications, and optimize patient outcomes.

Challenges to Implementing Agents

Summary for Physicians: Challenges in Implementing Newer Agents for ATTR-CM

As newer disease-modifying agents for transthyretin amyloid cardiomyopathy (

 become available, there are several challenges that may arise when implementing these therapies. Dr Soman discusses the key challenges, particularly around 

, and provides strategies to overcome them:

: One of the biggest challenges with newer agents is ensuring that patients have access to these medications through insurance coverage. High-cost therapies such as 

 may face barriers to coverage, particularly if the patient’s insurance plan has strict formulary requirements or does not recognize the latest treatments for rare conditions like ATTR-CM.

: To overcome this, health care providers can engage with insurance companies and specialty pharmacies to ensure the medications are covered. This may involve submitting letters of medical necessity, utilizing prior authorization processes, or advocating for the inclusion of newer agents in formulary reviews. Collaborating with patient assistance programs offered by pharmaceutical companies can also help provide financial support for patients struggling with access.

, are often costly. This high price point can create significant financial barriers for patients, especially for long-term treatment plans.

: Physicians can work with health care systems, patient advocacy groups, and pharmaceutical companies to explore financial assistance options. Many manufacturers offer patient assistance programs to help reduce out-of-pocket costs for eligible patients. Additionally, physicians should be aware of any discounts or co-payment assistance programs that might be available to lower the burden on patients.

, require frequent injections or infusions, which can be burdensome for patients, particularly those with advanced disease or comorbidities.

: Educating patients on the importance of adhering to treatment and how it can significantly impact their disease progression is key. For patients who struggle with frequent infusions, 

’s less-frequent dosing (quarterly subcutaneous injections) could be a preferred option. Additionally, support from nurse navigators or infusion specialists can help patients better manage treatment regimens and cope with any adverse effects.

: Newer agents may not be as well known to some health care providers, leading to concerns regarding their use and monitoring requirements.

: Ongoing education and training for health care providers, including access to clinical trial data, updated treatment guidelines, and expert opinions, can help physicians become more comfortable with these therapies. Regular multidisciplinary team discussions, including cardiologists, geneticists, and pharmacologists, can further improve understanding and implementation of the newest treatments.

: Although clinical trials have shown the efficacy and safety of these newer agents, long-term data, especially real-world experience, is still being gathered.

: Physicians should stay informed about the evolving data on the long-term use of these therapies and be proactive in collecting real-world evidence. Participation in registries and ongoing clinical trials will also help build a more comprehensive understanding of how these treatments perform over time.

: Although newer agents for ATTR-CM present exciting treatment options, challenges related to access, cost, patient adherence, and health care provider familiarity can hinder their widespread implementation. Overcoming these challenges requires a multifaceted approach, including insurance advocacy, financial assistance programs, patient education, and continuous professional development to ensure that these therapies are accessible and effectively utilized for optimal patient care.

Panelists discuss how challenges in implementing newer agents for transthyretin amyloid cardiomyopathy (ATTR-CM), such as access issues, high costs, patient adherence, and provider familiarity, can be addressed through strategies like insurance advocacy, financial assistance programs, patient education, and ongoing professional development.

Ahmad Masri, MD, MS

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