Treatment Options for ATTR-CM

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Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive and life-threatening condition characterized by the buildup of abnormal protein deposits called amyloid in the heart tissue. This article will explore the various treatment approaches for ATTR-CM, including FDA-approved medications, off-label therapies, emerging treatments and lifestyle modifications to help manage symptoms and improve quality of life.

FDA-Approved Medications for ATTR-CM

Tafamidis (Vyndamax and Vyndaqel)

Tafamidis is the first and only FDA-approved medication specifically for treating ATTR-CM. It works as a transthyretin stabilizer, binding to TTR protein and preventing its dissociation into monomers that can misfold and form amyloid fibrils.

• Effectiveness. In the landmark ATTR-ACT clinical trial, tafamidis demonstrated significant benefits. It reduced all-cause mortality by approximately 30%, decreased cardiovascular-related hospitalizations by 32% and slowed the decline in functional capacity and quality of life.
• Dosage and administration. Tafamidis is available in two formulations. Vyndaqel is taken as 80 mg once daily (four 20 mg capsules), while Vyndamax is taken as 61 mg once daily (single capsule, bioequivalent to Vyndaqel 80 mg).

TTR Silencers and Gene Therapy

Patisiran (Onpattro)

Originally approved for polyneuropathy in hereditary transthyretin-mediated amyloidosis, patisiran uses RNA interference (RNAi) technology to reduce TTR production in the liver.

• Mechanism. Patisiran targets and silences TTR messenger RNA, preventing the production of both normal and mutant TTR proteins, thereby reducing amyloid formation.
• Clinical evidence. The APOLLO-B trial demonstrated that patisiran improved functional capacity, quality of life and reduced cardiac stress biomarkers in patients with ATTR-CM. Based on these results, patisiran received FDA approval for ATTR-CM in 2023.
• Administration. Administered as an intravenous infusion once every three weeks.

Vutrisiran (Amvuttra)

A next-generation RNAi therapeutic, vutrisiran reduces the production of both wild-type and mutant TTR.

• Advantages. Requires less frequent dosing than other TTR silencers.
• Clinical development. In clinical trials, vutrisiran demonstrated sustained TTR reduction and is being evaluated specifically for ATTR-CM.
• Administration. Administered as a subcutaneous injection once every three months.

Conventional Heart Failure Management

Patients with ATTR-CM often receive standard heart failure therapies to manage symptoms, though these do not address the underlying amyloid deposition.

Diuretics

Diuretics like furosemide, bumetanide and torsemide help reduce fluid overload and relieve symptoms such as peripheral edema (swelling in legs and ankles), pulmonary congestion, shortness of breath and abdominal swelling (ascites).

Careful monitoring of kidney function and electrolytes is necessary during diuretic therapy. Dosing may need frequent adjustment based on symptoms and fluid status.

Blood Pressure Management

Maintaining appropriate blood pressure is essential in ATTR-CM patients, who often have issues with orthostatic hypotension (blood pressure drops upon standing).

Treatment typically involves careful titration of medications, sometimes permitting higher sitting blood pressure to avoid symptomatic hypotension when standing, compression stockings to improve venous return and proper hydration strategies.

Heart Rhythm Management

Arrhythmias are common in ATTR-CM and may require antiarrhythmic medications with careful monitoring, pacemaker implantation for conduction abnormalities, implantable cardioverter-defibrillator (ICD) for patients at high risk of sudden cardiac death and anticoagulation therapy (often with direct oral anticoagulants or warfarin) for atrial fibrillation to prevent stroke.

Organ Transplantation

Liver Transplantation

For hereditary ATTR-CM, liver transplantation eliminates the primary source of mutant TTR production.

Liver transplantation is most effective when performed early in the disease course. It does not address wild-type TTR production, so amyloid deposition may continue long-term. The procedure requires lifelong immunosuppression and is limited by organ availability and patient eligibility.

Heart Transplantation

In advanced ATTR-CM with severe heart failure, heart transplantation may be considered for eligible patients.

Heart transplantation faces several challenges including age limitations (many ATTR-CM patients are elderly), coexisting systemic amyloidosis may affect other organs, limited donor availability and risk of amyloid recurrence in the transplanted heart.

Combined Heart-Liver Transplantation

For younger patients with hereditary ATTR-CM and significant cardiac involvement, combined heart and liver transplantation may be considered to address both the cardiac damage and the source of mutant TTR.

Lifestyle Modifications and Supportive Care

Dietary Considerations

Nutrition plays an important role in managing ATTR-CM symptoms. Sodium restriction (typically 2,000 mg daily or less) helps minimize fluid retention. Adequate protein intake is important to maintain nutritional status. Fluid restriction may be needed based on heart failure symptoms. Regular meal timing and portion control can help avoid large fluctuations in blood pressure after eating.

Physical Activity

Appropriate exercise is beneficial but must be tailored to the individual. Light to moderate activity as tolerated is recommended, possibly through supervised cardiac rehabilitation programs. Patients should avoid intense isometric exercises, but maintain regular activity to preserve muscle mass and prevent deconditioning.

Supportive Devices

For patients with mobility or functional limitations, compression stockings for orthostatic hypotension, walking aids for stability and home modifications to conserve energy and enhance safety may be beneficial.

Psychological Support

The chronic and progressive nature of ATTR-CM takes a psychological toll. Connection with support groups and patient organizations, counseling or therapy as needed for anxiety and depression and palliative care consultation for symptom management and quality of life optimization are all important components of comprehensive care.