The Double-Drug Dilemma: Should We Combine Treatments in ATTR-CM Amyloidosis?

The Promise of Two, the Proof of One

For many living with ATTR-CM amyloidosis, recent advances have brought hope. In just seven years we have gone from no approved treatments to having a number of options. Stabilizers, silencers, and broader awareness leading to earlier diagnoses have all marked important progress. Yet as the treatment landscape evolves, new questions surface. One of the most common today: could combining treatments change the story, or does it simply add complexity?

Stabilizers such as tafamidis or acoramidis help prevent transthyretin (TTR) protein from falling apart and misfolding. Silencers like patisiran or vutrisiran reduce how much TTR the body produces.

On paper, using both together seems like a logical “double defense.” Many patients naturally ask: if one is good, is two not better?

Several phase 3 trials have permitted patients to remain on a stabilizer while receiving an RNA silencer. These studies offer an early glimpse into whether combination therapy provides added value. In the APOLLO-B trial of patisiran, a prespecified subgroup on background tafamidis showed no clear evidence of incremental benefit compared with placebo. Similarly, in the HELIOS-B study of vutrisiran, patients on tafamidis were included, but subgroup analyses were not designed or powered to demonstrate an advantage. Effect sizes were described as “consistent,” but not confirmatory.

At this point, no study has shown that two drugs work better than one, and costs of combination therapy can exceed $700,000 per patient per year.

In the U.S. list prices are about $268,000 per year for tafamidis, $244,000 for acoramidis, $450,000 on average for patisiran, $477,000 for vutrisiran, and $499,000 for eplontersen. Used together, total costs exceed $700,000 per patient per year. While Medicare’s new $2,000 out-of-pocket cap helps protect individuals, the broader impact on the healthcare system remains substantial. These are lifelong therapies, often begun early and continued indefinitely, raising difficult questions about sustainability and access.

Where does that leave patients today? In theory, combination therapy may sound appealing, but its benefits and risks are not yet established. More research is needed; larger, longer-term studies designed specifically to test dual therapy. These will be costly and take years, but they are critically important if we are to determine the best course of treatment.

Until then, decisions should be made by patients and their physicians, weighing current evidence, personal circumstances, and long-term considerations. Given the considerable costs, insurance coverage may ultimately determine access to both. The path forward will require careful study, but only then will we know whether in ATTR amyloidosis, “more” truly means “better.”