Eplontersen Misses Primary ATTR-CM Endpoint in CARDIO-TTRansform

Key Takeaways

• Among patients with transthyretin amyloid cardiomyopathy (ATTR-CM) receiving standard treatment, adding eplontersen did not significantly lower the composite of cardiovascular death and recurrent cardiovascular clinical events.
• The alternative composite of death from any cause and cardiovascular events did not establish a benefit from eplontersen.
• Serious adverse events affected 57.8% of eplontersen recipients versus 59.4% of placebo recipients.

Progressive transthyretin amyloid cardiomyopathy (ATTR-CM) results from deposition of misfolded transthyretin in the heart. Eplontersen is an antisense oligonucleotide that reduces transthyretin production in the liver. Whether adding it to standard treatment changes cardiovascular outcomes remained uncertain. Investigators compared eplontersen with placebo to assess that question.

Investigators conducted the international, double-blind CARDIO-TTRansform trial, randomly assigning patients with ATTR-CM to eplontersen or placebo alongside standard treatment. Participants received subcutaneous eplontersen 45 mg or placebo every four weeks for 140 weeks. The primary endpoint was a cumulative composite of cardiovascular death and recurrent cardiovascular clinical events through the treatment period. Investigators also assessed a cumulative composite that replaced cardiovascular death with death from any cause.

In the primary composite, investigators recorded 381 events with eplontersen and 392 with placebo. Those totals include recurrent events, so they are not counts of individual patients. The trial included 1,432 treated patients: 715 received eplontersen and 717 received placebo. At least one primary-endpoint event occurred in 210 patients (29.4%) receiving eplontersen and 231 patients (32.2%) receiving placebo, but the event totals alone do not establish a treatment effect.

The primary recurrent-event analysis yielded a rate ratio of 0.89 (95% confidence interval, 0.73–1.09; P=0.28). This difference was not statistically significant. The rate ratio describes the cumulative endpoint, not the percentage of patients who had an event.

For the distinct composite substituting death from any cause for cardiovascular death, the rate ratio was 0.86; its confidence interval included no difference between groups. Serious adverse events affected 413 eplontersen recipients and 426 placebo recipients. These counts represent patients with serious adverse events rather than the total number of adverse events.

The nonsignificant primary comparison does not prove that no possible benefit exists. The alternative composite did not establish benefit, and serious adverse-event totals alone cannot characterize the complete safety profile. The authors concluded that eplontersen did not significantly lower the primary cumulative cardiovascular composite relative to placebo during the assessed period.

Clinician Questions

How many cardiovascular deaths and cardiovascular clinical events contributed to the eplontersen ATTR-CM primary endpoint?

Cardiovascular deaths contributing to the primary composite numbered 74 with eplontersen and 70 with placebo.

Cardiovascular clinical events numbered 307 and 322, respectively.

Does the eplontersen ATTR-CM rate ratio represent the percentage of patients who experienced a cardiovascular event?

No. The rate ratio compares the cumulative composite of cardiovascular death and recurrent cardiovascular clinical events. Patient percentages instead describe the proportion who experienced at least one primary-endpoint event; the recurrent-event rate ratio cannot be read as an individual patient’s risk.