Treatments that target the transthyretin (TTR) protein, either by stabilizing it or reducing its production, were associated with about a one-third lower risk of death and cardiovascular hospitalizations in people with transthyretin amyloid cardiomyopathy (ATTR-CM).
That’s according to a systematic review and meta-analysis of clinical trial and real-world data from more than 5,000 ATTR-CM patients, comparing those who received targeted therapies with those who did not. Treatments included Vyndamax/Vyndaqel (tafamidis), Amvuttra (vutrisiran), Attruby (acoramidis), or Onpattro (patisiran).
“Targeted treatments for ATTR-CM significantly reduce mortality and cardiovascular hospitalizations,” the researchers wrote. “Early diagnosis and initiation of treatment are critical to [maximize] the clinical benefits and prolong patient survival.”
The study, “Real-world effectiveness of targeted therapies in ATTR cardiomyopathy: A meta-analysis integrating population-based data,” was published in ESC Heart Failure.
How misfolded TTR damages the heart in ATTR-CM
In ATTR, an unstable and misfolded TTR protein builds up as toxic aggregates, called amyloid fibrils, in tissues throughout the body, causing organ damage. The disease can be hereditary, caused by mutations in the TTR gene, or wild type, which develops sporadically with age, most often in older adults.
ATTR-CM is marked by the accumulation of amyloid fibrils primarily in the heart, leading to cardiomyopathy, or damage to the heart muscle. It may occur with or without TTR mutations.
Hereditary ATTR with polyneuropathy (hATTR-PN) is another form of the disease, in which TTR mutations cause amyloid buildup primarily in the peripheral nerves, leading to neurological symptoms.
“Recently, the availability of targeted ATTR treatments has drastically altered the disease course and improved patient quality of life,” the researchers wrote. “Targeted treatments represent a milestone in contemporary cardiology, as ATTR-CM was until recently considered a non-curable and progressive disease with patients being offered only symptomatic treatment.”
Such treatments include TTR gene-silencing therapies, which reduce TTR production (Amvuttra and Onpattro), and TTR stabilizers, which prevent the protein from misfolding and forming amyloid (Vyndamax/Vyndaqel and Attruby). In the U.S., Amvuttra, Vyndamax/Vyndaqel, and Attruby are approved for ATTR-CM, while Onpattro is approved for hereditary ATTR with polyneuropathy and may be used off-label in ATTR-CM.
Researchers in Greece analyze real-world and trial data
Here, a team of researchers in Greece examined how targeted therapies affect outcomes in people with ATTR-CM by combining data from clinical trials and real-world studies. The team systematically reviewed published studies through June and included 10 studies in the final meta-analysis, covering a total of 5,203 patients.
Across the studies, most participants (78% to 92%) were men, with average or median ages ranging from 61 to 85. Most participants (75% to 100%) had wild-type ATTR-CM. Five studies were appropriately controlled clinical trials that compared treatment with placebo, while the remaining five were observational studies comparing treated patients with those who did not receive therapy.
When data from all 10 studies were combined, TTR-targeted treatments significantly reduced the risk of death by 39% compared with placebo or no treatment. Similar results were seen when only appropriately controlled trials were analyzed, with targeted treatments associated with a 28% lower risk of death.
Five studies reported cardiovascular hospitalization rates and found that targeted therapies were associated with a 31% lower risk. However, results varied substantially between studies, limiting how confidently the findings can be applied.
When one observational study was excluded, variability between studies decreased, and the overall trend remained, with targeted treatments significantly reducing the risk of cardiovascular hospitalizations by 23%.
Targeted treatments for ATTR-CM significantly reduce mortality and cardiovascular hospitalizations. Early diagnosis and initiation of treatment are critical to [maximize] the clinical benefits and prolong patient survival.
The team then conducted an extrapolative analysis to estimate the potential impact of targeted therapies on the natural course of ATTR-CM, drawing on findings from a previous meta-analysis of 95 studies that included 18,238 untreated ATTR-CM patients.
Based on this dataset, researchers estimated a mortality rate of 26.7% at two years after diagnosis and 49.6% at five years in untreated patients. In contrast, the estimated mortality rate among patients receiving targeted therapies was 16.3% at two years and 30.3% at five years, corresponding to risk reductions of 10.4% and 19.3%, respectively.
The team also calculated the number needed to treat (NNT), which represents the average number of patients who would need to receive treatment to prevent one additional death. Based on the extrapolated data, the NNT was estimated to be 10 at two years and five at five years, “signifying a greater long-term benefit,” the researchers wrote.
“Future research should prioritize the refinement of treatment strategies, response to treatment and the value of dual ATTR therapies that target different parts of the TTR pathway (e.g., TTR formation and aggregation),” the researchers wrote. Also, “the evaluation of the long-term impacts of these therapies is crucial for understanding patient outcomes over extended periods of treatment.”