Blood TTR levels may predict Vyndaqel response in ATTR-CM patients
Lower baseline levels and smaller early increases linked to worse outcomes
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Blood levels of the transthyretin (TTR) protein at the start of Vyndaqel (tafamidis) treatment and after one month may help identify which patients with wild-type transthyretin amyloidosis with cardiomyopathy (ATTR-CM) are responding well and which remain at higher risk.
That’s according to a multicenter study in Italy, which found that lower initial levels of circulating TTR and smaller early increases after starting Vyndaqel identified patients at the highest risk of hospitalization due to heart failure or death.
Measuring circulating TTR “could help stratify clinical severity and risk, as well as personalize care for patients,” the researchers wrote. They noted, however, that larger studies are needed to confirm these findings.
Study suggests blood TTR levels may help predict patient outcomes
The findings were published as a brief report titled, “Serum Transthyretin Before and After Starting Tafamidis as Outcome Predictors in ATTR Cardiomyopathy,” in JACC.
ATTR-CM occurs when the TTR protein becomes unstable due to genetic mutations (hereditary) or aging (wild-type). Its typical four-unit structure breaks apart into individual units that can misfold and clump together. These toxic clumps, known as amyloid deposits, accumulate in the heart and cause it to stiffen.
Vyndaqel, a once-daily oral capsule marketed in the U.S. as Vyndamax, works by stabilizing TTR’s four-unit structure as it circulates in the blood, preventing it from breaking apart.
By stabilizing TTR, the therapy helps prevent new amyloid deposits from forming and accumulating in the heart, which may slow the progression of ATTR-CM. The Pfizer therapy is approved for adults with hereditary or wild-type ATTR-CM.
In clinical trials of Attruby (acoramidis), another TTR stabilizer approved for ATTR-CM, higher initial circulating TTR levels and greater increases after treatment were associated with better survival. This raised the question of whether the same pattern could be seen in patients treated with Vyndaqel in real-world clinical practice.
Researchers tracked TTR levels before and after starting Vyndaqel
To explore this, researchers followed 169 adults with wild-type ATTR-CM who began once-daily Vyndaqel (61 mg) at three Italian centers. Most (91%) were men, and the median age was 79. All were clinically stable at the start of treatment (baseline).
Blood TTR was measured at baseline and after 14 days, one month, three months, six months, and one year. Median TTR levels were 22.6 mg/dL at baseline. Levels increased significantly to 29.7 mg/dL after about one month of treatment, then leveled off by six months.
Baseline blood TTR levels “reflected disease severity,” the researchers wrote. Lower levels were associated with higher National Amyloidosis Centre stages, indicating more severe disease, as well as higher levels of heart damage markers and poorer heart function and exercise capacity.
Over a median follow-up of 19 months (about 1.5 years), 24 participants (14%) were hospitalized at least once for heart failure, and 13 (8%) died.
Higher baseline levels of circulating TTR were significantly associated with a lower risk of death. Each 1 mg/dL increase in blood TTR was linked to a 12% reduction in mortality risk. Further analyses identified 18 mg/dL as the best cut-off value to separate higher- and lower-risk patients.
Patients with levels below the cut-off “displayed a more advanced clinical and biomarker profile” and were significantly more likely to die, the researchers wrote.
In addition, a larger increase in circulating TTR early after starting treatment with Vyndaqel was linked to a lower risk of hospitalization for heart failure. Each 1 mg/dL increase in TTR was significantly associated with a 7% lower risk of a first heart failure-related hospitalization.
Early increases in TTR linked to lower risk of hospitalization
An increase of at least 7.5 mg/dL after one month best separated higher- and lower-risk patients. Those with smaller increases tended to have worse functional status and biomarker levels.
When researchers combined the two measures — baseline TTR levels and the early increase after treatment — three risk groups emerged: patients with both measures below the cut-offs, those with one below the cut-off, and those with both above the cut-offs.
Over the first two years of follow-up, patients with both lower initial TTR levels and a smaller early increase had the worst outcomes, with high rates of death (29%) and hospitalization for heart failure (25%). By contrast, patients whose values were above both cut-offs experienced no such events.
“Taken together, these observations support a classwide biological framework: effective TTR stabilizers increase [blood TTR], which carries prognostic information,” the researchers wrote. “The combination of baseline [blood TTR] and early [TTR increase] yields a simple, 2-point strategy that discriminates patients with excellent short-term outcomes from those who remain at high risk.”
The team emphasized, however, that larger studies are needed to confirm these risk thresholds and determine how TTR trends may work alongside other biomarkers of heart function.
