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MUNICH -- Treatment with the investigational drug tafamidis was associated with a reduction in all-cause mortality and cardiovascular hospitalizations in patients with transthyretin (TTR) amyloid cardiomyopathy, and improved functional capacity and quality of life, the phase III ATTR-ACT trial found.

The mortality rate at 30 months was 29.5% in the tafamidis-treated group compared with 42.9% in the placebo group (HR 0.70, 95% CI 0.51-0.96), reported Claudio Rapezzi, MD, of the University of Bologna in Italy, and colleagues.

"In patients with this terrible, severe, previously drug-orphan disease, tafamidis can reduce all-cause mortality and cardiovascular-related hospitalizations," said Rapezzi in a late-breaking clinical trial session here at the European Society of Cardiology (ESC) meeting.

The rate of cardiovascular-related hospitalizations during the trial was 0.48 per year with tafamidis vs 0.70 per year with placebo (relative risk ratio 0.68, 95% CI 0.56-0.81).

Martha Gulati, MD, of the University of Arizona in Phoenix, told 番茄社区app that until now there have only been limited options for treating TTR amyloid cardiomyopathy in patients who present clinically. "We had nothing we could offer them but symptomatic therapy," she said.

The trial looked at amyloid cardiomyopathy patients with pathogenic mutations in the transthyretin gene TTR (ATTRm), which typically occurs in patients in their 50s, and those with wild-type transthyretin protein (ATTRwt), which more often occurs in patients into their 70s. Tafamadis acts as a chaperone molecule to stabilize transthyretin in the correctly folded conformation to prevent pathological aggregation.

Outcome data were similar between the two etiologies -- the two primary endpoint curves were "quite superimposable," Rapezzi noted.

The prevalence of ATTRwt is not known, but among patients with heart failure and preserved ejection fraction (EF), some studies have reported a prevalence of 13%.

"It's a very important study," James Udelson, MD, of Tufts Medical Center in Boston, told 番茄社区app. "Now that there's a treatment, physicians should think about this in patients who present with heart failure and preserved EF. Always think about it."

Udelson and Gulati, who were not involved in the study, both highlighted that patients with New York Heart Association (NYHA) class I and II disease benefited most in the survival analysis. "So earlier the better," Udelson said.

From baseline to month 30, improvements with tafamidis over placebo were also seen in two key secondary endpoints: quality-of-life change on the 0-to-100 Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS) and change in functional decline, as measured by the 6-minute walk test.

Among patients on tafamidis, decline in quality of life on KCCQ-OS was 13.65 points better than those on placebo (P<0.001). And those on tafamidis were able to walk 75.68 more meters during the 6-minute walk test than those on placebo (P<0.001), as reported at ESC and simultaneously online in the . Differences for both were observed starting at 6 months into the study.

Every 6 months, patients on placebo were able to walk 30 meters less than those on active treatment. "Tafamidis can improve, can slow down, this decline," said Rapezzi.

When asked about diagnosing amyloid cardiomyopathy patients at earlier time points, such as NYHA Class I or II disease, Udelson said "it's conceivable genetic testing might be used in populations we know to be at some risk for this, like African Americans."

The most common amyloidogenic TTR variant -- Val122Ile, which is associated predominantly with a cardiac phenotype and has a late onset -- is present in 3% to 4% of African Americans.

"However, I think more important, broadly, is suspicion -- clinical suspicion," he said. "I think many of us think cardiac amyloid is very underdiagnosed."

In ATTR-ACT, all patients were diagnosed by biopsy, but since the start of the trial new non-invasive methods exist to diagnose the disease. Pyrophosphate imaging, for example, has both high specificity and sensitivity.

"The results of the ATTR-ACT trial raise questions about the mechanism of action of tafamidis, the time course of benefit, and the timing of treatment in the course of a patient's disease," wrote C. Cristina Quarta, MD, of University College London, and Scott D. Solomon, MD, of Brigham and Women's Hospital in Boston, in an that accompanied the study. "Reductions in cardiovascular-related hospitalizations were seen only after 9 months, and all-cause mortality after 18 months, which may reflect the time necessary to influence the underlying pathology."

In a 2:1:2 fashion, ATTR-ACT (Transthyretin Amyloidosis Cardiomyopathy Clinical Trial) randomized 441 patients to two doses of tafamidis (80 mg or 20 mg) vs placebo. The primary endpoint was incidence of all-cause mortality and frequency of cardiovascular hospitalizations using the Finkelstein-Schoenfeld method.

Quarta and Solomon praised the study's design, noting that the benefit in multiple cardiovascular hospitalizations was "far more impressive" than first hospitalization. "This benefit may have been overlooked in a trial that used a more traditional time-to-first-event approach," they wrote.

ATTR-ACT represents drugmaker Pfizer's second attempt to win FDA approval for tafamadis., the company's New Drug Application was turned down, with the FDA insisting on a new efficacy study before it would consider approving the drug. However, European regulators OK'd the drug in 2011, under the trade name Vyndaqel.

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