ATTR-ACT

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Maurer MS, et al. "Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy". The New England Journal of Medicine. 2018. 379(11):1007-1016.
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Clinical Question

In patients with cardiac amyloidosis, does the amyloid protein stabilizer tafamdis reduce mortality or cardiovascular hospitalization at 30 months compared to placebo?

Bottom Line

In patients with cardiac amyloidosis, the protein stabilizer tafamdis results in a 13.4% absolute reduction in overall mortality and a 22% absolute reduction in yearly cardiovascular hospitalization at 30 months compared to placebo. Tafamidis use was also associated with improvements in heart-failure related quality of life and functional status.

Major Points

Cardiac amyloidosis is increasingly recognized as a common etiology of infiltrative cardiomyopathy, particularly in patients of advanced age. Cardiac amyloidosis results from the deposition of abnormal misfolded proteins (amyloid) in the myocardium typically resulting in impaired cardiac systolic and diastolic function and conduction system disease. Transthyretin (TTR) cardiac amyloidosis is the most common form of cardiac amyloidosis, and typically results from deposition of TTR, a small protein produced by the liver that transports thyroxine and retinol-binding protein-retinol complex. TTR cardiac amyloidosis is typically encountered in two forms: (1) a familial form in which pathogenic mutations in TTR result in a predisposition to amyloid formation (termed mutated or mTTR amyloidosis) and (2) a sporadic form in which genetically normal TTR forms amyloid for unclear reasons (termed wild-type TTR).

Unfortunately, at the current time cardiac amyloidosis has no specific treatment other than supportive care for heart failure-related complications. Amyloidosis also has a poor prognosis, with median survival ranging from 2.5 years after a diagnosis of mTTR to 3.5 years after a diagnosis of wild-type TTR.[1][2]. Although TTR amyloidosis does frequently cause multisystem involvement, mortality in most cases is related to cardiac causes. Tafamidis is a promising new drug with TTR amyloid stabilizing properties, shown in small phase II studies to be safe for use in this population with a suggestion of reduced mortality.[3]. Thus, a larger, randomized controlled trial was needed to establish the efficacy of this drug for cardiac TTR amyloidosis.

The 2018 The Transthyretin Amyloidosis Cardiomyopathy Clinical Trial (ATTR-ACT) trial was a phase III randomized controlled trial in which 441 patients with TTR amyloidosis (either mTTR or wtTTR) were randomized in a 2:1:2 ratio to 80mg tafamidis, 20mg tafamidis, or matching placebo and assessed for a primary outcome of all-cause mortality followed hierarchically by cardiovascular-related hospitalizations. At 30 months, patients randomized to tafamidis (both doses pooled) had a 13.4% absolute reduction in overall mortality and a 22% absolute reduction in yearly cardiovascular hospitalization at 30 months compared to placebo. Tafamidis use was also associated with improvements in heart-failure related quality of life and functional status. There were no important safety concerns observed in the tafamidis group, and treatment discontinuation was more common in the placebo group. Interestingly, the observed benefit in overall survival and cardiovascular hospitalizations was seen after 18 months, although symptoms appeared to improve by 6 months, suggesting either that tafamidis has mechanisms of action other than amyloid stabilization (which would be expected to provide more rapid benefit), or that improvement in survival is secondary to positive cardiac remodeling, which can take many months to occur.

In summary, ATTR-ACT provides critical early evidence that the novel TTR amyloid-stabilizing drug tafamidis has efficacy in reducing the substantial mortality and morbidity associated with TTR amyloidosis with cardiac involvement. There is also no observed signal for important adverse effects. Longer-term follow-up and post-marketing surveillance will be needed to better understand long-term outcomes and ensure the drug remains safe over longer-term use. On the strength of the findings of ATTR-ACT, the FDA granted Breakthrough Therapy Designation (a status in which development and approval of the drug may be expedited by the FDA) in May 2018.

Guidelines

As of September 2018, no guidelines have been published that reflect the results of this trial.

Design

  • Multicenter, double-blind, three-arm, randomized, controlled trial
  • N=441
    • Tafamidis 20mg or 80mg (N=264)
    • Placebo (N=177)
  • Setting: 48 sites in 13 countries
  • Enrollment: December 2013 - August 2015
  • Duration of follow-up: 30 months
  • Analysis: Intention-to-treat
  • Primary Outcome: All-cause mortality followed hierarchically by cardiovascular hospitalization

Population

Inclusion Criteria

  • History of heart failure with at least one of the following:
    • History of hospitalization for heart failure
    • Clinical evidence of heart failure (signs or symptoms of volume overload or elevated intracardiac pressures) with past or current need for diuretic use
  • Evidence of cardiac amyloid by echocardiography with an end-diastolic interventricular septal wall thickness of > 12 mm
  • Presence of amyloid deposits in biopsy tissue and TTR precursor protein identification by mass spectrometry
  • An NTproBNP concentration ≥ 600 pg/mL
  • 6-minute walk test > 100 meters

Exclusion Criteria

  • NYHA class IV heart failure
  • Heart failure not related to TTR amyloid cardiomyopathy
  • Creatinine clearance ≤ 25 mL/min
  • Presence of light chain amyloidosis
  • History of heart or liver transplantation
  • Implanted cardiac device
  • Previous treatment with tafamidis
  • Liver transaminase levels exceeding two times the upper limit of normal
  • Severe malnutrition (modified body mass index < 600, calculated as the product of albumin in grams per liter times the conventional BMI)
  • Use of NSAIDs, tauroursodeoxycholate, doxycycline, calcium-channel blockers, or digitalis

Baseline Characteristics

From the placebo group.

  • Demographics: Age 74.1 years, male 88.7%, white 82.5%,
  • Comorbidities: Systolic BP 115.9, diastolic BP 71.0, heart rate 73.8, modified BMI 1066.4
  • Heart failure: NYHA I 7.3%, NYHA II 57.1%, NYHA III 35.6%, NTproBNP 3161.0

Interventions

  • Patients randomized 2:1:2 but intervention groups pooled
    • Tafamidis 20mg or 80mg (N=264)
    • Placebo (N=177)
  • Stratification of randomization performed by TTR status and baseline NYHA class
  • Study duration was 30 months, with option to enroll in extension study
  • Patients with adverse events that may have been related to study drug were given an option to receive a reduced dose
  • Primary outcome was all-cause mortality followed hierarchically by cardiovascular hospitalization

Outcomes

Comparisons are tafamidis versus placebo

Primary Outcomes

All-cause mortality
78/264 (29.5%) vs. 76/177 (42.9%); HR 0.70 (95% CI 0.51-0.96)
Cardiovascular hospitalization
0.48 per year vs. 0.70 per year; RR 0.68 (95% CI 0.56-0.81)

Secondary Outcomes

Reduction in decline from baseline to 30 months in 6-minute walk test
75.68 m (standard error 9.24 m), p < 0.001
Reduction in decline in the KCCQ-OS score
13.65 (standard error 2.13 m), p < 0.001

Adverse Events

Severe adverse event
62.1% vs. 64.4%
Severe adverse event requiring treatment discontinuation
21.2% vs. 28.8%

Subgroup Analysis

  • Across prespecified subgroups, the difference in all-cause mortality and frequency of cardiovascular hospitalizations were in favor of tafamidis other than in patients with NYHA class III, in which the rates of cardiovascular-related hospitalizations were higher among patients receiving tafamidis than among those receiving placebo

Criticisms

  • The reason for delayed effect on overall survival (emerging at 18 months) is unclear, and suggests tafamidis may have other mechanisms of efficacy in addition to amyloid stabilization. However, symptoms improved within 6 months, suggesting that the delay in improvement in survival/hospitalization may be related to time to achieve positive myocardial remodeling from tafamidis effect.
  • Given requirement for biopsy diagnosis of amyloidosis and the recent emergence of non-invasive means of diagnosing amyloidosis, it remains unclear whether the current findings can be generalized to patients diagnosed with amyloidosis using imaging alone.

Funding

  • Study supported by Pfizer, maker of the study drug
  • Sponsor involved in steering committee, trial design, and data analysis
  • Authors with multiple ties to industry, including study sponsor

Further Reading

  1. Grogan M et al. Natural History of Wild-Type Transthyretin Cardiac Amyloidosis and Risk Stratification Using a Novel Staging System. J. Am. Coll. Cardiol. 2016. 68:1014-20.
  2. Gillmore JD et al. A new staging system for cardiac transthyretin amyloidosis. Eur. Heart J. 2018. 39:2799-2806.
  3. Maurer MS et al. Tafamidis in transthyretin amyloid cardiomyopathy: effects on transthyretin stabilization and clinical outcomes. Circ Heart Fail 2015. 8:519-26.