Tafamidis emerges as first specific treatment for ATTR-CM

Treatment with tafamidis led to a reduction in all-cause mortality and cardiovascular (CV)-related hospitalizations among patients with transthyretin amyloid cardiomyopathy (ATTR-CM), according to the phase III ATTR-ACT* trial.

The international (48 sites in 13 countries) study population comprised 441 individuals aged 18–90 years (median age 75 years) with ATTR-CM. They were randomized 2:1:2 to receive tafamidis 80 mg, tafamidis 20 mg (n=264 in the pooled population comprising recipients of both doses), or placebo (n=177) once daily for 30 months. Twenty-four percent of the patients had pathogenic mutations in the transthyretin gene TTR (ATTRm), with Val122Ile, Thr60Ala, and Ile68Leu the most common mutations.

In a pooled analysis of both tafamidis doses, all-cause mortality was significantly lower among tafamidis compared with placebo recipients (29.5 percent vs 42.9 percent; hazard ratio, 0.70, 95 percent confidence interval [CI], 0.51–0.96). [N Engl J Med 2018;379:1007-1016]

CV-related hospitalization was also reduced among tafamidis vs placebo recipients (0.48 vs 0.70 per year; relative risk ratio, 0.68, 95 percent CI, 0.56–0.81).

“In the primary analysis that hierarchically assessed all-cause mortality, followed by frequency of CV-related hospitalization … treatment with tafamidis was superior to placebo over 30 months (p<0.001),” said the authors.

The greater reduction in all-cause mortality with tafamidis over placebo appeared to occur at approximately 18 months post-treatment, when the survival curves diverged. The mortality and hospitalization findings favouring tafamidis were also consistent regardless of TTR status (ATTRm or wild-type ATTR), NYHA** class (I or II vs III), and tafamidis dose (80 vs 20 mg).

However, patients with baseline NYHA class III had a higher rate of CV-related hospitalization with tafamidis vs placebo. The authors said this could be due to extended survival during a more severe disease. “[This underscores] the importance of early diagnosis and treatment of this fatal, progressive disease, which can be difficult to diagnose,” they said.

Tafamidis recipients also experienced improved functional capacity compared with placebo recipients, as demonstrated by a reduced decline in distance walked in six-minute walk test between baseline and 30 months (75.68 m; p<0.001). They also experienced improved quality of life compared with placebo recipients as per a reduced decline in Kansas City Cardiomyopathy Questionnaire–Overall Summary (KCCQ-OS) score (13.65; p<0.001), with the between-group difference for both outcomes first evident at 6 months into treatment.

Adverse event (AE) incidence was similar between tafamidis and placebo, with no apparent difference between tafamidis doses.

“ATTR-ACT showed that tafamidis is superior to placebo in reducing the combination of all-cause mortality and CV-related hospitalizations,” said the authors. “These findings indicate that tafamidis is an effective therapy for ATTR-CM.”

“Given the progressive nature of the disease and the mechanism through which tafamidis reduces amyloidogenesis – by specifically stabilizing transthyretin tetramers – the drug is expected to have greater benefit when administered early in the disease course,” they added.

 

 

KOL perspective

The role of tafamidis in treating ATTR-CM

Adjunct Associate Professor Tan Ru San

Senior Consultant

Department of Cardiology

National Heart Centre Singapore

 

Evidence on the prevalence of ATTR-CM in Singapore and Southeast Asia is scarce and mainly acquired through case studies. The condition is probably underdiagnosed, and screening is insufficient. MIMS Doctor did a one-on-one interview with Prof Tan on the role of the new agent tafamidis in adult patients with wild-type or hereditary ATTR-CM.

How common is hereditary vs wild-type ATTR-CM?

Wild-type ATTR-CM is more common than hereditary ATTR-CM. In Asia, data on ATTR-CM is primarily from Japan where a retrospective analysis of 23 million adults hospitalized in 2010–2018 showed a prevalence of 3–5 per million patients for hereditary ATTR-CM and 150–190 per million for wild-type ATTR-CM. [Cardiol Ther 2019;8:297-316] However, the true prevalence of wild-type ATTR-CM may be higher. In autopsy studies, about a quarter of hearts of persons aged ≥80 years contained wild-type TTR fibrils, regardless of the presence of symptoms.

How is ATTR-CM monitored in asymptomatic patients?

Physicians need to be watchful for early manifestations of ATTR-CM which include orthopaedic presentations such as bilateral carpal tunnel syndrome, biceps tendon rupture, and lumbar stenosis. There is no specific serological biomarker for ATTR-CM. However, among patients with heart failure (HF), disproportionately high N-terminal (NT)-pro hormone BNP (NT-proBNP) levels coupled with raised highly sensitive cardiac troponin, which suggests a certain degree of myocardial damage or injury, could signal ATTR-CM.

How important is early detection and treatment of ATTR-CM?

In the past, prognosis of ATTR-CM was dire, rendering timing of diagnosis immaterial. The introduction of specific anti-amyloid pharmacological treatment, which can reduce and even reverse amyloid deposition in the heart muscles, could lead to improved survival and quality of life.

Ideally, all patients with ATTR-CM should undergo genetic testing, regardless of ATTR-CM type. Hereditary ATTR-CM is an autosomal dominant disease and its manifestation is age-dependent. Detecting the mutation would enable screening of family members and guide treatment choice. For instance, patients with the Val30Met mutation of the transthyretin gene have a good prognosis following liver transplant. Early treatment could also avert many ATTR-CM complications.

Prior to tafamidis approval, how was ATTR-CM managed?

Most patients with ATTR-CM are managed symptomatically, primarily with diuretics to encourage fluid output and reduce systemic fluid overload. Guideline-recommended optimal medical therapy for HF does not apply to ATTR-CM and should be used with caution, if at all. If beta blockers are used, the possibility of conduction problems needs to be considered, and the potential use of prophylactic pacing may have to be instituted.

As abnormal ATTR is manufactured in the liver, liver transplant is a treatment option. It is effective in doubling the median survival in certain patients, especially those with Val30Met ATTR-CM. Unfortunately, this is not feasible for many patients due to age restriction, cost, and lack of access. Liver transplant may not cure ATTR-CM, nor does it guarantee removal of TTR from myocardial tissue. Among patients with Val30Met ATTR-CM who present with severe heart disease, their heart condition may potentially deteriorate after liver transplant. In these cases, patients may need to undergo the high-risk option of heart and liver transplants.

What is the benefit of tafamidis?

Past oral management strategies have not been very effective. Tafamidis is the first and only approved treatment for ATTR-CM. It has been assessed in a phase III trial (ATTR-ACT), where it demonstrated reduced all-cause mortality and CV-related hospitalization in patients with ATTR-CM who had prior hospitalization for HF.

Tafamidis can be used at all stages of ATTR-CM, from early in the disease course or as an alternative to liver transplant. It can also be used prior to or after liver transplant. For example, tafamidis could be a substitute for heart transplant after liver transplant in patients with mild-to-moderate cardiac dysfunction. Mechanistically, tafamidis helps stabilize the tetrameric transthyretin protein and ameliorate the deposition of abnormal amyloid fibrils in organs. As such, it is very plausible that early initiation of tafamidis may help prevent pathological changes.

Are there contraindications to prescribing tafamidis?

There are no major contraindications to using tafamidis. The ATTR-ACT study showed no serious safety signals with tafamidis compared with placebo. Urinary tract infections and diarrhoea were more common in the latter group. The drug is predominantly excreted in the liver, and there is no dose adjustment required in patients with abnormal kidney function. This is important as patients with kidney amyloid deposition may have renal impairment. While women of reproductive age are not the primary group affected by ATTR-CM, caution is however advised when prescribing tafamidis in this group, with concurrent advice for pregnancy planning and contraception warranted.