Vicky Wong LMPS Pharmacy Resident | VGH Journal Club December 5, 2018

Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy (ATTR-ACT) Trial NEJM. 2018 Sept 13;379 (11): 1007-16.

Background Amyloidosis is a group of rare diseases caused by extracellular deposition of insoluble fibril deposits in different organ sites

Transthyretin amyloid cardiomyopathy (TTR-CM) is caused by misfolded transthyretin (amyloid protein) infiltrating the cardiac tissue that manifests predominantly in males of the sixth decade and older

1) Familial mutated transthyretin gene TTR (ATTRm) 2) Wild type (non-mutant) transthyretin protein (ATTwt)

TTR-CM can lead to diastolic and systolic dysfunction, cardiomyopathy and heart failureo Similar presentation to heart failure with preserved ejection fractiono Complications: heart block, intracardiac thrombus, arrhythmias and sudden death

Median survival is approximately 2-3 years from diagnosis Current treatment is only supportive care, pacemakers, or transplantation Tafamidis is an amyloid protein stabilizer that binds to the thyroxine binding site of transthyretin and slows

and/or stops fibril formationDesign Multicenter, international double blind, placebo-controlled, phase 3 trial

Setting: 13 countries including Canada (December 2013 to August 2015) 441 patients underwent randomization in a 2:1:2 ratio (tafamidis 80mg: tafamidis 20mg: placebo) Follow up: 30 months Intention to treat analysis

PICO QuestionPopulation Inclusion Criteria:

Adults (18-90 years) with confirmed transthyretin amyloid cardiomyopathy (ATTRwt or ATTRm) in biopsy tissue and TTR precursor protein identified by mass spectrometry

Septal wall thickness > 12 mm History of heart failure (hospitalization or

clinical symptoms) NT-proBNP > 600 pg/mL 6 minute walk test distance > 100 meters

Exclusion Criteria: Heart failure ATTR-CM, Presence of light-chain amyloidosis NYHA class IV heart failure Un-interpretable echo for measurement of wall thickness

Liver or heart transplantation Implanted cardiac device Previous treatment with tafamidis Creatine clearance < 25 mL/min, liver transaminase levels

exceeding 2x upper limit of normal range mBMI<600 receiving concurrent treatment with NSAIDs,

tauroursodeoxycholate, doxycycline, diflunisal CCB, or digoxin

All patients received standard care i.e. diuretics Subjects continued to use concomitant medications except for those listed in the exclusion criteria Patients in 80 mg group with adverse effects due to treatment were given option to receive reduced dose to 40

mg Intervention Tafamidis 80 mg once daily

Tafamidis 20 mg once daily Control Placebo Outcomes Primary outcome: all-cause mortality, frequency of cardiovascular-related hospitalization (Finkelstein-Schoenfeld

method)Secondary outcome:

1) Change from baseline to month 30 for 6 minute walk test 2) Score on Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS)

Funding Study funded Pfizer; 8 authors were full time Pfizer employees /stockholders Results Study Size 441 patients randomized; 264 tafamidis and 177 placeboPatient Baseline Characteristic

Well balanced between two arms Mean age 74 years, male 90%, Caucasian 80%, ATTRm genotype (24%) and ATTRwt (76%)

Heart failure characteristics:o Majority of participants with heart failure NYHA Class II (59%) with NTproBNP ~3000 pg/mL o LVEF 49%, intraventricular wall thickness 16.5 mmo HR 70 bpm, BP 115/71 mm Hg, Creatinine clearance 58 mL/mino Baseline medications: 67% diuretics, antithrombotic (40%), B-blocker (29%), ACEi/ARB (27%)

Vicky Wong LMPS Pharmacy Resident | VGH Journal Club December 5, 2018

o Comorbidities: diabetes (7.5%), hypertension higher in tafamidis group (54.9% vs 47.5%) Tafamidis Placebo

All cause mortality 78/264 (29.5%)

76/177(42.9%) HR 0.7 95% CI( 0.51-0.96)

Cardiovascular hospitalization 0.48 per year 0.7 per year RR 0.68 95% (CI 0.56-0.81)

Outcomes

Subgroup NYHA Class III rates of cardiovascular-related hospitalization were higher in patients receiving tafamidis than those in placebo

Effects seen at month 6 but observed benefit in overall survival and cardiovascular hospitalizations was not seen until month 18Critique

Limitations Risk of sponsorship bias – involved in steering committee, trial design, data analysis, and statistical analysis Results were combination of tafamidis 20,40, 80 mg groups into one pooled group for analyses Unbalanced number of participants in treatment group and placebo group Primary outcome driven by non-North-American countries, mainly in Europe Authors multiple ties to industry

Strengths Regular follow up and high treatment adherence in all groups (97% from each group) Dose reduction uncommon Low loss-to-follow-up (0.3%)

ConclusionsArthur’s Conclusions Patients with transthyretin amyloid cardiomyopathy, tafamidis resulted in a 13.4% absolute risk reduction overall mortality and a

22% absolute reduction in yearly cardiovascular hospitalization at month 30 compared to placebo Tafamidis reduced the decline in functional capacity and quality of life as compared with placebo Application to Practice Cardiac amyloidosis should be considered as a differential diagnosis patients with HFpEF, septal wall thickness >12 mm, and with

non-ischemic etiology Tafamidis should be considered first line treatment for patients diagnosed with TTR-CM (NYHA Class I-III) No dose adjustment required in renal impairment (CrCl <25 mL/min patients excluded from study) Higher dose 80 mg/day did not show any additional benefit Further studies required for long term follow-up and post-marking surveillance to better understand efficacy and safety Other considerations: not yet available in Canada, cost (average cost 30 capsules in UK £10,685.00)

Finkelstein-Schoenfeld MethodWin Ratio: 1.70 (1.26-2.29) (95% CI)

Vicky Wong LMPS Pharmacy Resident | VGH Journal Club December 5, 2018