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What is this plain language summary about? This summary presents the results from an ongoing, long-term extension study that followed an earlier study called ATTR-ACT. People who took part in this extension study and ATTR-ACT have a type of heart disease known as transthyretin amyloid cardiomyopathy (ATTR-CM for short), which causes heart failure and death. In ATTR-ACT, people took either a medicine called tafamidis or a placebo (a pill that looks like the study drug but does not contain any active ingredients) for up to 2½ years. So far, in the long-term extension study, people have continued taking tafamidis, or switched from taking a placebo to tafamidis, for another 2½ years. Researchers looked at how many people died in ATTR-ACT and the extension study. The long-term extension study is expected to end in 2027, so these are interim (not final) results. What did researchers find out? In the extension study of ATTR-ACT, the risk of dying was lower in people who took tafamidis continuously throughout ATTR-ACT and the extension study than in people who took placebo in ATTR-ACT and switched to tafamidis in the extension study. What do the results mean? Taking tafamidis increases how long people with ATTR-CM live. People with ATTR-CM who take tafamidis early and continuously are more likely to live longer than those who do not. These results highlight the importance of early detection and treatment in people with ATTR-CM. Clinical Trial Registration: NCT01994889 ( ClinicalTrials.gov ) Clinical Trial Registration: NCT02791230 ( ClinicalTrials.gov )

What is this plain language summary about? This plain language summary describes some results of a study called ATTR-ACT. This was the first large study to include people with wild-type and hereditary transthyretin amyloid cardiomyopathy (ATTR-CM for short). ATTR-CM is a type of heart disease that happens when abnormal clumps of protein build up in the heart. This build-up prevents the heart from working properly, causing a condition called heart failure. Wild-type ATTR-CM happens for unknown reasons in some people as they get older. Hereditary ATTR-CM can happen because of changes in people's genes (known as gene variants or mutations). Important information about ATTR-ACT In this study, 441 people with ATTR-CM took either a medicine called tafamidis or a placebo (a capsule that looked like tafamidis but didn't contain any active medicine) by mouth for 30 months, once a day. The researchers' main aim was to find out how tafamidis treatment affected the risk of people dying or being admitted to the hospital for heart problems. They found that tafamidis lowered these risks by about one-third compared with placebo. What else did researchers find out in ATTR-ACT? As described in this summary, after ATTR-ACT was completed, researchers looked back at the results from people who took placebo to learn how ATTR-CM progressed without treatment. The researchers found that about 4 in 10 people with wild-type ATTR-CM who took placebo died and 6 in 10 were admitted to the hospital because of heart problems over 30 months. People who took placebo also could not walk as far at the end of the study as they did at the start because their heart function worsened over time. Why are these results important? By showing how ATTR-CM affects people's health when they do not take treatment, these results highlight the benefits of early diagnosis and treatment of ATTR-CM. ClinicalTrials.gov NCT number: NCT01994889

Introduction Atrial fibrillation (afib) and flutter (aflutter) are among the most common manifestations of transthyretin amyloid cardiomyopathy (ATTR-CM) [1–3]. Studies have suggested that afib does not influence mortality [3–6]. Tafamidis was approved for the treatment of ATTR-CM based on the landmark, placebo-controlled, Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT), where all-cause mortality was a primary efficacy outcome [7]. Purpose Evaluate whether afib/aflutter was prognostic for all-cause mortality in ATTR-ACT. Methods ATTR-ACT was a multinational, Phase 3, randomized study of patients with ATTR-CM receiving tafamidis meglumine (80 or 20 mg) or placebo over 30 months. This analysis describes the characteristics of patients with and without current/historical afib/aflutter at the baseline of ATTR-ACT. Current/historical afib/aflutter was then evaluated as an independent prognostic factor for all-cause mortality using Cox proportional hazards modelling. Results The 314/441 (71%) patients in ATTR-ACT with current/historical afib/aflutter were older, more commonly male, and White than those without (Table 1). A higher proportion of patients with current/historical afib/aflutter were NYHA class III and had a wild-type genotype than those without. Median 6MWT distance and the proportion of patients with preserved left ventricular ejection fraction (≥50%) were lower, GLS was less negative, and NT-proBNP and BUN were higher among those with current/historical afib/aflutter vs those without. In ATTR-ACT, treatment, genotype, and NYHA class were included in the pre-specified Cox proportional hazards model assessing all-cause mortality. Once current/historical afib/aflutter was added to this model, all variables were found to be significant independent predictors of all-cause mortality (P Conclusions Patients in ATTR-ACT with ATTR-CM and current/historical afib/aflutter were older, more likely to be male, have a wild-type genotype, and more advanced heart failure than those without. A Cox model including treatment, genotype, and NYHA class identified current/historical afib/aflutter as a significant independent predictor of all-cause mortality. In an expanded stepwise selection model current/historical afib/aflutter remained important but was less prognostic compared to other covariates. Overall, these results demonstrate the importance of afib/aflutter in patients with ATTR-CM. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): This study was sponsored by Pfizer.

This article analyzed the crime network of Nineveh province based on the concepts of Complex Networks. To this end, two networks were created; the first represented the crimes that were committed in Nineveh province, while the second was the network of crime regions. These two networks were visualized and then analyzed using network centrality measurements. The results showed that several pairs of crimes had strong relations to each other. Moreover, it was found that some crime regions were considered as the core of crimes in the province. The results also showed that few regions were considered as the most dangerous parts of the province and they had strong tendencies to replicate their behaviour to other regions. Finally, the authors believe this is the first kind of works that take the crime network of Nineveh province as a case study

Rare diseases are increasingly recognized as a global public health priority. Governments worldwide currently provide important incentives to stimulate the discovery and development of orphan drugs for the treatment of these conditions, but substantial scientific, clinical, and regulatory challenges remain. Tafamidis is a first-in-class, disease-modifying transthyretin (TTR) kinetic stabilizer that represents a major breakthrough in the treatment of transthyretin amyloidosis (ATTR amyloidosis). ATTR amyloidosis is a rare, progressive, and fatal systemic disorder caused by aggregation of misfolded TTR and extracellular deposition of amyloid fibrils in various tissues and organs, including the heart and nervous systems. In this review, we present the successful development of tafamidis spanning 3 decades, marked by meticulous laboratory research into disease mechanisms and natural history, and innovative clinical study design and implementation. These efforts established the safety and efficacy profile of tafamidis, leading to its regulatory approval, and enabled post-approval initiatives that further support patients with ATTR amyloidosis.

Hereditary transthyretin amyloidosis (ATTRv amyloidosis) results from pathogenic mutations in the transthyretin (The Transthyretin Amyloidosis Outcomes Survey (THAOS) is an ongoing, global, longitudinal, observational survey of patients with transthyretin amyloidosis, including both inherited and wild-type disease, and asymptomaticOf 740 asymptomaticMore than one-third of asymptomaticClinicalTrials.gov: NCT00628745.

In the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial, tafamidis significantly reduced all-cause mortality and cardiovascular-related hospitalizations in patients with transthyretin amyloid cardiomyopathy (ATTR-CM). ATTR-CM is associated with a significant burden of disease; further analysis of patient-reported quality of life will provide additional data on the efficacy of tafamidis. In the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial, 441 adult patients with ATTR-CM were randomized (2:1:2) to tafamidis 80 mg, tafamidis 20 mg, or placebo for 30 months, with pooled tafamidis (80 mg and 20 mg) compared with placebo. Change in Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) domain scores, EQ-5D-3L scores, and patient global assessment, were prespecified exploratory end points. A greater proportion of patients improved KCCQ-OS score at month 30 with tafamidis (41.8%) versus placebo (21.4%). Tafamidis significantly reduced the decline in all 4 KCCQ-OS domains (p

Objectives Tafamidis is an effective treatment for transthyretin amyloid cardiomyopathy (ATTR-CM), this study aimed to determine whether there is a differential effect between variant transthyretin amyloidosis (ATTRv) and wild-type transthyretin (ATTRwt). Background ATTR-CM is a progressive, fatal disorder resulting from mutations in the ATTRv or the deposition of denatured ATTRwt. Methods In pre-specified analyses from ATTR-ACT (Tafamidis in Transthyretin Cardiomyopathy Clinical Trial), baseline characteristics, all-cause mortality, and change from baseline to month 30 in 6-min walk test distance and Kansas City Cardiomyopathy Questionnaire Overall Summary score were compared in patients with ATTRwt and ATTRv. Results There were 335 patients with ATTRwt (201 tafamidis, 134 placebo) and 106 with ATTRv (63 tafamidis, 43 placebo) enrolled in ATTR-ACT. Patients with ATTRwt (vs. ATTRv) had less advanced disease at baseline and a lower rate of disease progression over the study. The reduction in all-cause mortality with tafamidis compared with placebo was not different between ATTRwt (hazard ratio: 0.706 [95% confidence interval (CI): 0.474 to 1.052]; p = 0.0875) and ATTRv (hazard ratio: 0.690 [95% CI: 0.408 to 1.167]; p = 0.1667). Tafamidis was associated with a similar reduction (vs. placebo) in the decline in 6-min walk test distance in ATTRwt (mean ± SE difference from placebo, 77.14 ± 10.78; p Conclusions Pre-specified analyses from ATTR-ACT confirm the poor prognosis of untreated ATTRv-related cardiomyopathy compared with ATTRwt, but show the reduction in mortality and functional decline with tafamidis treatment is similar in both disease subtypes. (Safety and Efficacy of Tafamidis in Patients With Transthyretin Cardiomyopathy [ATTR-ACT]; NCT01994889 )

Tafamidis, a non‐nonsteroidal anti‐inflammatory benzoxazole derivative, acts as a transthyretin (TTR) stabilizer to slow progression of TTR amyloidosis (ATTR). Tafamidis meglumine, available as 20‐mg capsules, is approved in more than 40 countries worldwide for the treatment of adults with early‐stage symptomatic ATTR polyneuropathy. This agent, administered as an 80‐mg, once‐daily dose (4 × 20‐mg capsules), is approved in the United States, Japan, Canada, and Brazil for the treatment of hereditary and wild‐type ATTR cardiomyopathy in adults. An alternative single solid oral dosage formulation (tafamidis 61‐mg free acid capsules) was developed and introduced for patient convenience (approved in the United States, United Arab Emirates, and European Union). In this single‐center, open‐label, randomized, 2‐period, 2‐sequence, crossover, multiple‐dose phase 1 study, the rate and extent of absorption were compared between tafamidis 61‐mg free acid capsules (test) and tafamidis meglumine 80‐mg (4 × 20‐mg) capsules (reference) after 7 days of repeated oral dosing under fasted conditions in 30 healthy volunteers. Ratios of adjusted geometric means (90%CI) for the test/reference formulations were 102.3 (98.0‐106.8) for area under the concentration‐time profile over the dosing interval and 94.1 (89.1‐99.4) for the maximum observed concentration, satisfying prespecified bioequivalence acceptance criteria (90%CI, 80‐125). Both tafamidis regimens had an acceptable safety/tolerability profile in this population.

This computational study investigates the effects of common defects that occur while fabricating arrays of plasmonic metal nanoparticles (NPs) on the absorbing layer of the solar cells for enhancing their opto-electronic performance. Several “defects” in an array of plasmonic NP arrays on solar cells were studied. The results demonstrated no major changes in the performance of solar cells in the presence of “defective” arrays when compared to a “perfect” array with defect-free NPs. The results indicate that relatively inexpensive techniques may be used to fabricate “defective” plasmonic NP arrays on solar cells and still obtain a significant enhancement in opto-electronic performance.

Background: The Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) demonstrated the effectiveness of tafamidis for the treatment of patients with transthyretin amyloid cardiomyopathy (ATTR-CM). Tafamidis reduced mortality in all subgroups of patients studied. Tafamidis also reduced observed frequency of cardiovascular (CV)-related hospitalizations in all subgroups except those who were New York Heart Association (NYHA) class III at baseline who, paradoxically, had a higher frequency of CV-related hospitalizations than placebo. Given the greater mortality rate with placebo, this analysis assessed the impact of the confounding effect of death on the frequency of CV-related hospitalization in ATTR-ACT. Methods: In ATTR-ACT, patients with ATTR-CM were randomized to tafamidis (n = 264) or placebo (n = 177) for 30 months. Post hoc analyses first defined and compared the effect of tafamidis treatment in the subset of NYHA class III patients from each treatment arm alive at month 30. The impact of a potential survivor bias was then adjusted for using principal stratification, estimating the frequency of CV-related hospitalization in NYHA class III patients who would have survived regardless of assigned treatment group (defined as the survivor average causal effect [SACE]). Results: In the subset of NYHA class III patients alive at month 30, tafamidis reduced the relative risk of CV-related hospitalization versus placebo (relative risk: 0.95 [95% CI: 0.55–1.65]). In the principal stratification analyses of those patients who would survive to 30 months regardless of treatment, tafamidis treatment was associated with a 24% lower risk of CV-related hospitalization (relative risk: 0.76 [95% CI: 0.45–1.24]). Similarly, there was a larger reduction in CV-related hospitalization frequency with tafamidis in NYHA class I or II patients in the SACE than was initially observed in ATTR-ACT. Conclusions: Initial data from ATTR-ACT likely underestimated the effect of tafamidis on CV-related hospitalizations due to the confounding effect of death. When SACE was used to adjust for survivor bias, there was a 24% reduction in the frequency of CV-related hospitalization in NYHA class III patients treated with tafamidis.

Introduction: Patients with transthyretin amyloid cardiomyopathy (ATTR-CM) experience a progressive decline in health and quality of life. Tafamidis is an effective treatment for patients with ATTR-CM, and was shown to reduce mortality and CV-related hospitalization in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT). As ATTR-CM is a progressive disease, either stabilization or improvement signifies an efficacious treatment. Methods: This was a post-hoc analysis of the proportion of patients in ATTR-ACT who stabilized or improved in clinical parameters. In ATTR-ACT, 441 adult patients with ATTR-CM (variant or wild-type) were randomized (2:1:2) to tafamidis 80 mg, tafamidis 20 mg, or placebo for 30 months, with pooled tafamidis (n=264) compared with placebo (n=177). Change from baseline was assessed at each study visit to determine patients who improved/did not change in: 6MWT distance; KCCQ-OS score; NT-proBNP concentration; PGA scale; and NYHA class. Any patient with missing data was considered not improved. Results: A significantly greater proportion of patients improved/did not change with tafamidis compared with placebo for each outcome at Month 30 ( Table ). Of patients who started treatment with tafamidis, 20-27% improved in 6MWT distance, KCCQ-OS score, and NT-proBNP concentration at Month 30, compared with 5-10% of patients with placebo. There were greater proportions who improved in these measures at earlier timepoints (32-42% with tafamidis vs 19-24% with placebo at Month 12; P Conclusions: While patients with ATTR-CM are expected to experience a progressive decline over time, a significant proportion of tafamidis-treated patients in ATTR-ACT had improvements in measures of functional capacity, health-related quality of life, and cardiac biomarkers within 12 months and through the study. These data provide further evidence of the clinical benefits with tafamidis in patients with ATTR-CM.

This plain language summary describes the results of a study called ATTR-ACT, which was published in the American Journal of Cardiology. In ATTR-ACT, researchers looked at the effects of tafamidis treatment in people with transthyretin amyloid cardiomyopathy (called ATTR-CM for short). Tafamidis is currently available in the USA and other countries as an oral treatment for adults with ATTR-CM. In ATTR-ACT, 441 people with ATTR-CM from 13 different countries took either tafamidis or placebo by mouth for 30 months. First, researchers looked at the effects of tafamidis on the risk of death and hospitalization due to heart problems between the start and the end of the study; they found that these risks were about one-third lower with tafamidis compared with placebo. As described in this summary, researchers also looked at the effects of tafamidis on people's heart failure symptoms, quality of life, and general health over the 30-month study. People who took part in ATTR-ACT rated these effects using questionnaires filled out before, during, and after the study. More people who took tafamidis saw improvement or no change in their heart failure symptoms and quality of life than people who took placebo. In addition, compared with people taking placebo, people taking tafamidis had less worsening of their general health during the study. These results show the benefits of tafamidis in reducing the declines in quality of life and health that often occur with this debilitating disease. To read the full Plain Language Summary of this article, click on the View Article button above and download the PDF. Clinical Trial Registration: NCT01994889 (ClinicalTrials.gov).

Background Hospitalisation has been widely used as a measure of morbidity in clinical trials for chronic heart failure. As previously reported in the Transthyretin Amyloidosis Cardiomyopathy Clinical Trial (ATTR-ACT), the observed frequency of cardiovascular (CV)-related hospitalisations favoured tafamidis over placebo in all analyses except in the NYHA Class III baseline subgroup with a relative risk of 1.41 [95% CI: 1.05, 1.90]1. However, the evaluation of the causal effect of treatment on hospitalisation is complicated in the presence of death as death precludes further hospitalisation and thus limits the evaluation of hospitalisation rates between groups. This confounding effect of death is particularly relevant in NYHA Class III participants who had higher mortality rates compared to Class I or II participants. Purpose This aim of this study was to assess the impact of the confounding effect of death on CV-related hospitalisation. Methods The effect of tafamidis treatment on CV-related hospitalisations was defined and compared in the subset of participants from either treatment arm who were alive at the end of the study (ie, Month 30); however the subset of participants who survive on the tafamidis arm would be expected to have different characteristics from the subset of participants who survive on the control arm and thus these analyses do not estimate the causal effect. To address this possible survivor bias, we additionally conducted a post hoc principal stratification analysis. Principal stratification is a statistical method to adjust for post treatment events, in this case mortality, by classifying participants according to their potential to survive under each treatment arm. Specifically, we sought to estimate the principal strata effect on CV-related hospitalisations in NYHA Class III participants who would survive irrespective of treatment assignment. Sensitivity analyses were performed to assess the model assumptions. Results The analysis within the subset of participants who survived at Month 30 demonstrated a relative risk of 1.1 (95% CI: 0.56, 2.16) between tafamidis and placebo. The principal stratification analyses of subjects who would survive to 30 months irrespective of treatment estimated a 0.75 (95% CI: 0.44, 1.23) relative risk between tafamidis and placebo, suggesting a 25% reduction in frequency of CV-related hospitalisations in the tafamidis arm. Conclusion The initial data reported in ATTR-ACT likely underestimated the true effect of tafamidis on CV-related hospitalisations due to the confounding effect of death. The analysis of treatment group among observed survivors estimated a smaller relative risk for NYHA Class III; however, this analysis does not fully address the possible survivor bias. The survivor average causal effect, which adjusts for the survival bias demonstrated a reduction in the frequency of CV-related hospitalisation in the tafamidis treated arm for NYHA Class III participants. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Pfizer

Background Transthyretin amyloid cardiomyopathy (ATTR-CM) is an often-overlooked form of heart failure with preserved ejection fraction (HFpEF). Previous studies have demonstrated that relatively high proportions of older patients with HFpEF have underlying ATTR-CM. However, while ATTR-CM should not be overlooked as a cause of HFpEF, it also should not be assumed that all patients with ATTR-CM present with HFpEF. Purpose To categorise patients with ATTR-CM from a large clinical trial by left ventricular ejection fraction (LVEF) at enrolment in order to describe the prevalence of HFpEF, HF with mildly reduced EF (HFmrEF), and HF with reduced EF (HFrEF). Methods The Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) enrolled 441 patients with ATTR-CM, including both hereditary (ATTRv) and wild-type (ATTRwt) patients. In ATTR-ACT, all patients underwent echocardiography at enrolment using a standardised protocol, and all images were reviewed and analysed at an independent central laboratory. In this analysis of patient data at enrolment, all patients in ATTR-ACT were categorised by LVEF as: HFpEF (LVEF ≥50%), HFmrEF (LVEF 41–49%), or HFrEF (LVEF ≤40%). The proportions of patients in these LVEF categories in the sub-groups of race, sex, genotype, and disease severity (by NYHA class) were assessed, together with myocardial contraction fraction (MCF) in each category. Results In ATTR-ACT, there were 220 (50.5%) patients with HFpEF, 119 (27.3%) with HFmrEF, and 97 (22.3%) with HFrEF (Table). Five subjects with missing LVEF at enrolment were not categorized. Asian patients had the highest proportion with HFpEF, followed by White, then Black patients. The ATTRwt group had a higher proportion of patients with HFpEF than the ATTRv group. There were significant differences (as assessed by Chi-square test; P=0.0001) in the proportion of patients in each EF category between NYHA class I or II and NYHA class III patients. Median MCF was higher in NYHA class I/II (16.6%) than NYHA class III (14.8%) patients, and higher in patients with HFpEF compared with HFmrEF and HFrEF. Conclusions Not all patients with ATTR-CM have HFpEF. In this analysis of patients at enrolment in ATTR-ACT half had mildly reduced or reduced LVEF, with even higher proportions of reduced EF observed in Black patients, ATTRv patients, and patients with worse functional class (NYHA class III). These data demonstrate that ATTR-CM should be considered as a possible diagnosis in all patients with HF regardless of EF. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Pfizer Table 1

Background: Tafamidis is approved in over 40 countries to delay neurologic progression in patients with transthyretin amyloid polyneuropathy (ATTR-PN). A comprehensive, integrated analysis of safety data from interventional, observational and surveillance studies of tafamidis in ATTR-PN patients was conducted. Methods: Safety data from all sponsored, completed, or ongoing, Phase 2/3 studies of tafamidis in ATTR-PN patients as of 3 January 2017 were pooled. Also assessed were safety data from the ongoing Transthyretin Amyloidosis Outcomes Survey (THAOS) as of 3 January 2017 and post-marketing surveillance reports as of 31 March 2017. Results: There were 137 patients in Phase 2/3 studies (mean duration of tafamidis exposure, 44.2 months), with 134 (97.8%) experiencing ≥1 treatment-emergent adverse event (TEAE) and 46 (33.6%) ≥1 treatment-emergent serious adverse event (TESAE). The most common TEAEs were diarrhoea (26.3%), urinary tract infection (UTI; 25.5%) and influenza (21.2%). In THAOS, 661 subjects had tafamidis exposure (mean duration, 27.6 months), with 250 (37.8%) experiencing ≥1 TEAE and 96 (14.5%) ≥1 TESAE. The most common TEAE was UTI (6.1%). Post-marketing surveillance reports generally reflected the known safety profile of tafamidis. Conclusions: This analysis did not reveal any significant new safety findings; tafamidis was generally safe and well tolerated in ATTR-PN patients. ClinicalTrials.gov: NCT00409175, NCT00791492, NCT00630864, NCT01435655, NCT00925002, and NCT00628745.

Introduction: Tafamidis was shown to be an effective treatment for patients with both hereditary/variant (ATTRv) and wild-type (ATTRwt) transthyretin amyloid cardiomyopathy (ATTR-CM) in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT). The higher dose of tafamidis (80 mg) was shown to be the optimal dose and is approved for the treatment of ATTR-CM. We hypothesized that longer term follow up would further characterize the benefit of higher dose tafamidis. Methods: In ATTR-ACT, patients were randomized to tafamidis meglumine (80 mg or 20 mg) or placebo for 30 months. Patients who completed ATTR-ACT were eligible to enroll in a long-term extension study (LTE) in which placebo-treated patients were randomized to tafamidis 80 mg or 20 mg. As of 20 July, 2018, all patients in the LTE were transitioned to tafamidis free acid 61 mg (a new formulation bioequivalent to tafamidis 80 mg). All-cause mortality (as of 1 Aug, 2019) was assessed in patients treated with tafamidis 80 mg in ATTR-ACT and the LTE who transitioned to tafamidis free acid 61 mg (tafamidis 80/61 mg) compared with patients treated with placebo in ATTR-ACT who transitioned to tafamidis in the LTE (placebo/tafamidis). Results: There were 85 ATTRv patients (42 tafamidis 80/61 mg [median treatment duration 53.8 months]; 43 placebo/tafamidis [48.1 months]) and 268 ATTRwt patients (134 tafamidis 80/61 mg [51.7 months]; 134 placebo/tafamidis [51.6 months]).In ATTRv patients, there were 25 (59.5%) deaths with tafamidis 80/61 mg and 30 (69.8%) deaths with placebo/tafamidis; a 39.8% reduction in risk of all-cause mortality with tafamidis 80/61 mg (hazard ratio vs placebo/tafamidis [95% CI], 0.6020 [0.3473, 1.0435]; P=0.0706). In ATTRwt patients, there were 50 (37.3%) deaths with tafamidis 80/61 mg and 78 (58.2%) deaths with placebo/tafamidis; a 40.1% reduction in risk of all-cause mortality with tafamidis 80/61 mg (0.5992 [0.4186, 0.8577]; P=0.0051). Conclusions: While there were fewer ATTRv patients in the study, longer-term follow-up demonstrated similarly improved survival with higher dose tafamidis in both ATTRv and ATTRwt patients. These data further highlight the benefit of tafamidis (80 mg meglumine or 61 mg free acid) in all patients with ATTR-CM.

Introduction: Tafamidis meglumine, available as 20 mg capsules, is approved in >40 countries for use in early stage, symptomatic transthyretin amyloidosis with polyneuropathy. It is also approved in a growing number of countries as an 80 mg daily dose (4 x 20 mg capsules) and as tafamidis free acid 61 mg (a single dose bioequivalent to tafamidis meglumine 80 mg) for the treatment of transthyretin amyloid cardiomyopathy (ATTR-CM). As some patients receiving tafamidis meglumine 20 mg may benefit from transition to tafamidis free acid 61 mg, we assessed the hypothesis that this transition is not associated with any new safety concerns. Methods: In the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) patients with ATTR-CM were treated with tafamidis meglumine 20 mg, 80 mg, or placebo for up to 30 months. Patients completing the trial could enroll in a long-term extension study (LTE) with placebo-treated patients randomized to tafamidis meglumine 20 mg or 80 mg. All patients in the LTE were later transitioned to tafamidis free acid 61 mg. Adverse events (AEs) emerging during the LTE were assessed in patients treated with tafamidis meglumine 20 mg in the LTE who transitioned to tafamidis free acid 61 mg (median exposure 19.8 months). AEs were compared with those emerging during ATTR-ACT in patients treated with tafamidis meglumine 20 mg (median exposure 29.7 months). Results: The 87 patients treated with tafamidis meglumine 20 mg in the LTE who transitioned to tafamidis free acid 61 mg had a similar incidence of the most common AEs by system organ class, and of specific AEs, as those treated with tafamidis meglumine 20 mg in ATTR-ACT (see Table ). The safety profile of tafamidis meglumine 20 mg was previously shown to be similar to placebo. Conclusions: While the duration of exposure to tafamidis free acid 61 mg was shorter than for tafamidis meglumine 20 mg, these data demonstrate that the transition to tafamidis free acid 61 mg is not associated with any new safety concerns.

Introduction: Tafamidis meglumine, available as 20 mg capsules, is approved around the world for the treatment of transthyretin amyloidosis in early stage polyneuropathy (20 mg) and more recently in cardiomyopathy (80 mg). A new formulation, tafamidis free acid 61 mg (a single capsule bioequivalent to tafamidis meglumine 80 mg), was subsequently developed as a more convenient option for patients with transthyretin amyloid cardiomyopathy (ATTR-CM) and further characterization of its safety profile would be of value. Methods: Patients who completed the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) were eligible to enroll in a long-term, extension study (LTE). The LTE was subsequently expanded to include ATTR-CM patients not previously enrolled in ATTR-ACT, with all patients receiving tafamidis free acid 61 mg (tafamidis 61 mg). As of 20 July, 2018, patients in the LTE were transitioned to tafamidis free acid 61 mg (data assessed for patients treated with tafamidis 80 mg in the LTE who transitioned to tafamidis free acid 61 mg [tafamidis 80/61 mg]). Adverse events (AEs) during the LTE are described (as of 1 Aug, 2019) and compared with AEs with tafamidis 80 mg in ATTR-ACT. Results: There were 164 patients treated with tafamidis 80/61 mg and 715 newly enrolled patients treated with tafamidis 61 mg; with 157 (95.7%) AEs with tafamidis 80/61 mg and 458 (64.1%) with tafamidis 61 mg. The most common AEs by system organ class were cardiac disorders ( Table ). AEs with tafamidis 80/61 mg were broadly similar to those with tafamidis 80 mg in ATTR-ACT (previously shown to be similar to placebo). While there were fewer AEs with tafamidis 61 mg, the notably shorter exposure time in this group limits direct comparisons. Nevertheless, no new safety concerns emerged in patients who transitioned to, or started, tafamidis 61 mg. Conclusions: For patients with ATTR-CM, tafamidis free acid 61 mg is a safe treatment which also offers improved patient convenience.

In the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT), tafamidis significantly reduced mortality and cardiovascular (CV)-related hospitalizations compared with placebo in patients with transthyretin amyloid cardiomyopathy (ATTR-CM). This analysis aimed to assess the causes of CV-related death and hospitalization in ATTR-ACT to provide further insight into the progression of ATTR-CM and efficacy of tafamidis. ATTR-ACT was an international, double-blind, placebo-controlled, and randomized study. Patients with hereditary or wild-type ATTR-CM were randomized to tafamidis (n = 264) or placebo (n = 177) for 30 months. The independent Endpoint Adjudication Committee determined whether certain investigator-reported events met the definition of disease-related efficacy endpoints using predefined criteria. Cause-specific reasons for CV-related deaths (heart failure [HF], arrhythmia, myocardial infarction, sudden death, stroke, and other CV causes) and hospitalizations (HF, arrhythmia, myocardial infarction, transient ischemic attack/stroke, and other CV causes) were assessed. Total CV-related deaths was 53 (20.1%) with tafamidis and 50 (28.2%) with placebo, with HF (15.5% tafamidis, 22.6% placebo), followed by sudden death (2.7% tafamidis, 5.1% placebo), the most common causes. The number of patients with a CV-related hospitalization was 138 (52.3%) with tafamidis and 107 (60.5%) with placebo; with HF the most common cause (43.2% tafamidis, 50.3% placebo). All predefined causes of CV-related death or hospitalization were less frequent with tafamidis than placebo. In conclusion, these data provide further insight into CV disease progression in patients with ATTR-CM, with HF the most common adjudicated cause of CV-related hospitalization or death in ATTR-ACT. Clinical trial registration ClinicalTrials.gov: NCT01994889.

Background The Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT), demonstrated that tafamidis was an effective treatment for patients with transthyretin amyloid cardiomyopathy (ATTR-CM). Tafamidis, at an 80 mg daily dose, was subsequently approved in several countries for the treatment of ATTR-CM. Patients who completed ATTR-ACT were eligible to enroll in an ongoing long-term extension study (LTE) which provides additional data on the long-term efficacy of tafamidis. Purpose To assess the long-term benefit of tafamidis in patients with ATTR-CM and to determine median survival times with treatment. Methods Patients with ATTR-CM who completed ATTR-ACT (in which they were randomized to tafamidis meglumine 80 mg, 20 mg or placebo for 30 months) could enroll in the ongoing LTE in which patients continued to be treated with the same dose of tafamidis or, if previously treated with placebo, were randomized to tafamidis meglumine 80 mg or 20 mg. Tafamidis free acid 61 mg is a new formulation (bioequivalent to tafamidis meglumine 80 mg) developed for patient convenience and all patients in the LTE transitioned to tafamidis free acid 61 mg as of 1 Aug, 2018. All-cause mortality (with heart transplant or cardiac mechanical assist device [CMAD] implantation counted as death) was assessed using a Cox proportional hazards model (as of 1 Aug, 2019). Patients treated with tafamidis meglumine 80 mg in ATTR-ACT and the LTE who transitioned to tafamidis free acid 61 mg (tafamidis 80/61 mg) were compared with patients treated with placebo in ATTR-ACT who transitioned to tafamidis in the LTE (placebo/tafamidis). Results There were a total of 176 tafamidis 80/61 mg patients and 177 placebo/tafamidis patients. Median treatment duration was 51.9 months with tafamidis 80/61 mg and 51.4 months with placebo/tafamidis. With tafamidis 80/61 mg, there were 75 (42.6%) all-cause deaths; consisting of 67 (38.1%) deaths, 6 (3.4%) heart transplants, and 2 (1.1%) CMAD implantations. With placebo/tafamidis, there were 108 (61.0%) all-cause deaths; consisting of 102 (57.6%) deaths and 6 (3.4%) heart transplants. There was a significant reduction of 41.1% in the risk of all-cause mortality with tafamidis 80/61 mg compared with placebo/tafamidis (hazard ratio [95% CI], 0.5888 [0.4370, 0.7931]; P=0.0004). Median survival time with placebo/tafamidis was 35.8 months but was not reached with tafamidis 80/61 mg. Conclusions Treatment with tafamidis significantly improves long-term survival in patients with ATTR-CM. The comparatively poorer survival in patients treated with placebo in ATTR-ACT who transitioned to tafamidis in the LTE highlights the importance of early diagnosis and treatment. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): This study was sponsored by Pfizer.

Background In the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT), tafamidis was shown to be an effective treatment for patients with transthyretin amyloid cardiomyopathy (ATTR-CM). Further assessment of the efficacy of tafamidis in patients with more advanced ATTR-CM would aid treatment decisions. Purpose To characterize the benefits of tafamidis in patients with advanced ATTR-CM. Methods In ATTR-ACT, ATTR-CM patients were randomized to tafamidis (n=264) or placebo (n=177) for 30 months. Efficacy outcomes included all-cause mortality and frequency of cardiovascular (CV)-related hospitalisations. Key secondary endpoints were change from baseline to Month 30 in 6MWT distance and KCCQ-OS score. Efficacy assessments in NYHA Class III patients at baseline (n=141) were a pre-specified analysis. In a post-hoc analysis, mortality and CV-related hospitalizations were assessed in all patients grouped into quartiles of increasing disease severity based on 6MWT distance at baseline. Longer-term all-cause mortality (as of 1 Aug 2019) was assessed in NYHA Class III patients utilizing data from ATTR-ACT patients who enrolled in a long-term, extension study (LTE) and continued treatment with higher dose tafamidis (n=55; median treatment duration 51.6 months); or, if previously treated with placebo, started tafamidis treatment (placebo/tafamidis; n=63 [50.1 months]). Results In advanced ATTR-CM patients (NYHA Class III), tafamidis reduced the risk of death (HR [95% CI] 0.837, [0.541, 1.295], P=0.4253), and the decline in 6MWT distance (LS mean [SE], 31.6 (22.1) m; P=0.1526) and KCCQ-OS score (LS mean [SE], 13.1 (5.0); P=0.0090), vs placebo. Paradoxically, there was a higher frequency of CV-related hospitalizations with tafamidis (RR [95% CI] vs placebo, 1.411 [1.048, 1.900]). In all patients by 6MWT quartile, CV-related hospitalizations/year with tafamidis and placebo increased with disease severity, with the exception that placebo-treated patients in the highest severity quartile had fewer CV-related hospitalisations (0.73) than those in the third quartile (0.92). Mortality with tafamidis and placebo increased, and was greater with placebo, in every quartile (Figure). Survival (NYHA Class III patients in ATTR-ACT and LTE) was improved with high dose tafamidis with longer term follow-up (HR vs placebo/tafamidis [95% CI], 0.6569 [0.4175, 1.0336]; P=0.0692). Conclusions These analyses, including longer-term follow-up, demonstrate that patients with advanced ATTR-CM benefit from tafamidis. The decrease in CV-related hospitalisations in more severe patients treated with placebo suggests that the comparatively greater hospitalisation frequency in NYHA Class III patients treated with tafamidis is a consequence of their lower mortality rate. Figure 1 Funding Acknowledgement Type of funding source: Private company. Main funding source(s): This study was sponsored by Pfizer

The effectiveness of tafamidis for the treatment of transthyretin familial amyloid polyneuropathy (TTR-FAP) was evaluated using data from the Transthyretin Amyloidosis Outcomes Survey (THAOS) registry.Subjects receiving tafamidis (n = 252) were compared with untreated subjects in a non-randomized, matched cohort analysis. Subjects were matched with up to four untreated controls by genetic mutation, region of birth, and mean treatment propensity score.The matched, treated sample consisted predominantly of subjects with the Val30Met genotype (92.5%), from Portugal, and with a mean age of 40.4 years. Over the course of the 2-year follow-up period, subjects treated with tafamidis showed significantly less deterioration on the Neuropathy Impairment Score for Lower Limbs (p 0.001) and its subscales (p 0.023) compared with untreated subjects. There was significantly less deterioration among tafamidis-treated subjects compared with untreated subjects on the Norfolk Quality of Life scale (p 0.001). There were no significant differences observed in functional (assessed by Karnofsky Performance Status Scale score) or nutritional (assessed by modified body mass index) status between the treated and untreated groups. The primary model which examined survival from baseline using the matched cohort was not able to yield estimates of the hazard ratio, as there were no deaths in the tafamidis-treated subjects.These findings support the results from clinical trials and strengthen evidence of the effectiveness of tafamidis beyond conventional clinical trials.ClinicalTrials.gov: NCT00628745 FUNDING: Pfizer.

Background: Tafamidis is approved in many countries for the treatment of transthyretin amyloid cardiomyopathy. This study reports data on the long-term efficacy of tafamidis from an ongoing long-term extension (LTE) to the pivotal ATTR-ACT (Tafamidis in Transthyretin Cardiomyopathy Clinical Trial). Methods: Patients with transthyretin amyloid cardiomyopathy who completed ATTR-ACT could enroll in an LTE, continuing with the same tafamidis dose or, if previously treated with placebo, randomized (2:1) to tafamidis meglumine 80 or 20 mg. All patients in the LTE transitioned to tafamidis free acid 61 mg (bioequivalent to tafamidis meglumine 80 mg) following a protocol amendment. In this interim analysis, all-cause mortality was assessed in patients treated with tafamidis meglumine 80 mg in ATTR-ACT continuing in the LTE, compared with those receiving placebo in ATTR-ACT transitioning to tafamidis in the LTE. Results: Median follow-up was 58.5 months in the continuous tafamidis group (n=176) and 57.1 months in the placebo to tafamidis group (n=177). There were 79 (44.9%) deaths with continuous tafamidis and 111 (62.7%) with placebo to tafamidis (hazard ratio, 0.59 [95% CI, 0.44–0.79]; P P =0.05) and wild-type transthyretin amyloidosis (0.61 [0.43–0.87]; P =0.006); and baseline New York Heart Association class I and II (0.56 [0.38–0.82]; P =0.003) and class III (0.65 [0.41–1.01]; P =0.06). Conclusions: In the LTE, patients initially treated with tafamidis in ATTR-ACT had substantially better survival than those first treated with placebo, highlighting the importance of early diagnosis and treatment in transthyretin amyloid cardiomyopathy. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01994889 and NCT02791230.

Introduction: In cardiac amyloidosis (CA), immunoglobulin-derived light chains (AL) and transthyretin (TTR) are the most common amyloidogenic proteins infiltrating the heart. 1 Identification of the specific precursor protein leading to amyloid deposition is needed to establish the correct therapeutic approach. 2 In both AL- and TTR-related CA, an early and accurate diagnosis is critical to achieving the best treatment outcomes. TTR amyloid cardiomyopathy (ATTR-CM) is often misdiagnosed as other causes of heart failure (HF), including AL CA. 3 While almost all patients with AL amyloidosis have elevated serum free light-chain (sFLC) levels and abnormal free kappa:lambda (κ:λ) ratios, 4 patients with ATTR-CM can also have abnormal sFLC levels due to either an unrelated monoclonal gammopathy or relative κ-predominance in renal dysfunction. 2,5 Because ATTR-CM most often occurs in elderly adults and is commonly accompanied by renal comorbidity, we theorized that patients with ATTR-CM may have κ:λ ratios that approach, or exceed, the upper limit of the normal reference range (0.26-1.65 6). High light-chain ratios in these patients have the potential to increase the likelihood of misdiagnosis of a monoclonal plasma cell disorder and may lead to unnecessary referrals to hematologists and/or inappropriate treatments. To explore this theory, we evaluated κ:λ ratios in patients with biopsy-proven ATTR-CM who were enrolled in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT). 7 Methods: In ATTR-ACT, a double-blind, placebo-controlled, randomized study, patients with biopsy-proven ATTR-CM, and without light-chain amyloidosis, received tafamidis or placebo for 30 months. In the current analysis, sFLC levels and κ:λ ratios were assessed in the intent-to-treat population (N=441), excluding patients with a prior diagnosis of monoclonal gammopathies (n=13; defined by MedDRA preferred terms: 'monoclonal gammopathy', 'plasma cell myeloma', 'plasma cell disorder', and 'hypergammaglobulinemia benign monoclonal'). Subgroup analyses were performed by estimated glomerular filtration rate (eGFR) category (≥60 vs ≥40 to Results: In 422 patients with ATTR-CM and available sFLC data, and without a prior diagnosis of monoclonal gammopathies, the mean κ:λ ratio was 1.45 (median, 1.20 [IQR, 0.98, 1.47]) (Figure). The ratio increased with declining renal function: eGFR ≥60 mL/min/1.73 m 2, mean, 1.25 (median [IQR], 1.11 [0.94, 1.38]); ≥40 to Conclusions: In patients with biopsy-proven ATTR-CM without known monoclonal gammopathies who were enrolled in ATTR-ACT, the mean κ:λ ratio showed a κ-predominance, often exceeding the upper range of normal in patients with more advanced kidney dysfunction. The findings suggest that individuals with ATTR-CM can have higher sFLC levels than those normally seen in the general population, and such elevations do not necessarily indicate the presence of monoclonal gammopathy of undetermined significance or AL CA. In an era when most patients with ATTR-CM and without monoclonal gammopathies are diagnosed noninvasively using bone scintigraphy, age- and renal-function-based sFLC norms are critical to ensure appropriate use of diagnostic testing modalities. References: 1. Maleszewski JJ. Cardiovasc Pathol. 2015;24:343-50. 2. Donnelly JP, et al. Cleve Clin J Med. 2017;84:12-26. 3. Witteles RM, et al. JACC Heart Fail. 2019;7:709-716. 4. Falk RH, et al. J Am Coll Cardiol. 2016;68:1323-41. 5. Geller HI, et al. Mayo Clin Proc. 2017;92:1800-5. 6. Katzmann JA, et al. Clin Chem. 2002;48:1437-44. 7. Maurer MS, et al. N Engl J Med. 2018;379:1007-16. Figure 1 Figure 1. Disclosures Hoffman: BMS, Celgene: Honoraria. Sultan: Pfizer: Current Employment, Current equity holder in publicly-traded company. Gundapaneni: Pfizer: Current Employment, Current equity holder in publicly-traded company. Witteles: Pfizer: Honoraria, Research Funding; Alnylam: Honoraria, Research Funding; Eidos: Research Funding.

BACKGROUND Transthyretin amyloid cardiomyopathy (ATTR-CM) is a fatal disease caused by destabilization of the transthyretin (TTR) tetramer resulting in the formation of amyloid fibrils that deposit in the heart, leading to heart failure and ultimately death. Tafamidis, a specific stabilizer of TTR, binds to the thyroxine binding sites and inhibits TTR dissociation, the rate limiting step in the amyloidogenic process. In ATTR-ACT, tafamidis significantly reduced all-cause mortality and cardiovascular-related hospitalizations in participants with ATTR-CM. Here, we evaluated the effects of tafamidis 80 mg on TTR stabilization and TTR plasma concentrations compared to placebo-treated patients in ATTR-ACT. METHODS AND RESULTS Patient blood samples were collected at baseline and Months 1, 6, 12, 18, 24 and 30. TTR tetramer stability was measured using an immunoturbidimetric assay with urea denaturation. The TTR tetramer plasma level was measured prior to and after urea denaturation. The pre-denaturation TTR level provided the TTR plasma concentration at each time point. A significantly greater proportion of participants in the tafamidis 80 mg group (144/164 [87.8%] demonstrated TTR stabilization at Month 1 than was observed for participants in the placebo group (6/170 [3.5%] (p CONCLUSION These results suggest more TTR was conserved in its tetrameric structure and less consumed in the amyloidogenic cascade supporting the robustness of tafamidis as a TTR stabilizer. Tafamidis 80 mg resulted in almost 90% of participants demonstrating TTR stabilization and mean TTR plasma levels were consistently elevated over the 30 months of ATTR-ACT. Stabilization of the TTR tetramer is an important consideration in the treatment of ATTR-CM allowing for the preservation of functional transthyretin in plasma for normal physiologic activity.

Introduction In the pivotal ATTR-ACT study, tafamidis was associated with a 30% lower mortality risk than placebo (PBO) in patients with transthyretin amyloid cardiomyopathy (ATTR-CM) over 30 months. Because patients receiving PBO in ATTR-ACT switched to tafamidis in the ongoing, open-label long-term extension (LTE), the long-term efficacy of tafamidis cannot be directly compared with PBO. A statistical extrapolation method has been used to estimate between-group differences in survival beyond the 30-month trial duration. Hypothesis Comparing observed long-term survival with tafamidis in the LTE with estimated survival with PBO extrapolated from ATTR-ACT will allow fuller assessment of tafamidis survival benefits. Methods In ATTR-ACT, patients with ATTR-CM received tafamidis (80 or 20 mg) or PBO for 30 months. In the LTE, patients previously receiving tafamidis continued on the same tafamidis dose, and those previously receiving PBO were randomized to tafamidis 80 mg or 20 mg. Based on a protocol amendment (July 20, 2018), all patients in the LTE transitioned to tafamidis free acid 61 mg (bioequivalent to tafamidis 80 mg). All-cause mortality was assessed using a Cox proportional hazards model for tafamidis 80/61 mg or PBO/tafamidis in ATTR-ACT/LTE. A gamma model based on patient-level data for the PBO group in ATTR-ACT and best model fitting criteria (AIC, BIC) was used to extrapolate survival beyond 30 months. Results In this interim analysis of all-cause mortality, 75/176 (42.6%) and 108/177 (61.0%) patients in the tafamidis 80/61 mg and PBO/tafamidis groups, respectively, died (median follow-up: 51.9 and 51.4 months). Long-term continuous tafamidis treatment was superior to PBO/tafamidis treatment (Figure). Mortality risk was reduced by 41.1% with tafamidis 80/61 mg (n = 176) vs PBO/tafamidis (n = 177) (hazard ratio, 0.5888 [95% CI: 0.4370-0.7931]; P = 0.0004). In the extrapolated PBO group, the estimated median overall survival was 35.2 months, vs 35.8 months in the observed PBO/tafamidis group. The curves for PBO/tafamidis and estimated PBO diverged after ∼44 months in favor of tafamidis. Conclusions Extrapolation of PBO data from ATTR-ACT was a valuable tool allowing comparison of potential outcomes with and without tafamidis treatment. Although these extrapolated data suggest that delayed initiation of tafamidis may provide some survival benefit, early continuous treatment with tafamidis results in significantly better survival outcomes in patients with ATTR-CM.

Background Transthyretin cardiomyopathy (ATTR-CM) is an underdiagnosed, fatal disease caused by the deposition of transthyretin amyloid fibrils in the heart leading to heart failure (HF). It can be hereditary due to mutations in the TTR gene (ATTRm) or acquired (wild-type [ATTRwt]). Tafamidis is a selective transthyretin stabilizer which prevents tetramer dissociation and amyloidogenesis. The Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) was an international, multicenter, double-blind, placebo-controlled, randomized trial of Tafamidis in patients with ATTR-CM. Objectives Given the limited number of patients with ATTR-CM, a novel study design was utilized to enable rigorous testing of the efficacy of tafamidis on hard cardiovascular (CV) endpoints in a study of relatively modest size compared with traditional CV trials. The primary results of this trial were further supported through the application of pre-specified sensitivity analyses. Methods Patients with ATTR-CM were randomized (2:1:2) to tafamidis (80 mg or 20 mg of tafamidis meglumine), or placebo (orally, once daily), for 30 months. Enrollment was stratified by NYHA class and genotype. The primary efficacy analysis was a hierarchical combination of all-cause mortality and frequency of CV-related hospitalizations comparing the pooled tafamidis groups (20 mg and 80 mg) vs. the placebo group using the Finkelstein-Schoenfeld (F-S) method. The primary efficacy analysis result was examined using a series of sensitivity analyses. Key secondary endpoints were change from baseline to Month 30 in the six-minute walk test distance and the Kansas City Cardiomyopathy Questionnaire (KCCQ) overall score. Safety assessments included adverse events, vital signs, and clinical laboratory tests. Results A total of 441 patients were randomized (tafamidis=264, placebo=177). Tafamidis was associated with a significant reduction in the hierarchical combination of all-cause mortality and CVrelated hospitalizations (P Conclusions ATTR-ACT, the largest randomized controlled trial in ATTR-CM, showed that tafamidis is the first treatment to improve survival and quality of life in ATTR-CM. Significant and clinically meaningful improvements were observed in functional capacity as measured by the six-minute walk distance and quality of life by KCCQ overall score. Sensitivity analyses confirmed the robustness of these results. Tafamidis was safe and well tolerated. The primary trial results, along with the sensitivity analyses described here, provide strong rationale for the use of tafamidis as first-line therapy in ATTR-CM.