tafamidis and Heart-Failure

Tafamidis was associated with a reduction in cardiovascular hospitalizations and all-cause mortality in patients with transthyretin amyloid cardiomyopathy (ATTR-CM) in the ATTR-ACT trial. However, real-world data on the efficacy of tafamidis are limited. We conducted a retrospective, observational cohort study using the TriNetX research network. Patients with wild-type TTR amyloidosis and heart failure (HF) were divided into 2 groups based on treatment with tafamidis. Propensity score matching (PSM) was performed, and rates of heart failure exacerbations (HFE) and all-cause mortality at 12 months were compared. After PSM, 421 patients were in each group (tafamidis vs nontafamidis). During the 12-month follow-up period, patients treated with tafamidis experienced significantly less HFE and all-cause mortality. A higher probability of event-free survival for HFE and all-cause mortality was noted with tafamidis. This real-world analysis supports that tafamidis use is associated with reduced HFE and all-cause mortality in patients with wild-type TTR amyloidosis and HF. Longer-term follow-up is needed to better understand the utility of tafamidis, given the increasing recognition of ATTR-CM and the high cost of tafamidis.

Topics: Amyloid Neuropathies, Familial; Cardiomyopathies; Heart Failure; Humans; Observational Studies as Topic; Prealbumin; Retrospective Studies

Transthyretin amyloid cardiomyopathy (ATTR-CM) is an underdiagnosed cause of heart failure and arrhythmia. This differential diagnosis should particularly be considered in older patients with left ventricular hypertrophy (LVH) who are also suffering from heart failure with preserved ejection fraction (HFpEF) or aortic valve stenosis. ATTR-CM is caused either by a genetic variation or by aging processes. The extracellular accumulation of amyloid fibrils in the heart causes a restrictive cardiomyopathy, which leads to typical heart failure symptoms as well as cardiac conduction and repolarization disturbances. Extracardiac problems such as a carpal tunnel syndrome can also be indicative for ATTR-CM. The disease can be diagnosed either by a myocardial biopsy or alternatively by a positive bone scintigraphy with the simultaneous exclusion of monoclonal proteins in blood and urine. Besides a symptomatic treatment, the transthyretin (TTR) stabilizer tafamidis is now available, which can significantly delay the disease progress. In the coming years, the approval of further drugs for the treatment of ATTR-CM is to be expected.. Kardiale Transthyretin-Amyloidosen (ATTR-Amyloidosen) sind eine unterdiagnostizierte Ursache von Herzinsuffizienz und Arrhythmien. Insbesondere bei älteren Patienten mit einer linksventrikulären Hypertrophie (LVH), die gleichzeitig an einer Herzinsuffizienz mit erhaltener Ejektionsfraktion (HFpEF) oder Aortenklappenstenose leiden, sollte an diese Differenzialdiagnose gedacht werden. ATTR-Amyloidosen sind entweder genetisch bedingt oder entstehen durch Alterungsprozesse. Durch die extrazelluläre Akkumulation von Amyloidfibrillen im Herzen kommt es zu einer restriktiven Kardiomyopathie, die zu typischen Herzinsuffizienzsymptomen sowie Erregungsleitungs- und Erregungsrückbildungsstörungen führt. Auch extrakardiale Probleme wie ein Karpaltunnelsyndrom können auf eine kardiale ATTR-Amyloidose hindeuten. Die Erkrankung kann durch eine Myokardbiopsie oder alternativ durch eine positive Skelettszintigraphie bei gleichzeitigem Ausschluss monoklonaler Proteine im Blut und Urin diagnostiziert werden. Neben einer symptomatischen Therapie steht mittlerweile mit dem Transthyretin(TTR)-Stabilisator Tafamidis ein Medikament zur Verfügung, das den Krankheitsverlauf signifikant verlangsamen kann. In den nächsten Jahren ist mit der Zulassung weiterer Medikamente zur Behandlung der kardialen ATTR-Amyloidose zu rechnen.

Topics: Aged; Amyloid Neuropathies, Familial; Benzoxazoles; Cardiomyopathies; Heart Failure; Humans; Prealbumin; Stroke Volume; Tomography, X-Ray Computed

Tafamidis is the only therapy shown to improve survival in transthyretin cardiac amyloidosis (ATTR) based on randomized controlled trial data. We sought to evaluate the impact of tafamidis on survival in a real-world community-based cohort. This was a prospective observational cohort study that included consecutive patients with confirmed ATTR based on biopsy or TcPYP imaging. Baseline characteristics were compared between patients taking tafamidis vs not, and Kaplan-Meier survival analysis was performed to compare survival between these groups. We examined the reasons that ATTR patients were not on tafamidis. Of 107 ATTR patients, median age was 83.9 years, 79% were men, and 63 (59%) of them were on tafamidis. Demographics and baseline cardiovascular risk factors did not differ significantly between those on vs off tafamidis, although there was a higher proportion of NYHA Class III or IV heart failure in those off tafamidis (76% vs 57%, P < 0.01). The most common reasons patients were not on tafamidis included delays in obtaining the drug or financial barriers (59%) and NYHA Class IV heart failure (19.5%). Patients taking tafamidis had a significantly higher median survival compared to those not on tafamidis (median survival 6.70 vs 1.43 years, P < 0.0001). Our study demonstrates significantly improved survival in ATTR patients taking tafamidis. Barriers exist to tafamidis initiation including delayed access and affordability, and efforts should be made to improve patient access.

Topics: Aged, 80 and over; Amyloid Neuropathies, Familial; Benzoxazoles; Cardiomyopathies; Female; Heart Failure; Humans; Male; Observational Studies as Topic; Prospective Studies

Cardiac amyloidosis is an underrecognized cause of heart failure. We review clinical clues to the diagnoses, a rational approach to testing, and current and emerging therapies.. Advances in the diagnosis of amyloid cardiomyopathy include (1) use of

Topics: Amyloid Neuropathies, Familial; Amyloidosis; Benzoxazoles; Cardiomyopathies; Heart Failure; Humans; Immunoglobulin Light-chain Amyloidosis

Cardiac amyloidosis (CA) is an infiltrative and restrictive cardiomyopathy that leads to heart failure, reduced quality of life, and death. The disease has two main subtypes, transthyretin cardiac amyloidosis (ATTR-CA) and immunoglobulin light chain cardiac amyloidosis (AL-CA), characterized by the nature of the infiltrating protein. ATTR-CA is further subdivided into wild-type (ATTRwt-CA) and variant (ATTRv-CA) based on the presence or absence of a mutation in the transthyretin gene. CA is significantly underdiagnosed and increasingly recognized as a cause of heart failure with preserved ejection fraction. Advances in diagnosis that employ nuclear scintigraphy to diagnose ATTR-CA without a biopsy and the emergence of effective treatments, including transthyretin stabilizers and silencers, have changed the landscape of this field and render early and accurate diagnosis critical. This review summarizes the epidemiology, pathophysiology, diagnosis, prognosis, and management of CA with an emphasis on the significance of recent developments and suggested future directions.

Topics: Amyloid Neuropathies, Familial; Amyloidosis; Arrhythmias, Cardiac; Benzoates; Benzoxazoles; Biopsy; Cardiac Pacing, Artificial; Cardiomyopathies; Diflunisal; Disease Progression; Early Diagnosis; Early Medical Intervention; Echocardiography; Electrocardiography; Heart Failure; Humans; Immunoglobulin Light-chain Amyloidosis; Immunologic Factors; Magnetic Resonance Imaging; Oligonucleotides; Prealbumin; Prognosis; Proteasome Inhibitors; Pyrazoles; Radionuclide Imaging; RNA, Small Interfering

Many patients with systemic amyloidosis are underdiagnosed. Overall, 25% of patients with immunoglobulin light chain (AL) amyloidosis die within 6 months of diagnosis and 25% of patients with amyloid transthyretin (ATTR) amyloidosis die within 24 months of diagnosis. Effective therapy exists but is ineffective if end-organ damage is severe.. To provide evidence-based recommendations that could allow clinicians to diagnose this rare set of diseases earlier and enable accurate staging and counseling about prognosis.. A comprehensive literature search was conducted by a reference librarian with publication dates from January 1, 2000, to December 31, 2019. Key search terms included amyloid, amyloidosis, nephrotic syndrome, heart failure preserved ejection fraction, and peripheral neuropathy. Exclusion criteria included case reports, non-English-language text, and case series of fewer than 10 patients. The authors independently selected and appraised relevant literature.. There was a total of 1769 studies in the final data set. Eighty-one articles were included in this review, of which 12 were randomized clinical trials of therapy that included 3074 patients, 9 were case series, and 3 were cohort studies. The incidence of AL amyloidosis is approximately 12 cases per million persons per year and there is an estimated prevalence of 30 000 to 45 000 cases in the US and European Union. The incidence of variant ATTR amyloidosis is estimated to be 0.3 cases per year per million persons with a prevalence estimate of 5.2 cases per million persons. Wild-type ATTR is estimated to have a prevalence of 155 to 191 cases per million persons. Amyloidosis should be considered in the differential diagnosis of adult nondiabetic nephrotic syndrome; heart failure with preserved ejection fraction, particularly if restrictive features are present; unexplained hepatomegaly without imaging abnormalities; peripheral neuropathy with distal sensory symptoms, such as numbness, paresthesia, and dysesthesias (although the autonomic manifestations occasionally may be the presenting feature); and monoclonal gammopathy of undetermined significance with atypical clinical features. Staging can be performed using blood testing only. Therapeutic decision-making for AL amyloidosis involves choosing between high-dose chemotherapy and stem cell transplant or bortezomib-based chemotherapy. There are 3 therapies approved by the US Food and Drug Administration for managing ATTR amyloidosis, depending on clinical phenotype.. All forms of amyloidosis are underdiagnosed. All forms now have approved therapies that have been demonstrated to improve either survival or disability and quality of life. The diagnosis should be considered in patients that have a multisystem disorder involving the heart, kidney, liver, or nervous system.

Topics: Algorithms; Benzoxazoles; Dexamethasone; Diagnosis, Differential; Gene Silencing; Heart Failure; Humans; Immunoglobulin Light-chain Amyloidosis; Liver Transplantation; Melphalan; Prognosis; Proteinuria; Stem Cell Transplantation

Transthyretin (TTR) related cardiomyopathy is an underdiagnosed cause of heart failure but is increasingly recognized in various settings - from patients admitted with heart failure to symptomatic aortic stenosis - and is rapidly becoming the most frequent form of systemic amyloidosis. Following the recent publication of the landmark ATTR-ACT trial that showed tafamidis to be the first treatment to improve survival in patients with TTR-related cardiac amyloidosis and heart failure, we reviewed the drug's rationale, characteristics and evidence supporting its use in TTR amyloidosis.

Topics: Amyloid Neuropathies, Familial; Benzoxazoles; Global Health; Heart Failure; Humans; Survival Rate

Transthyretin (TTR) is a tetrameric protein synthesized mostly by the liver. As a result of gene mutations or as an ageing-related phenomenon, TTR molecules may misfold and deposit in the heart and in other organs as amyloid fibrils. Cardiac involvement in TTR-related amyloidosis (ATTR) manifests typically as left ventricular pseudohypertrophy and/or heart failure with preserved ejection fraction. ATTR is an underdiagnosed disorder as well as a crucial determinant of morbidity and mortality, thus justifying the current quest for a safe and effective treatment. Therapies targeting cardiac damage and its direct consequences may yield limited benefit, mostly related to dyspnoea relief through diuretics. For many years, liver or combined heart and liver transplantation have been the only available treatments for patients with mutations causing ATTR, including those with cardiac involvement. The therapeutic options now include several pharmacological agents that inhibit hepatic synthesis of TTR, stabilize the tetramer, or disrupt fibrils. Following the positive results of a phase 3 trial on tafamidis, and preliminary findings on patisiran and inotersen in patients with ATTR-related neuropathy and cardiac involvement, we provide an update on this rapidly evolving field, together with practical recommendations on the management of cardiac involvement.

Topics: Amyloid; Amyloid Neuropathies; Amyloid Neuropathies, Familial; Benzoxazoles; Clinical Trials, Phase III as Topic; Combined Modality Therapy; Heart Failure; Heart Transplantation; Humans; Liver Transplantation; Mutation; Oligonucleotides; Prealbumin; RNA, Small Interfering; Stroke Volume

Transthyretin amyloid cardiomyopathy (ATTR-CM) is a life-threatening, progressive, infiltrative disease caused by the deposition of transthyretin amyloid fibrils in the heart, and can often be overlooked as a common cause of heart failure. Delayed diagnosis due to lack of disease awareness and misdiagnosis results in a poorer prognosis. Early accurate diagnosis is therefore key to improving patient outcomes, particularly in the context of both the recent approval of tafamidis in some countries (including the United States) for the treatment of ATTR-CM, and of other promising therapies under development. With the availability of scintigraphy as an inexpensive, noninvasive diagnostic tool, the rationale to screen for ATTR-CM in high-risk populations of patients is increasingly warranted. Here the authors propose a framework of clinical scenarios in which screening for ATTR-CM is recommended, as well as diagnostic "red flags" that can assist in its diagnosis among the wider population of patients with heart failure.

Topics: Age Factors; Amyloid Neuropathies, Familial; Benzoxazoles; Cardiomyopathies; Delayed Diagnosis; Diagnostic Errors; Early Diagnosis; Early Medical Intervention; Heart Failure; Humans; Stroke Volume

Transthyretin-cardiac amyloidoses (ATTR-CA) are an underdiagnosed but increasingly recognized cause of heart failure. Extracellular deposition of fibrillary proteins into tissues due to a variety of inherited transthyretin mutations in ATTRm or due to advanced age in ATTRwt eventually leads to organ failure. In the heart, amyloid deposition causes diastolic dysfunction, restrictive cardiomyopathy with progressive loss of systolic function, arrhythmias, and heart failure. While traditional treatments have consisted of conventional heart failure management and supportive care for systemic symptoms, numerous disease-modifying therapies have emerged over the past decade. From organ transplantation to transthyretin stabilizers (diflunisal, tafamidis, AG-1), TTR silencers (ALN-ATTR02, ISIS-TTR(Rx)), and degraders of amyloid fibrils (doxycycline/TUDCA), the potential for effective transthyretin amyloid therapy is greater now than ever before. In light of these multiple agents under investigation in human clinical trials, clinicians should be familiar with the systemic cardiac amyloidoses, their differing pathophysiology, natural histories, and unique treatment strategies.

Topics: Amyloid Neuropathies, Familial; Benzoxazoles; Biomarkers; Cardiomyopathies; Cyclooxygenase Inhibitors; Defibrillators, Implantable; Diflunisal; Doxycycline; Heart Failure; Humans; Oligonucleotides, Antisense; Organ Transplantation; Pacemaker, Artificial; RNA, Small Interfering

Patients with familial amyloidpolyneuropathies (FAP) require multidisciplinary neurologic and cardiologic management, including specific treatments to control the progression of systemic amyloidogenesis, symptomatic treatment of peripheral and autonomic neuropathies, and management of severe organ involvement (heart, eyes, kidneys). The first-line specific treatment of choice for met30 TTR-FAP is liver transplantation (LT) which suppresses the main source of mutant TTR, halts the progression of neuropathy in 70% of cases, and doubles the median survival time. Dual kidney-liver or heart-liver transplantation may be appropriate for patients with severe renal or cardiac failure. Tafamidis (Vyndaqel(R), Pfizer), a novel stabilizer of tetrameric TTR, has shown short-term effectiveness in slowing the progression of peripheral neuropathy in very early stages of met30 TTR-FAP This drug should thus be proposed for stage 1 symptomatic polyneuropathy. Other innovative medicines (RNA interference, antisense oligonucleotides) have been developed to block hepatic production of both mutant and wildtype TTR (noxious in late-onset forms of NAH after age 50 years), and to remove amyloid deposits (monoclonal anti-SAP). Clinical trials should first include patients with late-onset FAP or non-met30 TTR-FAP who are less responsive to LT7 and patients in whom Vyndaqel(R) is ineffective or inappropriate. Initial and periodic cardiac assessment is necessary, as cardiac impairment is inevitable and largely responsible for mortality. Symptomatic treatment is crucial to improve these patients' quality of life. Familial screening for carriers of the TTR gene mutation and regular clinical examination are essential to detect disease onset and to start specific therapy in a timely manner.

Topics: Amyloid Neuropathies, Familial; Antibodies, Monoclonal; Benzoxazoles; Clinical Trials as Topic; Diflunisal; Disease Progression; Doxycycline; Drug Therapy, Combination; Genetic Therapy; Heart Failure; Heart Transplantation; Humans; Kidney Failure, Chronic; Kidney Transplantation; Liver Transplantation; Myocardium; Oligonucleotides, Antisense; Renal Dialysis; RNA Interference; Serum Amyloid P-Component; Taurochenodeoxycholic Acid

Tafamidis is an effective treatment for transthyretin amyloid cardiomyopathy (ATTR-CM) in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT). While ATTR-ACT was not designed for a dose-specific assessment, further analysis from ATTR-ACT and its long-term extension study (LTE) can guide determination of the optimal dose.. In ATTR-ACT, patients were randomized (2:1:2) to tafamidis 80 mg, 20 mg, or placebo for 30 months. Patients completing ATTR-ACT could enrol in the LTE (with placebo-treated patients randomized to tafamidis 80 or 20 mg; 2:1) and all patients were subsequently switched to high-dose tafamidis. All-cause mortality was assessed in ATTR-ACT combined with the LTE (median follow-up 51 months). In ATTR-ACT, the combination of all-cause mortality and cardiovascular-related hospitalizations over 30 months was significantly reduced with tafamidis 80 mg (P = 0.0030) and 20 mg (P = 0.0048) vs. placebo. All-cause mortality vs. placebo was reduced with tafamidis 80 mg [Cox hazards model (95% confidence interval): 0.690 (0.487-0.979), P = 0.0378] and 20 mg [0.715 (0.450-1.137), P = 0.1564]. The mean (standard error) change in N-terminal pro-B-type natriuretic peptide from baseline to Month 30 was -1170.51 (587.31) (P = 0.0468) with tafamidis 80 vs. 20 mg. In ATTR-ACT combined with the LTE there was a significantly greater survival benefit with tafamidis 80 vs. 20 mg [0.700 (0.501-0.979), P = 0.0374]. Incidence of adverse events in both tafamidis doses were comparable to placebo.. Tafamidis, both 80 and 20 mg, effectively reduced mortality and cardiovascular-related hospitalizations in patients with ATTR-CM. The longer-term survival data and the lack of dose-related safety concerns support tafamidis 80 mg as the optimal dose.. ClinicalTrials.gov NCT01994889; NCT02791230.

Topics: Amyloid Neuropathies, Familial; Benzoxazoles; Cardiomyopathies; Heart Failure; Humans; Prealbumin

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.

Topics: Aged; Amyloid Neuropathies, Familial; Amyloidosis; Arrhythmias, Cardiac; Benzoxazoles; Cardiomyopathies; Cardiovascular Diseases; Cause of Death; Death, Sudden, Cardiac; Double-Blind Method; Female; Heart Failure; Hospitalization; Humans; Ischemic Attack, Transient; Male; Myocardial Infarction; Prealbumin; Proportional Hazards Models; Stroke

Transthyretin amyloid cardiomyopathy is caused by the deposition of transthyretin amyloid fibrils in the myocardium. The deposition occurs when wild-type or variant transthyretin becomes unstable and misfolds. Tafamidis binds to transthyretin, preventing tetramer dissociation and amyloidogenesis.. In a multicenter, international, double-blind, placebo-controlled, phase 3 trial, we randomly assigned 441 patients with transthyretin amyloid cardiomyopathy in a 2:1:2 ratio to receive 80 mg of tafamidis, 20 mg of tafamidis, or placebo for 30 months. In the primary analysis, we hierarchically assessed all-cause mortality, followed by frequency of cardiovascular-related hospitalizations according to the Finkelstein-Schoenfeld method. Key secondary end points were the change from baseline to month 30 for the 6-minute walk test and the score on the Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS), in which higher scores indicate better health status.. In the primary analysis, all-cause mortality and rates of cardiovascular-related hospitalizations were lower among the 264 patients who received tafamidis than among the 177 patients who received placebo (P<0.001). Tafamidis was associated with lower all-cause mortality than placebo (78 of 264 [29.5%] vs. 76 of 177 [42.9%]; hazard ratio, 0.70; 95% confidence interval [CI], 0.51 to 0.96) and a lower rate of cardiovascular-related hospitalizations, with a relative risk ratio of 0.68 (0.48 per year vs. 0.70 per year; 95% CI, 0.56 to 0.81). At month 30, tafamidis was also associated with a lower rate of decline in distance for the 6-minute walk test (P<0.001) and a lower rate of decline in KCCQ-OS score (P<0.001). The incidence and types of adverse events were similar in the two groups.. In patients with transthyretin amyloid cardiomyopathy, tafamidis was associated with reductions in all-cause mortality and cardiovascular-related hospitalizations and reduced the decline in functional capacity and quality of life as compared with placebo. (Funded by Pfizer; ATTR-ACT ClinicalTrials.gov number, NCT01994889 .).

Topics: Administration, Oral; Aged; Aged, 80 and over; Amyloid Neuropathies, Familial; Benzoxazoles; Cardiomyopathies; Disease Progression; Double-Blind Method; Female; Heart Failure; Hospitalization; Humans; Male; Middle Aged; Prealbumin; Quality of Life; Survival Analysis; Walk Test

A phase 2, open-label study in 21 patients with non-Val30Met and non-Val122Ile hereditary transthyretin amyloidosis showed that tafamidis (20 mg daily for 12 months) stabilized these transthyretin variants. We assessed cardiac amyloid infiltration and cardiac abnormalities in this same study population. At baseline, median age was 64.3 years, 11 patients were in NYHA class II, 13 had conduction abnormalities, 14 N-terminal pro-hormone brain natriuretic peptide concentrations >300 pg/ml, and 17 interventricular septal thickness >12 mm. Mean (SD) left ventricular ejection fraction was 60.3% (9.96). Patients with normal heart rate variability increased from 4/19 at baseline to 8/19 at month 12 (p < 0.05). Cardiac biomarkers remained stable. Although four patients had increases in interventricular septal thickness ≥ 2 mm, the remainder had stable septal wall thickness. There were no clinically relevant changes in mean echocardiographic/electrocardiographic variables and no safety concerns.

Topics: Adult; Aged; Amyloid Neuropathies, Familial; Benzoxazoles; Cardiomyopathies; Europe; Female; Fibrosis; Genetic Predisposition to Disease; Heart Failure; Humans; Male; Middle Aged; Mutation; Myocardium; Phenotype; Prealbumin; Risk Factors; Time Factors; Treatment Outcome; United States

Topics: Amyloid Neuropathies, Familial; Amyloidosis; Cardiomyopathies; Diphosphates; Heart Failure; Humans; Prealbumin; Radionuclide Imaging; Radiopharmaceuticals; Technetium

Tafamidis improves prognosis in patients with transthyretin amyloid cardiomyopathy (ATTR-CM). However, real-world data on the therapeutic effect of tafamidis are lacking. This study aimed to evaluate the clinical course, outcomes, and effectivity monitoring of the therapeutic effect of tafamidis in patients with ATTR-CM.. This is a single-centre, retrospective observational study. We evaluated the clinical characteristics and outcomes in 125 consecutive patients with wild-type ATTR-CM (ATTRwt-CM) treated with tafamidis (treatment group) and 55 untreated patients (treatment-naïve group). We monitored the therapeutic effect of tafamidis for 12 months by evaluating serial cardiac biomarker and imaging findings. The treatment group had significantly more favourable outcome in all-cause mortality and hospitalization due to heart failure than the treatment-naïve group in both the entire cohort (P < 0.01) and the propensity score-matched cohort (P < 0.05). Kaplan-Meier survival curves showed that tafamidis treatment significantly reduced all-cause mortality (P = 0.03, log-rank test), with the curves diverging after approximately 18 months of treatment in the propensity score-matched cohort. On inverse probability of treatment weighting analysis, tafamidis treatment showed a reduced all-cause mortality [hazard ratio (HR), 0.31; 95% confidence interval (CI), 0.11-0.93; P = 0.04]. High-sensitivity cardiac troponin T (hs-cTnT) > 0.05 ng/mL, B-type natriuretic peptide (BNP) > 250 pg/mL, and estimated glomerular filtration rate (eGFR) < 45 mL/min/1.73 m. The prognosis of patients with ATTRwt-CM treated with tafamidis was more favourable than that of untreated patients. Patient stratification combined with biomarkers (hs-cTnT, BNP, and eGFR) predicted clinical outcomes. hs-cTnT may be a useful biomarker for evaluating the therapeutic effect of tafamidis.

Topics: Amyloidosis; Biomarkers; Cardiomyopathies; Heart Failure; Humans; Prealbumin

This plain language summary describes the results of a study called ATTR-ACT, which was published in the

Topics: Adult; Amyloid Neuropathies, Familial; Benzoxazoles; Cardiomyopathies; Heart Failure; Humans; Language; Prealbumin; Quality of Life

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).. 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.. 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.

Topics: Aged; Aged, 80 and over; Amyloid Neuropathies, Familial; Benzoxazoles; Cardiomyopathies; Female; Heart Failure; Hospitalization; Humans; Male; Middle Aged; Prealbumin; Proportional Hazards Models; Time

Topics: Amyloid Neuropathies, Familial; Benzoxazoles; Cardiomyopathies; Heart Failure; Humans; Prealbumin

Topics: Amyloid Neuropathies, Familial; Benzoxazoles; Cardiomyopathies; Heart Failure; Humans; Prealbumin

Topics: Amyloid Neuropathies, Familial; Benzoxazoles; Cardiomyopathies; Heart Failure; Humans; Prealbumin; Prognosis

Transthyretin cardiomyopathy (ATTR-CM) is an under-recognized cause of heart failure, but it has received increasing attention due to the availability of treatment options. We present a case of hereditary transthyretin cardiomyopathy (A97S, an under-represented variant in current clinical studies) who presented with heart failure. Timely diagnosis and intervention with tafamidis demonstrated reversed cardiac remodelling via multiple imaging techniques (echocardiography, cardiac magnetic resonance imaging and technetium-99m pyrophosphate scintigraphy). The echocardiography and cardiac magnetic resonance imaging demonstrated improved global strain. Cardiac magnetic resonance imaging showed decreased extracellular volume. The technetium-99m pyrophosphate scintigraphy demonstrated decreased heart-to-contralateral ratio. This case highlights the potential reversible effect of tafamidis on A97S amyloidosis cardiomyopathy.

Topics: Amyloid Neuropathies, Familial; Cardiomyopathies; Diphosphates; Heart Failure; Humans; Prealbumin; Technetium; Ventricular Remodeling

Topics: Amyloid Neuropathies, Familial; Benzoxazoles; Cardiomyopathy, Restrictive; Compassionate Use Trials; Drug Approval; Drugs, Investigational; Heart Failure; Humans; Magnetic Resonance Imaging, Cine; Myocardial Perfusion Imaging; Treatment Outcome

Hereditary (ATTRv) and wild-type (ATTRwt) transthyretin amyloidosis are severe and fatal systemic diseases, characterised by amyloid fibrillar accumulation principally in the heart or peripheral nerves (or both). Since 2012, tafamidis has been used in France to treat patients with ATTRv with neuropathy (alone or combined with cardiomyopathy). Recently, the Phase III ATTR-ACT trial showed that tafamidis decreased the relative risk of mortality in ATTR amyloidosis with cardiomyopathy. The aims of this study were to assess the clinical characteristics of ATTR amyloidosis in a real-life population in comparison to the population included in the ATTR-ACT trial and to assess the impact of tafamidis treatment on major cardiovascular outcome (MCO)-free survival time without cardiac decompensation, heart transplant, or death.. From June 2008 to November 2018, 648 patients with ATTR amyloidosis (423 ATTRwt and 225 ATTRv) consecutively referred to the French Referral Center for cardiac amyloidosis were included. A total of 467 (72%) patients matched the inclusion criteria of the ATTR-ACT trial. For the 631 patients with cardiomyopathy, tafamidis treatment was associated with a longer median MCO-free survival time (n = 98): 1565 (1010-2400) days vs. 771 (686-895) days without treatment (log-rank P < 0.001). This association was confirmed after considering confounding factors (age at inclusion, N-terminal pro-B-type natriuretic peptide and amyloidosis type) with a propensity score (hazard ratio 0.546; P = 0.0132).. In a large cohort of ATTRwt and ATTRv patients, representative of the inclusion criteria of the ATTR-ACT trial, the present results show an association between tafamidis treatment and a lower occurrence of cardiovascular outcomes in a real-life population.

Topics: Amyloid Neuropathies, Familial; Benzoxazoles; France; Heart Failure; Humans

Topics: Benzoxazoles; Cardiomyopathies; Heart Failure; Humans; Prealbumin

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).. ATTR-CM is a progressive, fatal disorder resulting from mutations in the ATTRv or the deposition of denatured ATTRwt.. 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.. 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 < 0.0001) and ATTRv (79.61 ± 29.83 m; p = 0.008); and Kansas City Cardiomyopathy Questionnaire Overall Summary score in ATTRwt (12.72 ± 2.10; p < 0.0001) and ATTRv (18.18 ± 7.75; p = 0.019).. 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).

Topics: Benzoxazoles; Cardiomyopathies; Heart Failure; Humans; Prealbumin

Topics: Benzoxazoles; Cardiomyopathies; Heart Failure; Humans; Prealbumin

Topics: Benzoxazoles; Cardiomyopathies; Heart Failure; Humans; Prealbumin

Topics: Benzoxazoles; Cardiomyopathies; Heart Failure; Humans; Prealbumin

In this update, we focus on selected topics of high clinical relevance for health care providers who treat patients with heart failure (HF), on the basis of clinical trials published after 2017. Our objective was to review the evidence, and provide recommendations and practical tips regarding the management of candidates for the following HF therapies: (1) transcatheter mitral valve repair in HF with reduced ejection fraction; (2) a novel treatment for transthyretin amyloidosis or transthyretin cardiac amyloidosis; (3) angiotensin receptor-neprilysin inhibition in patients with HF and preserved ejection fraction (HFpEF); and (4) sodium glucose cotransport inhibitors for the prevention and treatment of HF in patients with and without type 2 diabetes. We emphasize the roles of optimal guideline-directed medical therapy and of multidisciplinary teams when considering transcatheter mitral valve repair, to ensure excellent evaluation and care of those patients. In the presence of suggestive clinical indices, health care providers should consider the possibility of cardiac amyloidosis and proceed with proper investigation. Tafamidis is the first agent shown in a prospective study to alter outcomes in patients with transthyretin cardiac amyloidosis. Patient subgroups with HFpEF might benefit from use of sacubitril/valsartan, however, further data are needed to clarify the effect of this therapy in patients with HFpEF. Sodium glucose cotransport inhibitors reduce the risk of incident HF, HF-related hospitalizations, and cardiovascular death in patients with type 2 diabetes and cardiovascular disease. A large clinical trial recently showed that dapagliflozin provides significant outcome benefits in well treated patients with HF with reduced ejection fraction (left ventricular ejection fraction ≤ 40%), with or without type 2 diabetes.

Topics: Amyloidosis; Angiotensin Receptor Antagonists; Benzoxazoles; Heart Diseases; Heart Failure; Humans; Mitral Valve Insufficiency; Neprilysin; Randomized Controlled Trials as Topic; Severity of Illness Index; Sodium-Glucose Transporter 2 Inhibitors; Stroke Volume