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MUNICH – The big news in the field of heart failure at the annual congress of the European Society of Cardiology concerned an obscure form of the disease traditionally considered rare: transthyretin amyloid cardiomyopathy (TAC).
It turns out that TAC is far more common than previously recognized; it can now be diagnosed and staged noninvasively; and – most important of all – there is for the first time an effective disease-modifying treatment in the form of a novel oral drug called tafamidis, as demonstrated in the Transthyretin Amyloidosis Cardiomyopathy Clinical Trial (ATTR-ACT) presented at the meeting.
“This is the first phase 3 trial that can offer a chance for people with a terrible, severe disease. And within the last year, while the trial was being conducted, it became clear that this disease is much more underdiagnosed than rare,” said Claudio Rapezzi, MD, ATTR-ACT principal investigator and director of the school of cardiovascular diseases at the University of Bologna, Italy.
ATTR-ACT participants randomized to tafamidis showed significant reductions in all-cause mortality and cardiovascular hospitalizations, compared with placebo-treated controls at 30 months follow-up. They also experienced significantly lesser declines in both quality of life as reflected in Kansas City Cardiomyopathy Questionnaire scores and in physical function as captured in 6-minute walk distance.
Designated discussant Jacob George, MD, was over the moon regarding the results.
“This is a pioneering, game-changing trial that is likely to transform the way we diagnose and treat patients with cardiac amyloidosis,” said Dr. George of Kaplan Medical Center in Rehovot, Israel.
“We’re now in an era that, to my opinion, any patient with nonischemic unexplained heart failure should be screened for the presence of amyloidosis because, first, we now know how to prognosticate these patients, and second, we can offer them a real disease-modifying agent,” he added.
An underdiagnosed disease
Transthyretin amyloid cardiomyopathy occurs when transthyretin, a transport protein, becomes destabilized and misfolds, promoting deposition of amyloid fibrils in the myocardium. This results in progressive ventricular wall thickening and stiffness, manifest as restrictive cardiomyopathy and progressive heart failure. The cause of transthyretin destabilization can be either autosomal dominant inheritance of any of more than 100 pathogenic mutations in the transthyretin gene identified to date or a spontaneous wild type protein.
Think of TAC as a sort of dementia of the heart. As Dr. George noted, the cardiac disease bears “remarkable similarities” to Alzheimer’s disease, with both conditions entailing extracellular deposition of amyloid.
In the heritable form of TAC, patients typically present with heart failure symptoms at about age 50-55, while the wild type form becomes symptomatic much later at a mean age of about 75. Average survival from time of diagnosis is only about 3 years.
Recent studies from multiple centers have reported that the prevalence of TAC was 16% in patients undergoing transcatheter aortic valve replacement for severe aortic stenosis, 13% among patients with heart failure with preserved ejection fraction, and 5% in patients who had been presumed to have hypertrophic cardiomyopathy: So, not a rare condition.
“In our clinic, vast and surprising numbers of patients with unexplained nonischemic heart failure are scan positive [for TAC],” according to Dr. George.
Breakthroughs in diagnosis and staging
The echocardiographic red flag for TAC in a patient with heart failure symptoms is symmetric hypertrophy with a normal end-diastolic volume and thickened ventricles. The end-diastolic interventricular septal wall thickness is typically about 15 mm. The left ventricular ejection fraction is typically in the normal range, “but the clue is not the preservation of the ejection fraction, it’s the [normal] quality of the volume,” Dr. Rapezzi said.
A clinical clue suggestive of TAC upon physical examination, even in the absence of heart failure symptoms, is development of bilateral carpal tunnel syndrome in an older man. That’s because the same disease process that results in TAC can involve deposition of amyloid fibrils in peripheral nerves. Indeed, tafamidis is already approved in Europe and Japan under the trade name Vyndaqel as a treatment for familial amyloid polyneuropathy. For TAC, however, tafamidis remains investigational with fast-track status provided by both the Food and Drug Administration and the European Medicines Agency.
When TAC is suspected, it’s no longer necessary to subject patients to an onerous myocardial biopsy. Total body scintigraphy with bone tracers has been shown to be nearly as sensitive and specific as biopsy for the diagnosis.
Staging can now be done noninvasively as well. Investigators at the U.K. National Amyloidosis Centre recently reported that patients with TAC can be accurately staged using two biomarkers: N-terminal pro-B-type natriuretic peptide (NT-proBNP) and estimated glomerular filtration rate (eGFR). In their series of 869 patients with TAC, median survival for those with stage I disease as defined by their protocol was 69 months, compared with 47 months for stage II disease and 24 months for those with stage III disease. This simple U.K. staging system was then validated in a separate French cohort of TAC patients (Eur Heart J. 2018 Aug 7;39[30]:2799-806).
The ATTR-ACT trial
Dr. Rapezzi reported on 441 patients with TAC who were randomized to oral tafamidis at either 20 mg or 80 mg per day or placebo and followed prospectively for 30 months in the 13-country, double-blind, phase 3 trial. At 30 months, all-cause mortality was 29.5% in patients who received tafamidis, compared with 42.9% in controls, for a 30% relative risk reduction. The rate of cardiovascular hospitalizations was 0.48 per year with tafamidis, compared with 0.70 per year with placebo, for a 38% relative risk reduction. The mortality benefit didn’t achieve significance until 15-18 months into the trial, as to be expected given tafamidis’ mechanism of action, which involves binding to transthyretin, gradually stabilizing it, and curbing amyloid fibril deposition.
Of note, the benefit was similar regardless of the dose used and whether patients had hereditary or wild type TAC.
Tafamidis proved safe and well tolerated, with a side-effect profile similar to placebo. While diarrhea and urinary tract infections have been an issue in tafamidis-treated patients with familial amyloid polyneuropathy, these adverse events were actually less common in TAC patients who received tafamidis than with placebo, according to Dr. Rapezzi.
A key point, the cardiologist emphasized, is that the benefits of active treatment were greatest in patients with earlier-stage disease. Therefore it’s vital that the diagnosis of TAC be made early, with prompt initiation of treatment to follow, in order to catch the disease at a more reversible stage. That could mean there will be a whole lot more bone scintigraphy being done in patients with unexplained nonischemic heart failure.
Dr. Rapezzi reported receiving research grants, speaker honoraria, and consulting fees from Pfizer, which sponsored the ATTR-ACT trial. Simultaneous with his presentation in Munich, the study results were published online at NEJM.org (doi: 10.1056/NEJMoa1805689). Dr. George reported no financial conflicts.
MUNICH – The big news in the field of heart failure at the annual congress of the European Society of Cardiology concerned an obscure form of the disease traditionally considered rare: transthyretin amyloid cardiomyopathy (TAC).
It turns out that TAC is far more common than previously recognized; it can now be diagnosed and staged noninvasively; and – most important of all – there is for the first time an effective disease-modifying treatment in the form of a novel oral drug called tafamidis, as demonstrated in the Transthyretin Amyloidosis Cardiomyopathy Clinical Trial (ATTR-ACT) presented at the meeting.
“This is the first phase 3 trial that can offer a chance for people with a terrible, severe disease. And within the last year, while the trial was being conducted, it became clear that this disease is much more underdiagnosed than rare,” said Claudio Rapezzi, MD, ATTR-ACT principal investigator and director of the school of cardiovascular diseases at the University of Bologna, Italy.
ATTR-ACT participants randomized to tafamidis showed significant reductions in all-cause mortality and cardiovascular hospitalizations, compared with placebo-treated controls at 30 months follow-up. They also experienced significantly lesser declines in both quality of life as reflected in Kansas City Cardiomyopathy Questionnaire scores and in physical function as captured in 6-minute walk distance.
Designated discussant Jacob George, MD, was over the moon regarding the results.
“This is a pioneering, game-changing trial that is likely to transform the way we diagnose and treat patients with cardiac amyloidosis,” said Dr. George of Kaplan Medical Center in Rehovot, Israel.
“We’re now in an era that, to my opinion, any patient with nonischemic unexplained heart failure should be screened for the presence of amyloidosis because, first, we now know how to prognosticate these patients, and second, we can offer them a real disease-modifying agent,” he added.
An underdiagnosed disease
Transthyretin amyloid cardiomyopathy occurs when transthyretin, a transport protein, becomes destabilized and misfolds, promoting deposition of amyloid fibrils in the myocardium. This results in progressive ventricular wall thickening and stiffness, manifest as restrictive cardiomyopathy and progressive heart failure. The cause of transthyretin destabilization can be either autosomal dominant inheritance of any of more than 100 pathogenic mutations in the transthyretin gene identified to date or a spontaneous wild type protein.
Think of TAC as a sort of dementia of the heart. As Dr. George noted, the cardiac disease bears “remarkable similarities” to Alzheimer’s disease, with both conditions entailing extracellular deposition of amyloid.
In the heritable form of TAC, patients typically present with heart failure symptoms at about age 50-55, while the wild type form becomes symptomatic much later at a mean age of about 75. Average survival from time of diagnosis is only about 3 years.
Recent studies from multiple centers have reported that the prevalence of TAC was 16% in patients undergoing transcatheter aortic valve replacement for severe aortic stenosis, 13% among patients with heart failure with preserved ejection fraction, and 5% in patients who had been presumed to have hypertrophic cardiomyopathy: So, not a rare condition.
“In our clinic, vast and surprising numbers of patients with unexplained nonischemic heart failure are scan positive [for TAC],” according to Dr. George.
Breakthroughs in diagnosis and staging
The echocardiographic red flag for TAC in a patient with heart failure symptoms is symmetric hypertrophy with a normal end-diastolic volume and thickened ventricles. The end-diastolic interventricular septal wall thickness is typically about 15 mm. The left ventricular ejection fraction is typically in the normal range, “but the clue is not the preservation of the ejection fraction, it’s the [normal] quality of the volume,” Dr. Rapezzi said.
A clinical clue suggestive of TAC upon physical examination, even in the absence of heart failure symptoms, is development of bilateral carpal tunnel syndrome in an older man. That’s because the same disease process that results in TAC can involve deposition of amyloid fibrils in peripheral nerves. Indeed, tafamidis is already approved in Europe and Japan under the trade name Vyndaqel as a treatment for familial amyloid polyneuropathy. For TAC, however, tafamidis remains investigational with fast-track status provided by both the Food and Drug Administration and the European Medicines Agency.
When TAC is suspected, it’s no longer necessary to subject patients to an onerous myocardial biopsy. Total body scintigraphy with bone tracers has been shown to be nearly as sensitive and specific as biopsy for the diagnosis.
Staging can now be done noninvasively as well. Investigators at the U.K. National Amyloidosis Centre recently reported that patients with TAC can be accurately staged using two biomarkers: N-terminal pro-B-type natriuretic peptide (NT-proBNP) and estimated glomerular filtration rate (eGFR). In their series of 869 patients with TAC, median survival for those with stage I disease as defined by their protocol was 69 months, compared with 47 months for stage II disease and 24 months for those with stage III disease. This simple U.K. staging system was then validated in a separate French cohort of TAC patients (Eur Heart J. 2018 Aug 7;39[30]:2799-806).
The ATTR-ACT trial
Dr. Rapezzi reported on 441 patients with TAC who were randomized to oral tafamidis at either 20 mg or 80 mg per day or placebo and followed prospectively for 30 months in the 13-country, double-blind, phase 3 trial. At 30 months, all-cause mortality was 29.5% in patients who received tafamidis, compared with 42.9% in controls, for a 30% relative risk reduction. The rate of cardiovascular hospitalizations was 0.48 per year with tafamidis, compared with 0.70 per year with placebo, for a 38% relative risk reduction. The mortality benefit didn’t achieve significance until 15-18 months into the trial, as to be expected given tafamidis’ mechanism of action, which involves binding to transthyretin, gradually stabilizing it, and curbing amyloid fibril deposition.
Of note, the benefit was similar regardless of the dose used and whether patients had hereditary or wild type TAC.
Tafamidis proved safe and well tolerated, with a side-effect profile similar to placebo. While diarrhea and urinary tract infections have been an issue in tafamidis-treated patients with familial amyloid polyneuropathy, these adverse events were actually less common in TAC patients who received tafamidis than with placebo, according to Dr. Rapezzi.
A key point, the cardiologist emphasized, is that the benefits of active treatment were greatest in patients with earlier-stage disease. Therefore it’s vital that the diagnosis of TAC be made early, with prompt initiation of treatment to follow, in order to catch the disease at a more reversible stage. That could mean there will be a whole lot more bone scintigraphy being done in patients with unexplained nonischemic heart failure.
Dr. Rapezzi reported receiving research grants, speaker honoraria, and consulting fees from Pfizer, which sponsored the ATTR-ACT trial. Simultaneous with his presentation in Munich, the study results were published online at NEJM.org (doi: 10.1056/NEJMoa1805689). Dr. George reported no financial conflicts.
MUNICH – The big news in the field of heart failure at the annual congress of the European Society of Cardiology concerned an obscure form of the disease traditionally considered rare: transthyretin amyloid cardiomyopathy (TAC).
It turns out that TAC is far more common than previously recognized; it can now be diagnosed and staged noninvasively; and – most important of all – there is for the first time an effective disease-modifying treatment in the form of a novel oral drug called tafamidis, as demonstrated in the Transthyretin Amyloidosis Cardiomyopathy Clinical Trial (ATTR-ACT) presented at the meeting.
“This is the first phase 3 trial that can offer a chance for people with a terrible, severe disease. And within the last year, while the trial was being conducted, it became clear that this disease is much more underdiagnosed than rare,” said Claudio Rapezzi, MD, ATTR-ACT principal investigator and director of the school of cardiovascular diseases at the University of Bologna, Italy.
ATTR-ACT participants randomized to tafamidis showed significant reductions in all-cause mortality and cardiovascular hospitalizations, compared with placebo-treated controls at 30 months follow-up. They also experienced significantly lesser declines in both quality of life as reflected in Kansas City Cardiomyopathy Questionnaire scores and in physical function as captured in 6-minute walk distance.
Designated discussant Jacob George, MD, was over the moon regarding the results.
“This is a pioneering, game-changing trial that is likely to transform the way we diagnose and treat patients with cardiac amyloidosis,” said Dr. George of Kaplan Medical Center in Rehovot, Israel.
“We’re now in an era that, to my opinion, any patient with nonischemic unexplained heart failure should be screened for the presence of amyloidosis because, first, we now know how to prognosticate these patients, and second, we can offer them a real disease-modifying agent,” he added.
An underdiagnosed disease
Transthyretin amyloid cardiomyopathy occurs when transthyretin, a transport protein, becomes destabilized and misfolds, promoting deposition of amyloid fibrils in the myocardium. This results in progressive ventricular wall thickening and stiffness, manifest as restrictive cardiomyopathy and progressive heart failure. The cause of transthyretin destabilization can be either autosomal dominant inheritance of any of more than 100 pathogenic mutations in the transthyretin gene identified to date or a spontaneous wild type protein.
Think of TAC as a sort of dementia of the heart. As Dr. George noted, the cardiac disease bears “remarkable similarities” to Alzheimer’s disease, with both conditions entailing extracellular deposition of amyloid.
In the heritable form of TAC, patients typically present with heart failure symptoms at about age 50-55, while the wild type form becomes symptomatic much later at a mean age of about 75. Average survival from time of diagnosis is only about 3 years.
Recent studies from multiple centers have reported that the prevalence of TAC was 16% in patients undergoing transcatheter aortic valve replacement for severe aortic stenosis, 13% among patients with heart failure with preserved ejection fraction, and 5% in patients who had been presumed to have hypertrophic cardiomyopathy: So, not a rare condition.
“In our clinic, vast and surprising numbers of patients with unexplained nonischemic heart failure are scan positive [for TAC],” according to Dr. George.
Breakthroughs in diagnosis and staging
The echocardiographic red flag for TAC in a patient with heart failure symptoms is symmetric hypertrophy with a normal end-diastolic volume and thickened ventricles. The end-diastolic interventricular septal wall thickness is typically about 15 mm. The left ventricular ejection fraction is typically in the normal range, “but the clue is not the preservation of the ejection fraction, it’s the [normal] quality of the volume,” Dr. Rapezzi said.
A clinical clue suggestive of TAC upon physical examination, even in the absence of heart failure symptoms, is development of bilateral carpal tunnel syndrome in an older man. That’s because the same disease process that results in TAC can involve deposition of amyloid fibrils in peripheral nerves. Indeed, tafamidis is already approved in Europe and Japan under the trade name Vyndaqel as a treatment for familial amyloid polyneuropathy. For TAC, however, tafamidis remains investigational with fast-track status provided by both the Food and Drug Administration and the European Medicines Agency.
When TAC is suspected, it’s no longer necessary to subject patients to an onerous myocardial biopsy. Total body scintigraphy with bone tracers has been shown to be nearly as sensitive and specific as biopsy for the diagnosis.
Staging can now be done noninvasively as well. Investigators at the U.K. National Amyloidosis Centre recently reported that patients with TAC can be accurately staged using two biomarkers: N-terminal pro-B-type natriuretic peptide (NT-proBNP) and estimated glomerular filtration rate (eGFR). In their series of 869 patients with TAC, median survival for those with stage I disease as defined by their protocol was 69 months, compared with 47 months for stage II disease and 24 months for those with stage III disease. This simple U.K. staging system was then validated in a separate French cohort of TAC patients (Eur Heart J. 2018 Aug 7;39[30]:2799-806).
The ATTR-ACT trial
Dr. Rapezzi reported on 441 patients with TAC who were randomized to oral tafamidis at either 20 mg or 80 mg per day or placebo and followed prospectively for 30 months in the 13-country, double-blind, phase 3 trial. At 30 months, all-cause mortality was 29.5% in patients who received tafamidis, compared with 42.9% in controls, for a 30% relative risk reduction. The rate of cardiovascular hospitalizations was 0.48 per year with tafamidis, compared with 0.70 per year with placebo, for a 38% relative risk reduction. The mortality benefit didn’t achieve significance until 15-18 months into the trial, as to be expected given tafamidis’ mechanism of action, which involves binding to transthyretin, gradually stabilizing it, and curbing amyloid fibril deposition.
Of note, the benefit was similar regardless of the dose used and whether patients had hereditary or wild type TAC.
Tafamidis proved safe and well tolerated, with a side-effect profile similar to placebo. While diarrhea and urinary tract infections have been an issue in tafamidis-treated patients with familial amyloid polyneuropathy, these adverse events were actually less common in TAC patients who received tafamidis than with placebo, according to Dr. Rapezzi.
A key point, the cardiologist emphasized, is that the benefits of active treatment were greatest in patients with earlier-stage disease. Therefore it’s vital that the diagnosis of TAC be made early, with prompt initiation of treatment to follow, in order to catch the disease at a more reversible stage. That could mean there will be a whole lot more bone scintigraphy being done in patients with unexplained nonischemic heart failure.
Dr. Rapezzi reported receiving research grants, speaker honoraria, and consulting fees from Pfizer, which sponsored the ATTR-ACT trial. Simultaneous with his presentation in Munich, the study results were published online at NEJM.org (doi: 10.1056/NEJMoa1805689). Dr. George reported no financial conflicts.
REPORTING FROM THE ESC CONGRESS 2018
Key clinical point: Tafamidis is the first-ever proven disease-modifying therapy for patients with a rapidly progressive form of cardiomyopathy.
Major finding: .
Study details: This 13-country, randomized, phase 3, double-blind trial included 441 patients with transthyretin amyloid cardiomyopathy.
Disclosures: The presenter reported receiving research grants, speaker honoraria, and consultant fees from Pfizer, which sponsored the ATTR-ACT trial.