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.