Title: Strength of Study Evidence Examined by the FDA in Premarket Approval of Cardiovascular Devices
Topic: General Cardiology
Date Posted: 1/15/2010
Author(s): Dhruva SS, Bero LA, Redberg RF.
Citation: JAMA 2009;302:2679-2685.
Clinical Trial: No
Study Question: What is the type and strength of evidence on which premarket approval (PMA)—the most stringent Food and Drug Administration (FDA) review process is based?
Methods: This was a systematic review of 123 summaries of safety and effectiveness data for 78 PMAs for high-risk cardiovascular devices that received PMA between January 2000 and December 2007. Examination of the methodological characteristics considered essential to minimize confounding and bias, as well as the primary endpoints of the 123 studies supporting the PMAs, was performed.
Results: Thirty-three of 123 studies (27%) used to support recent FDA approval of cardiovascular devices were randomized and 17 of 123 (14%) were blinded. Fifty-one of 78 PMAs (65%) were based on a single study. One hundred eleven of 213 primary endpoints (52%) were compared with controls and 34 of 111 controls (31%) were retrospective. One hundred eighty-seven of 213 primary endpoints (88%) were surrogate measures and 122 of 157 (78%) had a discrepancy between the number of patients enrolled in the study and the number analyzed.
Conclusions: The authors concluded that PMA of cardiovascular devices by the FDA is often based on studies that lack adequate strength and may be prone to bias.
Perspective: This analysis suggests that the evidence presented for FDA-approved cardiovascular device PMAs came mostly from studies that were not blinded or randomized. The FDA approval process is an important determinant of health care spending, and spending on new devices increases when the FDA approves devices more quickly. Cost containment would likely occur if rigorous clinical effectiveness reviews were used for new drugs and technologies, and spending concentrated on devices shown to benefit patients definitively. This study further suggests that the FDA device approval process would benefit from rigorous research, using meaningful clinical outcomes and valid, active (not historical) controls in randomized, blinded studies (when possible) conducted in populations that reflect the US population. The emphasis of FDA in the future should be research that meets rigorous scientific standards for evidence of benefit and lack of harm to patients. Debabrata Mukherjee, M.D., F.A.C.C.
Title: Familial Dilated Cardiomyopathy Caused by an Alpha-Tropomyosin Mutation: The Distinctive Natural History of Sarcomeric Dilated Cardiomyopathy
Topic: Heart Failure/Transplant
Date Posted: 1/18/2010 5:00:00 PM
Author(s): Lakdawala NK, Dellefave L, Redwood CS, et al.
Citation: J Am Coll Cardiol 2009;55:320-329.
Clinical Trial: No
Study Question: Are there sarcomere gene mutations responsible for dilated cardiomyopathy (DCM)?
Methods: Direct sequencing of six sarcomere genes was performed on 334 probands with DCM. A novel D230N missense mutation in the gene encoding alpha-tropomyosin (TPM1) was identified. Functional assessment was performed by the use of an in vitro reconstituted sarcomere complex to evaluate ATPase regulation and Ca2+ affinity as correlates of contractility.
Results: TPM1 D230N segregated with DCM in two large unrelated families. This mutation altered a conserved residue and was absent in >1,000 control chromosomes. In vitro studies demonstrated major inhibitory effects on sarcomere function with reduced Ca2+ sensitivity, maximum activation, and Ca2+ affinity compared with wild-type TPM1. Clinical manifestations ranged from decompensated heart failure or sudden death in those presenting early in life to asymptomatic left ventricular dysfunction in those diagnosed during adulthood.
Conclusions: Genetic segregation in two unrelated families and functional analyses demonstrate a pathogenic role for TPM1 mutations in DCM. In vitro results demonstrate contrasting effects of DCM and HCM mutations inTPM1, suggesting that specific functional consequences shape cardiac remodeling. Along with previous reports, data support a distinctive, age-dependent phenotype with sarcomere-associated DCM where presentation early in life is associated with severe, sometimes lethal disease.
Perspective: About one third of subjects with DCM have evidence of familial inheritance, most of whom show autosomal dominant transmission. Mutations in many genes have been linked to DCM, many of which are thought to affect myocyte force generation or energy production. While mutations in alpha-tropomysin are known to cause HCM, their role in DCM has been less conclusive. By showing segregation of TPM1 in two unrelated families, along with an in vitro phenotype, the current study provides very strong evidence for a causal role of TPM function in DCM. Interestingly, three of five infants with TPM1 showed marked recovery of left ventricular function. Additional studies aimed at determining mechanisms responsible for phenotypic heterogeneity and recovery potential of mutation carriers may lead to novel DCM screening and treatment strategies. Daniel T. Eitzman, M.D., F.A.C.C.
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