Biomarker-Guided Therapies in Heart Failure: A Forum for Unified Strategies

Abstract

The complexity of standard medical treatment for heart failure is growing, and such therapy typically involves 5 or more different medications. Given these pressures, there is increasing interest in harnessing cardiovascular biomarkers for clinical application to more effectively guide diagnosis, risk stratification, and therapy. It may be possible to realize an era of personalized medicine for heart failure treatment in which therapy is optimized and costs are controlled. The direct mechanistic coupling of biologic processes and therapies achieved in cancer treatment remains elusive in heart failure. Recent clinical trials and metaanalyses of biomarkers in heart failure have produced conflicting evidence. In this article, which comprises a summary of discussions from the Global Cardiovascular Clinical Trialists Forum held in Paris, France, we offer a brief overview of the background and rationale for biomarker testing in heart failure, describe opportunities and challenges from a regulatory perspective, and summarize current positions from government agencies in the United States and European Union. (J Cardiac Fail 2013;19:592e599) Key Words: Pharmacogenetics, biologic markers, clinical trials, cardiovascular diseases.Personalized medicine is the practice of obtaining nonobvious information, such as biomarkers, from an individual patient for the purpose of guiding therapeutic decisions tailored to that patient's needs. In the field of oncology, biomarker testing is used to identify treatments for highly specific molecular targets to match effective therapies to specific populations, thereby improving tolerance to treatments with toxicity profiles that would be unacceptable in an unselected population. 1e3 The clinical utility of biomarkers in the arena of cardiology is less clear, due in part to the fact that usual practice groups together several pathways leading to heart failure (HF) as well as the corresponding selection of therapies.In addition, the heterogeneity of HF compared with a given type of cancer adds a complicating factor. Oncotype diagnostic assays use multimarker profiling to assess therapeutic options in oncology. Most of these profile somatic alterations (eg, estrogen receptor or HERG2 status in tumor cells) that are usually related to tumor cell mutations. In cardiology, however, genetic variants likely to influence therapeutic decisions are typically germline and as such only indirectly modify disease prognosis or response to therapy. Historical and biologic factors affecting the focus of research to date may also explain the relatively more thorough investigation of biomarkers in oncology. For instance, estrogen receptor status in breast cancer directly

Lessons Learned and Insights Gained in the Design, Analysis, and Outcomes of the COMPANION Trial

“…In other words, if COMPANION had been conducted in a generalized HFrEF population without the lengthened QRS inclusion criterion, it almost certainly would have produced negative results. Enrichment of clinical trial populations through the use of biomarkers thatidentify responsive subpopulations is something that is highly desirable but difficult to attain(44), and COMPANION and CARE-HF demonstrate that this approach can be successful.…”

Pharmacogenetics of heart failure

“…GWAS studies and other large population studies along with enhanced mechanisms to analyze genetic data are critical for the progression of pharmacogenomics. However, many challenges still remain in applying pharmacogenetics to the clinical practice in heart failure management, and the clinical utility of pharmacogenetic testing in cardiovascular patients still remains elusive (30). Physicians and cardiologists will need to understand, communicate, and manage this new genomic information to provide the patient with appropriate education and management recommendations.…”

The Future of Pharmacogenetics in the Treatment of Heart Failure

“…All six studies showed mortality benefit in the BNP-guided therapy group compared to controls and no studies reported increased incidence of adverse effects in this group (74). Therefore eventually it may be possible to use a combination of pharmacogenetics and biomarker levels to guide HF therapy, which could further optimise the therapeutic benefit (75). Investigation into the proteomics of HF may also reveal variation that can be used to guide HF therapy hand-in-hand with biomarkers and pharmacogenomics, which would facilitate bridging the gap of genotype and phenotype.…”