Protein biomarkers identify patients unlikely to benefit from primary prevention implantable cardioverter defibrillators: findings from the Prospective Observational Study of Implantable Cardioverter Defibrillators (PROSE-ICD)

Abstract

Background: Primary prevention implantable cardioverter defibrillators (ICDs) reduce all-cause mortality, but the benefits are heterogeneous. Current risk stratification based on left ventricular ejection fraction has limited discrimination power. We hypothesize that biomarkers for inflammation, neurohumoral activation, and cardiac injury can predict appropriate shocks and all-cause mortality in patients with primary prevention ICDs.

Methods and results: The Prospective Observational Study of Implantable Cardioverter Defibrillators (PROSe-ICD) enrolled 1189 patients with systolic heart failure who underwent ICD implantation for primary prevention of sudden cardiac death. The primary end point was an ICD shock for adjudicated ventricular tachyarrhythmia. The secondary end point was all-cause mortality. After a median follow-up of 4.0 years, 137 subjects experienced an appropriate ICD shock and 343 participants died (incidence rates of 3.2 and 5.8 per 100 person-years, respectively). In multivariable-adjusted models, higher interleukin-6 levels increased the risk of appropriate ICD shocks. In contrast, C-reactive protein, interleukin-6, tumor necrosis factor-α receptor II, pro-brain natriuretic peptide (pro-BNP), and cardiac troponin T showed significant linear trends for increased risk of all-cause mortality across quartiles. A score combining these 5 biomarkers identified patients who were much more likely to die than to receive an appropriate shock from the ICD.

Conclusions: An increase in serum biomarkers of inflammation, neurohumoral activation, and myocardial injury increased the risk for death but poorly predicted the likelihood of an ICD shock. These findings highlight the potential importance of serum-based biomarkers in identifying patients who are unlikely to benefit from primary prevention ICDs.

Clinical trial registration url: clinicaltrials.gov; Unique Identifier: NCT00733590.

Keywords: arrhythmias, cardiac; death, sudden, cardiac; defibrillators, implantable; inflammation; prevention & control.

Conflict of interest statement

Conflict of Interest Disclosures: Dr. A Cheng received honoraria from Boston Scientific, Medtronic and St. Jude Medical. Dr. D. Dalal’s contributions to the study pre-dated his current employment with Novartis. Dr. Z. Eldadah received an honorarium from St. Jude Medical. Dr. K. Ellenbogen received honoraria from Medtronic, Boston Scientific, Biotronik, served as a consultant for Medtronic, Boston Scientific, St. Jude Medical and received fellowship support from Medtronic and Boston Scientific. Dr. D. Spragg received honoraria from Biotronik and Medtronic. All other authors have no relevant disclosures to report.

© 2014 American Heart Association, Inc.

Figures

Figure 1

Multivariable adjusted hazard ratios (HR) for appropriate ICD shocks (left), all-cause mortality (center) and all-cause mortality censored at the first appropriate ICD shock (right) by quartiles of biomarkers of inflammation, neurohumoral activation and myocardial injury. Hazard ratios were adjusted for age, sex, race, study center, smoking status, body mass index, NYHA class, atrial fibrillation, diabetes, hypertension, chronic kidney disease, and CRT device.

Figure 2

Probability of survival free from appropriate ICD shocks (top) and all-cause mortality (bottom) as a function of a combined biomarker score. The combined score was created by adding the quartile rank for CRP, IL-6, TNF-αRII, pro-BNP, and cTnT. The median score was 12 (range 5 to 20). The proportion of participants with scores 5 to 9, 10 to 14, and 15 to 20 were 27.2, 38.1, and 27.2%, respectively.