ADMIRE-HF Published: How Imaging Sympathetic Nerve Function Can Assess Risk in CHF

February 25, 2010

February 25, 2010 (Irvine, California) — More details about the role of imaging the sympathetic innervation of the heart as a prognostic tool in heart-failure patients in ADMIRE-HF have now been reported [1].

The ADMIRE-HF study, first presented at last year's American College of Cardiology (ACC) meeting, showed that nuclear imaging of sympathetic nerve function in the heart can identify which heart-failure patients are more likely to have a worse prognosis. The study has now been published online February 24, 2010 in the Journal of the American College of Cardiology.

Senior author of the paper, Dr Jagat Narula (University of California, Irvine School of Medicine), told heartwire that the paper contains new and expanded analyses compared with the 2009 ACC presentation. "There are more details concerning the independent prognostic information provided by 123I-mIBG myocardial scintigraphy and suggestions about which heart-failure patients might benefit from undergoing the procedure," he commented.

Narula noted that 123I-mIBG scintigraphy is used in the US for oncology, but the agent is not yet approved for imaging in cardiology. 123I-mIBG is approved for cardiac imaging in Europe and Japan, and the procedure is performed selectively in those locations, but it is not as widely used as myocardial perfusion imaging. He expects that use could well increase after the publication of these results. The scintigraphy test has been developed by GE Healthcare as AdreView, and a supplementary new drug application was submitted to the US FDA in May 2009.

Narula says the current data suggest that myocardial scintigraphy could be helpful in evaluation of heart-failure patients where there is uncertainty about event risk and the need for additional therapy, whether medical or device. "Identification of either high or low risk based on the scan could provide guidance for the clinician with regards to how best to proceed," he told heartwire . And although the trial did not specifically address the issue of helping to guide which patients should receive an implantable cardioverter defibrillator (ICD) or cardiac resynchronization therapy (CRT), he added, "The results indicated which patients had the highest risk for arrhythmic events and heart-failure progression, information that could be useful in decision-making for ICD and CRT use."

How It Works

In the paper, the authors explain that increased myocardial sympathetic activity is a prominent feature of heart failure and is characterized by increased neuronal release of norepinephrine (NE) and decreased neuronal NE reuptake. The decrease in the NE-reuptake mechanism can be assessed by radionuclide imaging with the iodine-123–labeled NE analog 123I-mIBG. Uptake of 123I-mIBG into myocardial sympathetic nerve endings is mediated by the NE transporter; reduced myocardial 123ImIBG uptake has been demonstrated to be an independent predictor of adverse long-term outcome, and improvement in 123I-mIBG uptake is observed in response to effective heart-failure therapy. However, most of these studies have been conducted at single centers involving relatively small numbers of patients and have not been performed under rigorous clinical-trial conditions. The ADMIRE-HF program was therefore conducted to provide definitive data on this imaging technique.

In the study, 961 subjects with NYHA functional class 2-3 heart failure and left ventricular ejection fraction (LVEF) <35% underwent 123I-mIBG myocardial imaging and myocardial perfusion imaging and were then followed for up to two years. For the 123I-mIBG myocardial imaging, quantification of cardiac uptake of the tracer was expressed as the ratio of counts between the heart and the upper mediastinum--the H/M ratio. A cutoff value of 1.6 was used, with values higher than this denoting high uptake and values below this denoting low uptake.

Results showed that 237 patients (25%) experienced a cardiac event (time to first occurrence of NYHA functional class progression, potentially life-threatening arrhythmic event, or cardiac death) at some time during the follow-up period. Two-year event rate was 15% for H/M >1.60 and 37% for H/M <1.60, giving a hazard ratio for H/M >1.60 of 0.40. All the individual components of the primary end point were also significantly reduced in the group with H/M >1.60.

ADMIRE-HF: Hazard Ratio for H/M >1.60 on Cardiac Events

Outcome Hazard ratio p
CHF progression/life-threatening arrhythmia/cardiac death 0.40 < 0.001
CHF progression 0.49 0.002
Life-threatening arrhythmia 0.37 0.020
Cardiac death 0.14 0.006
H/M ratio: heart/mediastinum ratio

The hazard ratio for continuous H/M was 0.22. Narula explained to heartwire that this means that for a one-unit increase in H/M, the risk of an event decreases by 78%. For example, if a patient with H/M=1.20 has a two-year probability of an outcome event of 50%, then a patient with H/M=2.20 has a two-year event probability of 11% (50% x 0.22).

The researchers also performed an analysis looking at which variables independently contribute to prediction of event occurrence. They found that four variables were statistically significant: H/M, LVEF, B-type natriuretic peptide (BNP), and NYHA class. "This indicates that regardless of the values for the other three variables, patient prognosis is worse as the value of the fourth variable becomes more abnormal. In other words, a patient with an H/M=1.10 has a higher probability of having an outcome event than a patient with H/M=1.60, regardless of the values of LVEF, BNP, and NYHA," Narula told heartwire .

Asked how the scintigraphy test would fit in with other markers of heart failure, Narula said he sees the test as complementary to LVEF and BNP for assessing risk in heart-failure patients. "As shown in the paper, patients with either a high BNP or a low LVEF have a relatively low risk of adverse outcomes if the H/M is 1.60 or higher. Conversely, subjects are at the highest risk of adverse outcomes if BNP, LVEF, and H/M are all abnormal."

The authors give many examples of how the test could add value to other markers. One example given is the 74 patients who were less than 50 years old and had BNP less than 100 ng/L. Of these, 47 had H/M <1.60, of whom 13 developed cardiac events, including one sudden death. Of these 47 patients, 27 did not have ICDs, including the subject who died suddenly. "Knowledge of the higher risk associated with abnormal cardiac innervation might have facilitated consideration of more aggressive treatment (such as earlier use of resynchronization therapy) in these subjects," they suggest.

This study was supported entirely by GE Healthcare. The lead author, Dr Arnold Jacobson, is an employee of GE Healthcare and owns shares in the company. Some of the other authors are consultants for and receive research grants from GE Healthcare, among other companies.