The safety and efficacy of AdreView were evaluated in two open label, multicenter trials in patients with New York Heart Association (NYHA) class II or III heart failure and left ventricular ejection fraction ≤ 35%. The trials excluded subjects with an acute myocardial infarction within the prior thirty days, subjects with a functioning ventricular pacemaker as well as subjects who had received defibrillation to treat a previous arrhythmic event. Subjects underwent AdreView myocardial imaging (planar and SPECT) and continued standard clinical care; AdreView results were not used in a patient's clinical care. Mortality was assessed for up to two years after AdreView imaging and the results from the trials were analyzed using a pre-specified data integration plan.

AdreView images in each trial were reviewed by three independent readers who assessed the H/M ratio on 3 hour 50 minute post-injection planar scintigraphy. Readers were masked to clinical information and the majority read value was used in analyses. The prognostic performance of the H/M ratio in estimating mortality was analyzed using the pre-specified 1.6 ratio cut-point to distinguish patients with higher risk from those with lower risk; other cut-points were also analyzed.

Within the two trials, 964 patients were enrolled; 80% were men, 83% were categorized as NYHA class II and 17% as class III. The average age was 62 years (range 20 - 90 years of age). Most patients had ischemic heart disease (66%) and a history of smoking (74%). The patients were on a stable regimen of cardiovascular medications, including angiotensin converting enzyme (ACE) inhibitors and/or angiotensin receptor blockers (ARBs) (93%) and beta-blockers (92%). The range of AdreView H/M ratios in these subjects was 1.0-2.4 [mean 1.4 (± 0.2 standard deviation)].

Within the two trials, 94 age-matched control subjects without heart disease were enrolled, 64% were men, average age was 59 years (range 29 - 82 years of age). The range of AdreView H/M ratios in these subjects was 1.1-2.4 [mean 1.8 (± 0.2 standard deviation)].

One Year Results: By 12 months following enrollment, 50 (5%) patients had died, 61 (6%) had missing follow-up information and three patients had missing H/M ratios.

Two Year Results: By 23 months following enrollment (the requirement for designation of two-year follow-up), 96 (10%) patients had died, 201 (21%) patients had missing follow-up information and three patients had missing H/M ratio data.

Table 6 summarizes the mortality results by categories of H/M ratio.

H/M Ratio Prognostic Performance Characteristics:

Follow-up mortality results were used to estimate the baseline H/M ratio prognostic performance characteristics. In these estimates, various H/M ratio "cut points" were used to group patients into those with higher versus lower H/M values, such as < 1.6 versus ≥ 1.6. The group of patients who died was examined to determine the probability of these patients having had a lower baseline H/M ratio (sensitivity). The group of patients who survived was examined to determine the probability of these patients having had a higher baseline H/M ratio (specificity). Based upon these results, the prognostic usefulness of any given H/M ratio in a patient was estimated by the positive predictive value (PPV) and the negative predictive value (NPV). The PPV is the probability of death given a lower H/M ratio; the NPV is the probability of survival given a higher H/M ratio.

Table 7 summarizes the performance characteristics by various H/M ratio categories for one year, the time point with the most complete data. Results were similar for the two year follow-up time point analyses.

Cox Proportional Hazards Analyses:

The association of potential risk factors with mortality for up to two years was analyzed in Cox multivariate proportional hazard modeling that included such variables as demographics, hypertension, dyslipidemia, diabetes, cardiovascular medications, smoking, and NYHA classification. The initial model included all pre-specified variables except for H/M ratio and used backward selection of variables found to be significant risk factors of all-cause mortality (p < 0.05) for inclusion in the final model. The final model consisted of the significant variables from the initial model plus the H/M ratio. In addition to age, in the final model, the H/M ratio was found to be a significant risk factor for mortality (Hazard Ratio < 0.08, p < 0.001). Left ventricular ejection fraction and brain natriuretic peptide (BNP) were not included in these models, and AdreView SPECT defect scores were not tested in these models.