A total of 249 subjects were evaluated in clinical trials (208 received activated DEFINITY® and 41 placebo). In this group, 154 (61.8%) were male and 95 (38.2%) were female; 183 (73.5%) were White, 38 (15.3%) were Black, 21 (8.4%) were Hispanic, and 7 (2.8%) were classified as other racial or ethnic groups. The mean age was 53.9 years (range 18 to 87).
Activated DEFINITY® was evaluated in four controlled clinical trials: Two open-label baseline controlled, unpaired blinded image evaluation studies and two identical placebo-controlled, unpaired blinded image evaluation studies. Subjects were eligible for these studies if they had two or more (of six) nonevaluable segments in either the apical 2- or 4-chamber view in non-contrast fundamental echocardiography.
In the baseline controlled studies, a total of 126 (67 in study A and 59 in study B) subjects received a bolus dose of 10 μL/kg activated DEFINITY®. The outcome measures in these studies included the blinded assessment of ejection fraction (EF), endocardial border length (EBL) obtained by direct measurement, and qualitative assessment of wall motion.
In the two placebo-controlled studies a total of 123 subjects were randomized in 1:2 ratio to receive two I.V. bolus doses of either saline (placebo) or activated DEFINITY® 10 μL/kg (17 placebo vs. 33 activated DEFINITY® patients and 24 placebo vs. 49 activated DEFINITY® patients, respectively). The outcome measure for assessing the effectiveness of activated DEFINITY® was the blinded assessment of improvement in ventricular chamber enhancement (measured by videodensitometry at end-diastole and end-systole).
Endocardial Border Length: As shown in Table 2, compared to baseline, a single bolus dose of 10 μL/kg activated DEFINITY® increased the length of endocardial border that could be measured at both end-systole and end-diastole. The mean change in border length from baseline at end-diastole was statistically significant for all readers in the apical 4-chamber view and for 3 out of 4 readers for the apical 2-chamber view. The mean change in border length from baseline at end-systole was statistically significant for 3 out of 4 readers for the apical 4-chamber view and for 2 out 4 readers for the apical 2-chamber view.
Ventricular Chamber Enhancement: Left ventricular chamber enhancement after an activated DEFINITY® dose of 10 μL/kg was significantly increased from baseline compared to placebo in both views at the mid-ventricular and apical levels at end-diastole. Similar results were noted at end-systole, with the exception of the 4-chamber view.
Wall Motion: In a retrospective analysis, in a subset of subjects (n=12 to 47,
depending on reader) having at least 2 adjacent segments non-evaluable on
non-contrast imaging, activated DEFINITY® converted a baseline non-evaluable
image to an evaluable image in 58 to 91% of the patients, depending on the
reader. In the converted images, the accuracy of wall motion (i.e., normal
versus abnormal) improved in 42-71% of the patients, depending on the
reader, however, improvement in the specific diagnostic accuracy (e.g.,
hypokinetic, akinetic etc.) was not established. Also, in 13 to 37% of the
patients, depending on the reader, activated DEFINITY® was found to obscure
the wall motion rendering the image non-evaluable.
Ejection Fraction: In the 2 baseline controlled studies, ejection fraction results were evaluated in comparison to MRI. The results were evaluated by 3 blinded, independent radiologists. In these studies, although there was a statistically significant increase in ventricular chamber enhancement, activated DEFINITY® did not significantly improve the assessment of ejection fraction compared to the baseline images.
MEAN (SD) ENDOCARDIAL BORDER LENGTH (CM) BY BOTH APICAL 2- AND
4-CHAMBER VIEWS AT END-SYSTOLE AND END-DIASTOLE BY STUDY, EVALUABLE SUBJECTS
|Study/View||Endocardial Border Length - Blinded Read|
|Reader 1||Reader 2||Reader 1||Reader 2|
|Study A: (N = 67)|
|Study B: (N = 59)|
| Activated DEFINITY® Bolus Dose = 10 µL/kg
*Significant change from baseline (paired t-test, p<0.05)
In an open administration, crossover trial, 64 patients were randomized to receive both bolus (10 μL/kg) and infusion (1.3 mL activated DEFINITY® in 50 mL saline at the rate of 4 mL/min) dosing of activated DEFINITY®. Outcome measures for this study included clinically useful ventricular cavity enhancement and endocardial border length. Similar results were seen as described above.
Optimal activated DEFINITY® doses and device settings for harmonic imaging have not been established.