Clinical Trials1
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.
| Table 1 MEAN (SD) ENDOCARDIAL BORDER LENGTH (CM) BY BOTH APICAL 2- AND 4-CHAMBER VIEWS AT END-SYSTOLE AND END-DIASTOLE BY STUDY, EVALUABLE SUBJECTS |
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| Study/View | Endocardial Border Length - Blinded Read | |||
| Mean (SD) at End-Diastole |
Mean (SD) at End-Systole |
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| Reader 1 | Reader 2 | Reader 1 | Reader 2 | |
| Study A: (N = 67) | ||||
| Apical 2-chamber | ||||
| Baseline | 8.0(3.4) | 4.7(2.8) | 7.1(3.3) | 4.3(2.6) |
| Post-DEFINITY® | 12.8(5.2)* | 5.8(2.6)* | 10.6(5.0)* | 4.4(2.3) |
| Apical 4-chamber | ||||
| Baseline | 8.1(3.3) | 4.5(2.6) | 7.6(3.2) | 4.5(2.7) |
| Post-DEFINITY® | 13.5(5.2)* | 6.8(3.3)* | 11.5(4.4)* | 5.3(3.1) |
| Study B: (N = 59) | ||||
| Apical 2-chamber | ||||
| Baseline | 4.3(2.6) | 7.8(5.3) | 4.1(2.4) | 6.5(5.1) |
| Post-DEFINITY® | 5.7(4.7)* | 8.2(6.5) | 5.5(4.4)* | 6.9(6.3) |
| Apical 4-chamber | ||||
| Baseline | 4.0(2.7) | 9.2(5.9) | 3.8(2.6) | 7.3(5.6) |
| Post-DEFINITY® | 7.1(5.5)* | 11.5(7.5)* | 5.9(5.3)* | 8.7(6.3)* |
| Activated DEFINITY® Bolus Dose = 10 µL/kg *Significant change from baseline (paired t-test, p<0.05) |
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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.
INDICATIONS
Activated DEFINITY® (Perflutren Lipid Microsphere) Injectable Suspension is indicated for use in patients with suboptimal echocardiograms to opacify the left ventricular chamber and to improve the delineation of the left ventricular endocardial border.
The safety and efficacy of DEFINITY® with exercise stress or pharmacologic stress testing have not been established.
CONTRAINDICATIONS
Do not administer DEFINITY® to patients with known or suspected right-to-left, bi-directional or transient right-to-left cardiac shunts, by intra-arterial injection, or to patients with known hypersensitivity to perflutren.
IMPORTANT SAFETY INFORMATION
WARNING: Serious Cardiopulmonary Reactions Serious cardiopulmonary reactions, including fatalities, have occurred during or following perflutren-containing microsphere administration.
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In post marketing use, rare but serious cardiopulmonary or anaphylactoid reactions have been reported during or shortly following perflutren-containing microsphere administration (see ADVERSE REACTIONS). The risk for these reactions may be increased among patients with pulmonary hypertension or unstable cardiopulmonary conditions. It is not always possible to reliably establish a causal relationship to drug exposure due to the presence of underlying cardiopulmonary disease.
Please See Full Prescribing Information and Letter to Healthcare Providers.
