Ultrasound contrast agent safety has received recent attention based on reports of associated serious adverse events. The US Food and Drug Administration requested this postmarketing study of the effects of Optison on pulmonary hemodynamics. The aim of this study was to compare Optison and a placebo for effects on pulmonary artery systolic pressure (PASP) and pulmonary vascular resistance (PVR) during right-sided cardiac catheterization. This was a single-blind, crossover, placebo-controlled, multicenter study of Optison in subjects referred for clinically indicated cardiac catheterization. Based on screening echocardiographic PASP, subjects were assigned to 1 of 2 strata (1 = normal PASP [≤35 mm Hg] and 2 = elevated PASP [>35 mm Hg]), in which they were randomized to treatment arm A (intravenous 0.5 ml Optison and then intravenous 0.5 ml placebo [5% dextrose] 15 minutes later) or arm B (intravenous 0.5 ml placebo [5% dextrose] and then 0.5 ml Optison 15 minutes later). Baseline pulmonary hemodynamics were obtained within 60 minutes before the first injection and 2, 6, and 10 minutes after each injection. Thirty patients each received their assigned treatments. There were no clinically relevant increases from baseline in mean PASP or PVR (Wood units) in either stratum alone or the combined strata. There were no serious adverse events. In conclusion, there is no change in PASP or PVR after intravenous injection of Optison at a clinically relevant dose in patients with normal or elevated baseline PASP.
In October 2007, the US Food and Drug Administration (FDA) issued a “black box” warning for the commercially available ultrasound contrast agents (UCA) Optison (Perflutren Protein Type A Microspheres Injectable Suspension; GE Healthcare, Buckinghamshire, United Kingdom) and Definity (Perflutren Lipid Microsphere Injectable Suspension; Lantheus Medical Imaging, North Billerica, Massachusetts). This regulatory action followed spontaneous reports of several deaths and multiple serious adverse events occurring after UCA administration. To better define the true benefit:risk profile for UCAs, the FDA in 2008 requested that GE Healthcare and Lantheus Medical Imaging each perform 3 clinical studies consisting of (1) a retrospective observational study using a large administrative database to determine mortality risk in critically ill patients undergoing echocardiography with or without a UCA, (2) an approximate 1,000-patient prospective registry to estimate the risk of serious adverse events in routine clinical practice, and (3) a prospective invasive pulmonary hemodynamic study to determine the effect of UCAs on pulmonary artery systolic pressure (PASP) and pulmonary vascular resistance (PVR). Preliminary results of these 6 studies were presented at a joint meeting of the FDA’s Cardiovascular and Renal Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee on May 2, 2011, and final results for 3 of these 6 studies have now been published. We hereby report results for the invasive pulmonary hemodynamic study in patients receiving Optison.
Methods
This was a single-blind, crossover, placebo-controlled, multicenter study of Optison and 5% dextrose (control) in patients referred for clinically indicated right-sided cardiac catheterization. The primary objective was to compare Optison and control for their effects on PASP and PVR in patients with normal or elevated baseline PASP. The protocol was approved by each of the local institutional review boards, and written informed consent was obtained before subject participation.
Subjects were prospectively stratified based on a screening Doppler-derived PASP obtained by transthoracic echocardiography within 30 days before the study. Patients were stratified to either stratum 1 (normal PASP [≤35 mm Hg]) or 2 (elevated PASP [>35 mm Hg]). Within each stratum, subjects were randomly assigned to 1 of 2 treatment arms. In arm A, subjects were assigned to receive a single intravenous injection of 0.5 ml Optison, followed by a single intravenous injection of 0.5 ml 5% dextrose (control), with 15 minutes between injections. In arm B, subjects were assigned to receive a single intravenous injection of 0.5 ml 5% dextrose, followed by a single intravenous injection of 0.5 ml Optison, with 15 minutes between injections. A total of 30 subjects (15 subjects per treatment arm) were anticipated. The study size was requested by the FDA and was not based on sample size calculations.
Subjects were eligible if they were aged ≥18 years, referred for clinically indicated right-sided cardiac catheterization, had normal sinus rhythm before the study without a history of arrhythmia believed likely to interfere with pulmonary hemodynamic assessment, and could provide written informed consent. A negative result of a pregnancy test was required before study participation in women of childbearing potential. Subjects were excluded for lactation, previously diagnosed intracardiac shunt, or hypersensitivity to Optison, perflutren, blood, blood products, or albumin. Patients scheduled for emergency coronary intervention were ineligible to participate, as were patients with current or recent (past 30 days) participation in a separate clinical trial.
All subjects underwent baseline determinations of vital signs, oxygen saturation, 12-lead electrocardiogram, laboratory parameters, and pulmonary hemodynamics within 1 hour before the first control or Optison injection. Pulmonary hemodynamic measurements (right atrial pressure, PASP, pulmonary diastolic pressure, pulmonary capillary wedge pressure, and thermodilution cardiac output) were repeated 2, 6, and 10 minutes after each injection. PVR was calculated as mean pulmonary artery pressure − pulmonary capillary wedge pressure/cardiac output. Limited echocardiography was performed immediately after injection of control or Optison to confirm left ventricular opacification. All subjects were monitored continuously for safety during the procedure and for approximately 2 hours after the final injection. A follow-up phone call on day 2 (approximately 24 hours after hospital discharge) was placed to assess for adverse events. The pulmonary hemodynamic tracings were interpreted at a blinded independent core laboratory (ICON Medical Imaging, Warrington, Pennsylvania). ICON Medical Imaging core laboratory personnel and the independent cardiologist over reader (CMG) were blinded to treatment (Optison or control).
A repeated-measures mixed model analysis of covariance was performed on change from baseline PASP and PVR at each time point. Analysis of covariance included fixed effects for treatment arm, treatment order, treatment (Optison or control), stratum (normal or elevated screening PASP), time, treatment-by-stratum, treatment-by-time, stratum-by-time, and treatment-by-stratum-by-time, a random effect for subject nested within treatment arm–by-stratum, and baseline measurement as a covariate. Based on the analysis of covariance, least-square means of change from baseline PASP and PVR were calculated for each time point for each treatment in each stratum. The difference between Optison and control and its 95% confidence interval was calculated for each stratum at each time point, as was the difference between Optison and control and its 95% confidence interval for each time point across strata.
Results
In total, 33 subjects were enrolled; of whom, 30 (91%) completed both injections 1 and 2. All had a medical history consistent with cardiac disease. Three were withdrawn before receiving any study drug because of poor quality waveform tracings, screen failure, and inability to establish a baseline PASP. Of the 30 subjects who completed the study, 11 were included in the normal PASP stratum and 19 were included in the elevated PASP stratum. Individual patient characteristics and pulmonary hemodynamic results are listed in Table 1 . The normal PASP stratum included more men and older patients than the elevated PASP stratum (73% men in the normal PASP stratum vs 32% men in the elevated PASP stratum; mean age of 64 years in the normal PASP stratum vs 52 years in the elevated PASP stratum); race, ethnicity, height, weight, and body mass index were similar between the 2 strata.
| Patient | Stratum | Age (yrs) | Gender | Baseline PASP (mm Hg) | Two-Minute PASP (mm Hg) | Six-Minute PASP (mm Hg) | Ten-Minute PASP (mm Hg) | Baseline PVR (Wood Units) | Two-Minute PVR (Wood Units) | Six-Minute PVR (Wood Units) | Ten-Minute PVR (Wood Units) |
|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | Normal PASP | 49 | M | 48 | 52 | 54 | 55 | 1.3 | 1.2 | 1.8 | 1.8 |
| 2 | Normal PASP | 53 | M | 52 | 47 | 48 | 43 | 1.2 | 0.4 | 1.9 | 1.5 |
| 3 | Normal PASP | 54 | M | 32 | 34 | 34 | 32 | 0.7 | 1.1 | 0.5 | 1.2 |
| 4 | Normal PASP | 58 | M | 26 | 28 | 31 | 27 | 1.1 | 1.3 | 1.8 | 0.6 |
| 5 | Normal PASP | 67 | W | 28 | 32 | 31 | 26 | 2.5 | 3.7 | 3.8 | 2 |
| 6 | Normal PASP | 67 | M | 34 | 43 | 33 | 31 | 1.9 | 3 | 1.2 | 2.1 |
| 7 | Normal PASP | 68 | M | 22 | 22 | 19 | 20 | 1 | 0.5 | 0.6 | 1 |
| 8 | Normal PASP | 69 | M | 29 | 35 | 40 | 38 | 1.6 | 1.5 | 1 | 1 |
| 9 | Normal PASP | 69 | M | 32 | 36 | 31 | 30 | 2.4 | 3.6 | 1.2 | 2.6 |
| 10 | Normal PASP | 77 | W | 30 ∗ | 21 | 21 | N/A | 1.9 ∗ | 1.4 | 1.7 | N/A |
| 11 | Normal PASP | 78 | W | 25 | 22 | 23 | 26 | 1.9 | 1.5 | 1.4 | 1.6 |
| 12 | Elevated PASP | 19 | W | 94 ∗ | 97 | 94 | 92 | 7.4 ∗ | N/A | 7 | 6.7 |
| 13 | Elevated PASP | 26 | W | 62 | 60 | 54 | 55 | 6.2 | 1.8 | 2 | 1.9 |
| 14 | Elevated PASP | 31 | M | 72 | 60 | N/A | 61 | 4.8 | 3.4 | N/A | 2.8 |
| 15 | Elevated PASP | 31 | W | 102 | 103 | 96 | 94 | 8.1 | 15.5 | 10.1 | 10.8 |
| 16 | Elevated PASP | 32 | W | 84 | 79 | 79 | 77 | 6.1 | 4.7 | 0.9 † | 0.1 † |
| 17 | Elevated PASP | 38 | W | 69 ∗ | 62 | 68 | 66 | 4.8 ∗ | 4.3 | 3.7 | 3.9 |
| 18 | Elevated PASP | 50 | M | 42 | 45 | 36 | 35 | 2.2 | N/A | 2 | N/A |
| 19 | Elevated PASP | 51 | W | 76 | 77 | 75 | 79 | 9.6 | 9.8 | 7.3 | 8.8 |
| 20 | Elevated PASP | 51 | M | 47 ∗ | 45 | 45 | 46 | 3.5 ∗ | 2.4 | N/A | N/A |
| 21 | Elevated PASP | 53 | W | 102 ∗ | 104 | 104 | 103 | 8.6 ∗ | 10.1 | 9.6 | 11.9 |
| 22 | Elevated PASP | 53 | W | 70 ∗ | 74 | 71 | 70 | 6.2 ∗ | 7.1 | 6.4 | 6.2 |
| 23 | Elevated PASP | 60 | W | 123 | 125 | 124 | 119 | 9 | 6 | N/A | 9.4 |
| 24 | Elevated PASP | 62 | W | 48 | 52 | 50 | 51 | 2.1 | 3.6 | 3.2 | 3.1 |
| 25 | Elevated PASP | 66 | W | 45 | 46 | 45 | 49 | 2.2 | 1.7 | 1.8 | 2.2 |
| 26 | Elevated PASP | 68 | W | 50 ∗ | 51 | 49 | 48 | 2.5 ∗ | 3.2 | 3.2 | 2.8 |
| 27 | Elevated PASP | 71 | M | 34 | 37 | 36 | 36 | 0.7 | 0.9 | 1.1 | 0.9 |
| 28 | Elevated PASP | 72 | M | 102 ∗ | 103 | 103 | 102 | 7.8 ∗ | 7 | 8 | 8 |
| 29 | Elevated PASP | 77 | W | 34 | 33 | 35 | 33 | 2.3 | 2.4 | 2.3 | 2.1 |
| 30 | Elevated PASP | 78 | M | 41 | 40 | 42 | 40 | 0.7 | 0.6 | 0.6 | 0.8 |
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