Background
The purpose of this study was to evaluate the pulmonary and systemic hemodynamic effects of Definity in patients with normal as well as those with elevated pulmonary artery pressure at baseline. Secondary objectives of the study were to evaluate safety and determine whether any potential immunologic reactions develop after Definity administration.
Methods
Patients with normal and elevated pulmonary artery systolic pressure undergoing right-heart catheterization received Definity (10 μL/kg) as a slow bolus over 30 to 60 sec. Multiple sequential measurements of right atrial pressure, pulmonary artery systolic pressure, pulmonary artery diastolic pressure, mean pulmonary artery pressure, cardiac output, and pulmonary capillary wedge pressure were made before and after Definity administration. Vital signs, electrocardiograms, and blood samples were taken at multiple time points. Patients were followed for the development of adverse events.
Results
A total of 32 patients (16 with elevated pulmonary artery systolic pressure > 35 mm Hg) were enrolled. No significant changes in any pulmonary or systemic hemodynamic parameters, vital sign values, electrocardiographic data, or laboratory variables were found for data obtained before versus after receipt of Definity.
Conclusions
The administration of Definity at the approved dosage does not change pulmonary or systemic hemodynamics in control patients or those with mild to moderate pulmonary hypertension. No significant changes were noted in a wide array of clinical and laboratory safety assessments after patients were exposed to Definity.
On October 12, 2007, the US Food and Drug Administration (FDA) issued “black box” warnings for Definity (Lantheus Medical Imaging, North Billerica, MA) and Optison (GE Healthcare, Buckinghamshire, UK) and contraindicated the use of these ultrasound contrast agents (UCAs) in patients with known or suspected acute myocardial infarction or acute coronary syndromes, worsening or clinically unstable congestive heart failure, serious ventricular arrhythmias or QT prolongation, respiratory failure, severe emphysema, pulmonary emboli, or pulmonary hypertension. On May 12, 2008, the warning on the use of UCAs was modified by the FDA but continued to recommend monitoring of vital signs, electrocardiography, and cutaneous oxygen saturation during and for ≥30 min after the administration of UCAs in patients with pulmonary hypertension or unstable cardiopulmonary conditions.
The FDA also mandated that prospective safety studies be performed in patients with pulmonary hypertension. Preclinical studies in swine with an unshelled microbubble had shown that repeated injections could result in progressive increases in pulmonary artery pressure and pulmonary vascular resistance and decreased arterial oxygen saturation, cardiac output, and stroke volume. Even though currently available UCAs in the United States are shelled, and individual microbubbles retain a stable size in the circulation, a small percentage of the microbubble population is >10 μm in diameter and could potentially cause pulmonary capillary obstruction. The main purpose of the present study was therefore to evaluate the pulmonary and systemic hemodynamic effects of Definity in patients with normal as well as those with elevated pulmonary artery pressure at baseline.
Secondary objectives of the study were to determine safety. Because severe allergic reactions to UCAs are believed to be caused by complement activation-related pseudoallergy, blood samples were collected to evaluate whether any potential immunologic reactions develop after Definity administration.
Methods
This was a phase 4, open-label, nonrandomized study performed at eight centers in the United States. The study was approved by a human investigation committee or an institutional review board at each center. All patients gave written informed consent to participate in the study. The right-heart catheterization (RHC) was conducted according to each center’s institutional and standard of practice.
All patients were >18 years of age and were scheduled to undergo RHC with measurement of pulmonary and systemic hemodynamics for clinical reasons. Exclusion criteria included known hypersensitivity or contraindication to receiving UCAs, known right-to-left intracardiac shunts, status post heart transplantation, severe pulmonary hypertension (defined as baseline pulmonary artery systolic pressure [PASP] > 75 mm Hg), uncontrolled ventricular arrhythmias, second-degree or greater heart block, left bundle branch block, pregnancy, or lactation.
A medical history was obtained and a physical examination performed at baseline. Vital signs (heart rate, systolic and diastolic blood pressures, respiratory rate, and oxygen saturation) were collected at baseline before the initiation of RHC, at 3 and 1 min before the administration of Definity, and at 3, 8, 13, 18, 23, 28, 33, and 60 min after the administration of Definity. Body temperature was measured at baseline and 60 min after Definity administration. All patients received the approved dosage of Definity (10 μL/kg) as a slow bolus over 30 to 60 sec, followed by a 10-mL saline flush. At the same time points as the vital signs listed above, right atrial pressure, PASP, pulmonary artery diastolic pressure, and mean pulmonary artery pressure were measured. Cardiac output and pulmonary capillary wedge pressure were collected 3 min before and 3 and 33 min after Definity administration. Systemic and pulmonary vascular resistance were calculated from the acquired data using standard formulas. Twelve-lead electrocardiograms were obtained at baseline and 60 min after Definity administration.
Blood samples were collected at baseline, 3 min before, and 3 and 60 min after Definity administration for complete blood counts, electrolytes, renal and liver function, blood glucose, creatine kinase, troponin, and other laboratory determinations. Blood samples were also collected at baseline, 3 min before, and 3, 18, 33, and 60 min after Definity administration for testing immune studies, which included tryptase, complement C3a, complement C5a, and interleukin-6.
Patients were contacted by telephone to query for the development of adverse events (AEs) at 1 and 4 days after receipt of Definity.
Statistical Analysis
Data are presented as mean ± SD. Comparisons between continuous variables were performed with repeated-measures analysis of variance. Interstage differences were confirmed using paired Student’s t tests. The changes in all hemodynamic parameters from baseline to each time point after Definity administration were compared between patients in groups 1 and 2. Differences were considered significant at P < .05 (two sided).
Results
A total of 32 patients (15 men) were enrolled in the study between August and December 2009. This sample size was not based on power calculations but was mandated by the FDA. The median age was 56 years (range, 25–82 years). Patients were divided into those with normal PASP (≤35 mm Hg; group 1) and those with elevated PASP (>35 mm Hg; group 2) measured at baseline (1 min before the administration of Definity). The mean PASP of group 1 patients ( n = 16) was 30.4 ± 3.4 mm Hg, while that of group 2 patients ( n = 16) was 50.9 ± 10.3 mm Hg. No significant differences in the baseline demographics were present between patients in group 1 compared with those in group 2 ( Table 1 ).
| Parameter | Group 1 ( n = 16) | Group 2 ( n = 16) | P |
|---|---|---|---|
| Median age (y) | 58 | 55 | .96 |
| Men | 6 (38%) | 9 (56%) | .48 |
| Mean BMI (kg/m 2 ) | 33.5 | 28.9 | .07 |
| Prior MI | 2 (13%) | 5 (31%) | .39 |
| Prior revascularization | 2 (13%) | 6 (38%) | .22 |
| Cardiomyopathy | 7 (44%) | 7 (44%) | 1.0 |
| CHF | 10 (63%) | 13 (81%) | .43 |
| NYHA class I | 1 (6%) | 1 (6%) | |
| NYHA class II | 5 (31%) | 6 (38%) | |
| NYHA class III | 4 (25%) | 5 (31%) | |
| NYHA class IV | 0 (0%) | 1 (6%) | |
| Diabetes | 6 (38%) | 6 (38%) | 1.00 |
| Renal disease/failure | 3 (19%) | 4 (25%) | 1.00 |
| Hepatic disease/failure | 2 (13%) | 2 (13%) | 1.00 |
| Smoking | 6 (38%) | 6 (38%) | 1.00 |
| COPD | 1 (6%) | 1 (6%) | 1.0 |
| Prior Definity | 3 (19%) | 5 (31%) | .69 |
Summated PASP and pulmonary artery diastolic pressure data for groups 1 and 2 are shown in Figure 1 . PASPs for individual group 1 patients are shown in Figure 2 A and those for group 2 patients in Figure 2 B. Mean pulmonary artery pressures for both groups of patients are shown in Figure 3 . Figure 4 shows systolic blood pressure, diastolic blood pressure, and mean arterial pressure data ( Figure 4 A), pulmonary capillary wedge pressure and right atrial pressure data ( Figure 4 B), cardiac output and cardiac index data ( Figure 4 C), and systemic vascular resistance and pulmonary vascular resistance data ( Figure 4 D) for both groups. The relative changes in hemodynamic parameters at any time point versus baseline were compared for patients in both groups 1 and 2, and no significant differences were found for any parameter. Vital signs not included in the figures are heart rate, respiratory rate, temperature, and oxygen saturation. No significant changes in any of these variables were found between baseline and any time point measured thereafter (heart rate, P = .99; respiratory rate, P = .47; temperature, P = 1.00; and oxygen saturation, P = .99).
In terms of safety data, electrocardiographic data from both groups combined are shown in Table 2 . No significant changes in any conduction intervals were found before versus after the administration of Definity. No significant changes in laboratory data (electrolytes, calcium, magnesium, phosphorus, blood urea nitrogen, creatinine, transaminase, creatine kinase, creatine kinase MB fraction, total protein, albumin, total and direct bilirubin, lactate dehydrogenase, troponin I, total cholesterol, triglyceride, uric acid, or blood counts) occurred before compared with after the administration of Definity. Immunologic data from both groups combined are shown in Table 3 . Definity did not result in any clinically significant increase in tryptase, complement C3a, complement C5a, or interleukin-6. The concentration of complement C3a increased after initiation of the RHC but before the administration of Definity (time = −3 min). The concentration of complement C3a then progressively declined throughout all subsequent time points tested.
