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Pulmonary Hemodynamic Effects of Dipyridamole Infusion in Patients with Normal and Elevated Pulmonary Artery Systolic Pressure Receiving PB127
Pulmonary Hemodynamic Effects of Dipyridamole Infusion in Patients with Normal and Elevated Pulmonary Artery Systolic Pressure Receiving PB127 Michael L. Main, MD, FACC, Alexander Ehlgen, MD, PhD, Tina R. Coggins, RDCS, Becky A. Morris, RDCS, Pam Lanza, RN, Thomas M. Tremblay, RN, Nelson B. Schiller, MD, FACC, and Jonathan H. Goldman, MD, FACC, Kansas City, Missouri; and San Francisco and San Carlos, California
Background: Intravenous administration of microspheres used as ultrasound contrast agents may potentially alter pulmonary hemodynamics. PB127 (POINT Biomedical Corp., San Carlos, CA) is an investigational ultrasound perfusion-imaging agent used in conjunction with dipyridamole to diagnose coronary artery disease. The effects of PB127 alone or in combination with dipyridamole on pulmonary hemodynamics have not been described. Methods: We studied 20 patients, including 10 with elevated screening pulmonary artery systolic pressure (>35 mm Hg). Doppler-derived pulmonary hemodynamics were determined before and after continuous infusion of PB127 (0.175 mg/kg diluted in 5% dextrose) or 5% dextrose. Patients then received
Myocardial perfusion echocardiography has emerged as a useful means of evaluating myocardial perfusion including detection of coronary artery disease in association with pharmacologic stress.1 PB127 is a novel ultrasound contrast agent consisting of nitrogen polymer/protein microspheres (mean diameter ⫽ 3.2 m) intended for use in dipyridamole perfusion echocardiography. Although no significant safety issues have been reported with human use of PB127 in more than 1300 patients, preclinical studies using another transpulmonary contrast agent revealed occlusion of the pulmonary microvasculature, pulmonary hypertension, and cardiovascular collapse after repetitive dosing.2 More recently, a second ultrasound contrast agent was From the Mid America Heart Institute, Kansas City, Missouri, University of California–San Francisco Medical Center (N.B.S.), and POINT Biomedical Corporation, San Carlos, California (A.E., T.M.T., J.H.G.). Reprint requests: Michael L. Main, MD, FACC, Cardiovascular Consultants, 4330 Wornall Rd, Suite 2000, Kansas City, MO 64111 (E-mail: [email protected]). 0894-7317/$32.00 Copyright 2006 by the American Society of Echocardiography. doi:10.1016/j.echo.2006.03.006
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dipyridamole (0.56 mg/kg) and hemodynamics were again assessed. Results: During PB127/dextrose infusion, there were no significant changes in pulmonary hemodynamics compared with baseline. After dipyridamole, there were small increases in pulmonary artery systolic pressure and in pulmonary flow and a reduction in pulmonary vascular resistance. These changes occurred in patients with normal and elevated pulmonary artery systolic pressure. Conclusion: PB127 infusion does not alter pulmonary hemodynamics. Mild alterations of pulmonary hemodynamics occur after dipyridamole administration. (J Am Soc Echocardiogr 2006;19:1038-1044.)
restricted to noncardiac imaging in Europe because of safety concerns.3 In addition, commercially available echocardiographic contrast agent package inserts recommend caution with use in patients with chronic pulmonary vascular disorders,4 severe emphysema, pulmonary vasculitis, or pulmonary emboli.5 The purpose of this study was to evaluate the pulmonary hemodynamic effects of PB127 infusion both alone and in association with dipyridamole using previously validated Doppler-derived measures of pulmonary artery systolic pressure (PASP), flow, and vascular resistance. In addition, patients were closely monitored for clinical signs of acute pulmonary hypertension.
METHODS Studied Population In all, 20 patients (12 women, mean age 69 years) with clinically suggested coronary artery disease were enrolled in this study between December 2003 and May 2004. Our institutional review board approved the study, and all patients gave written informed consent before participa-
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Main et al 1039
Table 1 Treatment groups and number of patients per stratum Stratum
Screening PASP
1
Normala
2
Arm
PB127/ control
No. of patients
Cohort
A
PB127
5
1A
B
Control
5
1B
A
PB127
5
2A
B
Control
5
2B
Elevatedb
PASP, Pulmonary artery systolic pressure. aPASP ⱕ 35 mm Hg. bPASP ⬎ 35 mm Hg
tion. All patients were appropriate candidates for dipyridamole stress, had no evidence of intracardiac shunting during screening noncontrast echocardiography, and had technically adequate echocardiographic windows from the parasternal, apical, and subcostal views. Exclusion criteria included pregnancy or lactation; allergy to blood products; heart block; systolic blood pressure greater than 200 mm Hg or less than 90 mm Hg; pulmonary hypertension with PASP greater than 100 mm Hg; prosthetic pulmonic valve; recent myocardial infarction, percutaneous coronary intervention or bypass operation within 7 days before the study; heart transplant; significant valvular disease; decompensated heart failure or unstable angina pectoris; atrial fibrillation or other significant atrial or complex ventricular arrythmias; chronic obstructive pulmonary disease or bronchospastic airway disease; and ingestion of caffeine or methylxanthine derivates within 24 hours before the study. All patients continued their prescribed medications, but no patient received nitrates in any form within 24 hours of the study. Medical history was obtained for all patients and complete physical examination was conducted within 4 hours before the study and on the day after the echocardiographic examination. Based on a screening echocardiographic evaluation of the PASP, patients were divided into stratum 1 (screening PASP ⱕ 35 mm Hg) or stratum 2 (screening PASP ⬎ 35 mm Hg). Within each stratum, patients were randomized to one of two treatment arms. Patients in arm A received a single 30-minute intravenous (IV) infusion of PB127 diluted in 5% dextrose, and patients in arm B received a single 30-minute IV control 5% dextrose infusion (Table 1).
Figure 1 PB127/control infusion was started at minute 0 and stopped at minute ⫹30. Dipyridamole infusion (DIPY) was started at minute ⫹15 and stopped at minute ⫹19. Echocardiographic evaluations and vital signs were assessed every 3 minutes starting at minute ⫺9 and ending at minute ⫹30. Echocardiographic images were obtained 3 times at each time point to average assessed measurements. Dipyridamole Administration All patients received a weight-adjusted dose of dipyridamole (0.56 mg/kg for patients weighing ⱕ 89.5 kg, and a maximum dose of 50 mg for patients weighing ⬎ 89.5 kg). Dipyridamole was administered IV over 4 minutes to induce hyperemia beginning 15 minutes after the start of the PB127/control infusion. Aminophylline was used to reverse the dipyridamole effects at study conclusion. Echocardiographic Study All ultrasound images were obtained using SONOS5500 ultrasound equipment (Philips Medical Systems, Andover, Mass) and B.2 software. The examination consisted of standard B-mode harmonic and Doppler imaging including pulsed wave and continuous wave Doppler assessments. Digital echocardiographic data were recorded on magneto-optical disk and analyzed offline using software (ProSolv Cardiovascular, Problem Solving Concepts, Indianapolis, Ind). An experienced echocardiographer, who was blinded to the patient’s treatment group or any other patient-related information, analyzed the images and performed measurements. Ultrasound images and Doppler data were obtained at specific time points relative to PB127/control infusion and dipyridamole administration as shown in Figure 1. Images were obtained 3 times in the same sequential order at each time point. An average of each assessed measurement was made. All ultrasound images were obtained with the patient in the left lateral supine position except for the subcostal view for right atrial pressure (RAP) assessment, which was done in the supine position.
Contrast and Control Infusion
Hemodynamic Assessments
In the PB127 group (arm A), the lyophilized PB127 was reconstituted with 2 mL of sterile water for injection before use. A weight-adjusted dose of 0.175 mg/kg PB127 was diluted into 150 mL of 5% dextrose. The solution was administered as a continuous single IV infusion at a flow rate of 150 mL/h for approximately 30 minutes using an inline flow regulator by peripheral IV catheter. In the control group (arm B), patients received only 5% dextrose. The control solution was administered as a continuous IV infusion at the same rate and duration as PB127 using the same type of flow regulator and IV set.
Pulmonary hemodynamic assessments included PASP, pulmonary flow (assessed as pulmonic valve velocity-time integral [VTI]), and pulmonary vascular resistance (PVR). PASP was determined with the modified Bernoulli equation using tricuspid valve regurgitation velocity (TRV) and RAP6: PASP ⫽ 4 ⫻ (TRV)2 ⫹ RAPbaseline [mm Hg] RAP at baseline was obtained by interrogation of the inferior vena cava response to respiration using the subcostal view.7
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Figure 2 Echocardiographic and Doppler evaluations from patient with normal pulmonary artery systolic pressure (PASP), pulmonary artery diastolic pressure (PADP), and pulmonary vascular resistance (PVR). Inferior vena cava collapsed with respiration (A) and right atrial pressure (RAP) is estimated at 5 mm Hg. Peak tricuspid regurgitation velocity (TRV) is 2.3 m/s (B). PASP is 4 ⫻ (TRV)2 ⫹ RAP ⫽ 4 ⫻ (2.3)2 ⫹ 5 ⫽ 26.2 mm Hg. Peak pulmonic regurgitation velocity (PRV) is 0.9 m/s (C). PADP is 4 ⫻ (PRV)2 ⫹ RAP ⫽ 4 ⫻ (0.9)2 ⫹ 5 ⫽ 8.2 mm Hg. Pulmonic valve velocity time integral (PVVTI) is 12.3 cm (D). Ratio of TRV/PVVTI ⫽ 2.3/12.3 ⫽ 0.2. PVR is 10 ⫻ TRV/PVVTI ⫽ 10 ⫻ 0.2 ⫽ 2.0 Wood U.
Pulmonary artery diastolic pressure (PADP) was also assessed to confirm the validity of significant changes in the PASP. PADP was determined with the modified Bernoulli equation using the pulmonary regurgitation velocity and RAP8:
surrogates for transpulmonary pressure gradient and transpulmonary flow, respectively. This method has previously been validated against invasive parameters. The equation estimates the PVR in Wood units:
PADP ⫽ 4 ⫻ (pulmonary regurgitation velocity)2 ⫹ RAPbaseline [mm Hg]
PVR ⫽ 10 ⫻ TRV ⁄ PVVTI [Wood units]
Pulmonary regurgitation velocity is the end-diastolic velocity (at the time of the R wave) of the pulmonic valve regurgitant jet in the parasternal short-axis view using continuous wave Doppler. The Doppler echocardiographic assessment of PVR was performed using the method described by Abbas et al,9 which uses TRV and pulmonic valve VTI (PVVTI) as
PVVTI was measured in the parasternal short-axis view, where a pulsed wave Doppler sample volume was placed in the right ventricular outflow tract (OT) just proximal to the pulmonic valve. The left ventricular OT VTI was measured in the apical 5-chamber view by pulsed wave Doppler. The left ventricular OT VTI was used to assess changes in systemic blood flow. Figure 2 shows an example of the echocardiographic and Dopp-
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Table 2 Effects of PB127/control and dipyridamole infusion on pulmonary hemodynamics PB127 infusion (cohorts 1A and 2A), N ⴝ 10 PASP, mm Hg
Baseline Prestress† Poststress‡ Change from baseline – prestress† Maximum change from baseline – poststress‡
33.7 34.4 37.8 ⫹0.7 ⫹4.1*
⫾ ⫾ ⫾ ⫾ ⫾
7.0 5.2 5.0 2.5 3.4
PVVTI, cm
17.2 17.0 20.0 ⫺0.1 ⫹2.8*
⫾ ⫾ ⫾ ⫾ ⫾
2.9 3.3 3.5 2.4 1.9
PVR, WU
1.6 1.6 1.4 ⫹0.1 ⫺0.2*
⫾ ⫾ ⫾ ⫾ ⫾
0.2 0.3 0.3 0.3 0.2
Control infusion (cohorts 1B and 2B), N ⴝ 10 PASP, mm Hg
35.1 34.9 39.4 ⫺0.3 ⫹4.3*
⫾ ⫾ ⫾ ⫾ ⫾
8.2 7.6 7.6 2.2 5.0
PVVTI, cm
16.9 17.6 19.9 ⫹0.6 ⫹2.9*
⫾ ⫾ ⫾ ⫾ ⫾
2.7 2.6 2.5 1.1 1.9
PVR, WU
1.6 1.6 1.5 ⫺0.1 ⫺0.2*
⫾ ⫾ ⫾ ⫾ ⫾
0.3 0.2 0.2 0.1 0.2
PASP, Pulmonary artery systolic pressure; PVR, pulmonary vascular resistance; PVVTI, pulmonic valve velocity time integral; WU, Wood units. *P ⬍ .05 compared with baseline; †prestress, minute ⫹15 (during PB127/control infusion, before dipyridamole infusion); ‡poststress, at maximum change from baseline (during PB127/control and diypridamole infusion).
ler evaluations from a patient with normal PASP, PADP, and PVR. Vital sign assessments included heart rate, blood pressure, and oxygen saturation. These parameters were obtained every 3 minutes starting at minute ⫺9 and 1 hour postinfusion and the following day. Adverse Events Adverse events were collected from the start of the PB127/control infusion through approximately 24 hours after the infusion. All adverse events were considered ongoing until completely resolved or, in the case of an intercurrent illness, returned to baseline status recorded before investigational product administration. Statistical Analysis Data are presented as mean ⫾ SD. Changes from baseline in PASP, PVR, and PVVTI were analyzed using paired t tests within each treatment arm (PB127 and control), and 2-sample t tests were used to test for differences between the two treatment arms within strata. A P value less than .05 was considered significant.
RESULTS All 20 patients were included in the analysis of hemodynamic parameters. The results for pulmonary hemodynamics comparing the PB127 treatment arm and the control treatment arm at baseline, prestress (minute ⫹15), poststress (at maximum change from baseline), change from baseline to prestress, and maximum change from baseline to poststress are presented in Table 2. In the PB127 arm, there were no statistically significant increases from baseline in PASP at any prestress time points. Small but statistically significant mean increases from baseline in PASP and PVVTI were observed after the start of dipyridamole infusion. Small but statistically significant mean decreases from baseline were observed in PVR values after the start of dipyridamole.
In the control arm, there was also no significant change from baseline in PASP at any prestress time point. Small but significant mean increases in PASP and PVVTI and small but significant decreases in mean PVR were observed after the start of dipyridamole administration. Mean PVR values showed a return toward baseline 15 minutes after dipyridamole administration. No patients in either treatment arm had an increase from baseline in PASP of more than 10 mm Hg or PVR of more than 30% before dipyridamole administration. Increases from baseline in the left ventricular OT VTI occurred in both the PB127 and control arms with dipyridamole stress, consistent with increases in PVVTI. No clear effect on PADP was evident with dipyridamole stress. In the PB127 arm, comparison of cohort 1A (normal PASP) and cohort 2A (elevated PASP) revealed similar patterns with insignificant changes in mean PASP, mean PVVTI, and mean PVR from baseline to prestress (Table 3). From baseline to maximum change poststress, small increases in mean PASP and mean PVVTI, and a slight decrease in PVR, were found in both cohorts. In the control arm, comparison of cohort 1B (normal PASP) and cohort 2B (elevated PASP) showed the same patterns with insignificant changes in mean PASP, mean PVVTI, and mean PVR from baseline to prestress (Table 3). From baseline to maximum change poststress, small increases in mean PASP and mean PVVTI, and a slight decrease in PVR, were noted in both cohorts. The mean changes from baseline in heart rate, systolic and diastolic blood pressure, and oxygen saturation did not indicate any clinically meaningful trends related to PB127 (Table 4). In both treatment arms, small mean increases from baseline in heart rate were observed after administration of dipyridamole. Small mean changes in blood pressure were noted from baseline to prestress
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Table 3 Effects of PB127/control and dipyridamole infusion on pulmonary hemodynamics in patients with normal and elevated screening pulmonary artery systolic pressure Normal screening PASP (<35 mm Hg) PB127 cohort 1A
Baseline Prestress* Poststress†
PASP, mm Hg
PVVTI, cm
PVR, WU
Control cohort 1B
PASP, mm Hg
PVVTI, cm
PVR, WU
28.5 ⫾ 5.8 30.3 ⫾ 3.8 34.2 ⫾ 4.9
15.6 ⫾ 2.7 15.0 ⫾ 2.8 18.5 ⫾ 3.8
1.6 ⫾ 0.3 1.7 ⫾ 0.4 1.5 ⫾ 0.4
Baseline Prestress* Poststress†
28.4 ⫾ 4.0 28.9 ⫾ 4.0 33.7 ⫾ 2.2
16.3 ⫾ 1.8 16.4 ⫾ 1.4 19.9 ⫾ 4.0
1.5 ⫾ 0.3 1.5 ⫾ 0.2 1.4 ⫾ 0.2
Elevated screening PASP (>35 mm Hg) PB127 cohort 2A
Baseline Prestress* Poststress†
PASP, mm Hg
PVVTI, cm
PVR, WU
Control cohort 2B
PASP, mm Hg
PVVTI, cm
PVR, WU
38.9 ⫾ 2.9 38.5 ⫾ 2.1 41.4 ⫾ 0.9
18.7 ⫾ 2.3 19.0 ⫾ 2.6 21.7 ⫾ 2.2
1.6 ⫾ 0.2 1.5 ⫾ 0.2 1.4 ⫾ 0.1
Baseline Prestress* Poststress†
41.9 ⫾ 4.6 40.8 ⫾ 5.2 46.0 ⫾ 2.7
17.6 ⫾ 3.5 18.7 ⫾ 3.2 20.5 ⫾ 3.5
1.8 ⫾ 0.3 1.6 ⫾ 0.2 1.6 ⫾ 0.2
PASP, Pulmonary artery systolic pressure; PVR, pulmonary vascular resistance; PVVTI, pulmonic valve velocity time integral; WU, Wood units. *Prestress, minute ⫹15 (during PB127/control infusion, before dipyridamole infusion); †poststress, at maximum change from baseline (during PB127/control and diypridamole infusion).
Table 4 Effects of PB127/control and dipyridamole infusion on systemic hemodynamics PB127 infusion (cohorts 1A and 2A), N ⴝ 10
HR, beats/min
Baseline
58.6 ⫾ 6.8
Prestress*
60.0 ⫾ 8.2
Poststress†
72.9 ⫾ 9.3
Change from baseline – prestress*
⫹1.4 ⫾ 3.6
Maximum change from baseline – poststress†
⫹14.3 ⫾ 8.0
SBP/DBP, mm Hg
123.8 56.5 132.6 59.8 128.5 62.9 ⫹8.8 ⫹3.3 ⫹4.7 ⫹6.4
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
36.2/ 11.0 34.8/ 9.7 29.3/ 9.2 15.6/ 5.1 18.6/ 10.8
Control infusion (cohorts 1B and 2B), N ⴝ 10
O2 Sat, %
HR, beats/min
95.0 ⫾ 2.6
62.5 ⫾ 5.9
95.8 ⫾ 2.5
64.5 ⫾ 6.0
97.4 ⫾ 1.7
78.3 ⫾ 13.0
⫹0.8 ⫾ 1.5
⫹2.0 ⫾ 2.7
⫹2.4 ⫾ 1.9
⫹15.8 ⫾ 10.2
SBP/DBP, mm Hg
131.3 65.0 135.6 60.9 128.3 58.1 ⫹4.3 ⫺4.1 ⫺3.0 ⫺6.9
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
22.2/ 15.0 23.2/ 10.3 21.3/ 11.5 8.7/ 8.7 8.1/ 10.7
O2 Sat, %
96.3 ⫾ 2.9 95.8 ⫾ 3.4 97.1 ⫾ 2.1 ⫺0.5 ⫾ 1.4 ⫹0.8 ⫾ 1.5
DBP, Diastolic blood pressure; HR, heart rate; O2 Sat, oxygen saturation; SBP, systolic blood pressure. *Prestress, minute ⫹15 (during PB127/control infusion, before dipyridamole infusion); †poststress, at maximum change from baseline (during PB127/control and diypridamole infusion).
and from baseline to poststress in both the PB127 and the control group. Oxygen saturation values did not change significantly during rest or stress time points for any patient. In all, 11 patients (55%) reported at least one adverse event including 4 patients in the PB127 arm and 7 patients in the control arm. A total of 14 adverse events were reported. No patient experienced a serious adverse event or had an adverse event that resulted in discontinuation of PB127. All were mild in severity. The most frequently reported adverse event was headache, which was reported by 8 patients (40%). The other reported adverse events were sensation of pressure in ear, nausea, stomach discomfort, injection site pain, pain in jaw, headache, and flushing. All of the symptoms were attributed to dipyridamole or unrelated to both dipyridamole and PB127.
DISCUSSION Myocardial contrast echocardiography is a useful means of evaluating myocardial perfusion, including detection of coronary artery disease in association with pharmacologic stress.1 Recently, however, safety concerns have emerged concerning both investigational and commercially available transpulmonary contrast agents, especially with regard to alterations of pulmonary hemodynamics.2,3 In the current study, continuous infusion of PB127 diluted in 5% dextrose did not significantly alter mean PASP, PVR, or PVVTI, and no patient had an increase from baseline in PASP of greater than 10 mm Hg or in PVR of greater than 30% before dipyridamole administration. Similarly, there was no evidence of an effect of PB127 on heart rate or blood pressure. The data
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suggest that PB127 at clinical doses has no significant systemic or pulmonary hemodynamic effects. These findings distinctly differ from a canine study using an early formulation of EchoGen, a liquid-in-liquid emulsion in water containing dodecafluoropentane, which converts to a dispersion of microspheres at body temperature after IV injection.2 The mean EchoGen microsphere diameter is 2 to 5 m.10 The study showed that frequent highdose administrations of a 2% dodecafluoropentane emulsion (0.5 mL/kg) resulted in an increase in pulmonary artery pressure and PVR, and decreased oxygen saturation, cardiac output, and stroke volume. Postmortem examination revealed gross accumulation of dodecafluoropentane in the lungs of the dogs. Subsequent changes in the EchoGen formulation allowed the use of much lower doses for human studies. A clinical study in 254 patients using EchoGen administered at a dose of 0.05 mL/kg revealed no significant changes in hemodynamic parameters.11 It is unclear whether the lack of hemodynamic effect in the clinical study compared with the animal study was a result of modification of the agent or the change in dose. Based at least in part on these data, commercially available contrast agent product inserts warn against administration in patients with chronic pulmonary vascular disorders.4,5 A related animal study of PB127 at several times the human dose did not show any histopathologic effects in the pulmonary vasculature (data on file at POINT Biomedical). The current study also showed that dipyridamole in doses of 0.56 mg/kg was associated with small mean changes from baseline in systolic and diastolic blood pressure, and small mean increases in heart rate and systemic flow. These hemodynamic changes were seen in both the PB127 and control arms, and in patients with normal and elevated screening PASP. Pulmonary flow parameters showed statistically significant increases in PASP and PVVTI, and a decrease in PVR. Dipyridamole injection at these doses is known to alter systemic and pulmonary hemodynamics by increasing cardiac output, cardiac stroke volume, and heart rate,12 and even very low doses of dipyridamole (0.07 mg/kg/min for 4 minutes) significantly reduce PVR in patients with chronic heart failure.13 Finally, the current study demonstrated a peak vasodilatory effect of dipyridamole 4 to 8 minutes after injection, consistent with previous studies.14 The overall safety profile of PB127 shown in this study did not reveal any clinically significant untoward effects of PB127 in patients with and without pulmonary hypertension. No patient showed dyspnea, tachycardia, chest pain, hypoxia, or any clinically relevant hemodynamic instability indicating acute pulmonary hypertension or acute obstruction of the pulmonary microvasculature. The adverse event profile of the PB127 arm was similar to that of
Main et al 1043
the control population. The reported minor adverse events are consistent with the adverse events reported in dipyridamole safety studies in large patient populations.15-17 These findings are consistent with the excellent safety profile of PB127 in other small published phase I and II studies.1,18 The lack of any pulmonary hemodynamic effect may relate to the small size of the PB127 diameter, the biocompatible outer shell, and the gaseous core filled with inert nitrogen. Limitations The number of studied patients was relatively small. In addition, we did not include patients with severe pulmonary hypertension (PASP ⬎ 100 mm Hg) and these safety data may not apply to that patient population. Conclusions In this study, PB127 infusion did not significantly alter PASP, PVR, or pulmonary flow. As expected, dipyridamole infusion showed a vasodilator effect with an increase in pulmonary flow and pulmonary pressure and a decrease in vascular resistance.
REFERENCES 1. Wei K, Crouse L, Weiss J, Villanueva F, Schiller NB, Naqvi TZ, et al. Comparison of usefulness of dipyridamole stress myocardial contrast echocardiography to technetium-99m sestamibi single-photon emission computed tomography for detection of coronary artery disease (PB127 multicenter phase 2 trial results). Am J Cardiol 2003;91:1293-8. 2. Grayburn PA, Erickson JM, Escobar J, Womack L, Velasco CE. Peripheral intravenous myocardial contrast echocardiography using a 2% dodecafluoropentane emulsion: identification of myocardial risk area and infarct size in the canine model of ischemia. J Am Coll Cardiol 1995;26:1340-7. 3. The European Agency for the Evaluation of Medicinal Products. Public statement on Sonovue (sulphur hexafluoride). New contraindication in patients with heart disease. Restriction of use to non-cardiac imaging, May 2004. London, UK. 4. Definity [package insert], 2003, Bristol-Myers Squibb Medical Imaging, Inc., N. Billerica, MA, USA. 5. Optison [package insert], 2003, Amersham Health Inc., Princeton, NJ, USA. 6. Yock PG, Popp RL. Noninvasive estimate of right ventricular systolic pressure by Doppler ultrasound in patients with tricuspid regurgitation. Circulation 1984;70:657-62. 7. Kircher BJ, Himelman RB, Schiller NB. Noninvasive estimation of right atrial pressure from the inspiratory collapse of the inferior vena cava. Am J Cardiol 1990;66:493-6. 8. Lee RT, Lord CP, Plappert T, Sutton MJ. Prospective Doppler echocardiographic evaluation of pulmonary artery diastolic pressure in the medical intensive care unit. Am J Cardiol 1989;64:1366-70. 9. Abbas AE, Fortuin FD, Schiller NB, Appleton CP, Moreno CA, Lester SJ. A simple method for noninvasive estimation of pulmonary vascular resistance. J Am Coll Cardiol 2003;41: 1021-7.
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10. Correas JM, Quay SD. EchoGen emulsion: a new ultrasound contrast agent based on phase shift colloids. Clin Radiol 1996;51:11-4. 11. Grayburn PA, Weiss JL, Hack TC, Klodas E, Raichlen JS, Vannan MA, et al. Phase III multicenter trial comparing the efficacy of 2% dodecafluoropentane emulsion (EchoGen) and sonicated 5% human albumin (Albunex) as ultrasound contrast agents. J Am Coll Cardiol 1998;32:230-6. 12. Marchant E, Pichard A, Rodriguez JA, Casanegra P. Acute effects of systemic versus intracoronary dipyridamole on coronary circulation. Am J Cardiol 1986;57:1401-4. 13. Cortigiani L, Baroni M, Picano E, Palmieri C, Boni A, Ravani M, et al. Acute hemodyanmic effects of endogenous adenosine in patients with chronic heart failure. Am Heart J 1998;136:37-42. 14. Picano E, Sicari R, Varga A. Dipyridamole stress echocardiography. Cardiol Clin 1999;17:481-99.
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15. Ranhosky A, Kempthorne-Rawson J, and the Intravenous Dipyridamole Thallium Imaging Study Group. The safety of intravenous dipyridamole thallium myocardial perfusion imaging. Circulation 1990;81:1205-9. 16. Lette J, Tatum JL, Fraser S, Miller DD, Waters DD, Heller G, et al. Safety of dipyridamole testing in 73806 patients: the multicenter dipyridamole safety study. J Nucl Cardiol 1995;2:3-17. 17. Picano E, Marini C, Pirelli S, Maffei S, Bolognese L, Chiriatti G, et al. Safety of intravenous high-dose dipyridamole echocardiography: the echo-Persantine international cooperative study group. Am J Cardiol 1992;70:252-8. 18. Raisinghani A, Wei KS, Crouse L, Villanueva F, Feigenbaum H, Schiller NB, et al. Myocardial contrast echocardiography (MCE) with triggered ultrasound does not cause premature ventricular complexes: evidence from PB127 MCE studies. J Am Soc Echocardiogr 2003;16:1037-42.
Background: Intravenous administration of microspheres used as ultrasound contrast agents may potentially alter pulmonary hemodynamics. PB127 (POINT Biomedical Corp., San Carlos, CA) is an investigational ultrasound perfusion-imaging agent used in conjunction with dipyridamole to diagnose coronary artery disease. The effects of PB127 alone or in combination with dipyridamole on pulmonary hemodynamics have not been described. Methods: We studied 20 patients, including 10 with elevated screening pulmonary artery systolic pressure (>35 mm Hg). Doppler-derived pulmonary hemodynamics were determined before and after continuous infusion of PB127 (0.175 mg/kg diluted in 5% dextrose) or 5% dextrose. Patients then received
Myocardial perfusion echocardiography has emerged as a useful means of evaluating myocardial perfusion including detection of coronary artery disease in association with pharmacologic stress.1 PB127 is a novel ultrasound contrast agent consisting of nitrogen polymer/protein microspheres (mean diameter ⫽ 3.2 m) intended for use in dipyridamole perfusion echocardiography. Although no significant safety issues have been reported with human use of PB127 in more than 1300 patients, preclinical studies using another transpulmonary contrast agent revealed occlusion of the pulmonary microvasculature, pulmonary hypertension, and cardiovascular collapse after repetitive dosing.2 More recently, a second ultrasound contrast agent was From the Mid America Heart Institute, Kansas City, Missouri, University of California–San Francisco Medical Center (N.B.S.), and POINT Biomedical Corporation, San Carlos, California (A.E., T.M.T., J.H.G.). Reprint requests: Michael L. Main, MD, FACC, Cardiovascular Consultants, 4330 Wornall Rd, Suite 2000, Kansas City, MO 64111 (E-mail: [email protected]). 0894-7317/$32.00 Copyright 2006 by the American Society of Echocardiography. doi:10.1016/j.echo.2006.03.006
1038
dipyridamole (0.56 mg/kg) and hemodynamics were again assessed. Results: During PB127/dextrose infusion, there were no significant changes in pulmonary hemodynamics compared with baseline. After dipyridamole, there were small increases in pulmonary artery systolic pressure and in pulmonary flow and a reduction in pulmonary vascular resistance. These changes occurred in patients with normal and elevated pulmonary artery systolic pressure. Conclusion: PB127 infusion does not alter pulmonary hemodynamics. Mild alterations of pulmonary hemodynamics occur after dipyridamole administration. (J Am Soc Echocardiogr 2006;19:1038-1044.)
restricted to noncardiac imaging in Europe because of safety concerns.3 In addition, commercially available echocardiographic contrast agent package inserts recommend caution with use in patients with chronic pulmonary vascular disorders,4 severe emphysema, pulmonary vasculitis, or pulmonary emboli.5 The purpose of this study was to evaluate the pulmonary hemodynamic effects of PB127 infusion both alone and in association with dipyridamole using previously validated Doppler-derived measures of pulmonary artery systolic pressure (PASP), flow, and vascular resistance. In addition, patients were closely monitored for clinical signs of acute pulmonary hypertension.
METHODS Studied Population In all, 20 patients (12 women, mean age 69 years) with clinically suggested coronary artery disease were enrolled in this study between December 2003 and May 2004. Our institutional review board approved the study, and all patients gave written informed consent before participa-
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Main et al 1039
Table 1 Treatment groups and number of patients per stratum Stratum
Screening PASP
1
Normala
2
Arm
PB127/ control
No. of patients
Cohort
A
PB127
5
1A
B
Control
5
1B
A
PB127
5
2A
B
Control
5
2B
Elevatedb
PASP, Pulmonary artery systolic pressure. aPASP ⱕ 35 mm Hg. bPASP ⬎ 35 mm Hg
tion. All patients were appropriate candidates for dipyridamole stress, had no evidence of intracardiac shunting during screening noncontrast echocardiography, and had technically adequate echocardiographic windows from the parasternal, apical, and subcostal views. Exclusion criteria included pregnancy or lactation; allergy to blood products; heart block; systolic blood pressure greater than 200 mm Hg or less than 90 mm Hg; pulmonary hypertension with PASP greater than 100 mm Hg; prosthetic pulmonic valve; recent myocardial infarction, percutaneous coronary intervention or bypass operation within 7 days before the study; heart transplant; significant valvular disease; decompensated heart failure or unstable angina pectoris; atrial fibrillation or other significant atrial or complex ventricular arrythmias; chronic obstructive pulmonary disease or bronchospastic airway disease; and ingestion of caffeine or methylxanthine derivates within 24 hours before the study. All patients continued their prescribed medications, but no patient received nitrates in any form within 24 hours of the study. Medical history was obtained for all patients and complete physical examination was conducted within 4 hours before the study and on the day after the echocardiographic examination. Based on a screening echocardiographic evaluation of the PASP, patients were divided into stratum 1 (screening PASP ⱕ 35 mm Hg) or stratum 2 (screening PASP ⬎ 35 mm Hg). Within each stratum, patients were randomized to one of two treatment arms. Patients in arm A received a single 30-minute intravenous (IV) infusion of PB127 diluted in 5% dextrose, and patients in arm B received a single 30-minute IV control 5% dextrose infusion (Table 1).
Figure 1 PB127/control infusion was started at minute 0 and stopped at minute ⫹30. Dipyridamole infusion (DIPY) was started at minute ⫹15 and stopped at minute ⫹19. Echocardiographic evaluations and vital signs were assessed every 3 minutes starting at minute ⫺9 and ending at minute ⫹30. Echocardiographic images were obtained 3 times at each time point to average assessed measurements. Dipyridamole Administration All patients received a weight-adjusted dose of dipyridamole (0.56 mg/kg for patients weighing ⱕ 89.5 kg, and a maximum dose of 50 mg for patients weighing ⬎ 89.5 kg). Dipyridamole was administered IV over 4 minutes to induce hyperemia beginning 15 minutes after the start of the PB127/control infusion. Aminophylline was used to reverse the dipyridamole effects at study conclusion. Echocardiographic Study All ultrasound images were obtained using SONOS5500 ultrasound equipment (Philips Medical Systems, Andover, Mass) and B.2 software. The examination consisted of standard B-mode harmonic and Doppler imaging including pulsed wave and continuous wave Doppler assessments. Digital echocardiographic data were recorded on magneto-optical disk and analyzed offline using software (ProSolv Cardiovascular, Problem Solving Concepts, Indianapolis, Ind). An experienced echocardiographer, who was blinded to the patient’s treatment group or any other patient-related information, analyzed the images and performed measurements. Ultrasound images and Doppler data were obtained at specific time points relative to PB127/control infusion and dipyridamole administration as shown in Figure 1. Images were obtained 3 times in the same sequential order at each time point. An average of each assessed measurement was made. All ultrasound images were obtained with the patient in the left lateral supine position except for the subcostal view for right atrial pressure (RAP) assessment, which was done in the supine position.
Contrast and Control Infusion
Hemodynamic Assessments
In the PB127 group (arm A), the lyophilized PB127 was reconstituted with 2 mL of sterile water for injection before use. A weight-adjusted dose of 0.175 mg/kg PB127 was diluted into 150 mL of 5% dextrose. The solution was administered as a continuous single IV infusion at a flow rate of 150 mL/h for approximately 30 minutes using an inline flow regulator by peripheral IV catheter. In the control group (arm B), patients received only 5% dextrose. The control solution was administered as a continuous IV infusion at the same rate and duration as PB127 using the same type of flow regulator and IV set.
Pulmonary hemodynamic assessments included PASP, pulmonary flow (assessed as pulmonic valve velocity-time integral [VTI]), and pulmonary vascular resistance (PVR). PASP was determined with the modified Bernoulli equation using tricuspid valve regurgitation velocity (TRV) and RAP6: PASP ⫽ 4 ⫻ (TRV)2 ⫹ RAPbaseline [mm Hg] RAP at baseline was obtained by interrogation of the inferior vena cava response to respiration using the subcostal view.7
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Figure 2 Echocardiographic and Doppler evaluations from patient with normal pulmonary artery systolic pressure (PASP), pulmonary artery diastolic pressure (PADP), and pulmonary vascular resistance (PVR). Inferior vena cava collapsed with respiration (A) and right atrial pressure (RAP) is estimated at 5 mm Hg. Peak tricuspid regurgitation velocity (TRV) is 2.3 m/s (B). PASP is 4 ⫻ (TRV)2 ⫹ RAP ⫽ 4 ⫻ (2.3)2 ⫹ 5 ⫽ 26.2 mm Hg. Peak pulmonic regurgitation velocity (PRV) is 0.9 m/s (C). PADP is 4 ⫻ (PRV)2 ⫹ RAP ⫽ 4 ⫻ (0.9)2 ⫹ 5 ⫽ 8.2 mm Hg. Pulmonic valve velocity time integral (PVVTI) is 12.3 cm (D). Ratio of TRV/PVVTI ⫽ 2.3/12.3 ⫽ 0.2. PVR is 10 ⫻ TRV/PVVTI ⫽ 10 ⫻ 0.2 ⫽ 2.0 Wood U.
Pulmonary artery diastolic pressure (PADP) was also assessed to confirm the validity of significant changes in the PASP. PADP was determined with the modified Bernoulli equation using the pulmonary regurgitation velocity and RAP8:
surrogates for transpulmonary pressure gradient and transpulmonary flow, respectively. This method has previously been validated against invasive parameters. The equation estimates the PVR in Wood units:
PADP ⫽ 4 ⫻ (pulmonary regurgitation velocity)2 ⫹ RAPbaseline [mm Hg]
PVR ⫽ 10 ⫻ TRV ⁄ PVVTI [Wood units]
Pulmonary regurgitation velocity is the end-diastolic velocity (at the time of the R wave) of the pulmonic valve regurgitant jet in the parasternal short-axis view using continuous wave Doppler. The Doppler echocardiographic assessment of PVR was performed using the method described by Abbas et al,9 which uses TRV and pulmonic valve VTI (PVVTI) as
PVVTI was measured in the parasternal short-axis view, where a pulsed wave Doppler sample volume was placed in the right ventricular outflow tract (OT) just proximal to the pulmonic valve. The left ventricular OT VTI was measured in the apical 5-chamber view by pulsed wave Doppler. The left ventricular OT VTI was used to assess changes in systemic blood flow. Figure 2 shows an example of the echocardiographic and Dopp-
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Main et al 1041
Table 2 Effects of PB127/control and dipyridamole infusion on pulmonary hemodynamics PB127 infusion (cohorts 1A and 2A), N ⴝ 10 PASP, mm Hg
Baseline Prestress† Poststress‡ Change from baseline – prestress† Maximum change from baseline – poststress‡
33.7 34.4 37.8 ⫹0.7 ⫹4.1*
⫾ ⫾ ⫾ ⫾ ⫾
7.0 5.2 5.0 2.5 3.4
PVVTI, cm
17.2 17.0 20.0 ⫺0.1 ⫹2.8*
⫾ ⫾ ⫾ ⫾ ⫾
2.9 3.3 3.5 2.4 1.9
PVR, WU
1.6 1.6 1.4 ⫹0.1 ⫺0.2*
⫾ ⫾ ⫾ ⫾ ⫾
0.2 0.3 0.3 0.3 0.2
Control infusion (cohorts 1B and 2B), N ⴝ 10 PASP, mm Hg
35.1 34.9 39.4 ⫺0.3 ⫹4.3*
⫾ ⫾ ⫾ ⫾ ⫾
8.2 7.6 7.6 2.2 5.0
PVVTI, cm
16.9 17.6 19.9 ⫹0.6 ⫹2.9*
⫾ ⫾ ⫾ ⫾ ⫾
2.7 2.6 2.5 1.1 1.9
PVR, WU
1.6 1.6 1.5 ⫺0.1 ⫺0.2*
⫾ ⫾ ⫾ ⫾ ⫾
0.3 0.2 0.2 0.1 0.2
PASP, Pulmonary artery systolic pressure; PVR, pulmonary vascular resistance; PVVTI, pulmonic valve velocity time integral; WU, Wood units. *P ⬍ .05 compared with baseline; †prestress, minute ⫹15 (during PB127/control infusion, before dipyridamole infusion); ‡poststress, at maximum change from baseline (during PB127/control and diypridamole infusion).
ler evaluations from a patient with normal PASP, PADP, and PVR. Vital sign assessments included heart rate, blood pressure, and oxygen saturation. These parameters were obtained every 3 minutes starting at minute ⫺9 and 1 hour postinfusion and the following day. Adverse Events Adverse events were collected from the start of the PB127/control infusion through approximately 24 hours after the infusion. All adverse events were considered ongoing until completely resolved or, in the case of an intercurrent illness, returned to baseline status recorded before investigational product administration. Statistical Analysis Data are presented as mean ⫾ SD. Changes from baseline in PASP, PVR, and PVVTI were analyzed using paired t tests within each treatment arm (PB127 and control), and 2-sample t tests were used to test for differences between the two treatment arms within strata. A P value less than .05 was considered significant.
RESULTS All 20 patients were included in the analysis of hemodynamic parameters. The results for pulmonary hemodynamics comparing the PB127 treatment arm and the control treatment arm at baseline, prestress (minute ⫹15), poststress (at maximum change from baseline), change from baseline to prestress, and maximum change from baseline to poststress are presented in Table 2. In the PB127 arm, there were no statistically significant increases from baseline in PASP at any prestress time points. Small but statistically significant mean increases from baseline in PASP and PVVTI were observed after the start of dipyridamole infusion. Small but statistically significant mean decreases from baseline were observed in PVR values after the start of dipyridamole.
In the control arm, there was also no significant change from baseline in PASP at any prestress time point. Small but significant mean increases in PASP and PVVTI and small but significant decreases in mean PVR were observed after the start of dipyridamole administration. Mean PVR values showed a return toward baseline 15 minutes after dipyridamole administration. No patients in either treatment arm had an increase from baseline in PASP of more than 10 mm Hg or PVR of more than 30% before dipyridamole administration. Increases from baseline in the left ventricular OT VTI occurred in both the PB127 and control arms with dipyridamole stress, consistent with increases in PVVTI. No clear effect on PADP was evident with dipyridamole stress. In the PB127 arm, comparison of cohort 1A (normal PASP) and cohort 2A (elevated PASP) revealed similar patterns with insignificant changes in mean PASP, mean PVVTI, and mean PVR from baseline to prestress (Table 3). From baseline to maximum change poststress, small increases in mean PASP and mean PVVTI, and a slight decrease in PVR, were found in both cohorts. In the control arm, comparison of cohort 1B (normal PASP) and cohort 2B (elevated PASP) showed the same patterns with insignificant changes in mean PASP, mean PVVTI, and mean PVR from baseline to prestress (Table 3). From baseline to maximum change poststress, small increases in mean PASP and mean PVVTI, and a slight decrease in PVR, were noted in both cohorts. The mean changes from baseline in heart rate, systolic and diastolic blood pressure, and oxygen saturation did not indicate any clinically meaningful trends related to PB127 (Table 4). In both treatment arms, small mean increases from baseline in heart rate were observed after administration of dipyridamole. Small mean changes in blood pressure were noted from baseline to prestress
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1042 Main et al
Table 3 Effects of PB127/control and dipyridamole infusion on pulmonary hemodynamics in patients with normal and elevated screening pulmonary artery systolic pressure Normal screening PASP (<35 mm Hg) PB127 cohort 1A
Baseline Prestress* Poststress†
PASP, mm Hg
PVVTI, cm
PVR, WU
Control cohort 1B
PASP, mm Hg
PVVTI, cm
PVR, WU
28.5 ⫾ 5.8 30.3 ⫾ 3.8 34.2 ⫾ 4.9
15.6 ⫾ 2.7 15.0 ⫾ 2.8 18.5 ⫾ 3.8
1.6 ⫾ 0.3 1.7 ⫾ 0.4 1.5 ⫾ 0.4
Baseline Prestress* Poststress†
28.4 ⫾ 4.0 28.9 ⫾ 4.0 33.7 ⫾ 2.2
16.3 ⫾ 1.8 16.4 ⫾ 1.4 19.9 ⫾ 4.0
1.5 ⫾ 0.3 1.5 ⫾ 0.2 1.4 ⫾ 0.2
Elevated screening PASP (>35 mm Hg) PB127 cohort 2A
Baseline Prestress* Poststress†
PASP, mm Hg
PVVTI, cm
PVR, WU
Control cohort 2B
PASP, mm Hg
PVVTI, cm
PVR, WU
38.9 ⫾ 2.9 38.5 ⫾ 2.1 41.4 ⫾ 0.9
18.7 ⫾ 2.3 19.0 ⫾ 2.6 21.7 ⫾ 2.2
1.6 ⫾ 0.2 1.5 ⫾ 0.2 1.4 ⫾ 0.1
Baseline Prestress* Poststress†
41.9 ⫾ 4.6 40.8 ⫾ 5.2 46.0 ⫾ 2.7
17.6 ⫾ 3.5 18.7 ⫾ 3.2 20.5 ⫾ 3.5
1.8 ⫾ 0.3 1.6 ⫾ 0.2 1.6 ⫾ 0.2
PASP, Pulmonary artery systolic pressure; PVR, pulmonary vascular resistance; PVVTI, pulmonic valve velocity time integral; WU, Wood units. *Prestress, minute ⫹15 (during PB127/control infusion, before dipyridamole infusion); †poststress, at maximum change from baseline (during PB127/control and diypridamole infusion).
Table 4 Effects of PB127/control and dipyridamole infusion on systemic hemodynamics PB127 infusion (cohorts 1A and 2A), N ⴝ 10
HR, beats/min
Baseline
58.6 ⫾ 6.8
Prestress*
60.0 ⫾ 8.2
Poststress†
72.9 ⫾ 9.3
Change from baseline – prestress*
⫹1.4 ⫾ 3.6
Maximum change from baseline – poststress†
⫹14.3 ⫾ 8.0
SBP/DBP, mm Hg
123.8 56.5 132.6 59.8 128.5 62.9 ⫹8.8 ⫹3.3 ⫹4.7 ⫹6.4
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
36.2/ 11.0 34.8/ 9.7 29.3/ 9.2 15.6/ 5.1 18.6/ 10.8
Control infusion (cohorts 1B and 2B), N ⴝ 10
O2 Sat, %
HR, beats/min
95.0 ⫾ 2.6
62.5 ⫾ 5.9
95.8 ⫾ 2.5
64.5 ⫾ 6.0
97.4 ⫾ 1.7
78.3 ⫾ 13.0
⫹0.8 ⫾ 1.5
⫹2.0 ⫾ 2.7
⫹2.4 ⫾ 1.9
⫹15.8 ⫾ 10.2
SBP/DBP, mm Hg
131.3 65.0 135.6 60.9 128.3 58.1 ⫹4.3 ⫺4.1 ⫺3.0 ⫺6.9
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
22.2/ 15.0 23.2/ 10.3 21.3/ 11.5 8.7/ 8.7 8.1/ 10.7
O2 Sat, %
96.3 ⫾ 2.9 95.8 ⫾ 3.4 97.1 ⫾ 2.1 ⫺0.5 ⫾ 1.4 ⫹0.8 ⫾ 1.5
DBP, Diastolic blood pressure; HR, heart rate; O2 Sat, oxygen saturation; SBP, systolic blood pressure. *Prestress, minute ⫹15 (during PB127/control infusion, before dipyridamole infusion); †poststress, at maximum change from baseline (during PB127/control and diypridamole infusion).
and from baseline to poststress in both the PB127 and the control group. Oxygen saturation values did not change significantly during rest or stress time points for any patient. In all, 11 patients (55%) reported at least one adverse event including 4 patients in the PB127 arm and 7 patients in the control arm. A total of 14 adverse events were reported. No patient experienced a serious adverse event or had an adverse event that resulted in discontinuation of PB127. All were mild in severity. The most frequently reported adverse event was headache, which was reported by 8 patients (40%). The other reported adverse events were sensation of pressure in ear, nausea, stomach discomfort, injection site pain, pain in jaw, headache, and flushing. All of the symptoms were attributed to dipyridamole or unrelated to both dipyridamole and PB127.
DISCUSSION Myocardial contrast echocardiography is a useful means of evaluating myocardial perfusion, including detection of coronary artery disease in association with pharmacologic stress.1 Recently, however, safety concerns have emerged concerning both investigational and commercially available transpulmonary contrast agents, especially with regard to alterations of pulmonary hemodynamics.2,3 In the current study, continuous infusion of PB127 diluted in 5% dextrose did not significantly alter mean PASP, PVR, or PVVTI, and no patient had an increase from baseline in PASP of greater than 10 mm Hg or in PVR of greater than 30% before dipyridamole administration. Similarly, there was no evidence of an effect of PB127 on heart rate or blood pressure. The data
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suggest that PB127 at clinical doses has no significant systemic or pulmonary hemodynamic effects. These findings distinctly differ from a canine study using an early formulation of EchoGen, a liquid-in-liquid emulsion in water containing dodecafluoropentane, which converts to a dispersion of microspheres at body temperature after IV injection.2 The mean EchoGen microsphere diameter is 2 to 5 m.10 The study showed that frequent highdose administrations of a 2% dodecafluoropentane emulsion (0.5 mL/kg) resulted in an increase in pulmonary artery pressure and PVR, and decreased oxygen saturation, cardiac output, and stroke volume. Postmortem examination revealed gross accumulation of dodecafluoropentane in the lungs of the dogs. Subsequent changes in the EchoGen formulation allowed the use of much lower doses for human studies. A clinical study in 254 patients using EchoGen administered at a dose of 0.05 mL/kg revealed no significant changes in hemodynamic parameters.11 It is unclear whether the lack of hemodynamic effect in the clinical study compared with the animal study was a result of modification of the agent or the change in dose. Based at least in part on these data, commercially available contrast agent product inserts warn against administration in patients with chronic pulmonary vascular disorders.4,5 A related animal study of PB127 at several times the human dose did not show any histopathologic effects in the pulmonary vasculature (data on file at POINT Biomedical). The current study also showed that dipyridamole in doses of 0.56 mg/kg was associated with small mean changes from baseline in systolic and diastolic blood pressure, and small mean increases in heart rate and systemic flow. These hemodynamic changes were seen in both the PB127 and control arms, and in patients with normal and elevated screening PASP. Pulmonary flow parameters showed statistically significant increases in PASP and PVVTI, and a decrease in PVR. Dipyridamole injection at these doses is known to alter systemic and pulmonary hemodynamics by increasing cardiac output, cardiac stroke volume, and heart rate,12 and even very low doses of dipyridamole (0.07 mg/kg/min for 4 minutes) significantly reduce PVR in patients with chronic heart failure.13 Finally, the current study demonstrated a peak vasodilatory effect of dipyridamole 4 to 8 minutes after injection, consistent with previous studies.14 The overall safety profile of PB127 shown in this study did not reveal any clinically significant untoward effects of PB127 in patients with and without pulmonary hypertension. No patient showed dyspnea, tachycardia, chest pain, hypoxia, or any clinically relevant hemodynamic instability indicating acute pulmonary hypertension or acute obstruction of the pulmonary microvasculature. The adverse event profile of the PB127 arm was similar to that of
Main et al 1043
the control population. The reported minor adverse events are consistent with the adverse events reported in dipyridamole safety studies in large patient populations.15-17 These findings are consistent with the excellent safety profile of PB127 in other small published phase I and II studies.1,18 The lack of any pulmonary hemodynamic effect may relate to the small size of the PB127 diameter, the biocompatible outer shell, and the gaseous core filled with inert nitrogen. Limitations The number of studied patients was relatively small. In addition, we did not include patients with severe pulmonary hypertension (PASP ⬎ 100 mm Hg) and these safety data may not apply to that patient population. Conclusions In this study, PB127 infusion did not significantly alter PASP, PVR, or pulmonary flow. As expected, dipyridamole infusion showed a vasodilator effect with an increase in pulmonary flow and pulmonary pressure and a decrease in vascular resistance.
REFERENCES 1. Wei K, Crouse L, Weiss J, Villanueva F, Schiller NB, Naqvi TZ, et al. Comparison of usefulness of dipyridamole stress myocardial contrast echocardiography to technetium-99m sestamibi single-photon emission computed tomography for detection of coronary artery disease (PB127 multicenter phase 2 trial results). Am J Cardiol 2003;91:1293-8. 2. Grayburn PA, Erickson JM, Escobar J, Womack L, Velasco CE. Peripheral intravenous myocardial contrast echocardiography using a 2% dodecafluoropentane emulsion: identification of myocardial risk area and infarct size in the canine model of ischemia. J Am Coll Cardiol 1995;26:1340-7. 3. The European Agency for the Evaluation of Medicinal Products. Public statement on Sonovue (sulphur hexafluoride). New contraindication in patients with heart disease. Restriction of use to non-cardiac imaging, May 2004. London, UK. 4. Definity [package insert], 2003, Bristol-Myers Squibb Medical Imaging, Inc., N. Billerica, MA, USA. 5. Optison [package insert], 2003, Amersham Health Inc., Princeton, NJ, USA. 6. Yock PG, Popp RL. Noninvasive estimate of right ventricular systolic pressure by Doppler ultrasound in patients with tricuspid regurgitation. Circulation 1984;70:657-62. 7. Kircher BJ, Himelman RB, Schiller NB. Noninvasive estimation of right atrial pressure from the inspiratory collapse of the inferior vena cava. Am J Cardiol 1990;66:493-6. 8. Lee RT, Lord CP, Plappert T, Sutton MJ. Prospective Doppler echocardiographic evaluation of pulmonary artery diastolic pressure in the medical intensive care unit. Am J Cardiol 1989;64:1366-70. 9. Abbas AE, Fortuin FD, Schiller NB, Appleton CP, Moreno CA, Lester SJ. A simple method for noninvasive estimation of pulmonary vascular resistance. J Am Coll Cardiol 2003;41: 1021-7.
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10. Correas JM, Quay SD. EchoGen emulsion: a new ultrasound contrast agent based on phase shift colloids. Clin Radiol 1996;51:11-4. 11. Grayburn PA, Weiss JL, Hack TC, Klodas E, Raichlen JS, Vannan MA, et al. Phase III multicenter trial comparing the efficacy of 2% dodecafluoropentane emulsion (EchoGen) and sonicated 5% human albumin (Albunex) as ultrasound contrast agents. J Am Coll Cardiol 1998;32:230-6. 12. Marchant E, Pichard A, Rodriguez JA, Casanegra P. Acute effects of systemic versus intracoronary dipyridamole on coronary circulation. Am J Cardiol 1986;57:1401-4. 13. Cortigiani L, Baroni M, Picano E, Palmieri C, Boni A, Ravani M, et al. Acute hemodyanmic effects of endogenous adenosine in patients with chronic heart failure. Am Heart J 1998;136:37-42. 14. Picano E, Sicari R, Varga A. Dipyridamole stress echocardiography. Cardiol Clin 1999;17:481-99.
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15. Ranhosky A, Kempthorne-Rawson J, and the Intravenous Dipyridamole Thallium Imaging Study Group. The safety of intravenous dipyridamole thallium myocardial perfusion imaging. Circulation 1990;81:1205-9. 16. Lette J, Tatum JL, Fraser S, Miller DD, Waters DD, Heller G, et al. Safety of dipyridamole testing in 73806 patients: the multicenter dipyridamole safety study. J Nucl Cardiol 1995;2:3-17. 17. Picano E, Marini C, Pirelli S, Maffei S, Bolognese L, Chiriatti G, et al. Safety of intravenous high-dose dipyridamole echocardiography: the echo-Persantine international cooperative study group. Am J Cardiol 1992;70:252-8. 18. Raisinghani A, Wei KS, Crouse L, Villanueva F, Feigenbaum H, Schiller NB, et al. Myocardial contrast echocardiography (MCE) with triggered ultrasound does not cause premature ventricular complexes: evidence from PB127 MCE studies. J Am Soc Echocardiogr 2003;16:1037-42.