Incidence of Adverse Events Associated With Use of Perflutren Contrast Agents for Echocardiography FREE

To the Editor: Perflutren cardiac ultrasound agents improve diagnostic accuracy in patients whose imaging is technically difficult.¹ In October 2007, the US Food and Drug Administration issued a health care provider advisory² (“black box warning”) regarding use of Definity (perflutren lipid microsphere: formerly Bristol-Myers Squibb Medical Imaging, New York, New York; now Lantheus Medical Imaging, North Billerica, Massachusetts) and Optison (perflutren protein-type A microspheres for injection; GE Healthcare, Princeton, New Jersey). These agents are now contraindicated in patients for whom their clinical use is considerable: those with unstable congestive heart failure, acute coronary syndrome, respiratory failure, and severe emphysema. The advisory was prompted by identification of 4 fatalities secondary to cardiopulmonary events within 30 minutes of perflutren administration and 11 fatalities overall within 12 hours of administration.²

The echocardiography database at Hennepin County Medical Center (Minneapolis, Minnesota), begun in March 1986, comprises 112 776 echocardiographic studies and includes data on use of and complications associated with perflutren. All patients receiving Optison or Definity were identified; a separate nonelectronic file of all adverse events reported by nursing staff was reviewed. A 30-minute interval after perflutren administration (the Food and Drug Administration health care advisory time frame) was chosen for analysis. Patients had been routinely observed for at least 30 minutes by hospital nursing staff or by echocardiography laboratory nurses or sonographers.

For patients with adverse advents, individual electronic charts were abstracted for additional data, including allergy history. Informal adjudication of the temporal relationship of nonfatal events with perflutren administration was performed. Nonfatal complications known to be attributable to stress testing (eg, transient atrial fibrillation during dobutamine infusion) were excluded. Adverse event frequencies were compared using Fisher exact test. A 95% confidence interval (CI) for all adverse events and an exact confidence limit for serious events (those requiring immediate physician attention) were calculated. Means were compared using t test. Statistical significance was defined by 2-sided P<.05. Analyses were performed using SAS version 9.1 (SAS Institute, Cary, North Carolina). The study (with waiver of consent) was approved by the Hennepin County Medical Center human subjects research committee.

Perflutren was received by 16 025 patients (Table 1). From February 1998 to February 2002, 3051 patients received Optison; no adverse events were recorded. From February 2002 to October 2007, 12 974 received Definity; 20 events were recorded (18 ascertained from the database, 2 from the nursing reporting file), 4 of which were serious. The adverse event rate overall was 0.12% (95% CI, 0.08%-0.16%) and for Definity was 0.15% (95% CI, 0.09%-0.24%) (Optison vs Definity, P = .03 for all events; P = .86 for serious events).

Adverse events included severe back pain typically lasting 5 to 10 minutes (12 patients); transient vasodepressor episode (1); pruritus (2); seizure (1); serious but nonfatal cardiopulmonary events (suggestive of anaphylactoid-type reactions) without sequelae (chest pain with dyspnea [1], back and chest pain with transient arterial desaturation [1], dyspnea with chest and back pain [1], and acute bronchospasm [1]) (Table 2). There were no fatalities. Incidence of serious events was 0.031% (exact confidence limit, 0.01%-0.08%). Of patients with adverse events, 13 (65%) had a history of allergy and 13 (65%; P = .07) were women (Table 2).

Incidence of serious nonfatal reactions with perflutren was similar to that reported after low-osmolar iodinated radiocontrast media (0.04%),³ and the potential risk factors of allergic history (higher prevalence than expected⁴ ) and female sex have been linked to increased risk of serious radiocontrast reactions.⁵ The most common adverse event was severe back pain.

Study limitations include potential underestimation of adverse event incidence due to incomplete registry ascertainment, occurrence more than 30 minutes after perflutren administration, or occurrence in sedated or unconscious patients. Conversely, because many patients receiving perflutren are seriously ill, some adverse events may not have been causally related to perflutren administration.⁶ As a single-site study, the results may not be generalizable to all settings. Nevertheless, they suggest a relatively low rate of adverse events due to perflutren.