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“Product Safety” Compromises Patient Safety (an Unjustified Black Box Warning on Ultrasound Contrast Agents by the Food and Drug Administration)

Published:January 29, 2008DOI:https://doi.org/10.1016/j.amjcard.2007.11.036
      In October 2007, the United States Food and Drug Administration (FDA)
      US Food and Drug Administration
      Definity®: vial for (perflutren lipid microsphere) injectable suspension: for intravenous use.
      issued an alert requesting “black-box” warnings on the perflutren-based ultrasound contrast agents Definity (Bristol-Myers Squibb Medical Imaging, North Billerica, Massachusetts) and Optison (Amersham Health, Amersham, UK). Additionally, the FDA recommended that these agents “be contraindicated in patients with unstable cardiopulmonary status, including patients with unstable angina, acute myocardial infarction (MI), respiratory failure, or recent worsening congestive heart failure.” According to the FDA’s Web site, there have been postmarketing reports of 10 deaths after the administration of Definity and 1 after the administration of Optison. At least 6 of these occurred 1 to 12 hours after dosing and were attributed to serious underlying conditions and/or other medications. Four fatal cases, however, occurred <30 minutes after the administration of Definity: 1 after a stress test, 2 in patients with severe heart failure, and 1 in a ventilated patient with severe respiratory failure, sepsis, and multiple pulmonary emboli. These 4 deaths occurred over a 6-year period. During that period, >2 million doses were administered (Bristol-Myers Squibb Medical Imaging, personal communication). Thus, the fatal event rate was approximately 1 in 500,000. This rate is far less than the fatal event rate of a treadmill exercise test (1 in 2,500)
      • Stuart Jr, R.J.
      • Ellestad M.H.
      National survey of exercise stress testing facilities.
      or a transesophageal echocardiogram (1 in 10,000).
      • Daniel W.G.
      • Erbel R.
      • Kasper W.
      • Visser C.A.
      • Engberding R.
      • Sutherland G.R.
      • Grube E.
      • Hanrath P.
      • Maisch B.
      • Dennig K.
      Safety of transesophageal echocardiography A multicenter survey of 10,419 examinations.
      In fact, this extremely low event rate testifies to the safety of these agents, considering that they are frequently used in critically ill patients. It is almost certain that the 4 fatal cases were consequences of severe underlying cardiovascular disease and were not caused by the contrast agent.
      • Main M.L.
      • Goldman J.H.
      • Grayburn P.A.
      Thinking outside the “box”: the ultrasound contrast agent controversy.
      According to the FDA’s Web site, the FDA “has the responsibility for assuring the safety and efficacy of all regulated marketed medical products.” Product safety is not the same as patient safety. The FDA is concerned with whether a regulated drug or medical device has a potential adverse safety profile. Thus, the FDA focuses on the term “product safety.” Patient safety lies within the domain of the physician-patient relationship and is not the concern of the FDA. For example, consider the case of an elderly, debilitated patient with symptomatic, severe aortic stenosis. After extensive evaluation, her cardiologist determines that although aortic valve replacement with an FDA-approved bioprosthesis would relieve the aortic stenosis, the procedure is contraindicated because of her debilitated state and advanced co-morbidities. The cardiologist determines that in this case, valve replacement is likely to accelerate the patient’s death rather than delay it. This decision invokes the time-honored tradition of primum non nocere and places patient safety ahead of product safety. The FDA is not qualified to make this decision for this patient, nor is it in their domain.
      In the case of the black-box warning on perflutren-based ultrasound contrast agents, the FDA has inadvertently compromised patient safety while intending to ensure product safety. Here’s why.
      Ultrasound contrast agents are indicated for left ventricular (LV) cavity opacification and the delineation of endocardial borders. As such, the FDA views this as a diagnostic, not a therapeutic, indication and therefore has zero tolerance for adverse effects. The FDA has no understanding of daily life in intensive care units, where the improved diagnostic accuracy of echocardiography obtained with ultrasound contrast agents may lead to lifesaving changes in therapy.
      Consider the critical issue of LV rupture with pseudoaneurysm formation after acute ST-elevation MI. The American College of Cardiology and American Heart Association practice guidelines for ST-elevation MI state that there are approximately 500,000 ST-elevation MIs in the United States annually, of which 1% to 6% involve LV free wall rupture.
      • Antman E.M.
      • Anbe D.T.
      • Armstrong P.W.
      • Bates E.R.
      • Green L.A.
      • Hand M.
      • Hochman J.S.
      • Krumholz H.M.
      • Kushner F.G.
      • Lamas G.A.
      • et al.
      ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction; a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction).
      Although often fatal, free wall rupture may also result in pseudoaneurysm, whereby the extravasation of blood into the pericardial sac is prevented by adherence of the parietal pericardium to the underlying epicardium. As stated in the guidelines, “prompt surgical correction is always indicated for pseudoaneurysm to prevent rupture.”4 In the largest study reported, the sensitivity of transthoracic echocardiography for the diagnosis of LV pseudoaneurysm was only 26%, often because of inadequate imaging windows or failure to obtain a tomographic view through the small LV laceration.
      • Frances C.
      • Romero A.
      • Grady D.
      Left ventricular pseudoaneurysm.
      However, the appearance of an intravenous contrast agent in the pericardial space is not dependent on tomographic slice and is diagnostic of LV pseudoaneurysm.
      There have been 19 cases of the use of ultrasound contrast agents for the diagnosis of LV pseudoaneurysm.
      • Atik F.A.
      • Navia J.L.
      • Vega P.R.
      • Gonzalez-Stawinski G.V.
      • Alster J.M.
      • Gillinov A.M.
      • Svensson L.G.
      • Pettersson B.G.
      • Lytle B.W.
      • Blackstone E.H.
      Surgical treatment of postinfarction left ventricular pseudoaneurysm.
      • Naik H.
      • Sherev D.
      • Hui P.Y.M.
      The rapid diagnosis of pseudoaneurysm formation in left ventricular free wall rupture.
      • Hannouche da Trindade M.L.Z.
      • Tsutsui J.M.
      • Rodrigues A.C.T.
      • Caldas M.A.
      • Ramires J.A.F.
      • Mathias Jr, W.
      Left ventricular free wall impeding rupture in post-myocardial infarction period diagnosed by myocardial contrast echocardiography.
      • Mittle S.
      • Makaryus A.N.
      • Mangion J.
      Role of contrast echocardiography in the assessment of myocardial rupture.
      • Moreno R.
      • Zamorano J.L.
      • Almería C.
      • Rodrigo J.L.
      • Villate A.
      • Serra V.
      • Alvarez L.
      • Aubele A.
      • Sánchez-Harguindey L.
      Usefulness of contrast agents in the diagnosis of left ventricular pseudoaneurysm after acute myocardial infarction.
      • Waggoner A.D.
      • Williams G.A.
      • Gaffron D.
      • Schwarze M.
      Potential utility of left heart contrast agents in diagnosis of myocardial rupture by 2-dimensional echocardiography.
      • Thanigaraj S.
      • Pérez J.E.
      Diagnosis of cardiac rupture with the use of contrast-enhanced echocardiography.
      • Ishida T.
      • Yasu T.
      • Arao K.
      • Kawakami M.
      • Saito M.
      Bedside diagnosis of cardiac rupture by contrast echocardiography.
      • Wilkenshoff U.M.
      • Albaei A.A.
      • Kuersten B.
      • Pauschinger M.
      • Schwimmbeck P.
      • Hetzer R.
      • Schultheiss H.-P.
      Contrast echocardiography for detection of incomplete rupture of the left ventricle of acute myocardial infarction.
      • Uno K.
      • Takenaka K.
      • Asada K.
      • Ebihara A.
      • Sasaki K.
      • Komuro T.
      • Nagai R.
      • Motomura N.
      • Ono M.
      • Takamoto S.
      Diagnosis of subacute cardiac rupture by contrast echocardiography.
      • García-Fernández M.A.
      • Macchioli R.O.O.
      • Moreno P.M.-A.
      • Yangüela M.M.
      • Thomas J.B.
      • Sendón J.L.L.
      • López de Sa E.
      • Abdou Y.H.
      Use of contrast echocardiography in the diagnosis of subacute myocardial rupture after myocardial infarction.
      Of these, contrast was required to make the diagnoses in 13. In 4 others, the diagnoses were suspected by noncontrast echocardiography but confirmed by contrast administration. In 2 others, suspected LV pseudoaneurysm was ruled out by contrast echocardiography, thereby preventing unnecessary emergent operations. For the FDA to declare contrast agents “contraindicated” in acute MI amounts to a death sentence for perhaps hundreds of patients with LV pseudoaneurysm. Yet LV pseudoaneurysm is only the tip of the iceberg.
      Contrast agents frequently result in the diagnosis of LV apical thrombus in acute MI, which is a major risk factor for death or stroke.
      • Mansencal N.
      • Nasr I.A.
      • Pillière R.
      • Farcot J.-C.
      • Joseph T.
      • Lacombe P.
      • Dubourg O.
      Usefulness of contrast echocardiography for assessment of left ventricular thrombus after acute myocardial infarction.
      Failure to appropriately institute anticoagulation in a patient with LV thrombus after acute MI could result in a catastrophic stroke. Conversely, inappropriate anticoagulation for a near-field artifact mistaken for apical thrombus could lead to a life-threatening hemorrhage.
      It is common to encounter cases in which contrast agents result in potentially lifesaving changes in therapy in critically ill patients with hypotension, heart failure, or respiratory failure.
      • Reilly J.P.
      • Tunick P.A.
      • Timmermans R.J.
      • Stein B.
      • Rosenzweig B.P.
      • Kronzon I.
      Contrast echocardiography clarifies uninterpretable wall motion in intensive care unit patients.
      • Yong Y.
      • Wu D.
      • Fernandes V.
      • Kopelen H.
      • Shimoni S.
      • Nagueh S.F.
      • Callahan J.D.
      • Bruns D.E.
      • Shaw L.J.
      • Quinones M.A.
      • Zoghbi W.A.
      Diagnostic accuracy and cost-effectiveness of contrast echocardiography on evaluation of cardiac function in technically very difficult patients in the intensive care unit.
      One such example is a patient being treated for heart failure; echocardiography was not diagnostic, but contrast administration subsequently revealed right ventricular dilatation and thrombus in transit. The diagnosis of pulmonary embolus resulted in a change of therapy from diuretics and vasodilators to thrombolytic therapy. Another example is a small, elderly woman with hypotension and signs of hypoperfusion treated with inotropic agents. After contrast administration, echocardiography showed a small, hyperdynamic, hypertrophied left ventricle with dynamic outflow tract obstruction. Inotropes were discontinued and replaced with β blockers and fluids; she promptly improved. Contrast agents are more valuable in patients in intensive care units than in any other setting because the stakes are enormous, and is it often difficult to obtain good image quality because of immobility and respiratory problems.
      Given the obvious benefits of ultrasound contrast agents and the absence of evidence that they are unsafe, how could the FDA declare them to be contraindicated in patients with acute coronary syndromes, respiratory failure, or ventricular arrhythmias? In my opinion, this can be explained only by a flaw in the organizational structure and a failure to follow appropriate process. The organizational flaw is that contrast agents are regulated by the Office of Oncology Drug Products of the Division of Medical Imaging and Hematology Products. There is no cardiologist on the panel, and the physicians on this panel lack any qualifications to decide what is or is not indicated for acute MI, unstable angina pectoris, heart failure, or ventricular arrhythmias. The flaw in process is the failure of the Division of Medical Imaging and Hematology Products to follow established FDA procedure, in which either a nonqualified or nonexpert panel would refer to the cardiorenal panel or a special emphasis panel would be created composed of experts in the field. This was not done.
      Fortunately, there are remedies to rescue our patients from this major faux pas by the FDA. First, the black-box warnings on Definity and Optison need to revised to remove the erroneous statement that these agents are contraindicated in acute MI, heart failure, ventricular arrhythmias, and respiratory failure. In most of these circumstances, the benefit of ultrasound contrast agents far outweighs their risk. Second, it would seem wise for the FDA to form a new special emphasis panel to evaluate ultrasound contrast agents. Such a panel should include clinical cardiologists and radiologists (who are experts in imaging agents and their bioeffects). Third, contrast agent manufacturers need to implement a strong postmarketing surveillance plan, with prospective expert adjudication of all serious adverse events, as well as collection of cases in which lives were potentially saved by the judicious use of contrast. Had the sponsors already done this, perhaps the FDA would not have made such a serious mistake. Finally, cardiologists need to speak up for the safety and well-being of their patients, individually and through the organizations that represent them.

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