Aprotinin--are there lessons learned?

THIS PAST YEAR HAS BEEN A COMPLICATED ONE FOR aprotinin, an antifibrinolytic serine protease inhibitor used to lessen bleeding in patients undergoing cardiac surgery with cardiopulmonary bypass. Thirteen years after the initial approval of aprotinin by the US Food and Drug Administration, the report by Mangano and colleagues in this issue of JAMA will intensify the debate about the benefits and risks associated with use of this drug. Perhaps more important, this aprotinin story illuminates the larger issue of postmarket safety evaluation surrounding drugs and devices in the current medical environment. In this article, the investigators report 5-year, all-cause mortality data from patients enrolled in an international registry of on-pump coronary artery bypass graft surgery. The authors conclude that use of aprotinin in routine and complex coronary artery bypass graft surgery is associated with an increased risk of late mortality as compared with use of no hemorrhage-sparing agent and with use of aminocaproic acid and tranexamic acid, 2 lysine analog antifibrinolytics that are less expensive and less toxic. The 3876 patients from 62 of 69 centers were observed (87% follow-up rate) for 5 years. The authors used extensive statistical analytical techniques to address bias inherent in observational analyses, and referenced select randomized clinical trial data to support their observational findings. This current study by Mangano et al follows an earlier publication from 2006 addressing the perioperative risk of aprotinin therapy. The same registry was used for both studies and consisted of prospectively collected clinical data (7500 variables/patient) from 69 cardiac surgery sites in North and South America, Europe, and Asia. The earlier study analyzed 4374 patients, nonrandomly enrolled into the same 4 groups (ie, control, aminocaproic acid, tranexamic acid, aprotinin). Propensity-adjusted, multivariable logistic regression analysis demonstrated that as compared with control, aprotinin was associated with increased perioperative risk of death, acute renal failure, myocardial infarction, and stroke/ encephalopathy. The lysine analogs were not associated with any of these adverse outcomes. Importantly, the perioperative observational study findings seemed to conflict with findings from several dozen randomized trials, 2 meta-analyses, a Cochrane Collaboration summary on aprotinin use, and an evaluation by the US Food and Drug Administration. The challenges in translating clinical trial data into the “real world” are well known. Possible reasons that randomized trial results might not be available for assessment of adverse events with pharmacologic therapies include the fact that trials powered for efficacy are often too small to detect adverse events and too short to detect events requiring longer exposure. In addition, there are limited industry incentives to fund trials to quantify adverse events for drugs or devices, and head-to-head comparison of adverse events between different manufacturers may not be available. Moreover, observational-based studies (of the type reported by Mangano et al) might be a model for the future in assessing adverse effects from drugs. A variety of observational data sets exist in cardiovascular disease, including large administrative databases (Medicare, other payer, and hospitalor network-based systems), industry-sponsored postmarket registries, and comprehensive databases and registries from professional organizations (the Society of Thoracic Surgeons, the American College of Cardiology, and the American Heart Association). If observational data sets and analyses specific to those data sets are potential candidates for use in the safety evaluation process for drugs and devices, 4 criteria will need to be met: (1) the data sets must be sources of information that cannot be acquired through other mechanisms; (2) the reason patients receive the drug/device therapy must be determinable; (3) integration of both periprocedural data and long-term data are necessary; and (4) observational database systems will need to be modified and prospectively integrated into the overall process of evaluation for safety and efficacy. All of these criteria impact this aprotinin story. The studies by Mangano et al are important because they have generated new information not otherwise available about aprotinin use. However, it is not clear that the reasons patients received any specific agent (or no agent) are determinable. In the registry used by Mangano et al, the use of