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EDITORIAL

Aprotinin Use During Cardiac Surgery: A New or Continuing Controversy?

Charles W. Hogue, MD^*, and Martin J. London, MD

From the *Department of Anesthesiology and Critical Care Medicine, Johns Hopkins Hospital, Baltimore, Maryland; and Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, California.

Address correspondence and reprint requests to Charles W. Hogue, MD, Department of Anesthesiology and Critical Care Medicine, Johns Hopkins Hospital, 600 North Wolfe St, Tower 711, Baltimore, MD 21287. Address e-mail to chogue2{at}jhmi.edu.

	Introduction

Top Introduction REFERENCES

 
Excessive bleeding during and after cardiac surgery is a serious complication that exposes patients both to the risks of transfusion of blood products and to those associated with mediastinal re-exploration (1,2). Cardiac anesthesiologists and cardiac surgeons, have thus long sought pharmacologic means to reduce bleeding resulting from nonsurgical sources. Interest in these efforts was intensified in 1982 when the transmission of the human immunodeficiency virus by allogeneic blood transfusion was reported (1,3). The use of aprotinin for reducing blood loss has been of particular interest. This serine protease inhibitor has a long history of use in clinical medicine including its use in cardiac surgery as far back as in the 1960s (4–6). There was a resurgence of interest in aprotinin in the 1980s following the reports from the United Kingdom by Royston et al. (7,8) who demonstrated its blood-sparing effects during cardiac surgery. Favorable results from randomized, double-blind and placebo-controlled trials in the United States led to the approval of aprotinin by the Food and Drug Administration (FDA) in 1993 for patients undergoing re-operative coronary artery bypass graft (CABG) surgery or for those at high-risk for excessive bleeding (9). This approval was later extended to all CABG patients in 1998.

The international cardiac anesthesiology and cardiac surgery communities now face a controversy regarding aprotinin after the publication of two reports suggesting a higher incidence of adverse events (e.g., renal, cardiovascular, and central nervous system) in patients who receive aprotinin. Mangano et al. (10) performed a retrospective analysis of 4374 patients enrolled in the Multicenter Study on Perioperative Ischemia Research Group international database. In that study, aprotinin use was associated with an increased risk of renal dysfunction (controls, 2% vs aprotinin group, 5%, P < 0.001) and renal failure (controls, 1% vs aprotinin group, 5%, P < 0.01) for patients undergoing primary CABG or complex CABG surgery. Renal dysfunction was defined as serum creatinine level in the first postoperative week, of at least 177 µmol/L (approximately 2 mg/dL) or an increase from baseline of 62 µmol/L. They also noted a 55% increase in the risk for myocardial infarction or heart failure and a 181% increase in risk for stroke or encephalopathy for patients undergoing primary CABG surgery who received aprotinin when compared with control patients. Karkouti et al. (11) performed a propensity score case-control comparison of 898 high-transfusion risk patients undergoing cardiac surgery who received either aprotinin or tranexamic acid. They found that aprotinin did not result in higher rates of myocardial infarction, stroke, or death. A greater percentage of patients receiving aprotinin developed renal dysfunction in the first postoperative week when compared with those receiving tranexamic acid (24% vs 17%, P = 0.01). They defined renal dysfunction as a 50% increase in creatinine concentration to >100 µmol/L in women or >110 µmol/L in men, or the use of renal dialysis. Others have suggested that the combination of preoperative angiotensin converting enzyme inhibitors and intraoperative aprotinin increases the risk for elevation in creatinine after cardiac surgery (12). Preoperative angiotensin converting enzyme inhibitor therapy was not included in the reports by Mangano et al. (10) or Karkouti et al. (11).

Two articles (13,14) in this issue of Anesthesia &Analgesia addressing aprotinin use during cardiac surgery provide a contrast to the analyses by Mangano et al. (10) and Karkouti et al. (11). Dietrich et al. (13) examined the relationship between aprotinin dose and its efficacy using analysis of data from 8281 patients undergoing cardiac surgery using cardiopulmonary bypass. In this series, all patients were given 5–6 x 10⁶ kallekrein inhibiting units of aprotinin. Because body weight varies, the authors were able to retrospectively calculate the aprotinin dose on a kallikrein inhibiting units/kg basis, then normalized for the duration of surgery. The patients were categorized into quartiles of aprotinin dose/minute of surgery. The results showed a significant inverse relationship between aprotinin dose and chest tube drainage, allogeneic blood transfusion, and the risk for mediastinal re-exploration for bleeding. The higher dose quartiles in essence identify smaller patients, a group normally at higher risk for bleeding and transfusion (15). An obvious question is whether the lower quartile dosing groups (larger body weight) were under-dosed with aprotinin. Regardless, the results suggest that aprotinin dose should be individualized. Of interest, the frequency of renal impairment, defined as the percentage of patients with serum creatinine >2 mg/dL in the first postoperative week, was not different between dosing groups (lowest quartile group, 10.0% vs highest quartile group, 6.4%, P < 0.01). Renal failure requiring dialysis after surgery was also not different between the dosing groups (lowest quartile group, 3.3% vs highest quartile group, 2.3%, P < 0.01). As there was no placebo control group, it is difficult to determine whether the incidence of renal impairment was affected by aprotinin.

Royston et al. (14) report a retrospective analysis of data from 1723 patients enrolled in five prospectively randomized, double-blind, placebo-controlled studies of aprotinin. These data represent those used by the manufacturer (Bayer Corporation, West Haven, CT) in their 1998 application to the US FDA for approval of aprotinin for the indication of prophylactic use during CABG surgery to reduce blood loss and blood transfusion. Royston et al. (14) found that, when compared with the 861 patients treated with placebo, the 862 patients treated with aprotinin had a reduced incidence of cerebrovascular outcomes (odds ratio, 0.42, 95% CI, 0.19–0.93, P = 0.03), but no difference in the frequency of death (OR = 1.00, 95% CI 0.54–1.85; P = 1.0) or myocardial infarction (OR 0.92, 95% CI 0.64–1.31; P = 0.6). Patients receiving aprotinin were observed to have a reduced requirement for cardiovascular support with inotropic drugs (odd ratio, 0.79, 95% CI, 0.64–0.97, P = 0.02), vasopressors (odds ratio, 0.74, 95% CI 0.61–0.90, P < 0.01), and antiarrhythmics (odds ratio, 0.79, 95% CI, 0.65–0.96, P = 0.02) when compared with placebo-treated patients. The frequency of investigator-reported renal dysfunction was not different between placebo and aprotinin-treated patients (2% in both groups). Renal end-points were not specifically reported, but reference is given to the product insert where the frequency of an increase in creatinine from baseline of >0.5 mg/dL was not different between aprotinin and placebo-treated patients.

In general, many of the results reported by Royston et al. (14) are not surprising and have been published as separate studies or in nonpeer-reviewed forms, including the package insert (16). The new information presented is the finding of less need for pharmacologic support for patients receiving aprotinin versus placebo. There was no specific protocol for use of these drugs. The randomized, double-blind study design implies that the indications for use of vasoactive drugs, though, should have been similar between aprotinin and placebo-treated patients (particularly within a particular study site). This study design should further ensure that the likelihood of requiring this therapy would be equal between the groups before surgery. Neither assumption is assured, however, by their analysis. At face value, the findings of less pharmacologic therapy might seem to be less interesting than the results for "harder outcomes." The reduced requirement for vasoactive drugs with aprotinin treatment might indicate a previously under-appreciated effect of the drug on organ dysfunction after cardiac surgery. As aprotinin attenuates inflammatory processes associated with CABG surgery, these data could represent a modulating effect of the drug on organ ischemia–reperfusion processes (17). However, the retrospective study design and other methodological issues preclude drawing conclusions about any organ-protective effects of aprotinin during CABG surgery.

How might clinicians now judge the available data regarding aprotinin? The benefits of aprotinin for reducing bleeding complications from cardiac surgery are not disputed, albeit its relative efficacy when compared with the lysine analogs antifibrinolytics tranexamic acid and -aminocaproic acid is not completely resolved, particularly for patients at high risk for bleeding. The major question on clinicians' mind is the safety profile of aprotinin. Prospectively randomized, double-blind, placebo-controlled studies, such as that reported by Royston et al. (14), remain the "gold standard" for evaluating the efficacy of a compound in clinical trials. Many such trials contain far too few patients to adequately assess the safety of the drugs with respect to low frequency complications. A stringent meta-analysis of prospectively randomized trials involving 7027 patients found no evidence of higher rates of myocardial infarction, stroke, or renal dysfunction with aprotinin (18). In this meta-analysis, blood-sparing efficacy was similar between aprotinin and tranexamic acid. Both of these antifibrinolytic drugs were superior to -aminocaproic acid in this regard.

While providing a large set of data for examining low frequency complications, a concern with the retrospective analysis by Managano et al. (10) and Karkouti et al. (11) is that the decision regarding use of aprotinin was not part of a protocol. A bias toward the use of aprotinin in high-risk patients is possible, such that the use of the drug might serve as a marker for patients likely to have worse outcomes regardless of antifibrinolytic therapy. Indeed, the patients in the study by Mangano et al. (10) seem to have a higher prevalence of risk factors such as diabetes, hypertension, heart failure, carotid stenosis, complex surgery, and other variables. Propensity-adjusted analysis as used by Mangano et al. (10) is meant to adjust for their differences between controls and treatment groups. In the study by Karkouti et al. (11), only patients at high risk for transfusion were included in the analysis that also used propensity scoring. Nonetheless, despite these statistical adjustments, it remains possible that some unmeasured variable (or bias) in favor of aprotinin use for higher risk patients persists. Renal dysfunction, for example, identifies patients more likely to have severe atherosclerosis of the ascending aorta, which is itself associated with higher rates of stroke and other adverse outcomes (19,20). This important risk factor was not reported by Mangano et al. (10) or Karkouti et al. (11) leaving open the question of whether the patients receiving aprotinin were indeed of similar risk for adverse events as those not receiving the drug.

Adverse events associated with aprotinin may arise from direct organ toxicity of the drug or from prothrombotic complications. Concerns about the potential for aprotinin to lead to intravascular thrombosis are not new, and were noted early after its introduction into clinical practice (21,22). This was before it was widely known that aprotinin could artifactually prolong the celite-based activated clotting time (ACT). Current recommendations in the aprotinin package insert for monitoring of heparin's effect during cardiopulmonary bypass are to use a kaolin-based ACT, to maintain the celite-based ACT >750 s, to monitor heparin concentrations, or to administer heparin in a time-dependent fixed schedule. Conditions of a closely monitored protocol used for a randomized clinical trial might have ensured adequate anticoagulation when compared with "real world" use of aprotinin, providing another explanation for the discrepancy between the accumulated data from prior trials and the studies by Mangano et al. (10) Karkouti et al. (11) and Kincaid et al. (12).

Upcoming issues of Anesthesia &Analgesia will feature several articles regarding aprotinin, including a Pro/Con debate and State-of-the-Art reviews. Hopefully, these articles will provide clinicians with further information to help their clinical decision-making regarding antifibrinolytic therapy during cardiac surgery. Certainly, anesthesiologists and cardiac surgeons throughout the world anxiously await the results of the Blood Conservation using Antifibrinolytics: Randomized Trial (BART) nearing completion in Canada (23). Interim safety results suggesting no differences in important clinical outcomes among patients receiving aprotinin, tranexamic acid, or -aminocaproic acid were recently reported at the Annual Meeting of the Society of Cardiovascular Anesthesiologists. In US, the controversy regarding aprotinin use in cardiac surgery has been acknowledged by the FDA, who are evaluating the implications of the recent publications suggesting potential harm from the drug (24). In their communications, the FDA wisely suggests that physicians should consider limiting aprotinin use to those situations where the clinical benefit of reduced blood loss is deemed essential to patient management. They also advise careful monitoring of heart, central nervous system, and kidneys for potential toxicity and to report adverse events to the manufacturer and to FDA MedWatch (25). We would further advise clinicians to review a statement by the Society of Cardiovascular Anesthesiologists (http://www.scahq.org) regarding the use of antifibrinolytic drugs during cardiac surgery and to carefully monitor this internet website for future developments.

Note Added in Proof:
As this issue was going to press, there were several developments regarding aprotinin (Trasylol, Bayer Pharmaceuticals, West Haven, CT) use during cardiac surgery. On September 21, 2006, the FDA's Cardiovascular and Renal Drug Advisory Committee met to review recent data regarding the safety of aprotinin. The panel concluded that aprotinin is safe and effective for reducing bleeding for patients undergoing heart bypass surgery but that the product labeling needed updating. On September 29, 2006, the FDA released a public health advisory stating that it had learned that Bayer Pharmaceuticals failed to reveal a retrospective database study it had conducted involving 67,000 patients undergoing CABG surgery. Preliminary analysis of this study suggested that aprotinin use was associated with risk for death, kidney dysfunction, congestive heart failure, and stroke. This study was not reported during the September 21, 2006 Advisory Committee meeting. The FDA reports that it is considering this new information and it advises that aprotinin use should be limited to patients in whom the risks for blood loss outweigh the drug's risks. (www.fda.gov/cder/drug/InfoSheets/HCP/aprotininHCP.htm)

	Footnotes

 
Accepted for publication July 27, 2006.

Dr. Hogue has received honorarium for participation in continuing medical education programs indirectly sponsored by Bayer Corporation. Dr. London reports no conflicts of interest.

	REFERENCES

Top Introduction REFERENCES

 

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