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Original Articles: Adult Cardiac

Invited Commentary

The Dartmouth Institute for Health Policy and Clinical Practice, One Medical Center Drive, Lebanon, NH 03756

(Email: jbrown{at}dartmouth.edu).

Ngaage and colleagues [1] investigated a single center 9-year experience with aprotinin (Trasylol; Bayer Pharmaceuticals Corp, West Haven, CT) among patients undergoing primary coronary artery bypass or valve surgery, or both. The premise of this study was to provide a uniform, single-center analysis on aprotinin in contrast with the lack of uniformity in the multicenter approaches. Propensity score matching was used to balance a subgroup of patients receiving or not receiving the full-dose aprotinin regimen. Primary outcomes of the analysis were 30-day mortality, ST segment elevated myocardial infarction, neurologic dysfunction (ie, confusion or cognitive decline), and renal insufficiency (ie, a serum creatinine > 200 µm/L or > 2.3 mg/dL). Secondary outcomes included total blood loss, transfusion, and re-exploration for bleeding or tamponade.

The authors discovered that patients receiving the aprotinin regimen were significantly older with more baseline comorbidities, and these patients underwent more complex procedures compared with the group not receiving aprotinin. Patients receiving aprotinin had significantly higher 30-day mortality, renal insufficiency, dialysis, and neurologic complications. However, after multivariable analysis, using known baseline confounders, aprotinin was not an independent predictor of these outcomes. Among propensity-matched patients, no significant differences were observed in the primary endpoints; however, aprotinin had twice as many deaths compared with the no aprotinin propensity-matched group.

Prospective and retrospective cohort analyses of aprotinin have been widely criticized for their lack of ability to adjust for surgeon preference for aprotinin use. The current study is another example of this limitation. Although patient and operative characteristics may be meticulously collected prospectively, set criterion for aprotinin use is usually nonexistent. The authors described the aprotinin regimen used; however, there was no description of the criteria used by the surgeons to select patients for the aprotinin regimen nor was there a description of the protocol for patients not receiving aprotinin.

The most important comparison of these findings is that with the blood conservation using anti-fibrinolytics in a randomized trial (BART) [2]. The authors contested their findings differed from the BART trial; however, they found the same univariable statistical difference in 30-day mortality as did the BART trial (p = 0.05) [2]. In addition, the authors contested their study had an advantage over the BART trial in that their operative procedures were equivalent in each arm; however, in Table 1 they reported a statistically significant difference in operative procedure between aprotinin groups (p < 0.0001). The current study provides a single-center report on their use of aprotinin for the past 9 years. Although the analysis was well conducted, the issues of unmeasured confounding and selection bias abound and limit the generalizability of the results. Cardiac surgeons must rely on the current highest level of evidence—meta-analyses and randomized controlled trials—to determine the clinical usefulness of aprotinin. The current reality from the BART trial demonstrated lysine analogues tranexamic acid and aminocaproic acid are safe alternatives to the use of aprotinin. Furthermore, after the BART trial publication, Bayer Pharmaceuticals issued a report to the United States Food and Drug Administration stating their intent to remove aprotinin from all hospital pharmacies and warehouses [3]. In a recent editorial, published along with the BART trial, Ray and Stein concluded that "in all likelihood, this is the end of the aprotinin story" [4]. We must move forward from aprotinin and focus our attention on ways to limit blood loss and transfusion that are safe and effective for patients undergoing cardiac surgery.

	References

Top References

 

1. Ngaage DL, Cale AR, Cowen ME, Griffin S, Guvendik L. Aprotinin in primary cardiac surgery: operative outcome of propensity score-matched study Ann Thorac Surg 2008;86:1195-1203.[Abstract/Free Full Text]
2. Fergusson DA, Hebert PC, Mazer CD, et al. A comparison of aprotinin and lysine analogues in high-risk cardiac surgery N Engl J Med 2008;358:2319-2331.[Abstract/Free Full Text]
3. Manufacturer Removes Remaining Stocks of Trasylol Access Limited to Investigational Use. May 14, 2008. United States Food and Drug Administrationhttp://www.fda.gov/bbs/topics/NEWS/2008/NEW01834.html 2008Accessed July 30, 2008.
4. Ray WA, Stein CM. The aprotinin story–is BART the final chapter? N Engl J Med 2008;358:2398-2400.[Free Full Text]

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