Aprotinin: Old drug, new ideas

shenxiu2

Aprotinin: Old drug, new ideas
Antifibrinolytic agents, such as aprotinin, are used to reduce bleeding and the need for transfusions in complex surgery. Aprotinin inhibits the activity of plasmin and other serine proteases, and its efficacy has been studied in multiple randomized, placebo-controlled trials. [1]

Recent studies examining adverse events have assessed data from observational databases. [2–4] The underlying question to any analysis using observational data from non-randomized patients is why a patient receives a particular therapy. In observational studies, clinicians control the treatment assigned, thus higher risk patients receive different therapies. Patients at risk for bleeding also receive allogeneic blood products,  factors that might influence surgery outcomes. [5–8]

The Blood conservation using Antifibrinolytics in a Randomized Trial (BART) was a prospective study that randomized 2331 high-risk cardiac surgery patients to three different antifibrinolytic agents: 781 received aprotinin, 770 received tranexamic acid, and 780 received aminocaproic acid. [9]

The primary outcome was massive postoperative bleeding; secondary outcomes included death from any cause at 30 days. A total of 74 patients (9.5%) in the aprotinin group had severe bleeding, compared with 93 (12.1%) in the tranexamic acid group and 94 (12.1%) in the aminocaproic acid group.

At 30 days, the relative risk of death in the aprotinin group was 1.53 (95% Confidence Interval [CI] 1.06– 2.22) compared with that of both groups receiving lysine analogues. This particular study resulted in an FDA-requested marketing suspension of aprotinin. The most recent FDA update was in May 2008, reporting that they would review the data from the BART study and would re-assess both the status of aprotinin and access to the product once the review was complete.

(http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders
/ucm142720.htm)

Karkouti et al recently reported a retrospective single-center cohort analysis to determine the risk-benefit ratio of using aprotinin for reducing bleeding following cardiac surgery. [10]

A total of 15,365 patients were included in the study, of which 1017 patients received aprotinin and 14,358 received tranexamic acid. The authors used propensity score methods to create a matched-pair cohort (n=1544) that was then adjusted for between-group differences. Unlike previous reported studies, the authors matched the influence of patients’ risk status with use of aprotinin associated with in-hospital mortality, morbidity, and blood loss. Aprotinin was only associated with an increased incidence of acute kidney injury. [10]

The underlying risk status of patients significantly influenced the associations of aprotinin use with increased mortality, acute kidney injury, and massive blood loss. Karkouti and colleagues noted that among high-risk patients, the respective odds ratios were 0.6 (CI 0.3–1.0), 1.1 (CI 0.7–1.7), and 0.7 (CI 0.4 –1.04), respectively, but differed in the low-to-moderate risk patients (1.5 CI 0.9 –2.7, 2.2 CI 1.4 –3.5, and 1.2 (CI 0.9 –1.07), respectively). The authors concluded that aprotinin has a better risk-benefit profile than tranexamic acid in high-risk patients, but not in low-to-moderate risk patients, and that suggests use of aprotinin in high-risk cases might, therefore, be warranted. [10]

Although the study by Karkouti et al is retrospective, it is important to note that most other reported studies examining adverse events are also retrospective with the exception of BART. [9]

In a quantitative overview of published, randomized, controlled trials from 35 coronary artery bypass grafting trials (n = 3879), aprotinin therapy was not associated with increased mortality (relative risk 0.96, 95% CI 0.65–1.40), myocardial infarction (relative risk 0.85, 95% CI 0.63–1.14), or renal failure (relative risk 1.01, 95% CI 0.55–1.83) risk, but it was associated with a reduced risk of stroke (relative risk 0.53, 95% CI 0.31–0.90). [1]

One additional important consideration for surgical studies, especially heart surgery, is the role of the surgeon in patient outcomes. [11] Karkouti et al controlled for multiple measures of comorbidity, including both surgical complexity and the individual surgeon. In addition, the study lacks a placebo-control group and, therefore, provides no information on the risk-benefit ratio of using antifibrinolytic drugs in general for heart surgery.

It is clear from the work presented by Karkouti and colleagues that adverse effects associated with aprotinin use are significantly influenced by the individual patient’s risk status; use of aprotinin tended to be associated with lower massive blood loss and adverse event rates in high-risk patients, but not in low-to-moderate risk patients. As the authors suggest, the use of aprotinin might be warranted in patients whose risk status is high — as determined by their comorbidities, surgical acuity, and complexity — however, these results still need to be corroborated by randomized, controlled trials in high-risk patients.


References
1. Sedrakyan A, Treasure T, Elefteriades JA. Effect of aprotinin on clinical outcomes in coronary artery bypass graft surgery: a systematic review and meta-analysis of randomized clinical trials. J Thorac Cardiovasc Surg 2004; 128: 442-448.
2. Mangano DT, Tudor IC, Dietzel C. The risk associated with aprotinin in cardiac surgery. N Engl J Med 2006; 354: 353-365.
3. Shaw AD, Stafford-Smith M, White WD et al.The effect of aprotinin on outcome after coronary-artery bypass grafting. N Engl J Med 2008; 358: 784-793.
4. Schneeweiss S, Seeger JD, Landon J, Walker AM. Aprotinin during coronary-artery bypass grafting and risk of death. N Engl J Med 2008; 358: 771-783.
5. Levy JH, Despotis GJ, Spitznagel E. Should aprotinin continue to be used during cardiac surgery? Nat Clin Pract Cardiovasc Med 2006; 3: 360-361.
6. Furnary AP, Wu Y, Hiratzka LF, Grunkemeier GL, Page US. Aprotinin does not increase the risk of renal failure in cardiac surgery patients. Circulation 2007; 116: I127-1133.
7. Spiess BD, Royston D, Levy JH et al. Platelet transfusions during coronary artery bypass graft surgery are associated with serious adverse outcomes. Transfusion 2004; 44: 1143-1148.
8. Koch CG, Li L, Sessler DI et al. Duration of red-cell storage and complications after cardiac surgery. N Engl J Med 2008; 358: 1229-1239.
9. 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.
10. Karkouti K, Wijeysundera DN, Yau TM et al. The risk-benefit profile of aprotinin versus tranexamic acid in cardiac surgery. Anesth Analg 2010; 110: 21-29.
11. Ott E, Mazer CD, Tudor IC et al. Coronary artery bypass graft surgery-care globalization: the impact of national care on fatal and nonfatal outcome. J Thorac Cardiovasc Surg 2007; 133: 1242-1251.

封女士

有奖中英文一句话互译