Antifibrinolytics Found to Reduce Bleeding Safely in Elective Surgery

NEWCASTLE, Australia, Oct. 17 -- Three antifibrinolytic agents each reduced blood loss and red-cell transfusions associated with elective surgery, without an increased risk of thrombosis, according to a literature review.

The drugs provided worthwhile reductions in blood loss, particularly after high-risk cardiac surgery, without an additional risk of vascular occlusion or death, David A. Henry, M.B., FRCP, of the University of Newcastle here, and other Cochrane reviewers, reported online.

The three drugs were aprotinin (Trasylol), a non-specific serine protease inhibitor with anti-fibrinolytic properties, and two lysine analogues, tranexamic acid (TXA) (Cyclocapron) and epsilon aminocaproic acid (EACA) (Amicar).

Antifibrinolytic drugs are widely used, particularly in cardiac surgery, and previous reviews have found them effective in reducing the need for allogeneic red-cell transfusions.

To assess the comparative drug effects and adverse events, the reviewers identified and reviewed 211 randomized controlled trials with 20,781 participants. The searches were last updated in July 2006.

Data from placebo and inactive controlled trials, and from head-to-head trials suggested an advantage for aprotinin over TXA and EACA in terms of operative blood loss, but the differences were small, the reviewers said.

Aprotinin reduced the probability of requiring red-cell transfusions by a relative 34% (relative risk [RR] 0.66, 95% confidence interval 0.61 to 0.71).

The relative risk for transfusion with TXA was 0.61 (CI 0.54 to 0.69) and 0.75 (CI 0.58 to 0.96) with EACA.

When the pooled estimates from the head-to-head trials of the two lysine analogues were combined and compared with aprotinin alone, aprotinin appeared superior in reducing the need for red-cell transfusions (RR 0.83 [CI 0.69 to 0.99]).

Aprotinin reduced the need for re-operation due to bleeding: RR 0.48 (95% CI 0.35 to 0.68). This translated into an absolute risk reduction of just under 3% with a number needed-to-treat of 37 (CI 27 to 56).

Similar trends were seen with TXA and EACA, but the data were sparse and the differences failed to reach statistical significance, the reviewers said.

The transfusion data in the studies were heterogeneous and funnel plots indicated that the trials of aprotinin and the lysine analogues may have been subject to publication bias.

Evidence of publication bias was not observed in trials reporting re-operation rates. Adjustment for these effects reduced the size of the estimated benefits but did not negate treatment effects.

However, the apparent small advantage of aprotinin over the lysine analogues may be explained by publication bias and non-equivalent drug doses, the reviewers said.

As for the safety of aprotinin, the drug did not increase the risk of myocardial infarction (RR 0.92, CI 0.72 to 1.18), stroke (RR 0.76, CI 0.35 to 1.64) renal dysfunction (RR 1.16, CI 0.79 to 1.70), or overall mortality (RR 0.90, 95% CI 0.67 to 1.20).

Nevertheless, the researchers said that the benefits from these drugs did not translate into reduced mortality in the available trials.

The analyses of myocardial infarction and death included data from the majority of individuals in the aprotinin. However, under-reporting of renal events could explain the narrow findings seen with aprotinin.

Similar trends were seen with the lysine analogues but data were sparse.

In discussing the findings, the reviewers said that in most circumstances the lysine analogues are probably as effective as aprotinin and are substantially cheaper. The evidence, they said is stronger for TXA than for EACA.

In high-risk cardiac surgery, where there is a substantial risk of serious blood loss, aprotinin, which has been more extensively studied, may be preferred over TXA, they said.

Still, they added, it may be reasonably concluded that TXA is as effective as aprotinin, particularly when used as an adjunct to non-cardiac surgical procedures. The data for EACA are sparser and thus not so convincing, they said.

Aprotinin did not appear to be associated with an increased risk of vascular occlusion and death, but the data (relative risk of 1.16) do not exclude an increased risk of renal failure, they said.

"There is no need for further placebo-controlled trials of aprotinin or lysine analogues in cardiac surgery," the reviewers said.

The principal need is for larger comparative trials to assess the relative efficacy, safety, and cost-effectiveness of anti-fibrinolytic drugs in different surgical procedures, they concluded.