Elsevier

The Lancet

Volume 354, Issue 9194, 4 December 1999, Pages 1940-1947
The Lancet

Articles
Pharmacological strategies to decrease excessive blood loss in cardiac surgery: a meta-analysis of clinically relevant endpoints

https://doi.org/10.1016/S0140-6736(99)01264-7Get rights and content

Summary

Background

Excessive bleeding may complicate cardiac surgery, and is associated with increased morbidity and mortality. Pharmacological strategies to decrease perioperative bleeding have been investigated in a large number of controlled trials, most of which have shown a decrease in blood loss. However, most studies lacked sufficient power to detect a beneficial effect on clinically more relevant outcomes. We did a meta-analysis of all randomised, controlled trials of the three most frequently used pharmacological strategies to decrease perioperative blood loss (aprotinin, lysine analogues [aminocaproic acid and tranexamic acid], and desmopressin).

Methods

Studies were included if they reported at least one clinically relevant outcome (mortality, rethoracotomy, proportion of patients receiving a transfusion, or perioperative myocardial infarction) in addition to perioperative blood loss. In addition, a separate meta-analysis was done for studies concerning complicated cardiac surgery.

Findings

We identified 72 trials (8409 patients) that met the inclusion criteria. Treatment with aprotinin decreased mortality almost two-fold (odds ratio 0·55 [95% CI 0·34-0·90]) compared with placebo. Treatment with aprotinin and with lysine analogues decreased the frequency of surgical re-exploration (0·37 [0·25-0·55], and 0·44 [0·22-0·90], respectively). These two treatments also significantly decreased the proportion of patients receiving any allogeneic blood transfusion. By contrast, the use of desmopressin resulted in a small decrease in perioperative blood loss, but was not associated with a beneficial effect on other clinical outcomes. Aprotinin and lysine analogues did not increase the risk of perioperative myocardial infarction; however, desmopressin was associated with a 2·4-fold increase in the risk of this complication. Studies in patients undergoing complicated cardiac surgery showed similar results.

Interpretation

Pharmacological strategies that decrease perioperative blood loss in cardiac surgery, in particular aprotinin and lysine analogues, also decrease mortality, the need for rethoracotomy, and the proportion of patients receiving a blood transfusion.

Introduction

Although the complication rate of coronary-artery bypass grafting or heart-valve replacement has decreased, excessive perioperative bleeding is still common.1 Management of perioperative blood loss requires transfusion of packed cells and other blood products; these procedures increase the risk of immunological complications, and of transmission of infectious agents. In some medical centres, at least a quarter of all blood-product use is for patients undergoing cardiac surgery, which imposes a substantial burden on the limited supply of these products. Moreover, excessive postoperative bleeding may result in the need for re-exploration, which is associated with additional morbidity and mortality.1, 2

Factors that contribute to blood loss in cardiac surgery are related to surgical damage to large blood vessels and acquired defects in haemostasis. The impaired function of the haemostatic system is due to several factors, such as loss of platelets and impairment of platelet function, haemodilution, administration of heparin during cardiopulmonary bypass, and inadequate functioning of the fibrinolytic system.3

Several approaches which aim to keep blood loss to a minimum and to decrease transfusion requirements in patients undergoing cardiac surgery have been developed. Among these strategies, administration of pharmacological agents, of which there are three main types,4 is the most widely used. One such agent is aprotinin-a 58-aminoacid polypeptide, mainly derived from bovine lung, parotid gland, or pancreas-which directly inhibits the activity of various serine proteases, including plasmin, coagulation factors (such as kallikrein and thrombin), or coagulation inhibitors. Aprotinin can preserve platelet function and inhibit accelerated fibrinolysis during cardiopulmonary bypass. Lysine analogues, such as aminocaproic acid and tranexamic acid, are potent inhibitors of fibrinolysis. Treatment with these agents can decrease blood loss in various bleeding disorders. Desmopressin (deamino D-arginine vasopressin [DDAVP]) is a vasopressin analogue that induces release of the contents of endothelial-cell-associated Weibel-Palade bodies, including von Willebrand factor. The administration of desmopressin results in a pronounced increase in the plasma concentration of von Willebrand factor (and associated coagulation factor VIII), leading to potentiation of primary haemostasis.

All three pharmacological interventions have been studied in a large number of clinical trials, many of which used a randomised, controlled study design. Owing to their size, most of the trials, however, lacked sufficient power to detect significant differences in important clinical outcomes, such as mortality and the need for reexploration. Two previous meta-analyses of such trials (including 33 and 60 studies, respectively) focused mainly on perioperative blood loss and the need for transfusion.5, 6 Both analyses found that these interventions significantly decreased the perioperative exposure of cardiac surgery patients to blood products. We now report our findings of a meta-analysis of 72 randomised, controlled trials of the effect of pharmacological strategies that decrease perioperative blood loss on mortality, rethoracotomy, the number of patients receiving any transfusion, and the occurrence of adverse effects, in particular perioperative myocardial infarction.

Section snippets

Literature search

We did a literature search of MEDLINE and EMBASE databases for the period 1966 to December, 1998. Terms used for the search were both MESH terms and (part of) the textwords “heart surgery”, “heart valve prosthesis”, “myocardial revascularization”, “coronary artery bypass”, or “heart bypass”, in combination with “hemostatics”, “antifibrinolytic agents”, “aprotinin”, “trasylol”, “tranexamic acid”, “cyklokapron”, “aminocaproic acid”, “caprolest”, “desmopressin”, or “DDAVP”. The search results were

Literature search and methodological grading

The search yielded 128 clinical trials, and reference cross-checking resulted in 14 additional studies. Of these 142 trials, 95 were apparently randomised, controlled studies. 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88

Discussion

Our meta-analysis shows that pharmacological interventions that significantly decrease perioperative blood loss in cardiac surgery may also have a beneficial effect on clinically more relevant outcomes, such as perioperative mortality, the need for rethoracotomy, and the need for a blood transfusion. In particular, treatment with aprotinin and lysine analogues appears to be effective in this regard. When the analysis was limited to studies in complicated cardiac surgery, defined as repeat

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