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Original Article

Recombinant activated factor VII in cardiac surgery

Ranucci, M.; Isgrò, G.

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European Journal of Anaesthesiology: June 2007 - Volume 24 - Issue - p 83-88
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Abstract

Recombinant activated factor VIIa (rFVIIa): pharmacological characteristics and mechanism of action

rFVIIa (eptacog alpha activated, Novoseven{L-End} ®) was introduced in clinical practice at the beginning of the '80s. It is a recombinant preparation of activated blood coagulation factor VII.

Its action is basically thought to be double-sided: on one side it acts locally at the site of the tissue injury and vessel wall disruption, binding to exposed tissue factor and generating small amount of thrombin (initiation) that activate platelets (amplification). On the other side, rFVIIa may act directly on the surface of the activated platelets, generating much more thrombin (propagation) and ultimately triggering the conversion of fibrinogen to fibrin [1].

rFVIIa is currently approved by the Food and Drug Administration (FDA) for the use in patients with congenital or acquired hemophilia and inhibiting antibodies toward factor VIII or IX.

rFVIIa off-label use

In recent years, a consistent and growing amount of reports and scientific publications have suggested many ‘off-label’ indications of rFVIIa in bleeding disorders associated to surgical procedures in patients without any known congenital haemostasis and coagulation defects.

The existent literature is mainly composed by case reports [2-17] and case series [18-34] apparently describing a positive experience. Some retrospective studies with historical controls [35-38] and prospective, randomised trials [39-48] have been published, but at present the results seem conflicting or biased by the underpower of many studies.

Cardiac surgery, both for paediatric and adults patients, is probably the surgical scenario were the major experience with rFVIIa is reported.

rFVIIa in cardiac surgery

At a systematic review of the PubMed online database (search terms ‘rFVIIa’, ‘Novoseven’, ‘recombinant activated factor VIIa’ and ‘cardiac surgery’), 35 articles could be retrieved (Table 1).

Table 1
Table 1:
rFVIIa in cardiac surgery: articles retrieved.

There are 11 case reports, 12 case series, 5 review articles, 3 retrospective studies, 2 letters to the Editor, and only one prospective, double-blinded, randomized clinical trial (RCT).

(a) Efficacy of the treatment

Basically, the majority of the case reports and case series retrieved in the literature report the successful use of rFVIIa as a “savage” treatment in patients with intractable bleeding after cardiac operations. Both adult and paediatric patients are reported.

Of course, these anedoctical series represent a very weak demonstration of the efficacy of rFVIIa in cardiac surgery patients demonstrating severe bleeding after the operation.

A more sound information is given by the retrospective studies [36, 38, 58] and by the only RCT (48).

The efficacy of a treatment aimed to reduce severe bleeding after cardiac operations can be addressed using different endpoints: (a) perioperative blood loss; (b) number of patients needing allogeneic blood products; (c); amount of allogeneic blood products used; and (d) associated morbidity and mortality.

Karkouti and coworkers [36], in 2005, compared 51 cardiac patients who received rFVIIa for intractable blood loss after cardiac surgery with 51 matched controls. However, due to the retrospective nature of the study, no propensity score matching with respect to surgical reexploration, allogeneic blood products use, and blood loss was possible, being these three last variables higher in the rFVIIa group. The rFVIIa group was suffering from massive bleeding before treatment in 92% of the patients vs. 60% in control group. Therefore, no direct comparison between treated and control patients with respect to the efficacy of the treatment was possible. However, after rFVIIa administration, blood loss was significantly reduced. Patients receiving rFVIIa had a slower postoperative recovery and a higher incidence of acute renal dysfunction. The authors conclude that rFVIIa may be an effective rescue therapy for patients with intractable haemorrhage after cardiac surgery.

Von Heymann and coworkers [38] did a retrospective cohort analyisis comparing 24 patients treated with rFVIIa with matched pair controls. The authors demonstrated that after rFVIIa administration there was a significant reduction in blood loss and transfusions. No differences were seen between rFVIIa and control group both on the side of efficacy and postoperative outcome. The authors concluded that the treatment is safe but not efficacious.

In 2006, Romagnoli and coworkers [58] did a retrospective study of patients treated with small (1.2 mg) doses of rFVIIa compared to matched controls. They could demonstrate a significantly lower blood loss in treated patients, together with a reduction in allogeneic blood products use. Treated patients had a better postoperative outcome and the authors concluded that the treatment with small doses of rFVIIa showed encouraging results.

Finally, Diprose and coworkers [48] published in 2005 a RCT on patients undergoing non-coronary, complex cardiac surgery. 40 patients were randomly allocated to receive rFVIIa or placebo. A strict transfusional protocol was applied. The number of patients needing allogeneic blood products was significantly lower in the treated group, and the total amount of units transfused was significantly reduced. No differences were seen with respect to blood loss. The authors conclude that rFVIIa is effective in limiting the transfusional needs after complex cardiac surgery.

(b) Safety of the treatment

The pharmacological action of rFVIIa is primarily based on its ability to determine a burst of thrombin formation. Therefore, not surprisingly many authors raised the concern that this treatment may be associated to thromboembolic events. Some reports in the literature suggest this possibility, that is considered in a recent article [49] reporting guidelines for the use of rFVIIa.

Of course the cardiac surgery scenario is probably the environment where the risk of thromboembolic events is higher, both due to the patients' characteristics, the presence of districts of critical blood flow (coronary grafts) and the presence of thromboembolic events in the postoperative course of untreated patients (perioperative myocardial infarction, stroke, mesenteric infarction, pulmonary and peripheral thromboembolism). Depite this, to our knowledge the reports of thromboembolic events associated with the use of rFVIIa are outside the cardiac surgical scenario, and all the already quoted retrospective and RCT studies failed in demonstrating a higher rate of thromboemblic complications in treated patients.

However, we are lacking the important information about how rFVIIa is reacting with the ‘procoagulant’ drugs commonly used in cardiac surgery (aprotinin, tranexamic acid, desmopressin…), and therefore all the authors maintain a certain caution when addressing safety issues involved in rFVIIa treatment.

(c) What is the dose?

Not surprisingly, being the use of rFVIIa in cardiac surgery an off-label, rescue indication, the problem of the dosage is quite confusing. No clear protocol is reported in literature, unless for two studies. Romagnoli and coworkers [58] propose a low-dose regimen (about 20 μg/kg) and Diprose and coworkers [48] a much higher dose of 90 μg/kg at the end of cardiopulmonary bypass.

The study of Karkouti and coworkers [36] reports a retrospective experience with a dose ranging from 40 to 60 μg/kg, and von Heymann a first dose of 60 μg/kg followed in 42% of the patients by a second dose and in 8% by a third dose. Therefore, a dose range from 20 to 180 μg/kg is reported. No information is available with respect to the dose-response efficacy.

Conclusions

Bleeding after cardiac surgery is still one of the major concerns for the clinician. However, it appears quite clear that not bleeding itself, but allogeneic blood products are the determinants of morbidity and mortality, and not by chance the majority of the studies address the problem using the transfusion rate and amount as the primary endpoint for testing the efficacy of the treatment.

At present, we are lacking a large RCT to say the final word about the efficacy of rFVIIa for the treatment of intractable bleeding after cardiac surgery, but the general trend is in favour of this option. However, this information is limited to lifethreatening cases, that after cardiac surgery are rare, but however possible in selected categories of patients (emergent ascending aorta or aortic arch surgery; grown up congenital heart patients…). In this specific environment, many case reports demonstrate a life-saving effect of the drug. Considering the pharmacological action of rFVIIa, an important point is probably the correct timing of the intervention: theoretically, this expensive treatment should be considered before using too many allogeneic blood products, in order to maintain the cost-effectiveness of the treatment and most importantly to reduce the transfusion-related morbidity. At the same time, an early, “prophylactic” treatment does not seem appropriate at the light of the only RCT available, where a limited, albeit significant effect of the drug was demonstrated in terms of allogeneic blood transfusions (9 units per patients): as a matter of fact, considering the cost of the treatment, a mean savage of at least 25 packed red cells units per patients is needed to cover the cost of the therapy. Moreover, in the decisional process other issues should be considered, such as the possibility of a surgical bleeding and the risk for thromboembolic complications. Rapid, point-of-care coagulation tests (platelet function and thromboelastography) could be useful decisional tools.

In conclusion, rFVIIa appears as a possible weapon within our armamentarium whenever facing a lifethreating haemorrage after cardiac surgery; however, no clear information is available with respect to the adequate dose, timing, indications, and possible complications.

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                                        Keywords:

                                        coagulation factors; blood transfusions; surgery

                                        © 2007 European Society of Anaesthesiology