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[JAMA述评]:心脏外科术后纤维蛋白原浓缩物能否替代冷沉淀?
2019年11月25日 研究点评, 进展交流 暂无评论

Editorial October 21, 2019

Should Fibrinogen Concentrate Replace Cryoprecipitate in Cardiac Surgery?

Aaron S. Hess, John R. Hess, Douglas B. Coursin

JAMA. Published online October 21, 2019. doi:10.1001/jama.2019.17313

Excessive bleeding presents a critical medical challenge. Many of the problems encountered at the bedside, such as inadequate measures of coagulation, challenges in delivering blood components, uncertain role of prothrombotic drugs or antifibrinolytics, dilutional coagulopathy, varied clinical settings, and patient comorbidities, have occupied a great deal of recent research effort and still have only imperfect solutions. Fibrinogen is an essential component of hemostasis: it is cleaved by thrombin into fibrin, which polymerizes into factor XIII–crosslinked fibers that have important functions in adhesion, platelet aggregation, and inflammation.1 A low fibrinogen level is an ominous finding in patients with bleeding, but it has been difficult to prove the utility of direct fibrinogen replacement.2 More than 20 small trials have suggested that using fibrinogen concentrate reduces bleeding and transfusions in various clinical situations, but any general conclusions are limited by the study sizes, quality, and heterogeneity in methods.3,4

Concentrated fibrinogen is available in either prepared fibrinogen concentrates or cryoprecipitate. Fibrinogen concentrate is human-derived, and both forms commercially available in North America come as 1 g of lyophilized fibrinogen. The powder is stable for at least 3 years at refrigerator temperature, does not require thawing or blood bank handling, and is treated for inactivation of several viruses that may be transmitted via transfusion.5,6 Reconstitution requires 50 mL of fluid and 5 to 10 minutes of gentle swirling to avoid foaming and denaturation, and the reconstituted product is stable for 24 hours at room temperature.

Cryoprecipitate is a blood component created by thawing units of frozen plasma at 1°C to 6°C and collecting the precipitated proteins by centrifugation.7 It is usually supplied in 5-unit pools of approximately 100 mL. Cryoprecipitate contains a concentration of fibrinogen similar to that of reconstituted fibrinogen concentrate but also contains fibronectin, von Willebrand factor, factor VIII, and factor XIII. In vitro comparison shows that cryoprecipitate is better at attenuating tissue plasminogen activator–induced fibrinolysis than fibrinogen concentrate, consistent with the hypothesis that factor XIII will support a well–cross-linked fibrin polymer.8 Cryoprecipitate requires 2 to 10 minutes to thaw after ordering and must be used within 4 hours.7 Infectious risk is increased because of pooling, but attempts to apply pathogen-inactivation technology have resulted in reduced potency.9 Cryoprecipitate is perhaps 4 to 10 times less expensive per gram of fibrinogen than fibrinogen concentrate, although the total costs including clinical outcomes, labor, and operating room time may be closer to equivalent under certain local circumstances.10

In this issue of JAMA, Callum and colleagues11 present the results of the FIBRES trial, a multicenter, single-blind, randomized, comparator-controlled, noninferiority clinical trial of fibrinogen concentrate vs cryoprecipitate in patients undergoing cardiac surgery and experiencing major bleeding. The trial enrolled adults undergoing cardiac surgery who had clinically significant bleeding requiring fibrinogen replacement after cardiopulmonary bypass. Participants in the intervention group received commercially available fibrinogen concentrate in 4-g doses, and those in the control group received 10-unit doses of cryoprecipitate. The study interventions continued as indicated for 24 hours after cardiopulmonary bypass, after which all participants received cryoprecipitate if further fibrinogen replacement was indicated. Total postoperative follow-up was for 28 days. Use of tranexamic acid to prevent fibrinolysis was routine at all trial centers but not standardized by protocol. The primary outcome was the total number of allogeneic blood products used in the 24 hours after cardiopulmonary bypass, not including cryoprecipitate. Secondary outcomes included total allogeneic transfusions through postoperative day 7, individual use of red blood cell, plasma, and platelet units, bleeding severity during the 24 hours after cardiopulmonary bypass, and pretreatment and posttreatment fibrinogen levels. The authors estimated that 1200 participants would provide more than 90% power to detect noninferiority with a 20% margin, assuming a 10% loss to follow-up.

A total of 827 participants were enrolled at 11 participating Canadian centers, of whom 735 were included in the primary analysis. The trial was stopped after the interim analysis because the prespecified noninferiority criterion was met. The mean number of allogeneic blood component transfusions in the 24 hours after cardiopulmonary bypass was 16.3 (95% CI, 14.9 to 17.8) units in the fibrinogen concentrate group and 17.0 (95% CI, 15.6 to 18.6) units in the cryoprecipitate group, and the mean ratio was 0.96 (1-sided 97.5% CI, -∞ to 1.09; P < .001 for noninferiority). Fibrinogen concentrate was also noninferior with respect to the secondary outcomes of individual blood component use, cumulative 7-day component use, and component use in the 24 hours after first dose of study product. Among adverse events, there were no differences between the fibrinogen concentrate and cryoprecipitate groups in mortality (35 [9.4%] vs 27 [7.4%]; unadjusted hazard ratio, 1.28 [95% CI, 0.77 to 2.12]) or thromboembolic events (26 [7.0%] vs 35 [9.6%]; unadjusted odds ratio, 0.70 [95% CI, 0.42 to 1.20]).

This trial has many important strengths. It is the largest randomized, comparator-controlled clinical trial of fibrinogen concentrates in severe bleeding, more than doubling the previous number of studied patients. The interventional and control groups used doses and protocols that correspond well to current fibrinogen replacement strategies in North America. The trial was also well conducted, with good adherence to protocol, less than 5% loss to follow-up, and thoughtful analyses.

The trial also has several important limitations. First, it is not clear whether participants in the 2 study groups received equal amounts of fibrinogen. The fibrinogen concentration of cryoprecipitate is often indicated to be 250 to 300 mg per unit, although published measurements are sometimes lower, and the AABB (formerly the American Association of Blood Banks) requires only that the fibrinogen level is greater than 150 mg per unit.7,12 The authors state, with reference to a private communication, that units of cryoprecipitate from the Canadian Blood Services (CBS) contain an average of 400 mg of fibrinogen. The CBS Circular of Information for plasma derivatives published during the enrollment period reports a mean dose per unit of 285 (SD, 88) mg.13 If this is correct, then the average participant in the cryoprecipitate group received only 2.9 g of fibrinogen initially and 3.6 g in total, compared with 4 g initially and 4.8 g in total in the fibrinogen concentrate group. Put another way, participants in the cryoprecipitate group may have received 70% of the initial and 75% of the total fibrinogen doses received by participants in the fibrinogen concentrate group. Assuming normal body weights and blood volumes, a difference in mean posttransfusion serum fibrinogen concentration of about 0.2 g/L in favor of the concentrate group would be expected, which is in fact what was observed (median increase, 0.9 [interquartile range, 0.6–1.2] g/L vs 0.7 [interquartile range, 0.5–1.0] g/L; P < .001). On the other hand, if these results are unrelated and the average cryoprecipitate unit in the trial had 400 mg of fibrinogen, then some adjustment will need to be made when comparing the findings with the less fibrinogen-rich cryoprecipitate in the US supply.

The analysis plan also has some limitations. Sixty-one randomized participants were excluded from the primary analysis because of rapid cessation of bleeding. This type of post hoc exclusion removes the protection of the randomization and introduces confounding.14 Inclusion of these participants in a proper intention-to-treat analysis would presumably have diluted the confidence intervals around the effect estimate and mildly prolonged the enrollment period. On the other hand, the individual study sites were not accounted for in the primary analysis, although this was done post hoc. Adjustment for stratification variables is recommended because stratification induces correlation, and a simple analysis may rob the study of power.15 It would be impossible to say if these 2 points balance each other out, but it seems unlikely that either would have fundamentally altered the result.

The FIBRES trial is the first large, comparator-controlled randomized trial of fibrinogen concentrates and is focused on a relevant population: patients with severe bleeding. The trial found that 4 g of fibrinogen concentrate appears noninferior to 10 units of cryoprecipitate, with the possibility that fibrinogen concentrate might not be quite equivalent on a gram-per-gram basis. Still, the ease of storage, handling and administration, speed of preparation, and the reduced risk of infection and other transfusion reactions with fibrinogen concentrate are recognized advantages. However, this is not quite the end of cryoprecipitate. Similar well-designed, comparator-controlled trials in other bleeding states need to be pursued, such as trauma, obstetrics, and liver transplantation. It is possible that in settings where prophylactic antifibrinolytic therapy is not universal or routine, such as among patients undergoing liver transplant surgery, cryoprecipitate may still have some advantages over pure fibrinogen replacement in providing stable clot. Other nonsurgical scenarios such as inherited dysfibrinogenemia, disseminated intravascular coagulation, and uremic bleeding often use cryoprecipitate supplementation, and alternatives have not been well-studied. In the meantime, the findings from the FIBRES trial should encourage a wider use of fibrinogen concentrates for patients who have undergone cardiac surgery and experience major bleeding.

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