Sharif Al-Ruzzeh

The "Off-Label" Role of Recombinant Factor VIIa in Surgery: Is the Problem Deficient Evidence or Defective Concept?

a h m ecombinant factor VIIa (rFVIIa) (NovoSeven; Novo ordisk) was originally developed and described by Heder and Kisiel in 1983 for use in treating two patients resenting with hemophilia A complicated with high-titer lloantibodies. In 1999, the US FDA licensed rFVIIa to reat bleeding episodes in patients with hemophilia A or B ith inhibitors (antibodies) to factor VIII or IX, respecively. Subsequently, the license for rFVIIa was extended in 005 to include use in surgical procedures in hemophilia A nd B patients with inhibitors, congenital factor VII defiiency, and Glanzmann thromboasthenia. Within the ame year of the initial FDA approval, rFVIIa was also uccessfully used in the treatment of one trauma and two urgical patients. These early “off-label” successes raised he potential for using rFVIIa in the treatment of virtually ll types of bleeding in patients with “intractable hemorhage,” regardless of the cause of bleeding. As a result, umerous case reports and series have emerged demontrating both remarkable successes and dramatic failures or rastic complications in off-label use of rFVIIa. Complying ith its role, the FDA did an excellent job in analyzing the eported adverse events of rFVIIa use for all patients in the irst 5 years after the initial licensure in 1999. Thrombombolic complications, including serious myocardial and erebral infarctions and pulmonary embolism, happened n about 90% of these reports because of off-label use of FVIIa in patients, most of whom (68%) were actively leeding at the time of administration. In addition, 72% of eported deaths were proved to be a result of these thromoembolic events and 52% of these events happened in the irst 24 hours, proving a temporal association. The aim of the current review is provide an overview of ff-label use of rFVIIa in three different types of surgery, ie, epatic, cardiac, and trauma, in which hemorrhage is a ajor and frequent complication that can be detrimental o the procedure and patient survival. This review does not

The first Latin-American risk stratification system for cardiac surgery: can be used as a graphic pocket-card score

This study aims to develop the first Latin-American risk model that can be used as a simple, pocket-card graphic score at bedside. The risk model was developed on 2903 patients who underwent cardiac surgery at the Spanish Hospital of Buenos Aires, Argentina, between June 1994 and December 1999. Internal validation was performed on 708 patients between January 2000 and June 2001 at the same center. External validation was performed on 1087 patients between February 2000 and January 2007 at three other centers in Argentina. In the development dataset the area under receiver operating characteristics (ROC) curve was 0.73 and the Hosmer-Lemeshow (HL) test was P=0.88. In the internal validation ROC curve was 0.77. In the external validation ROC curve was 0.81, but imperfect calibration was detected because the observed in-hospital mortality (3.96%) was significantly lower than the development dataset (8.20%) (P<0.0001). Recalibration was done in 2007, showing excellent level of agreement between the observed and predicted mortality rates on all patients (P=0.92). This is the first risk model for cardiac surgery developed in a population of Latin-America with both internal and external validation. A simple graphic pocket-card score allows an easy bedside application with acceptable statistic precision.

The incorporated aortomitral homograft: A new surgical option for double valve endocarditis

From the Cleveland Clinic, Cleveland, Ohio. Disclosures: J.L.N. serves as a consultant to Cryolife Inc, Kennesaw, Ga. Received for publication May 1, 2009; accepted for publication May 17, 2009; available ahead of print July 13, 2009. Address for reprints: Jose L. Navia MD, FACC, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195. J Thorac Cardiovasc Surg 2010;139:1077-81 0022-5223/

Hemodynamic differences between the awake and anesthetized conditions in normal calves

36.00 Copyright 2010 by The American Association for Thoracic Surgery doi:10.1016/j.jtcvs.2009.05.017

Caution with the published database reviews analyzing the off-label use of recombinant activated factor VII (rFVIIa) in cardiac surgery

There is insufficient information in the literature about baseline circulatory parameters in normal calves in the anesthetized versus postoperative awake conditions under which a large volume of medical research is conducted. Eleven calves (mean body weight, 78.1xa0±xa014.3xa0kg) were implanted with a flow probe and fluid-filled pressure lines to measure cardiac output (CO), aortic (AoP), central venous (CVP), pulmonary arterial (PAP), and left atrial pressures (LAP). Systemic (SVR) and pulmonary vascular resistance (PVR) were also calculated. We obtained the above hemodynamic data (nxa0=xa011) and epicardial echocardiography (nxa0=xa07) during open-chest surgery under isoflurane anesthesia. After full recovery from surgery, animals were evaluated in the awake condition on postoperative days 6–9 using transthoracic echocardiography (nxa0=xa07) and the hemodynamic monitoring lines and probes noted (nxa0=xa011). CO, AoP, and PAP levels in the anesthetized condition were significantly lower than in the awake condition. Other hemodynamic parameters (CVP, LAP, SVR, and PVR) were not significantly different. In conclusion, data from this study quantify changes in CO, AoP, and PAP in anesthetized calves that may affect the hemodynamic response to experimental therapeutics such as new cardiac assist devices, prosthetic valves, and surgical interventions. Our study also provides baseline data for the translation of the hemodynamic data obtained in acute in vivo calf studies to that of an awake subject.

Letter by Al-Ruzzeh and Navia Regarding Article, “Safety and Efficacy of Recombinant Activated Factor VII: A Randomized Placebo-Controlled Trial in the Setting of Bleeding After Cardiac Surgery”

We read with interest the comprehensive Canadian review of the off-label use of recombinant activated factor VII (rFVIIa) in cardiac surgery by Karkouti and colleagues published recently in Circulation [1]. This observational study showed the pattern of use of rFVIIa in Canadian cardiac centers and highlighted the difference between the centers of high and low treatment rates. In that respect the authors fulfilled one of the objectives they set out to achieve. However, when it comes to the second and probably the main objective of the study as was stated in the background section of the abstract, the assessment of predictors of effectiveness and risk, we do not believe the authors were as successful. The only bivariate analysis shown in the manuscript was the one that was run between survivors and non-survivors of the surgery to identify predictors of in-hospital mortality, where the more important bivariate analysis would have been the one that was run between responders to rFVIIa and non-responders in order to identify ‘‘predictors of effectiveness”, i.e., efficacy. We find out from the results section that responders were (380, 78%) patients who received 65 RBC units during the 24 h after rFVIIa therapy and apparently did not all survive (344, 68.4%) despite that. This group of (36, 7.2%) patients who responded to rFVIIa therapy, i.e., stopped bleeding, but yet died would have been an interesting group to analyze. The authors listed the ‘‘independent predictors of failure to respond” as a result of multivariate analysis in the results section without explaining to the reader what potential predictors they did chose to run through that multivariate analysis or why. On the other hand, since no analysis could be run to ‘‘identify predictors of risks or morbidity or mortality caused by rFVII administration”, i.e., safety, because both survivors and non-survivors received rFVIIa. Instead, the authors ran a comparative analysis with a ‘‘comparison cohort”, where rFVIIa was not administered, and concluded no difference in morbidity and mortality with the ‘‘study cohort” despite the fact that they were ‘‘markedly higher” in the latter. The question that comes to mind: how can a comparison between two groups of dying bleeding patients with mortality of 30–40% and morbidity of

Implantation technique and early echocardiographic performance of newly designed stentless mitral bioprosthesis

To the Editor:nnWe read with interest the recent article by Gill et al on recombinant factor VIIa (rFVIIa) in cardiac surgery.1 We would like to raise the following issues. The authors’ conclusion that “for the first time, a hemostatic agent has the possibility of being an effective alternative to allogenic transfusion in cardiac surgery patients with uncontrolled postoperative bleeding” is imprecise. The 3 randomization arms in the trial received “allogenic transfusion,” and the concluded beneficial effect of rFVIIa in the trial was that it significantly increased the percentage of patients who avoided transfusions. In other words, rFVIIa was an adjunct, not a …

Con: The role of recombinant factor VIIa in the control of bleeding after cardiac surgery.

This article describes the implantation techniques of two new stentless mitral bioprosthesis and their early echocardiographic performance in 12 acute sheep model. The first stentless mitral bioprosthesis (stentless bileaflet valve [SBV]) was designed as a bileaflet valve with sewing ring to suture down to the native mitral annulus. The other one (SBV with chordae) has two chordae-like structures to be attached to the head of the native papillary muscles. Valvar performance and cardiac function were evaluated by epicardial echocardiography at postimplant (Rest) and during dobutamine (DOB) stimulation. Postimplant echocardiography revealed normal leaflet opening with a large orifice area and unrestricted leaflets motion. In both valves, leaflet closure showed no systolic anterior motion, prolapse, or tethering. Mitral regurgitation grade 2 or higher was not detected in any of the experiments. Transvalvar pressure gradients at Rest and DOB were 2.3 ± 1.6 mm Hg and 2.5 ± 2.2 mm Hg in SBV and 1.8 ± 1.1 mm Hg and 2.3 ± 1.2 mm Hg in SBV with chordae, respectively. Both stentless bioprosthesis showed reliable valve performance and preserved cardiac function in the acute phase. Further chronic study is needed to evaluate the reliability of implantation procedures, valvar performance, and biocompatibility.