Adverse events occurred at similar frequency and severity between treatment groups. Overall, the adverse event profile was similar between rFVIIa-treated and placebo-treated patients in both trials, and there were no apparent treatment-dependent patterns in the types of adverse events reported. As can be expected in these severely injured patient populations, the three most frequently reported serious adverse events were ARDS, MOF, and sepsis.
A total of 12 thromboembolic adverse events were reported by the investigators during the two trials: 6 in rFVIIa-treated patients and 6 in placebo-treated patients. In patients with blunt trauma, two cases of pulmonary embolism and one subclavian vein thrombosis (after central line placement) were recorded in the placebo group, whereas one jugular vein thrombosis (after central line placement) and one arterial limb thrombosis were recorded in rFVIIa-treated patients. In patients with penetrating trauma, one cerebral infarction and one deep vein thrombosis was noted in each treatment group. In addition, a mesenteric vein thrombosis was recorded in the placebo group and an intestinal infarction (at the site of operation) and an event of phlebothrombosis were noted in the rFVIIa group.
In these two trials in severely traumatized patients, we found evidence of the efficacy of rFVIIa as an adjuvant therapy in the management of hemorrhage caused by trauma. Among blunt trauma patients, rFVIIa significantly reduced the need for RBC transfusion and massive blood transfusions. We found similar trends in penetrating trauma patients, without reaching statistical significance. These trials demonstrate that rFVIIa is safe in trauma patients because it not only did not increase the incidence of adverse events, including thromboembolism and systemic coagulation, but was also associated with a trend toward fewer critical complications such as MOF and ARDS.
Statistical significance was not reached on the RBC transfusion endpoints in the penetrating trauma population. This is likely explained by the higher proportion of surgically treatable bleeding in penetrating trauma. Furthermore, blunt trauma patients required nearly twice as many RBC units than penetrating trauma patients, and the power to detect a reduction in RBC requirement was consequently lower for the penetrating trauma population.
The trends toward improved clinical outcome (as reflected by the incidence of critical complications, ventilator requirement, and days in ICU) are encouraging and collectively point toward a possible benefit of rFVIIa. It should be emphasized that the studies were not powered for these endpoints. Two mechanisms may account for the trends toward improved clinical outcome with rFVIIa. First, and as a direct effect of rFVIIa, reduced severity of hypovolemic shock and hypoperfusion could be an explanation for the reduction in the incidence of organ failure.31,32 Second, and mediated indirectly through the reduction in RBC transfusion, rFVIIa may contribute to a reduction in the late complications, as blood transfusion previously has been identified as a consistent risk factor for postinjury MOF and ARDS,8,9 and a clear dose-dependent correlation between RBC transfusion and postinjury infection has been observed in a prospective study in approximately 1,500 trauma patients.7
Some limitations of the study should be noted. First, as the majority of blunt trauma patients were still in the hospital at the end of the 30-day follow-up period, the effect of treatment on days in ventilator dependency and hospitalization requirement could have been more optimally assessed if the observation period had been extended beyond 30 days. Second, data on thromboembolic complications were collected through adverse event reporting only, and Doppler examination was not systematically performed across trial sites. Underreporting of asymptomatic thromboembolic events is likely to explain the apparent low overall incidence of thromboembolic complications in this patient population, where thromboembolic adverse events were recorded for 4% of all patients. Third, the selection criteria were specifically targeted at severely bleeding trauma patients who had already been given 6 units of RBCs within a 4-hour period at the time of randomization. Although a selected trauma population, we believe that this constitutes the subgroup of trauma patients most likely to benefit from rFVIIa treatment. Including patients too early in the course of treatment might have resulted in too many patients with no therapeutic need for a hemostatic agent (i.e., patients in whom surgical hemostasis would be obtained satisfactorily with conventional treatment). In contrast, including patients too late would include too many patients in whom treatment would be futile because of surgically uncontrollable bleeding and irreversible hemorrhagic shock. Fourth, bias in investigator assessments might have been introduced in cases where routine monitoring of prothrombin time could have potentially revealed whether a patient received rFVIIa or placebo. Because of the emergency medical nature of the trial population and the requirement of adherence to protocol-defined transfusion guidelines, we judge the effect of such bias on trial results to be small if not negligible. Finally, because of the complexity of the study population and the diversity of choices faced by trauma teams in the management of these patients, differences in patient management across regions and trial centers were anticipated despite adherence to the trial protocol. Although there may have been minor differences in local transfusion guidelines between the participating centers, each center essentially acted as its own control inasmuch as patients were equally randomized to rFVIIa and placebo within each center. The potential influence of site-specific effects on the statistically significant RBC reduction was assessed by a parametric analysis of the ranks including a site effect and a site-treatment interaction. The effect of treatment was independent of site (p = 0.24 for the site-vs.-treatment interaction). We also examined the effect on outcomes of removing the patients from each of the three largest sites and found no change in the results.
In conclusion, rFVIIa significantly improved bleeding control—as reflected by the decrease in RBC transfusion requirements and the number of patients requiring massive transfusion—in a population of blunt trauma patients with severe bleeding and coagulopathy secondary to the traumatic injury. Similar trends were observed in a population of patients with penetrating trauma. The safety of rFVIIa was established in these two trauma populations for the investigated dose. The incidence of adverse events including thromboembolic events was not increased by rFVIIa dosing in either trial, and no indications of induction of systemic coagulation were observed. Trends toward improved clinical outcome were observed in both trials. Administration of rFVIIa appears to be a promising adjunct to existing therapy within trauma, as it directly targets the coagulopathy, thereby helping to break the vicious cycle of coagulopathy, acidosis, and hypothermia.
We thank the patients, trial coordinators, and nurses and physicians who participated in this trial; and the study’s data and safety monitoring board for their time and commitment.
Data and safety monitoring board: Howard Champion, MD, Annapolis, Maryland (Chairman); Abe Fingerhut, MD, Paris, France; Richard Weiskopf, MD, San Francisco, California; and Miguel A. Escobar, MD, Houston, Texas. Ad hoc member: Torben Soerensen, MSc (statistician), StatCon Aps, Alleroed, Denmark. Sponsor: Novo Nordisk A/S, Bagsvaerd, Denmark. Statistician: Tine Soerensen, MSc, Novo Nordisk, Bagsvaerd, Denmark.
NovoSeven Trauma Study Group members and trial centers are as follows: South Africa: K. D. Boffard, Johannesburg Hospital, University of the Witwatersrand, Johannesburg; B. L. Warren, Tygerberg Hospital, Cape Town; A. Nicol, MD, Groote Schuur Hospital, Cape Town; R. Tracey, MD, Unitas Hospital, Centurion; J. S. S. Marx, MD, Pretoria Academic Hospital, Pretoria; E. Degiannis, Chris Hani Baragwanath Hospital, University of the Witwatersrand, Johannesburg; J. Goosen, MD, Milpark Hospital, Johannesburg; F. Plani, MD, Union Hospital, Alberton; L. M. Fingleson, MD, Sunninghill Hospital, Sandton. France: B. Riou, Hôpital Pitié-Salpêtrière, Paris; J. F. Payen de La Garanderie, Hôpital Michallon, Grenoble; J. Marty, Hôpital Beaujon, Clichy; R. Krivosic-Horber, Hôpital Roger Salengro, Lille; M. Freysz, Hôpital Général, Dijon; J. E. de La Coussaye, Centre Hospitalier Universitaire, Nîmes; J. Duranteau, Hôpital de Bicêtre, Le Kremlin Bicêtre; B. Francois, MD, Hôpital Dupuytren, Limoges; N. Smail, MD, PhD, Hôpital Purpan, Toulouse; P. Petit, Hôpital Edouard Herriot, Lyon. Germany: Dr. R. Rossaint, Klinik für Anästhesie Universitätsklinikum Aachen, Aachen; H. K. van Aken, Universitätsklinikum Münster, Münster; Dr. G. Hempelmann, Universitätsklinikum Giessen, Giessen. Israel: Y. Kluger, Sourasky Medical Centre, Tel Aviv; A. I. Rivkind, Hadassah Medical Organisation, Jerusalem; G. Shaked, MD, Soroka Medical Centre, Be’er Sheva; Michaelson, MD, Rambam Medical Centre, Haifa. Singapore: P. Iau Tsau Choong, MD, National University Hospital; A. Yeo Wan Yan, MD, Singapore General Hospital. Canada: S. B. Rizoli, MD, Sunnybrook Health Sciences Centre, Toronto; S. M. Hameed, MD, Foothills Medical Centre, Calgary. United Kingdom: G. S. Samra, MD, The Royal London Hospital, London. Australia: G. J. Dobb, MD, Royal Perth Hospital, Perth.
The author group contributed significantly to the development of the protocol. In addition, the following contributed: J. A. Asensio, Los Angeles, California; W. Biffl, Denver, Colorado; K. Mattox and J. Holcomb, Houston, Texas; J. H. Patton, Detroit, Michigan; F. Lewis, Pittsburgh, Pennsylvania; M. Lynn, Miami, Florida; P. O’Neil, Brooklyn, New York; J. T. Owings, Sacramento, California; A. Pietsman and S. Tisherman, Pittsburgh, Pennsylvania; T. M. Scalea, Baltimore, Maryland; and M. Schreiber, Portland, Oregon.
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Dr. Howard R. Champion (Annapolis, Maryland): Dr. Mizobata, Peitzman, Croce: I’d like to thank both organizations for the opportunity to discuss this important study on this important drug, which is being used widely in the United States off label as an adjuvant for hemorrhage control in both trauma and transplant surgery.
The authors reported two parallel studies, blunt and penetrating injury, conducted in 32 hospitals in eight countries powered to a specific endpoint which was transfusion reduction.
They concluded that rfVIIa assisted in the control of bleeding and resulted in significant reduction in red blood cell use in blunt trauma. They also allayed the fears of many that microvascular thrombi in non-injured areas of the body could increase the incidences of organ failure in this patient population.
No one should underestimate the difficulty of acute resuscitation research in this high-risk nocturnal population. This study was a formidable and ground-breaking undertaking.
As chair of the Independent Data Safety Management Board, I observed up close and can testify to the steep learning curve engaged in by the researchers, the company sponsor and the contact research organizations. I must congratulate all of those concerned for writing and responding to the many challenges involved in standing up this project. All of us will benefit from absorbing lessons learned in this study.
I have a number of general questions, and I would be remiss if I didn’t solicit further comment on the following topics. Uniformity of care is a big issue in research.
In the European Union, multi-institutional trial cancer researchers regard the surgeon as a confounding variable in outcomes research and insist on proctored detailed standardization of the operative surgery.What steps were taken to standardize care? In particular, please comment on transfusion therapy. This could be regarded by many as a confounding variable in this study, and yet, it is used as the primary dependent variable. Is there some comment you’d like to offer of the use of a confounding variable, potentially serious confounding variable as a primary dependent variable?
Can you comment on the indications for this drug, its cost benefit, and whether the dose could be reduced? Could you elucidate as to why the success was seen in the blunt group as opposed to the penetrating group? You made one comment with respect to that, but there are others that you probably would like to make.
Your data supports the conclusion regarding reduction in red cell use. You also conclude that you reduced hemorrhage. Is this a warranted or unwarranted extrapolation or a type 3 error in your conclusions?
Plans are underway to stand up a U.S. study that will convince the FDA to label this drug for use in trauma. How have you advised your U.S. colleagues towards achieving that goal?
This drug is changing our practice. Its value needs to be documented. This study represents an important and critical step in that process. Thank you.
Dr. Charles Lucas (Detroit, Michigan): That was a nice study, Dr. Boffard, but I do have some questions on the physiology of coagulation. We all know that factor VII has the lowest molecular weight, the shortest half-life, and that about 55% of it is present in the interstitial fluid space.
We also know that the influence or the efficacy that factor VII would have on the factor VIII, factor IX complex in the intrinsic pathway or the thrombin in the common pathway is comparable to the influence that a forceful fart by Dr. Erwin Thal would have in a wind storm. (Laughter)
We also know that if you have a heparinized patient where you have blocked both the intrinsic pathway and the common pathway, that you could give the whole wind storm full of factor VII, and you’d never get a clot.
So my first question is: Is this a selective decrease in factor VII which, of course, converts to VIIA intravascularly that you’re describing in this patient? If it is a selective decrease, why aren’t the patients clotting through the intrinsic and the common pathways? We’re getting back to the first year of medical school.
Now, one of the commonly used protocols in patients with multiple transfusions is to initiate fresh frozen plasma and to give two units of fresh frozen plasma for every five transfusions. It’s very efficacious. If anyone in this room doesn’t use it, I’ll tell you over chardonnay tonight why you ought to use it.
Now, in your two groups of patients you should have had about an average of three units of fresh frozen plasma in your two groups of patients who received about 7.5 transfusions of red blood cells.
In your patients who received 20 units of red blood cells, whom are the current patients you’re really concerned about, you should have given about eight units of fresh frozen plasma.
So what I want to know is in your dose, which is 600 pg of activated rfVIIa per person, how does that compare to three units of the rfVIIa, which is present in all of us in patients who got 7.5 transfusions and how many micrograms – in other words, how many micrograms of factor VII is present in a unit of plasma? I enjoyed your presentation.
Dr. Errington Thompson (Tyler, Texas): Errington Thompson from Tyler, Texas. I really enjoyed your discussion. It seems that in East Texas, we have a large elderly population that comes to retire there, and for some reason, they all get put on one of the three deadly drugs or one combination of all the three deadly drugs which would include: Plavix, Coumadin and aspirin.
My question to you is in these head injury patients that we see, these elderly patients that fall, what role do you think factor VII would have in these elderly patients? Thank you.
Dr. Steve Ross (Camden, New Jersey): Ross from Camden, New Jersey. As a procoagulant, knowing whether or not we’ve got increased use of red cells is important, but further, is the impact on the use of other transfusions. Is there data regarding the use of differential use of FFP in these populations or coagulopathy?
Dr. Gregory J. Jurkovich (Seattle, Washington): Jurkovich, Seattle. Ken, just two questions, and they both relate to the matching of the two populations, the placebo and the activated VIIa.
Would you give us insight into the number of operations or the type of operations that were performed within that first window of time between the two groups? Were those different?
Similarly, could you give us some insight into the type of injuries that occurred such as AIS scores or specific organ injury body cavities between the two groups? Was there any difference in that part of their population, and which parts of the body were injured? Thank you.
Dr. Mauricio Lynn (Miami, Florida): Mauricio Lynn from Miami. First of all, I wanted to congratulate you, Ken, for this great presentation and this great study.
I only have one question. Since you presented that only 2% of the patients get 20 units of blood or more, then therefore, 98% got less than 20 units –- correct?
Those were the numbers; therefore, if you randomize them, or you include in the study of eight units, and the majority would get somewhere around 10 to 12 units, would it be reasonable to randomize them early on when you have the first clinical signs of bleeding? Maybe when they get the first or second unit of blood, but they are true indicators that they are bleeding; therefore, at the end of the road, you can actually show a larger decrease in blood transfusion. Thank you.
Dr. Lawrence Pitts (San Francisco, California): Pitts, San Francisco. I know that you excluded coma scores of less than eight from your study, but did you have enough patients in the moderate head injury category with intracranial hemorrhage to have any feeling about effect of the activated factor VII on delayed traumatic cranial hemorrhage?
Dr. Martin A. Croce (Memphis, Tennessee): I’ll take the privilege of the podium and ask the final question. Ken, you did a great job of presenting. To be fair, I was wondering if you would comment on the control for transfusions for this particular study, since transfusions was one of the outcomes in addition to ventilator weaning, since ventilator-free days was also one of the outcomes.
Dr. Kenneth D. Boffard (closing): I’d like to thank all of the discussants for their comments, and Dr. Champion, both for running a very careful data set monitoring board and also his insightful comments on some of the complexities that we faced.
With regard to the specific questions, in terms of the uniformity of care, the trouble with trauma patients is that the confounding variable is the patient rather than the surgeons, as some would have us believe.
What we relied upon was that the patients who entered the trial as placebo versus those who entered the trial as rfVIIa, acted to some extent as their own control across the census.
The uniformity of care has been analyzed in terms of overall outcomes and would appear to have been similar across the census. We did not attempt to dictate to individual centers, “thou shalt do this or the other,” in the hope that, the standard of practice for most of the centers that were selected was compatible both with each other, and with what we would regard as the upper level of standard of care.
The indications are there. The question is where is the cost benefit? There is no doubt that the substance at the moment is extremely expensive. But I think we’re only a little way down that line.
I think that the first statement is this stuff is safe. I’ll come back to it in traumatic brain injuries. If it’s safe, in which case, what dose is the most optimum dose? The dose that was chosen was at the upper limit of normal, because this was intended as a safety trial as much as anything else. So the reduction in dose– if it works, and we feel it does– and the increased production is going to make a big difference to the cost of the drug itself. If you add into that, the number of ICU days and ventilator days it may be possible to save, then becomes a cost-effective drug. But I think the greater research is still required for that.
The question was raised of why our increased successes in blunt injury? I think, as all of us are surgeons know there are three sorts of bleeding. There is the bleeding that you can see that you can press on. There is the bleeding that you can hear. In other words, a bleeding you can feel rather which is you can put your finger on. Then there is that audible bleeding, which no amount of drug is ever going to stop. Audible bleeding is going to continue to need a surgeon in an operating room.
But I think with blunt injury, there is a significant amount of smaller vessel bleeding, which is too small to embolize, too small to surgically stop, but it’s asking to be stopped in a pharmacological fashion, and I think that’s where the strength of this study is.
In terms of the question of how to advise our U.S. colleagues and the FDA on a future trial in America: fortunately, American surgery, although there is variation because it is within one country, tends to be a little bit more controllable, I think that particularly, with the penetrating injury the standard of care can be controlled.
I would exclude extremity injury for obvious reasons. I think laying down closer transfusion requirements and that moves me a little bit onto Dr. Lucas’ question.
No two centers quite define massive transfusion with the same numbers. No two centers apply quite the same amount of cryoprecipitation, fresh frozen plasma is the next one.
I think that that has to be standardized. I think the second thing that does have to be standardized is the way patients are removed from a ventilator or removed from an intensive care unit. For example, if you have a patient who has major surgery who would come off a ventilator, but the orthopedist is going to do some big operation tomorrow, will you keep them on the ventilator over night or take them off?
The drug provides a much higher level in the plasma than cryo or any of the fresh frozen plasmas. The total dose given was 400 pg/kg, and that was targeted to achieve a dose in the plasma of roughly 40 ng/L.
Fresh frozen plasma and cryo only approaches about a third of that, bearing in mind also that you have a dilutional aspect as you tend to transfuse these patients with lactated Ringer’s or anything else.
Dr. Thompson, the head injury patients are the source of a separate research project, which will be presented at a later stage, but at this stage we do not see any dangers in those particular patients.
Dr. Ross, we don’t have data on the use of FFP for the reasons I have given. Dr. Jurkovich, to answer your question, the AIS scores on one, two, and three bodily systems were identical between the various groups.
We do not have specific data on which operations were performed, other than to say that most surgery took place within the first 24 hours, and the surgery was similar between the two groups.
To answer Dr. Mauricio’s question, remember that these patients received eight units of blood. In principle, nobody is going to transfuse blood until you’ve lost blood. Very few people are going to transfuse until they’ve lost maybe four or five units already; their hemoglobin is down to somewhere around 10. So these patients had received eight units and probably lost 12 before they were entered.
I think that they should be randomized earlier, and this is the subject of discussion for a future trial with the FDA. Dr. Croce, would you care to repeat your question? I’d like to thank, again, both organizations and a number of airlines for the privilege of being here. (Laughter)