Jerry Avorn, MD; Aaron Kesselheim, MD, JD, MPH
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University of Toronto and Emory University School of Medicine
April 29, 2011
The off-label use of recombinant activated factor VII
To the Editor;
Commenting on recent systematic reviews of the off-label use of recombinant activated factor VII (rFVIIa),(1) Dr. Avorn raises concern about the "rapidly increasing use of a treatment that does not benefit patients and increases the risk for dangerous thrombotic events - and which ... costs $10,000 per dose." This concern, however, fails to consider the clinical context in which clinicians choose to administer rFVIIa, which is refractory blood loss.
When presented with a patient who continues to bleed despite administration of all available therapies, clinicians have only two choices: they can keep administering the standard interventions that have failed to work in that patient, or they can administer a novel therapy like rFVIIa. Based on the increasing in-hospital off-label usage of rFVIIa,(2) clinicians seem to be choosing the second option. What would compel them to make this "unhelpful, dangerous, and costly" decision?(1)
Perhaps they recognize that: a) unless they gain control of the blood loss in a timely manner, patients will fare poorly; b) standard interventions - which, incidentally, have also not been shown to benefit patients, have inherent risks, and are expensive - are unlikely to gain control of the blood loss in a timely manner; c) based on an expanding body of observational data,(3) and some randomized trial data in bleeding patients,(4) rFVIIa is likely to reduce the blood loss; d) the efficacy and safety data from most existing randomized trials do not apply because they did not study patients with refractory blood loss; e) even if the safety data from existing randomized trials do apply, which indicate that rFVIIa doubles the risk of thrombotic complications,(5) this risk is likely dwarfed by the risk of allowing blood loss to continue unabated; f) and applicable data from placebo-controlled randomized trials will not be forthcoming because of feasibility issues (e.g., difficulty in obtaining informed consent in a timely manner, ethical concern of administering a placebo to patients with refractory blood loss, and lacking standardized alternative therapies).
We believe that comments on the off-label use of rFVIIa that do not consider the clinical context in which the drug is being used may be flawed. All procoagulant agents have the risk for potential adverse responses, but their individualized risk-benefit profile is largely dependant on the clinical context.
Keyvan Karkouti Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
Jerrold H Levy Emory University School of Medicine, Atlanta, Georgia
Potential Conflicts of Interest: Both authors have conulted for and have received research funding from Novo Nordisk
(1) Avorn J, Kesselheim A. A hemorrhage of off-label use. Ann Intern Med 2011; 154:566-567.
(2) Logan AC, Yank V, Stafford RS. Off-Label Use of Recombinant Factor VIIa in U.S. Hospitals: Analysis of Hospital Records. Ann Intern Med 2011; 154:516-522.
(3) Karkouti K, Beattie WS, Arellano R, Aye T, Bussieres JS, Callum JL et al. Comprehensive Canadian Review of the Off-Label Use of Recombinant Activated Factor VII in Cardiac Surgery. Circulation 2008; 118:331-338.
(4) Gill R, Herbertson M, Vuylsteke A, Olsen PS, von HC, Mythen M et al. Safety and efficacy of recombinant activated factor VII: a randomized placebo-controlled trial in the setting of bleeding after cardiac surgery. Circulation 2009; 120:21-27.
(5) Levi M, Levy JH, Andersen HF, Truloff D. Safety of recombinant activated factor VII in randomized clinical trials. N Engl J Med 2010; 363:1791-1800.
Both authors have consulted for and have received research funding from Novo Nordisk.
May 26, 2011
To the editor:
We sympathize with the plight of the physician described by Karkouti and Levy, trying to emergently manage a patient with refractory, life- threatening bleeding. However, in the review by Yank et al. that demonstrated that recombinant activated Factor VII (rFVIIa) confers little or no benefit along with a significant elevation of risk of thrombotic events, the vast majority of patients studied were given this product under just such emergent conditions. The same was found in another recent comprehensive review of the literature, of which Dr. Levy was a co- author, and this conclusion was highlighted in an accompanying editorial comment. The cited randomized trial by Gill et al. did report a reduction in bleeding-related events, but it also found a striking increase in death, stroke, and gut infarction in patients given rFVIIa, though the trial was under-powered to measure these rates with precision.
Management of active blood loss is a stressful and challenging clinical crisis, yet these patients still deserve treatment based on the most comprehensive available evidence. Physicians in emergency settings face an understandable desire to take some action in the face of a deteriorating situation. But this perceived need should not justify administering agents that are harmful and ineffective. Emergent care of the bleeding patient should not follow a flawed algorithm that states, in effect, "We must do something. This is something. Therefore, we must do it."
Even in urgent situations, if the bulk of available data suggests that an intervention will not benefit the patient and will increase the risk of an important harm, then such therapeutic activism is not in the patient's interest, however understandable and well-intentioned it may be. Science-based care requires the treating physician to rise above the "availability heuristic" --the tendency to base decisions on the events which are most apparent at the time (diminution of bleeding) rather than on more complete risk-benefit information. In this case, that would have to include treatment-induced complications that occur after the bleeding has stopped, such as myocardial infarctions, strokes, or other thrombotic events precipitated by a hypercoagulable state generated by rVIIa.
Systematic reviews of all available evidence provide the best available prediction of the outcome of a given treatment in a particular clinical situation. The danger of invoking the need for an "individualized risk-benefit profile" is that this approach, if not guided by data, can be used to justify anecdotally-based decisionmaking that does not take full account of all that is known about actual benefits and harms.
Jerry Avorn, M.D.
Aaron S. Kesselheim, M.D., J.D., M.P.H.
1. Yank V, Tuohy CV, Logan AC, Bravata DM, Staudenmayer K, Eisenhut R, et al. Systematic review: benefits and harms of in-hospital use of recombinant Factor VIIa for off-label indications. Ann Intern Med. 2011;154(8):529-40.
2. Levi M, Levy JH, Andersen HF, Truloff D. Safety of recombinant activated Factor VII in randomized clinical trials. N Engl J Med. 2010;363:1791-1800.
3. Aledort LM. Off-label use of recombinant activated Factor VII - safe or not safe? New Engl J Med. 2010;363:1853-4.
4. Elstein AS. Heuristics and biases: selected errors in clinical reasoning. Acad Med. 1999;74:791-94.
5. Berg A and Morton S, eds. Finding what works in health care: standards for systematic reviews. Washington, D.C.: National Academic Press, 2011.
Avorn J, Kesselheim A. A Hemorrhage of Off-Label Use. Ann Intern Med. 2011;154:566–567. doi: https://doi.org/10.7326/0003-4819-154-8-201104190-00010
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Published: Ann Intern Med. 2011;154(8):566-567.
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