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Balancing risk and reward The question of natalizumab.

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Balancing Risk and Reward:
the Question of Natalizumab
In the pursuit of doing everything possible for all of our
patients, we cause considerable harm to some. Preventable medical errors, inexcusable causes of harm, have appropriately engaged the attention of all of us as the
magnitude of this problem has become recognized.1 A far
more common source of harm, however, results from the
known, i.e. “expected,” complications of our treatments.
These are not caused by obvious errors in oversight or
judgment, but rather by adverse outcomes resulting from
standard-of-practice care inherent in the complication
rates of interventions. Examples include toxic reactions
to medications or poor outcomes from surgical or interventional procedures. Such complications are particularly
unsettling whenever the decision to treat in the first place
is debatable. What factors determine whether a patient
undergoes an endarterectomy for asymptomatic carotid
stenosis, an intervention for a vascular malformation that
has not bled, or treatment with natalizumab for multiple
sclerosis (MS)? Although evidence-based medicine strives
to reduce medical decision-making to standardized, codified principles, when applied to many real-life situations it
is the judgment of the clinician and the personal choice of
the patient that ultimately determine the treatment plan.
This is especially true when the decision involves accepting the risk of an unlikely but potentially catastrophic adverse event. Often, the treatment decision is driven by
how the risk and reward of a proposed treatment is perceived, both by the patient and by the clinician.
There is nothing unique about decisions that we make
about our health – we often make “qualitative” decisions
at odds with the “quantitative” reasoning of experts. Some
of us are risk-takers and others are risk-averse. Whether or
not a patient feels lucky can profoundly influence a health
care decision,2 especially when in a gray zone of medical
practice. Some patients place greater value on near-term
than long-term outcomes, and not surprisingly our cultural and religious backgrounds, prior experiences, and
family responsibilities may all play roles. In one study, a
high risk for a complication that is not particularly frightening – a swollen leg from phlebitis – was preferred by
many over a tiny but much more frightening risk, cerebral hemorrhage; patients who weigh the rare adverse
event heavily are, not surprisingly, more likely to refuse
prophylactic anticoagulation.3 A variety of risk analysis
methods have been developed to quantitate the relative
values (“utilities”) that individuals apply to health care de-
cision-making. As examples, the standard gamble method
weighs the importance of the range of possible outcomes
plus willingness to accept risk; the time trade-off method
considers the benefit of early compared to late outcomes,
and the willingness to pay model estimates the financial
value for a specified improvement in health.4-6 Although
none of these scales is readily applied at the bedside, they
do serve to focus our attention on the underlying and
often subconscious factors that can profoundly influence
medical decision-making and compliance to recommended treatment plans.
In many situations, patients prefer to leave medical decisions to their physicians’ best judgment.7 For many,
such informed trust may be more important than a wish to
have control over treatment decisions. Some delegate decision-making responsibility because they have confidence
in the professional expertise and opinion of their physicians, and others do so because they are overwhelmed by
the situation or unable to grasp the nuances of the factors
that come into play. Whatever the underlying motive, implicit in the patient’s transfer of decision-making responsibility is the assumption that all actions will be in his or
her best interest, and in such situations the responsibility
for risk-reward analysis falls entirely to the physician.
Risk-reward decision-making is brought into sharp
focus with the α4integrin receptor antagonist therapy, natalizumab (Tysabri). Natalizumab is a wonderfully effective therapy for relapsing forms of MS; it is approximately
twice as effective as the β interferons or glatiramer acetate.
However, use of natalizumab carries with it a small risk of
progressive multifocal leukoencephalopathy (PML), estimated at approximately 1:6,000 annually (11 cases have
been identified to date). The risk is probably much lower
during the first year of therapy, and for this reason some
experts advocate that its use be limited whenever possible
to 6-12 month treatment cycles. Not surprisingly, the
PML cases have sensitized the neurologic community to
potential risks of natalizumab, and this could result in the
over-reporting of unrelated conditions (for example
melanoma)8 in natalizumab-treated patients. In this issue
of the Annals, Bethele9 reports a case of primary CNS lymphoma associated with natalizumab therapy, and in our
editorial pages we’ve asked several experts to offer their
perspectives on this anecdotal observation.10-13 All concur
that the current case (and a single previously identified
one) offer insufficient evidence to implicate natalizumab
© 2009 American Neurological Association
at this time as a risk factor for primary CNS lymphoma.
Bozic, et al (representing the manufacturer, Biogen/IDEC)
argue that the number of cases identified to date conforms
to the expected rate of primary CNS lymphoma, given
more than 56,000 patients have been treated thus far with
natalizumab.10 This said, the case report is notable – and
deserving of publication – given the preexisting concern
about natalizumab’s safety profile, especially with respect
to immunodeficiency-associated CNS complications.
As physicians, we are taught from the first days of medical school that the first obligation is to do no harm; riskaverse decision-making is encouraged. We are also subject
to many qualitative biases influenced by our individual
personalities, values, and perspectives. One potential bias
that we bring to our daily professional lives has been categorized as the availability heuristic, in which the recall of
a recent case or experience – for example an adverse outcome – can unduly influence subsequent decision-making.14 For one of us (SLH), an unforgettable personal
experience with one of the original patients with natalizumab-associated PML led subsequently to a fear of prescribing and less use of the drug than may have been
appropriate. Unfortunately, there is no current way to predict individual risk for any natalizumab-associated complication.
In the absence of science to rationalize and simplify
decision-making, we must practice the art of medicine
whenever the choice is not clear-cut. In doing so, we need
to remember that, whereas all therapeutic decisions are ultimately in the hands of our patients, their decisions are
heavily influenced by the manner in which we present the
choices to them. Awareness of our own biases may allow
us to present the alternatives more accurately thus making
us better practitioners. Although the first precept may be
“do no harm,” if this were taken too far to mean that we
should eliminate the risks of all complications, we would
be selling short many interventions that on average produce benefits.
1. Aspen P, on behalf of Committee on Identifying and Preventing Medication Errors. Preventing Medical Errors: Quality
Chasm Series. Institute of Medicine Report. Washington,
DC: The National Academies Press, 2006.
2. Teigen KH. Hazards mean luck: counterfactual thinking in
reports of dangerous situations and careless behavior. Scand J
Psychol 1998;39:235.
3. O’Meara JJ, McNutt RA, Evans AT, et al. A decision analysis
of streptokinase plus heparin as compared with heparin alone
for deep-vein thrombosis. N Engl J Med 1994;330:1864.
4. Kassirer JP. Incorporating patients' preferences into medical
decisions. N Engl J Med 1994;330:1895.
5. Torrance GW, Thomas WH, Sackett DL. A utility maximization model for evaluation of health care programs. Health
Serv Res 1972;7:118.
6. Thompson MS. Willingness to pay and accept risk to cure
chronic disease. Am J Public Health 1986; 76:392-6.
7. Mangset M, Berge E, Førde R, et al. ‘‘Two per cent isn’t a lot,
but when it comes to death it seems quite a lot anyway:” patients’ perception of risk and willingness to accept risks associated with thrombolytic drug treatment for acute stroke. J
Med Ethics 2009;35;42-46.
8. Mullen JT, Vartanian TK, Atkins MB. Melanoma complicating treatment with natalizumab for multiple sclerosis. N Engl
J Med 2008;358:647-648.
9. Schweikert A, Kremer M, Ringel F, et al. Primary central
nervous system lymphoma in a patient treated with natalizumab. Ann Neurol 2009;66:403-406
10. Ransohoff RM. Natalizumab, multiple sclerosis and primary
central nervous system lymphoma: Enigma, wrapped in mystery, enclosed in conundrum. Ann Neurol 2009;66:259-261
11. Bozic C, LaGuette J, Panzara M, et al. Natalizumab and
central nervous system lymphoma: no clear association. Ann
Neurol 2009;66:261-262
12. DeAngelis L. Natalizumab: a double-edged sword? Ann
Neurol 2009;66:262-263
13. Goebels N, Kappos L. Another complication of natalizumab
treatment? Taking the challenge. Ann Neurol 2009;66:263-265
14. Salem-Schatz SR, Avorn J, Soumerai SB. Influence of clinical knowledge, organizational context, and practice style on
transfusion decision making. Implications for practice change
strategies. JAMA 1990;264:476.
Stephen L. Hauser MD and S. Claiborne Johnston MD, PhD
Αnnals of Neurology
Vol 66 No 3 September 2009
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reward, balancing, questions, natalizumab, risk
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