LETTERS
Teaching Professionalism to Medical Students
To the Editor: Dr Swick and colleagues1 have provided a sur-
vey of US medical schools that reflects the current interest in
teaching professionalism to medical students. Much of this
interest is fueled by the growing awareness that the “corpora-
tization” and “bureaucratization” of medicine are changing
the traditional patient-physician covenant. Some physicians,
including many in positions of influence in US medical
schools, are merely changing their expectations to meet the
current reality and seeking to position themselves most
advantageously in the new paradigm. Many students see no
other choice but to bury their dreams and accept their new
role in an environment in which the patient-physician cov-
enant is now a contract, the profession has become a busi-
ness, and patients have become “biological structures that
yield future cash flows.”2
But physicians who have not let go of the torch of passion
for the medical profession can be found in many places and in
especially large numbers among those who have chosen to care
for the poor and medically uninsured. This choice reflects the
commitment to place the interests of patients above financial
self-interest. The desire of such physicians to see the benefits
of medical achievements more equally distributed in society
is concrete evidence that the medical profession cares about
its social contract with communities. These physicians find sat-
isfaction in being a part of the solution instead of part of the
problem.3
The poor have always been at the center of the history of
medicine as a healing profession4 and the future of the pro-
fession likewise will be inextricably linked with the critical
issue of how we will care for the poor in our country.
Physicians-in-training always have learned at the bedside of
the poor, and today’s physicians must be brought there
again. As in the past, student physicians will learn much
about the process of disease, but more important, they will
be offered the opportunity to be in relationships—both with
the poor who have so few options and with the physicians
who have chosen to care for the poor as a practice of the
age-old traditions of our profession. Isolating these role
models from the professional formation of students will
result in an abiding cynicism of the future physician work-
force and of society as a whole in regard to the medical pro-
fession.
Bob Cutillo, MD
Exempla Saint Joseph Hospital
Denver, Colo
1. Swick HM, Szenas P, Danoff D, Whitcomb ME. Teaching professionalism in
undergraduate medical education. JAMA. 1999;282:830-832.
2. Reinhardt UE. Economics: Hippocrates and the “securitization” of patients. JAMA.
1997;277:1850-1851.
©2000 American Medical Association. All rights reserved.
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3. Li LB, Williams SD, Scammon DL. Practicing with the urban underserved: a quali-
tative analysis of motivations, incentives and disincentives. Arch Fam Med. 1995;
4:124-133.
4. Council on Ethical and Judicial Affairs, American Medical Association. Caring
for the poor. JAMA. 1993;269:2533-2537.
In Reply: As Dr Cutillo suggests, many forces have affected
the practice of medicine, and those forces have compelled both
medical educators and practicing physicians to respond to the
perceived conflict between professional and business values.1
While some physicians may seek only “to position themselves
most advantageously in the new paradigm,” many others con-
tinue to adhere to professional values and behaviors. Our sur-
vey demonstrated that most schools of medicine have incor-
porated in their curriculum some explicit attention to
professionalism.2 We do not share Cutillo’s pessimism that medi-
cal students see no choice but to “bury their dreams.” Most stu-
dents now entering medical school do so with a refreshing com-
mitment to service.
The Association of American Medical Colleges’ Medical
School Objectives Project3 has articulated the desired qualities
for physicians, the first of which must be altruism. The objec-
tives state that physicians must demonstrate “a commitment
to advocate at all times the interests of one’s patients over
one’s own interests.” Furthermore, the Medical School Objec-
tives Project stresses the need for physicians to have knowl-
edge of the economic, social, and cultural factors that contrib-
ute to health and call for “a commitment to provide care to
patients who are unable to pay and to be advocates for access
to health care for members of traditionally underserved popu-
lations.” Such advocacy is an important part of the patient-
physician covenant that Cutillo identifies. In our survey, we
found that an increasing number of schools are addressing the
important social contract that must continue to exist between
individual physicians, the medical profession, and the com-
munities they serve. Caring for patients from disadvantaged
backgrounds is an effective way to introduce students to their
professional responsibility to strive for social justice. Cutillo
also correctly stresses the importance of having students learn
GUIDELINES FOR LETTERS. Letters discussing a recent JAMA article should
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MD, Deputy Editor; Stephen J. Lurie, MD, PhD, Fishbein Fellow.
JAMA, January 12, 2000—Vol 283, No. 2 197
 LETTERS

from physicians who are effective role models for the compas-
Figure. Responses to Survey About Importance of Characteristics
sionate care of patients, especially those who are poor or Home Sample Collection HIV Tests
medically uninsured.
250
Herbert M. Swick, MD 1 Accuracy 5 Speed of Obtaining Results

Phillip Szenas, MS 2 Confidentiality 6 Availability of Counseling

Deborah Danoff, MD 200 193
3 Safety 7 Ease of Collecting Sample
179 179
Michael E. Whitcomb, MD 4 Convenience 8 Affordability

No. of Respondents
Association of American Medical Colleges
150
Washington, DC 134 131 134

1. Swick HM. Academic medicine must deal with the clash of business and pro- 110
fessional values. Acad Med. 1998;73:751-755. 100 86
2. Swick HM, Szenas P, Danoff D, Whitcomb ME. Teaching professionalism in
68
undergraduate medical education. JAMA. 1999;282:830-832. 61
56 54
3. Medical School Objectives Writing Group. Learning objectives for medical stu- 46
dent education—guidelines for medical schools: report I of the Medical Schools 50 37
29 26
Objective Project. Acad Med. 1999;74:13-18. 16 15
9 12
4 5 5
1
0
1 2 3 4 5 6 7 8 1 2 3 4 5 6 7 8 1 2 3 4 5 6 7 8
Extremely or Very Somewhat Important Not Very or Not at All
Home Sample Collection for HIV Testing Important Important
Importance of Test Characteristics
To the Editor: We agree with Dr Branson’s1 conclusion that home
sample collection (HSC) human immunodeficiency virus (HIV) Questions were asked using a 5-point scale, 1 = extremely important through
5 = not at all important. Responses were grouped into 3 categories as shown in
tests are an important alternative testing method, but we have 2 the figure.
concerns. First, many points raised are similar to those dis-
cussed in a background paper2 that was presented at a Kaiser
type of home test [22% (42/189) chose true home tests and 6%
Family Foundation Forum held prior to publication of the JAMA
(11/188) chose HSC tests]. Testing at physicians’offices or pub-
article. A 1-page summary of this presentation appeared in the
lic clinics was perceived to be more accurate, safe, and afford-
Foundation’s report on the forum.3 Also, a report with similar
able than HSC tests or true home tests. True home tests were
conclusions, although with more limited data, was previously
preferred more often than HSC tests because they were per-
issued and distributed via the Internet by a test manufacturer,
ceived to provide faster results and greater confidentiality.
along with an editorial by Branson.4 These papers and reports
These results support previous conclusions that home
were not cited or acknowledged in the JAMA article.
HIV testing offers an attractive alternative for many indi-
Second, as Branson notes, the correct effect of HSC tests on
viduals, especially those concerned about confidentiality.
access to testing currently may be small because of low usage.
Three nationally representative surveys found that 14% to 17% Kathryn A. Phillips, PhD
of the US population stated they would be very likely to use HSC Steve Morin, PhD
Tom Coates, PhD
tests.5 In contrast, in the first year of their availability less than
University of California
0.1% of the US population older than age 18 years used these San Francisco
tests, suggesting that there may be barriers to their use. How- Susan Fernyak, MD, MPH
ever, little is known about what types of HIV tests individuals San Francisco Department of Public Health
prefer. We mailed a survey in July 1998 to 411 individuals, of San Francisco
whom 204 (50%) responded, about their preferences for differ- Abby Marsh
ent testing alternatives. Of the respondents, 131 (64%) came from Dartmouth College
3 sites: 27 students at the University of California, San Fran- Hanover, NH
cisco (UCSF), 44 students at Dartmouth College (Hanover, NH), Leslynette Ramos-Irizarry
and 60 staff and faculty at UCSF’s Center for AIDS Prevention University of Puerto Rico
Studies. Others were faculty, students, and members of the com- San Juan
munity from other sites. Mean (SD) age was 29 (10.5) years, and 1. Branson B. Home sample collection tests for HIV infection. JAMA. 1998;280:
1699-1701.
66% (133/201) had previously heard about HSC tests. 2. Phillips K, Branson B, Fernyak S, Bayer R, Morin S. The home collection HIV
Individuals reported that accuracy, confidentiality (privacy), test: past, present, and future. Paper presented at: Understanding the Impact of
and safety were the test characteristics most important to them, New Treatments in HIV Testing (forum); January 28-30, 1998; University of Cali-
fornia, San Francisco.
followed by convenience, speed of obtaining results, ease of col- 3. Kaiser Family Foundation. Forum summary. From: Understanding the Impact
lecting the sample, and availability of counseling. Affordability of New Treatments in HIV Testing (forum); January 28-30, 1998; University of
California, San Francisco.
was considered least important (FIGURE). Thirty-seven percent 4. Home Access Health Corporation. Home Access HIV Counseling and Testing
(72/193) of respondents said they would prefer venipuncture test- Report. Was available at: http://www.homeaccess.com. Accessed December 1,
1997.
ing at physicians’ offices, 36% (70/192) would choose standard 5. Phillips KA, Flatt SJ, Morrison KR, Coates TJ. Potential use of home HIV test-
testing at public clinics, and 27% of respondents preferred some ing. N Engl J Med. 1995;332:1308-1310.

198 JAMA, January 12, 2000—Vol 283, No. 2 ©2000 American Medical Association. All rights reserved.

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In Reply: Timely dissemination of information about the use
of HSC tests was the intent of the Food and Drug Administra-
tion when it required HSC sponsors to collect this informa-
tion and share it with the Centers for Disease Control and Pre-
vention. Dr Phillips and colleagues mention several venues
where we provided preliminary analyses on the use of HSC tests.
Their awareness of these presentations suggests that we suc-
ceeded in our efforts to make this information accessible to per-
sons responsible for public health policy and planning con-
cerning HIV testing. However, it is not customary to cite such
preliminary presentations, especially when they have not been
peer reviewed. Some of the data presented in our article had
been posted on the manufacturer’s Web site,1 as Phillips et al
indicate, and I informed JAMA of this fact.
I do not find the discrepancy between the first-year use of HSC
and the proportion of persons who responded affirmatively to a
hypothetical survey question to be as striking as Phillips et al
suggest. The survey did not assess intentions to use HSC dur-
ing its first year of availability. I would indeed be surprised if
14% to 17% of the entire US population sought HIV testing dur-
ing a single year using HSC or any other technique. Subsequent
data from the manufacturer suggest that demand for HSC re-
mains steady, similar to that observed during the first year.
The mail survey results from 204 persons are interesting, but
I would hesitate to conclude that affordability of HIV tests is
unimportant from a survey conducted primarily among col-
lege students. In our article, we referred to the importance of
cost in a study of 2300 high-risk persons in 9 states inter-
viewed for the Centers for Disease Control and Prevention’s
HIV Testing Survey.2 Among another 2093 persons surveyed
at publicly funded testing sites in California, 59% said they would
use a home HIV test if it were available, but 61% said they would
pay no more than $10 for it (Steven R. Truax, PhD, California
Office of AIDS, written communication, December 1996).
I agree that it is important to identify and eliminate barriers
to voluntary HIV testing so that the many persons infected with
HIV who have been unaware of their infection can benefit from
the advances in therapy and prevention. Because many of these
barriers vary with different populations, a variety of ap-
proaches is needed.
Barnard M. Branson, MD
Centers for Disease Control and Prevention
Atlanta, Ga
1. Home Access Health Corporation. Home Access HIV Counseling and Testing
Report. Was available at: http://www.homeaccess.com. Accessed December 1,
1997.
2. Colfax GJ, Lehman J, Hecht FM, et al. Likelihood of at-risk individuals using
home HIV test collection kits. Paper presented at: Society of General Internal Medi-
cine, 20th Annual Meeting; May 2, 1997; Washington, DC.
Lyme Disease Vaccine
To the Editor: In the Medical News & Perspectives article by
Dr Jefferson,1 several statements about the Lyme disease vac-
cine, require clarification to avoid misrepresenting the effi-
cacy and safety of the vaccine.
©2000 American Medical Association. All rights reserved.
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LETTERS
Jefferson noted that “ . . . vaccine is not the first-line pre-
vention for Lyme disease; prevention of tick bites is much more
important.” While personal protective measures have been ad-
vocated as the cornerstone of Lyme disease prevention, the in-
cidence of Lyme disease continues to increase. Hayes et al2 sug-
gest that either this intervention is not effective or that too few
individuals are engaged consistently enough for the interven-
tion to be effective. Several studies have failed to show that per-
sonal protective measures (eg, tucking pants into socks, check-
ing for ticks) have a statistically significant effect in preventing
Lyme disease.2-4 Vaccination with the Lyme disease vaccine is
the only method proven clinically and statistically to prevent
Lyme disease in a large, double-blind, randomized, placebo-
controlled trial.5
We acknowledge that varicella and Lyme disease present dif-
ferent clinical concerns and therefore different issues regard-
ing the corresponding vaccines. Regarding the efficacy of the
Lyme disease vaccine, following completion of the primary
3-dose series, the vaccine was shown to be 78% effective against
laboratory-confirmed disease and 100% effective against asymp-
tomatic infection, which may be a significant factor in the cause
of late Lyme disease. As the stated efficacy of the varicella vac-
cine (ie, 70%-90%) is considered by the author to be accept-
able, it seems inconsistent that the efficacy of Lyme disease vac-
cine, with a similar efficacy rate, would be characterized as “not
great.”
Jefferson noted that a small number of vaccinated persons
developed autoimmune arthritis. As would be expected in a
large efficacy study (N = 10 936) evaluating individuals with a
mean age of 46 years (range, 15-70 years), with almost 2
years of follow-up, adverse events of arthritis were observed.5
However, in the trial there was no statistical difference in the
incidence of arthritis between the vaccine and placebo
groups. Also, the incidence of inflammatory arthropathy was
specifically addressed in a post hoc analysis by the data safety
monitoring board, an outside independent panel of experts.
They did not detect a statistical difference between the vac-
cine group and the placebo group. A double-blind, placebo-
controlled trial to assess the safety and immunogenicity of the
vaccine in 4000 subjects as young as 4 years of age is cur-
rently under way.
David H. Schofield, PharmD
Dennis Parenti, MD
SmithKline Beecham Pharmaceuticals
Philadelphia, Pa
1. Jefferson T. Pediatricians alerted to five new vaccines. JAMA. 1999;281:1973-
1975.
2. Hayes EB, Maupin GO, Mount GA, Piesman J. Assessing the prevention effec-
tiveness of local Lyme disease control. J Public Health Manage Pract. 1999;5:84-
92.
3. Smith PF, Benach JL, White DJ, Stroup DF, Morse DL. Occupational risk of Lyme
disease in endemic areas of New York state. Ann N Y Acad Sci. 1988;539:289-
301.
4. Ley C, Olshen E, Reingold A. Case-control study of risk factors for incident Lyme
disease in California. Am J Epidemiol. 1995;142:S39-S47.
5. Steere AC, Sikand VK, Meurice F, et al. Vaccination against Lyme disease with
recombinant Borrelia burgdorferi outer-surface lipoprotein A with adjuvant. N Engl
J Med. 1998;339:209-215.
JAMA, January 12, 2000—Vol 283, No. 2 199
 LETTERS

To the Editor: While the vaccines described in the article by mood shifts, irritability, and suspicion are recognized out-
Dr Jefferson1 are new, the method for administering deltoid in- comes of inorganic mercury poisoning.2
jections is not. I was therefore surprised that the photograph By analyzing samples of Jackson’s hair, Deppisch et al claim
in this article showed the clinician administering the vaccine to have disposed of the calomel hypothesis. The problem with
not wearing gloves. Furthermore, the surprisingly calm pa- their explanation is that inorganic mercury is not readily
tient is lending a “helping hand” to hold up his shirt sleeve. incorporated into hair, so their data are impossible to inter-
This “helping hand” is dangerously near the needle’s path and pret. They apparently have confused inorganic mercury with
is, therefore, ill-advised. In light of these 2 objections, the il- the organic form, methylmercury, which is incorporated into
lustration should be updated to reflect proper technique. the matrix of the hair root and remains embedded in the hair
Ingrid Kohlstadt, MD, MPH shaft.3
Johns Hopkins Center for Human Nutrition A correspondence between blood levels of inorganic mer-
Baltimore, Md cury and deposition into other tissues and hair has yet to be
1. Jefferson T. Pediatricians alerted to five new vaccines. JAMA. 1999;281:1973-
demonstrated. This is illustrated by data from our laboratory
1975. (TABLE) for 5 individuals exposed to inorganic mercury in the
form of vapor or mercury salt. Despite extremely high blood
In Reply: Drs Schofield and Parenti point out that there was levels of inorganic mercury, the hair level is barely raised above
no statistically significant difference in the incidence of new the normal range and shows no correlation with blood levels.
arthritis diagnoses between the placebo and vaccine groups dur- In contrast, after exposure to methylmercury, hair levels are
ing the 20 months of follow-up in 1 study of outer-surface pro- proportional to blood levels and are about 250 times higher
tein A (OspA) vaccine with adjuvant.1 However, reservations than the concentration in blood.4
were expressed by members of the US Food and Drug Admin- Hair analysis is often advocated as a technique for determin-
istration advisory committee regarding the relatively brief fol- ing levels of metals in body tissues or as a marker of dietary
low-up periods, particularly with regard to the development intake. Suzuki’s5 cautionary note still stands: “Except for meth-
of late manifestations of Lyme disease, such as arthritis.2,3 One ylmercury, no detailed examination regarding the relation-
month after the publication of the vaccine trial results, Gross ship of hair (or nail) concentrations to organ (or tissue) or body
et al4 identified an autoantigen that was cross-reactive with OspA. fluid concentrations has been conducted.”
The authors hypothesized that OspA-primed T cells in syno-
Elsa Cernichiari, MS
vial fluid might remain activated by stimulation from the cross- Gary M. Myers, MD
reacting peptide, even after adequate treatment with antibiot- Thomas W. Clarkson, PhD
ics. Continued surveillance of vaccine recipients for development Bernard Weiss, PhD
of arthritis appears prudent. University of Rochester School of Medicine and Dentistry
Dr Kohlstadt correctly emphasizes the importance of dem- Rochester, NY
onstrating proper injection technique in our illustrations. The 1. Deppisch LM, Centeno JA, Gemmel DL, Torres NL. Andrew Jackson’s expo-
consistent use of universal precautions is now a critical and in- sure to mercury and lead: poisoned president? JAMA. 1999;282:569-571.
2. Environmental Health Criteria 118: Inorganic Mercury. Geneva, Switzerland:
dispensable part of every procedure, including immunization. World Health Organization; 1991.
3. Cernichiari E, Toribara TY, Liang L, et al. The biological monitoring of mercury
Thomas C. Jefferson, MD in the Seychelles study. Neurotoxicology. 1995;16:613-628.
JAMA 4. Environmental Health Criteria 101: Methylmercury. Geneva, Switzerland: World
Chicago, Ill Health Organization; 1990.
5. Suzuki T. Hair and nails: advantages and pitfalls when used in biological moni-
1. Steere AC, Sikand VK, Meurice F, et al. Vaccination against Lyme disease with toring. In: Clarkson TW, Friberg L, Nordberg GF, Sager PR, eds. Biological Moni-
recombinant Borrelia burgdorferi outer-surface lipoprotein A with adjuvant. N Engl toring of Toxic Metals. New York, NY: Plenum; 1988:623-640.
J Med. 1998;339:209-215.
2. Marwick C. Guarded endorsement for Lyme disease vaccine. JAMA. 1998;
279:1937-1938.
3. Rutter T. Lyme disease vaccine given guarded approval in the US. BMJ. 1998;
316:1695. Table. Blood, Urine, and Hair Mercury Levels in Individuals Exposed
4. Gross DM, Forsthuber T, Tary-Lehmann M, et al. Identification of LFA-1 as a to Inorganic Mercury as Inhaled Vapor, Injected Metallic Mercury,
candidate autoantigen in treatment-resistant Lyme arthritis. Science. 1998;281: or Ingested Mercuric Salt*
703-706.
Blood, Urine, Hair,
ng/mL ng/mL ng/mg
(Normal (Normal (Normal
Did Andrew Jackson Have Mercury Poisoning? Exposure Cause ,10 ng/mL) ,10 ng/mL) ,2 ng/mg)
Metallic mercury Aspiration 400 512 3.0
To the Editor: Contrary to the report by Dr Deppisch and col- Metallic mercury Self-injected 335 1320 2.4
leagues,1 Andrew Jackson might well have had mercury poi- Mercury vapor Heating mercury 285 234 2.8
soning. Jackson’s physicians, like others of their time, pre- Mercury vapor Workplace 54 210 2.5
scribed calomel (mercurous chloride) for a broad range of Mercury chloride Suicide attempt 854 472 2.7
ailments. Jackson’s kidney problems, tooth loss, excessive sali- *Normal values listed in column headings from World Health Organization, Environmen-
tal Health Criteria 118: Inorganic Mercury.2
vation, tremor, and personality quirks such as unpredictable
200 JAMA, January 12, 2000—Vol 283, No. 2 ©2000 American Medical Association. All rights reserved.

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In Reply: We hold to our contention that President Andrew
Jackson did not die from calomel (mercurous chloride) poi-
soning. Although we recognize the controversy over the use-
fulness of hair analysis as a determinant of heavy metal expo-
sure, we believe that the results of our analysis of Jackson’s hair
support our conclusion.
A number of researchers have used hair as a measure of ex-
posure to mercury, whether the mercury is in the form of el-
emental mercury1 or an inorganic salt.2 Suzuki et al2 reported
a case of acute mercury poisoning due to the deliberate inges-
tion of mercuric chloride. Hair analysis revealed a substantial
elevation in organic mercury that corresponded to the time of
mercury ingestion. The authors speculated that there are al-
ternative avenues for inorganic mercury to enter the hair other
than incorporation via the matrix of the hair and root sheath,
(eg, sebum, eccrine sweat, apocrine sweat, and desquamated
epidermis).
Second, a literature search identified only a rare case of calo-
mel-induced renal failure3 and just 2 examples of calomel-
initiated psychological dysfunction,4 despite the enormous popu-
larity of this agent as a therapeutic during the Jacksonian era
and beyond. This is not surprising since mercurous ion is poorly
absorbed across the gastrointestinal mucosa.5
We believe that concerns of both medical historians and Jack-
son’s biographers about his mercury poisoning have been over-
stated.
Ludwig M. Deppisch, MD
Northeastern Ohio Universities College of Medicine
Rootstown, Ohio
David J. Gemmel, MA
Youngstown State University
Youngstown, Ohio
1. Foo SC, Khoo NY, Heng A, et al. Metals in hair as biological indices for expo-
sure. Int Arch Occup Environ Health. 1993;65(suppl 1):S83-S86.
2. Suzuki T, Hongo T, Matsuo N, et al. An acute mercuric mercury poisoning: chemi-
cal speciation of hair mercury shows a peak of inorganic mercury value. Hum Exp
Toxicol. 1992;11:53-57.
3. Wands JR, Weiss SA, Yardley J, Maddrey W. Chronic inorganic mercury poi-
soning due to laxative abuse. Am J Med. 1974;57:92-101.
4. David LE, Wands JR, Weiss SA, Price DL, Girling EF. Central nervous system
intoxication from mercurous chloride laxatives. Arch Neurol. 1974;30:428-431.
5. Koos BJ, Longo LD. Mercury toxicity in the pregnant woman, fetus, and new-
born infant: a review. Am J Obstet Gynecol. 1976;126:390-409.
Sildenafil and Nonnitrate
Antihypertensive Medications
To the Editor: The vasodilatory properties of sildenafil (Vi-
agra) are well established and many of sildenafil’s adverse ef-
fects (headache, flushing, dyspepsia, dizziness) result from va-
sodilation. Sildenafil-related myocardial infarction and sudden
death also may be related to its vasodilatory effects.
Sildenafil alone has been associated with episodes of hypo-
tension and the concomitant use of sildenafil and nitrate vaso-
dilators is contraindicated because of hypotensive crises.
Thus, there is some question whether the use of sildenafil in
patients taking nonnitrate antihypertensive drugs might pre-
©2000 American Medical Association. All rights reserved.
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LETTERS
sent an increased risk. Certainly, many antihypertensive
drugs alone cause vasodilation and hypotension. According to
the package insert, “Controlled studies of drug interactions
between Viagra and other antihypertensive medications
[except amlodipine] have not been performed.”1 It would be
helpful for clinicians to know the results of a study involving
sildenafil and, for example, doxazosin mesylate or terazosin
hydrochloride, which are well known to cause hypotensive
reactions in some patients.
To determine whether current data might indicate an in-
creased risk among patients taking sildenafil in combination
with nonnitrate antihypertensives, I requested, in December
1998, the case reports of sildenafil-related adverse drug reac-
tions (ADRs) that had been submitted to the US Food and Drug
Administration (FDA). I received the list of ADR reports from
April to June 28, 1998.2 The list contained 439 ADRs. Of these,
127 (29%) occurred in patients taking antihypertensive drugs.
Twenty of these cases involved nitrates. Removing these cases,
107 (25.5%) of the remaining 419 reports involved other an-
tihypertensive drugs. However, the FDA list contained many
apparent redundancies and often lacked key information such
as patients’ ages or details of adverse events. Removing the re-
dundancies, 360 cases remained. Of these, 87 patients (24.2%)
were taking nonnitrate antihypertensive drugs.
Thus, overall, about 24% of sildenafil-related ADRs re-
ported to the FDA from April 22, through June 28, 1998 oc-
curred in patients taking nonnitrate antihypertensive drugs. This
percentage exceeds the approximately 13% of American adults
receiving treatment for hypertension,3 but it is less than the 33%
of subjects taking antihypertensives in the placebo-controlled
sildenafil trials.4 Whether the fact that nearly one quarter of
sildenafil reports to the FDA also involved antihypertensive
drugs indicates an increased risk factor, a reporting bias, a sta-
tistical error secondary to incomplete information in the FDA
reports, or a reflection of an older and less healthy patient popu-
lation taking sildenafil is not known.
Physicians should be aware of the possibility of hypoten-
sive reactions in patients taking antihypertensive drugs and silde-
nafil and should alert patients about this potential adverse ef-
fect.5
Jay S. Cohen, MD
Del Mar, Calif
1. Viagra [package insert]. New York, NY: Pfizer Inc; November 1998.
2. US Food and Drug Administration. FDA: Adverse Event Reporting System (AERS),
Freedom of Information Report. Washington, DC: Dept of Health and Human Ser-
vices; August 3, 1998.
3. Burt VL, Whelton P, Roccella EJ, et al. Prevalence of hypertension in the US
adult population: results from the the third National Health and Nutrition Exami-
nation Survey, 1988-1991. Hypertension. 1995;25:305-313.
4. Morales A, Gingell C, Collins M, Wicker PA, Osterloh IH. Clincal safety of oral
sildenafil (Viagra) in the treatment of erectile dysfunction. Int J Impot Res. 1998;
10:69-74.
5. Cheitlin MD, Hutter AM Jr, Bridis RG, et al. Use of sildenafil (Viagra) in pa-
tients with cardiovascular disease. J Am Coll Cardiol. 1999;33:273-282.
In Reply: The FDA’s adverse event reporting system is intended
to identify safety signals. Pfizer, the FDA, and regulatory authori-
ties in more than 80 countries where sildenafil has been ap-
JAMA, January 12, 2000—Vol 283, No. 2 201
 LETTERS
proved closely monitor the postmarketing experience. With more
than 10 million prescriptions having been filled by more than 5
million men (representing more than 100 million tablets dis-
pensed), there is a substantial body of evidence that sildenafil is
safe when used in accordance with the product label.
The number of reports to the FDA’s adverse event reporting
system and the quality of information reported depend on a
number of factors, including the amount of publicity a prod-
uct receives. As such, the FDA advises that “it is not possible
to calculate a true incidence rate of a particular event for a speci-
fied drug” based on data from the adverse event reporting sys-
tem,1 as neither the true numerator nor the true denominator
are known.
Because hypertension is a well-recognized risk factor for erec-
tile dysfunction, it is not surprising that a significant percent-
age of men taking sildenafil also would be taking concomitant
antihypertensive medications. A combined analysis2-4 was con-
ducted of 18 double-blind, placebo-controlled, phase 2 and 3
sildenafil clinical trials, in which 1393 (32.6%) of 4274 pa-
tients were taking concomitant antihypertensives including
b-blockers, a-blockers, diuretics, angiotensin-converting en-
zyme inhibitors, and calcium channel blockers, either singly
or in combination. In the sildenafil-treated patients, no in-
crease in the overall frequency of adverse events with any class
of antihypertensive existed.2-4 The frequency of adverse events
related to blood pressure regulation, such as dizziness or hy-
potension, was comparable for patients who took sildenafil with
or without concomitant antihypertensive medication. There were
no treatment-related cases of syncope or postural hypoten-
sion in patients treated with concomitant antihypertensive medi-
cations.2-4
Sildenafil has modest effects on blood pressure and is not,
as Dr Cohen suggests, associated with marked hypotension.
Single oral doses of 100 mg administered to healthy volun-
teers produced mean maximum decreases in supine blood pres-
sure of 8.4/5.5 mm Hg. The decrease in blood pressure among
patients taking and not taking antihypertensive medications
was comparable.5
In the clinical trials (based on .6000 person-years of expo-
sure), myocardial infarctions and deaths occurred with com-
parable frequency in the sildenafil and placebo treatment groups
(A. Hackett, MD, unpublished data, May 1999).2
Robert A. Kloner, MD, PhD
Good Samaritan Hospital
Los Angeles, Calif
Richard L. Siegel, MD, MS
Pfizer Inc
New York, NY
Financial Disclosure: Dr Kloner has received research funding from and has served
as a consultant to and speaker for Pfizer Inc.
1. Food and Drug Administration. Viagra information. Available at: http://
www.fda.gov/cder/consumerinfo/viagra/default.htm. Accessed November 12,
1999.
2. Zusman RM, Morales A, Glasser D, Osterloh I. Overall cardiovascular profile
of sildenafil citrate. Am J Cardiol. 1999;83:35C-44C.
3. Prisant M, Brown M, for the Sildenafil Study Group. Sildenafil citrate: well-
202 JAMA, January 12, 2000—Vol 283, No. 2
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tolerated by patients with erectile dysfunction taking concomitant antihyperten-
sive therapy. Am J Hypertens. 1999;12:10A.
4. Kloner R, Brown M, for the Sildenafil Study Group. Safety of sildenafil citrate
in men with erectile dysfunction taking multiple antihypertensive agents. Am J Hy-
pertens. 1999;12:37A.
5. Zusman RM, Collins M. Effect of sildenafil on blood pressure in men with erec-
tile dysfunction taking concomitant antihypertensive medication. J Am Coll Car-
diol. 1999;33(suppl):238A.
Research Letter
Acceptability of Prophylactic Mastectomy
in Cancer-Prone Women
To the Editor: About 7% of breast cancers are associated with a
mutation of BRCA1 or BRCA2.1 Preventive management in the
population of women with genetically determined breast cancer
is challenging because there are limited data about strategies, ef-
ficacy, and risk-benefit ratios. Women who test positive for a
BRCA1 or BRCA2 mutation face difficult decisions about whether
to undergo prophylactic mastectomy. A substantial benefit of pro-
phylactic mastectomy was recently documented in women with
a family history of breast cancer.2 However, from a public health
point of view, the impact of any treatment depends not only on
efficacy but also on availability, affordability, and acceptability
of the procedure. On the assumption that availability and afford-
ability could be achieved, we investigated the acceptability of the
procedure.
Methods. Two surveys were conducted in France, one of
patients and the other of physicians. The opinions of patients
were ascertained with a preconsultation, self-administered ques-
tionnaire administered during a 1-year period to all attend-
ees of 5 cancer genetics clinics chosen for representative geo-
graphical location (northern, central, and southern France and
2 institutes in Paris). Women were asked whether prophy-
lactic mastectomy would be acceptable at specific ages to a
women with a BRCA1 or BRCA2 mutation. The physicians’
survey was a national sample of practitioners involved in breast
cancer management, randomly selected from a comprehen-
sive database. Expected impact of prophylactic mastectomy
was estimated using the rate at which women would accept
the intervention and efficacy of 90%,2 weighted by the per-
centage of patients already diagnosed with the disease (since
surgery would no longer be prophylactic) according to pen-
etrance and the age at which surgery is performed3 in women
affected by breast cancer before the age at which they might
have accepted the intervention.
Results. The overall response rate was 98% (473/481) for
patients and 60% (700/1169) for physicians. Sixty percent
(n = 286) of patients belonged to cancer-prone families; mean
(SD) age was 43.9 (12.2) years; parity was 1.8 (1.3); 45%
(212) had an educational level beyond high school; 53.5%
(253) were cancer free. The physicians had a mean (SD) age
of 45.4 (7.8) years; parity was 2.3 (1.2); and 47% (325) of
respondents were women. Only 20.3% (96) and 33.7% (236)
of patients and physicians, respectively, agreed that pro-
©2000 American Medical Association. All rights reserved.

Figure. Acceptability Reported by Patients and Computed
Effectiveness of Prophylactic Mastectomy by Age at Surgery
Effectiveness
Acceptability
100
90
81
80
73
60
Rate, %
44
40
20.3
20
11.6
4.7 6.6
0 Funding/Support: This study was funded by the National Institute for Health and
<35 35-40 41-50 >50
Age at Which Prophylactic Mastectomy
Is Hypothetically Scheduled, y
The acceptability of prophylactic mastectomy to women potentially at risk was
assessed prior to the first cancer genetic consultation. We plotted the rate at which
women and physicians said surgery would be acceptable according to age at which
the intervention is hypothetically scheduled. Effectiveness (Ef) of the strategy was
computed using the following formula: Ef = C (Dfw), where Dfw is the propor-
tion of cancer-prone women still disease free who accept prophylactic mastec-
tomy at a given age based on Breast Cancer Linkage Consortium penetrance data,3
and C is the efficacy of the intervention (90%) as given by Hartmann et al.2
phylactic mastectomy should be performed (FIGURE). Re-
spondents’ answers were not correlated with women’s age
at the time of the survey, their disease status, or their ge-
netic risk. In contrast, the age at which surgery hypotheti-
cally would be scheduled was strongly associated with the
acceptability of prophylactic mastectomy. Only 4.7% (22)
of patients and 10.9% (76) of physicians found the surgical
intervention acceptable in women younger than age 35 years.
Comment. Although prophylactic mastectomy may pro-
long life in women with a BRCA1 or BRCA2 mutation who
accept the intervention, if the intervention is unacceptable
to most women, particularly when suggested to women
younger than 35 years, the age at which the benefit is ex-
pected to be the highest, prophylactic mastectomy is un-
likely to have a substantial impact. The convergence of pa-
tient aversion, physician reluctance, and cautious institutional
guidelines4 will likely make prophylactic mastectomy a rarely
©2000 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a University of St. Andrews Library User on 05/24/2015
LETTERS
performed procedure in France, even if other populations
may find this strategy more acceptable.4-6
Francois Eisinger, MD
Claire Julian-Reynier, MD
Hagay Sobol, MD
INSERM
Marseille, France
Dominique Stoppa-Lyonnet, MD
Curie Institute
Paris, France
Christine Lasset, MD
Leon Berard Centre
Lyon, France
Catherine Nogues, MD
Rene Huguenin Centre
Saint-Cloud, France
Medical Research (INSERM decision No. 4M612C, by the Association for Cancer
Research (ARC) and by the National Coalition Against MD Cancer (LNCC) and its
Local Committee (Bouches du Rhone)
Acknowledgment: We thank the patients and physicians and Philippe Vermin, MD,
H. Mignotte, MD, and Françoise Chabal, RN, for their valuable contribution to
this work (data collection).
1. Claus EB, Schildkraut JM, Thompson JM, Risch NJ. The genetic attributable risk
of breast and ovarian cancer. Cancer. 1996;77:2318-2324.
2. Hartmann LC, Schaid DJ, Woods JE, et al. Efficacy of bilateral prophylactic mas-
tectomy in women with a family history of breast cancer. N Engl J Med. 1999;
340:77-84.
3. Easton DF, Ford D, Bishop DT, and the Breast Cancer Linkage Consortium. Breast
and ovarian cancer incidence in BRCA1-mutation carriers. Am J Hum Genet. 1995;
56:265-271.
4. Eisinger F, Geller G, Burke W, Holtzman N. Cultural basis for differences be-
tween US and French clinical recommendations for women at increased risk of
breast and ovarian cancer. Lancet. 1999;353:919-920.
5. Meijers-Heijboert EJ, van Geel AN, Seynaeve C, et al. Uptake presymptomatic
DNA test and preventive measures in families with inherited breast and/or ovar-
ian cancer. Am J Hum Genet. 1997;61(suppl):A403.
6. Geller G, Bernhardt BA, Doksum T, Helzlsouer KJ, Wilcox P, Holtzman NA. De-
cision-making about breast cancer susceptibility testing: how similar are the atti-
tudes of physicians, nurse practitioners, and at-risk women? J Clin Oncol. 1998;
16:2868-2876.
CORRECTION
Incorrect Wording: In the Original Contribution entitled “Relationship Between
Cancer Patients’ Predictions of Prognosis and Their Treatment Preferences,” pub-
lished in the June 3, 1998, issue of THE JOURNAL (1998;279:1709-1714), there was
incorrect wording in a table. On page 1712, in Table 2, in the first row under the
column “Proportion of Patients Favoring Life-Extending Therapy” the numbers
that read “148/390” should have read “198/390.” In the third row, under the
column “Proportion of Patients Favoring Life-Extending Therapy” “16/50” should
have read “16/56.”
JAMA, January 12, 2000—Vol 283, No. 2 203