cidofovir for cytomegalovirus retinitis

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Cidofovir for Cytomegalovirus Retinitis

To the Editor: The demonstration of the effectiveness of cidofovir to treat cytomegalovirus (CMV) retinitis adds a welcome third drug to the list of anti-CMV therapies. However, it is most disturbing to find that the two clinical studies of this compound (1, 2) compared it with no treatment ("deferred therapy").

There is no doubt that the natural history of untreated CMV retinitis is one of relentless progression and that ganciclovir (3) and foscarnet (4) are both effective. Therefore, the withholding of proven therapy (even with close follow-up) in the context of a clinical trial to demonstrate the effectiveness of cidofovir is unacceptable. The rationalization that only patients with peripheral retinitis were enrolled is irrelevant and of questionable prudence because 4 of 23 patients in the no-treatment group developed sight-threatening retinitis and another patient developed extraocular CMV infection.

The provision of informed consent by the participants of these studies does not render the withholding of proven therapies for the purposes of demonstrating cidofovir's effectiveness any less unethical. I must admit that I was surprised that these studies were approved by the study institutions' ethics review boards. Similarly, regulatory requirements and the fact that previous studies of anti-CMV therapies have been compared with placebo provide no justification for the nontreatment of an opportunistic infection in an experimental protocol. We would not consider withholding therapy for Pneumocystis carinii pneumonia or cryp-tococcal meningitis to prove that a new compound is efficacious.

Surely, there must have been enough suspicion of the potential effectiveness of cidofovir to allow for a direct comparison with ganciclovir or foscarnet. This would have been far more ethically acceptable and would have gone far to delineate the potential role of cidofovir in the treatment of CMV retinitis.

Stephen Kravcik, MD, FRCPC Ottawa General Hospital Ottawa, Ontario K1H 8L6, Canada

References 1. Lalezari JP, Stagg RJ, Kuppermann BD, Holland GN, Kramer F, Ives

DV, et al. Intravenous cidofovir for peripheral cytomegalovirus retinitis in patients with AIDS. A randomized, controlled trial. Ann Intern Med. 1997;126:257-63.

2. Studies of Ocular Complications of AIDS Research Group in Collaboration with the AIDS Clinical Trial Group. Parenteral cidofovir for cytomegalovirus retinitis in patients with AIDS: the HPMPC Peripheral Cytomegalovirus Retinitis Trial. A randomized, controlled trial. Ann Intern Med. 1997;126:264-74.

3. Collaborative DHPG Study Group. Treatment of serious cytomegalovirus infections with 9-(l,3-dihydroxy-2-propoxymethyl) guanine in patients with AIDS and other immunodeficiencies. NEngl J Med. 1986; 314:801-5.

4. Studies of Ocular Complications of AIDS Research Group, in collaboration with the AIDS Clinical Trial Group. Mortality in patients with the acquired immunodeficiency syndrome treated with either ganciclovir or foscarnet for cytomegalovirus retinitis. N Engl J Med. 1992;326:213-20.

In response: Dr. Kravcik raises several issues related to the design of clinical trials evaluating promising anti-CMV therapies. Although untreated CMV retinitis spreads throughout the retina, it does so relatively slowly. Patients with small peripheral CMV retinitis lesions are not at risk for immediate loss of visual acuity and do not require immediate institution of therapy. In clinical practice, initiation of therapy may be deferred for a short period for personal reasons. "Small peripheral" retinitis studies, such as the two clinical trials of cidofovir reported in Annals, enroll only patients who are at low risk for visual loss, and they use a threshold for "progression" that is sufficiently small (750 /im) that patients are not at an increased risk for loss of visual acuity. Dr. Kravcik's assertion that deferral of therapy for patients with peripheral retinitis was "irrelevant" and "of questionable prudence" is incorrect. The HPMPC Peripheral CMV Retinitis Trial provides long-term follow-up data on visual outcomes, and no differences in visual acuity outcomes were seen between persons assigned to deferred therapy and those assigned to immediate therapy. Furthermore, Dr. Kravcik's assertion that we know the natural history of CMV retinitis may be incorrect in the era of highly active antiretroviral therapy; anecdotal reports suggest that progression may be slower in some patients.

Dr. Kravcik's opinion that these studies were "unethical" was not shared by the 23 institutional review boards at the centers participating in these two trials and the two data and safety monitoring committees, all of which approved these studies. Dr. Kravcik's comparison with withholding therapy for P. carinii pneumonia or cryptococcal meningitis is spurious. The pace of these disorders is different from that of CMV retinitis, and delaying the initiation of therapy for them has adverse consequences that do not occur with peripheral CMV retinitis.

Dr. Kravcik seems to suggest that the initial study of any promising anti-CMV agent should be a comparison with established therapy. This suggestion presumes that the investigator knows that the drug is safe and effective before such a trial begins. We believe that it is unethical to treat patients with posteriorly located, newly diagnosed CMV retinitis (that is, zone 1 disease), who are at risk for immediate visual loss, with a drug that is not known to be effective; doing so would place patients at risk for severe visual loss if the drug is ineffective. Trials designed to show the equivalence of two anti-CMV agents require a sample size of approximately 240 patients for adequate power. Because patients with "small peripheral" retinitis lesions account for only one quarter of patients with CMV retinitis (1), doing an equivalence study in this population would take substantially longer and hence delay general use if the drug proves effective. Conversely, trials involving deferred therapy for peripheral retinitis require fewer patients. If the drug is effective, approval is hastened; if the drug is ineffective or toxic, fewer patients are placed at risk.

If a promising new agent is less effective than standard therapy and the trial showing this is the only one done, it is unclear

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whether the drug is 1) less effective but still effective and potentially of value or 2) ineffective and of no value. Given the occurrence of resistance in patients requiring long-term therapy for CMV retinitis (2), new agents, which may not be equivalent to existing agents but have different mechanisms of action, may be of great value in the long-term management of this chronic disease. Hence, U.S. Food and Drug Administration disapproval of a drug because it is less effective than another drug may deprive patients with CMV disease of important options for long-term management. When the entire picture is evaluated, trials comparing a brief period of deferral with therapy for a new agent of unproven value are not only ethical but superior.

Finally, we agree with Dr. Kravcik that a study comparing a new treatment with "standard" therapy is an important step in the development of any new anti-CMV agent. Comparative studies permit treating physicians to better understand the relative merits and the role of a new agent, and we believe that all new agents with demonstrated efficacy should be tested against standard therapy.

Douglas A. Jabs, MD Johns Hopkins University School of Medicine Baltimore, MD 21205

Curtis L. Meinert, PhD Johns Hopkins University School of Hygiene and Public Health Baltimore, MD 21205

Jacob P. Lalezari, MD Quest Clinical Research San Francisco, CA 94115

References 1. Jabs DA. Ocular manifestations of HIV infection. Trans Am Ophthal

mol Soc. 1995;93:623-83. 2. Drew WL, Miner RC, Busch DF, Follansbee SE, Gullet J, Mehalko SG,

et al. Prevalence of resistance in patients receiving ganciclovir for serious cytomegalovirus infection. J Infect Dis. 1991;163:716-9.

Polycystic Ovaries and Coronary Artery Disease

To the Editor: Birdsall and colleagues (1) recently discussed the association of polycystic ovaries and the extent of coronary artery disease in women having cardiac catheterization. They stated that anovulation with reduced estradiol production may be associated with coronary artery disease. However, elevated testosterone production seems to be one of the atherogenic influences in polycystic ovaries. As shown in their Table 2, the free testosterone values in women with polycystic ovaries were significantly greater than those in women with normal ovaries. This finding would also explain the diminished high-density lipoprotein cholesterol values found in women with polycystic ovaries. Estradiol levels were not measured during the study or addressed in the review of patients. Many women with polycystic ovaries exceed their ideal body weight and therefore tend to have normal circulating levels of estrogen, often as estrone (2, 3).

I wholeheartedly agree with Birdsall and colleagues' suggestion that further studies must be undertaken to investigate the natural history and current treatments for polycystic ovaries—not only to alleviate the physical symptoms of androgen excess (which are devastating to many women) but also to reduce the occurrence of long-term complications and even death.

Polycystic ovaries may be one variant of syndrome X—just the "female influence." If so, we should evaluate the influence of pregnancies and use of oral contraceptives on the risk for developing cardiac disease. The role of insulin resistance and the association of polycystic ovaries independent of androgen excess is another possible atherogenic risk factor in these women (4, 5).

Nancy M. McBride, MD Lakewood, OH 44107

References 1. Birdsall MA, Farquhar CM, White HD. Association between polycystic

ovaries and extent of coronary artery disease in women having cardiac catheterization. Ann Intern Med. 1997;126:32-5.

2. Poison DW, Adams J, Wadsworth J, Franks S. Polycystic ovaries—a common finding in normal women. Lancet. 1988;1:870-2.

3. Poison DW, Franks S, Reed MJ, Cheng RW, Adams J, James VH. The distribution of oestradiol in plasma in relation to uterine cross-sectional area in women with polycystic or multifollicular ovaries. Clin Endocrinol (Oxf). 1987;26:581-8.

4. Poretsky L. On the paradox of insulin-induced hyperandrogenism in insulin-resistant states. Endocr Rev. 1991;12:3-13.

5. Geffner ME, Kaplan SA, Bersch N, Golde DW, Landaw EW, Chang RZ. Persistence of insulin resistance in polycystic ovarian disease after inhibition of ovarian steroid secretion. Fertil Steril. 1986;45:327-33.

Transdermal Nicotine for Ulcerative Colitis

To the Editor: Sandborn and colleagues (1) state that their placebo-controlled trial showed that "transdermal nicotine at the highest tolerated dosage (<22 mg/d) has a clinically significant therapeutic benefit in active ulcerative colitis after 4 weeks." How could they make this statement if only 39% of their patients improved clinically (compared with 9% of those who received placebo)? I do not consider a 30% response (39% - 9%) in ulcerative colitis to be clinically meaningful, especially because 77% of patients who received nicotine patches had various side effects; in 13%, these effects were severe enough to discontinue use of the patches.

Also puzzling is the authors' statement that "these results are particularly striking given the fact that the study patients had chronically active ulcerative colitis that was resistant to first-line therapy." How could their patients be considered resistant to therapy if their study protocol mandated that no more than 20 mg of prednisone per day be given? Why exclude patients who received higher doses? Why not administer 40, 60, or 80 mg of prednisone; nine or twelve 5-aminosalicylic acid capsules; or 150 to 200 mg of 6-mercaptopurine or azathioprine before we call these patients "resistant to therapy"? Why use low-dose prednisone therapy as a litmus test of refractoriness to justify giving these patients "the highest tolerated dosage" of nicotine?

Any conclusion about the inadequacy of response to under-treatment or inappropriate therapy is inherently flawed and misleading. I believe that in a direct comparison with an adequate and appropriate therapy, nicotine patches would have proven significantly inferior in the treatment of ulcerative colitis and would have been associated with an unacceptably high rate of side effects.

Michael Mogadam, MD Alexandria, VA 22304

Reference 1. Sandborn WJ, Tremaine WJ, Offord KP, Lawson GM, Petersen BT,

Batts KP, et al. Transdermal nicotine for mildly to moderately active ulcerative colitis. A randomized, double-blind, placebo-controlled trial. Ann Intern Med. 1997;126:364-71.

To the Editor: I read with interest the report by Sandborn and colleagues (1) on the efficacy of transdermal nicotine for mildly to moderately active ulcerative colitis. They reported that the highest tolerated dosage of nicotine improved clinical activity but did not induce histologic remission.

I am of the opinion that chronic effects by an intensive exposure to nicotine should be carefully assessed before patients received nicotine therapy in clinical practice. Several N-nitro-samines, such as 4-(methylnitrosamino)-l-(3-pyridyl)-l-butanone (NNK), are synthesized from nicotine; these carcinogens would increase the risk for cancer (2, 3). In Sandborn and colleagues' study, the serum levels of nicotine in the patients who received the 22-mg patch consistently exceeded 13 ng/mL. This finding is in agreement with the maximal increment level of nicotine (14.3 ng/mL) seen after patients in another study smoked a cigarette containing 1 mg of nicotine (4). This would mean that the patients were exposed to as much nicotine as would have been

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seen had they smoked cigarettes ceaselessly all day long during therapy. To date, patients with such an intensive exposure to nicotine have not been proven safe from an increased risk for cancer.

Current therapy can cause remission in almost 90% of patients with acute ulcerative colitis (5). Hence, risk for developing cancer is an important factor in determining the long-term prognosis of this disease. I am afraid that the small quality-of-life benefit may not compensate for the latent risk for cancer in patients with such benign disease.

Yuichi Ando, MD Nagoya University School of Medicine Nagoya, Japan

References 1. Sandborn WJ, Tremaine WJ, Offord KP, Lawson GM, Petersen BT,


2. Hecht SS, Chen CB, Ornaf RM, Jacobs E, Adams JD, Hoffmann D. Reaction of nicotine and sodium nitrite: formation of nitrosamines and fragmentation of the pyrrolidine ring. Journal of Organic Chemistry. 1978;43:72-6.

3. Amin S, Desai D, Hecht SS, Hoffmann D. Synthesis of tobacco-specific N-nitrosamines and their metabolites and results of related bioassays. Crit Rev Toxicol. 1996;26:139-47.

4. Benowitz NL, Porchet H, Sheiner L, Jacob P 3d. Nicotine absorption and cardiovascular effects with smokeless tobacco use: comparison with cigarettes and nicotine gum. Clin Pharmacol Ther. 1988;44:23-8.

5. Glickman RM. Inflammatory bowel disease: ulcerative colitis and Crohn's disease. In: Wilson JD, Braunwald E, Isselbacher KJ, Pe-tersdorf RG, Martin JB, Fauci AS, et al, eds. Harrison's Principles of Internal Medicine. 12th ed. New York: McGraw-Hill; 1991:1268-81.

To the Editor: We read with great interest the paper by Sand-born and colleagues (1) on transdermal nicotine for ulcerative colitis. In agreement with their data, we also reported that transdermal nicotine, when added to mesalamine, induces clinical alleviation of mild to moderate ulcerative colitis (2). In fact, nicotine patches allowed most patients with a history of poor tolerance to corticosteroids to avoid prednisone therapy (2). Although if administered alone, transdermal nicotine seems less effective than oral steroids in active disease (3) and no better than placebo as maintenance treatment (4), we also observed that patients who responded to nicotine were still in clinical remission several weeks after nicotine therapy was discontinued (the previously ongoing maintenance treatment with mesalamine was continued). We also studied patients who had mild to moderate clinical relapses of left-sided ulcerative colitis during maintenance treatment with 1 g of mesalamine twice daily. These patients were randomly allocated to 5 weeks of additional treatment with either transdermal nicotine (15 mg/d) or prednisone (initial dosage, 30 mg/d for 1 week; the dose was then tapered by decreases of 5 mg every 5 days).

The first consecutive 15 patients per group with clinical and endoscopic signs of remission were followed for 6 months while receiving continuous maintenance treatment with mesalamine. Clinical and endoscopic relapses of active colitis occurred in 20% of patients formerly treated with nicotine and 60% of patients in the prednisone group (P = 0.027). Relapses occurred earlier in the latter group. Our results confirm once again that nicotine is beneficial in cases of mild or moderate active ulcerative colitis and indicate that remissions induced by nicotine may last longer than those obtained with oral corticosteroids. The reasons for this phenomenon.remain unknown.

Mario Guslandi, MD Alberto Tittobello, MD University of Milan Milan, Italy

References 1. Sandborn WJ, Tremaine W, Offord KP, Lawson GM, Petersen BT,


2. Guslandi M, Tittobello A Pilot trial of nicotine patches as an alternative to corticosteroids in ulcerative colitis. J Gastroenterol. 1996;31: 627-9.

3. Thomas GA, Rhodes J, Ragunath K, Mani V, Williams GT, Newcombe RG, et al. Transdermal nicotine compared with oral prednisolone therapy for active ulcerative colitis. Eur J Gastroenterol Hepatol. 1996;8: 769-76.

4. Thomas GA, Rhodes J, Mani V, Williams GT, Newcombe RG, Russell MA, et al. Transdermal nicotine as maintenance therapy for ulcerative colitis. NEngl J Med. 1995;332:988-92.

In response: Drs. Mogadam, Ando, and Guslandi and Tittobello raise many interesting points. Dr. Mogadam states that a 30% response (39% for nicotine compared with 9% for placebo) is not clinically meaningful. We strongly disagree. Studies of drugs that we accept as efficacious for ulcerative colitis and that led to U.S. Food and Drug Administration approval had very similar response rates. For example, Asacol (mesalamine, Procter & Gamble, Inc., Cincinatti, Ohio) at 2.4 g/d showed 26% clinical improvement (49% for Asacol and 23% for placebo) (1), and Pentasa (mesalamine, Hoechst Marion Roussel, Kansas City, Missouri) at 4.0 g/d showed 23% treatment success, defined as marked improvement of symptoms (59% for Pentasa and 36% for placebo) (2). We believe that the 30% beneficial effect of nicotine compares favorably to the effects of these other drugs and is clinically meaningful. We also believe that it is reasonable to define first-line therapy as sulfasalazine, rectal or oral 5-aminosalicylate, and rectal or low-dose oral corticosteroids and to designate other, more toxic therapies (such as high-dose oral corticosteroids, 6-mercaptopurine, and azathioprine) as second-line agents.

Dr. Ando states that N-nitrosamines are synthesized from nicotine and that these carcinogens would increase the risk for cancer. Nicotine itself is not a carcinogen but is a precursor of N-nitrosamines, such as 4-(methylnitrosamino)-l-(3-pyridyl)-l-bu-tanone, which are believed to contribute to tobacco-induced cancer (3). Whether there is endogenous formation of these N-nitrosamines in humans exposed to nontobacco sources of nicotine is unknown (4). Dr. Ando's note of caution seems reasonable. Further research is warranted to analyze the urine of nonsmoking persons who use transdermal patches for evidence of endogenous production of N-nitrosamines. In addition, long-term treatment studies that address the safety (that is, risks for cancer and cardiovascular disease) of transdermal nicotine are needed for diseases in which smoking is protective and nicotine may be efficacious. These diseases include ulcerative colitis, Alzheimer disease, the Tourette syndrome, and Parkinson disease. To further improve the safety of nicotine, we are developing rectal enema and delayed-release oral nicotine formulations that provide a "topical" therapeutic effect in the colon while significantly reducing blood concentrations of nicotine (5).

Drs. Guslandi and Tittobello report that transdermal nicotine may be of benefit for steroid-sparing and remission maintenance treatment in patients with ulcerative colitis. We have had the same experience on an anecdotal basis. These potential treatment indications should be evaluated in randomized, double-blind, placebo-controlled, dose-ranging clinical trials.

William I. Sandborn, MD William J. Tremaine, MD Richard D. Hurt, MD Mayo Clinic Rochester, MN 55905

References 1. Sninsky CA, Cort DH, Shanahan F, Powers BJ, Sessions JT, Pruitt RE,

et al. Oral mesalamine (Asacol) for mildly to moderately active ulcerative colitis. Ann Intern Med. 1991;115:350-5.

2. Hanauer S, Schwartz J, Robinson M, Roufail W, Arora S, Cello J, et al. Mesalamine capsules for treatment of active ulcerative colitis: results of a controlled trial. Am J Gastroenterol. 1993;88:1188-97.

3. Hecht SS, Hofmann D. The relevance of tobacco-specific nitrosamines to human cancer. Cancer Surveys. 1989;8:273-94.

4. Carmella SG, Borukhova A, Desai D, Hecht SS. Evidence for endogenous formation of tobacco-specific nitrosamines in rats treated with tobacco alkaloids and sodium nitrite. Carcinogenesis. 1997;18:587-92.

5. Sandborn WJ, Tremaine WJ, Leighton JA, Lawson GM, Zins BJ, Compton RF, et al. Nicotine tartrate liquid enemas for mildly to mod-



erately active, left-sided ulcerative colitis unresponsive to first-line therapy: a pilot study. Aliment Pharmacol Ther. 1997; [In press].

Acute Renal Failure and Ketorolac

To the Editor: For more than 15 years, nonsteroidal antiinflammatory drugs (NSAIDs) have been associated with acute renal failure as a potential side effect. However, this phenomenon occurs only when renal blood flow significantly depends on renal vasodilator prostaglandin production (1). In "normal" persons without risk factors for NSAID-related acute renal failure, only one clearcut report has described an NSAID overdose causing acute renal failure (2). Thus, the relative incidence of NSAID-induced acute renal failure in any population depends on the prevalence of known risk conditions (such as chronic renal failure, cirrhosis, and heart failure) in that population and the severity of those conditions. The incidence of NSAID-induced acute renal failure in 1 million persons without risk conditions would probably be almost zero.

Feldman and colleagues (3) retrospectively compared the rate of renal failure in hospitalized patients who received ketorolac with the rate in those treated with opioids. Patients were matched only by hospital, admitting service, and date of initiation of therapy. The authors concluded that "when used for 5 days or less . . . ketorolac does not increase the risk for acute renal failure." They also note that "ketorolac may [our emphasis] be associated with an elevated risk for acute renal failure" when used for more than 5 days. We believe that these conclusions cannot be safely drawn from the data presented. First, the authors report that the incidence of a history of chronic renal failure, papillary necrosis, and the nephrotic syndrome was statistically significantly higher in the opioid group (before they received opioids) than in the ketorolac group. This finding suggests that the opioid group had a higher risk for acute renal failure while hospitalized, possibly offsetting a relatively higher rate of ketorolac-induced acute renal failure. Moreover, this finding suggests a likely bias that is present in any such retrospective study; we hope that the prescribers of these medications knew that patients with risk factors for NSAID-induced acute renal failure should not receive ketorolac and preferentially treated such patients with opioids instead. No retrospective multivariate adjustment can control for this sort of bias.

Although more than 10 000 courses of analgesic therapy were analyzed, the study may not have been powerful enough to detect ketorolac-induced acute renal failure. We are not told how many patients in each group had underlying renal insufficiency, cirrhosis, the nephrotic syndrome, or heart failure or used diuretics, nor do we have any index of the severity of such conditions. Despite multivariate adjustment for these risk conditions, if only a handful of patients in the ketorolac group had major risk conditions or if the opioid group consisted of many more such persons with risk factors for acute renal failure, then the comparison between groups would probably not be able to detect ketorolac-induced acute renal failure.

Finally, the authors note that the overall incidence of acute renal failure was low (1.1%) in the population analyzed (as compared with the 4.9% incidence reported by Hou and colleagues [4]). What was the overall incidence of acute renal failure in all patients hospitalized during the study? Because the basis for the selection of patients was the use of parenteral ketorolac, the investigators may have preselected a group at very low risk for NSAID-induced acute renal failure. This preselection would have occurred because physicians who prescribe ketorolac would avoid prescribing the drug to patients at risk for NSAID-induced acute renal failure.

Because of data from prospective studies, other retrospective analyses, case reports on NSAID-induced acute renal failure (even occurring early in the course of ketorolac therapy [5]), and our concerns, we urge all physicians to use caution when using any NSAID in patients at risk for NSAID-induced acute renal failure.

Gregory K Buller, MD Mark A. Perazella, MD Yale University School of Medicine New Haven, CT 06520

References 1. Clive DM, Stoff JS. Renal syndromes associated with nonsteroidal

anti-inflammatory drugs. N Engl J Med. 1984;310:563-72. 2. Buller GK, Perazella MA. Can ibuprofen cause acute renal failure in a

normal individual? Am J Kidney Dis. 1991;18:600-1. 3. Feldman HI, Kinman JL, Berlin JA, Hennessy S, Kimmel SE, Farrar J,

et al. Parenteral ketorolac: the risk for acute renal failure. Ann Intern Med. 1997;126:193-9.

4. Hou SH, Bushinsky DA, Wish JB, Cohen JJ, Harrington JT. Hospital-acquired renal insufficiency: a prospective study. Am J Med. 1983;74: 243-9.

5. Perazella MA, Buller GK. NSAID nephrotoxicity revisited: acute renal failure due to parenteral ketorolac. South Med J. 1993;86:1421-4.

In response: Drs. Buller and Perazella state that studies of acute renal failure associated with NSAIDs should be limited to persons at risk for this condition. We agree with this view, but hospitalized patients ill enough to receive parenteral analgesics are at risk for acute renal failure, which in some cases is blamed on NSAIDs (1). Furthermore, a substantial minority have conditions (such as volume depletion or hypotension) in which renal function depends on vasodilator prostaglandins; this may place them at higher risk for acute renal failure from such cyclooxy-genase inhibitors as ketorolac.

Drs. Buller and Perazella questioned whether our study had sufficient power to detect an effect of ketorolac among patients who are exposed to diuretics or have a history of renal disease, cirrhosis, or heart failure. We, too, were concerned about a potentially enhanced toxicity from ketorolac in this subgroup. We therefore explored whether there was a statistically significant interaction between membership in this subgroup and the occurrence of ketorolac-induced acute renal failure, but we found no such interaction. Thus, ketorolac was not differentially toxic in this subgroup, and we did not present a subanalysis for these 3891 patients (2111 in the opioid group and 1780 in the ketorolac group). However, to respond to Drs. Buller and Perazella's specific inquiry, we have calculated the hazard ratio in this subgroup for the comparison of ketorolac with opioids (hazard ratio, 0.86 [95% CI, 0.63 to 1.17]); this confirms our previous finding of no enhanced risk in this subgroup.

We are puzzled by Drs. Buller and Perazella's statement that multivariate adjustment cannot account for baseline differences between our study groups. This is exactly the goal of multivariate analysis (to control for the potential confounding influence of measured baseline characteristics) (2). It is conceivable that unmeasured differences in our study groups could have led to bias, but we believe that multivariate adjustment for previous renal disease and many other measured characteristics makes such a potential bias very unlikely.

Drs. Buller and Perazella note that we observed a rate of acute renal failure that was lower than that cited in Hou and colleagues' report of hospital-acquired acute renal failure (3). There are several reasons for these differences in the rates of acute renal failure, each related to differences between Hou and colleagues' objective and our objective. Our study was designed to evaluate the comparative risk for acute renal failure in patients receiving parenteral analgesics. First, the definition of acute renal failure that we used was more stringent. For example, we required an elevation of serum creatinine level of 44.2 /uxnol/L if the baseline level was less than 132.6 /utmol/L, whereas Hou and colleagues used an elevation of 44.2 /Limol/L for baseline levels as high as 168 /imol/L. Second, we looked for acute renal failure only during the period of analgesic administration and for 3 days thereafter rather than at any time during the hospital stay. Finally, we examined only hospitalized patients who received parenteral analgesics, not all hospitalized patients.

We emphasize that caution should be used when parenteral ketorolac is administered for a prolonged period.

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Harold L Feldman, MD, MS Judith L. Kinman, MA Brian L. Strom, MD, MPH University of Pennsylvania Medical Center Philadelphia, PA 19104

References 1. Corelli RL, Gericke KR. Renal insufficiency associated with intramus

cular administration of ketorolac tromethamine. Ann Pharmacother. 1993;27:1055-7.

2. Kleinbaum DG, Kupper LL, Morgenstern H. Epidemiologic Research. Belmont, CA: Lifetime Learning Publications; 1982.

3. Hou SH, Bushinsky DA, Wish JB, Cohen JJ, Harrington JT. Hospital-acquired renal insufficiency: a prospective study. Am J Med. 1983;74: 243-8.

Public Policy and Risk of a Haircut

To the Editor: The brief study of the potential risks of a haircut reported by Gitlin and colleagues (1) has led to an amendment to the public health codes in New York State. This report had shown that hepatitis C virus RNA was not destroyed by the antiseptic solutions used in barber shops. The study highlighted the risks of the nondisposable razors often used for shaves and trimming of the sideburns and the back of neck. After reading this letter, I visited my local barber shop and discovered that some barbers were still using old-fashioned straight razors. I brought this to the attention of the State Health Department. However, it was the investigative efforts of a reporter for Staten Island's local newspaper (2) that caused the Health Department to realize that the existing rules for disposable razors (applicable to cosmetologists and beauty salons) did not cover barber shops. The codes are now being amended. This is a fine example of the quick translation of efforts of the medical community into a policy to protect the public health.

Khalid L. Rehman, MD St. Vincent's Medical Center Staten Island, NY 10310

References 1. Gitlin N, Nolte FS, Weiss M. Hepatitis C: risk of a haircut [Letter].

Ann Intern Med. 1997;126:410-1. 2. Eisner R. Say so long to the old fashioned shaves. The Staten Island

Advance. 12 May 1997:1.

Impaired Hepatic Catabolism of Melatonin in Cirrhosis

To the Editor: Prompted by Garfinkel and Zisapel's comment (1) on our paper, published in August 1995 (2), we present some consecutive data. We postulated that elevated plasma melatonin levels and an altered 24-hour profile of the hormone we found in patients with liver cirrhosis (2) could represent an altered output of the circadian clock (3), causing a central disturbance of Orcadian rhythmicity.

Garfinkel and Zisapel suggested that we measure the urinary metabolite of melatonin, 6-sulfatoxymelatonin, to determine whether increased production in the pineal gland or decreased catabolism by the liver is the main reason for elevated serum melatonin levels in patients with liver cirrhosis.

We therefore measured urinary 6-sulfatoxymelatonin levels in 21 hospitalized cirrhotic patients with normal renal function (14

Figure. Total urinary 6-sulfatoxymelatonin excretion from 10:00 p.m. to 6:00 a.m. in cirrhotic patients and controls. The horizontal line represents the median.

men and 7 women; median age, 50 years [range, 29 to 80 years]; Child class A, 7 patients; class B, 11 patients; class C, 3 patients) and in 9 healthy persons (3 men and 7 women; median age, 49 years [range, 32 to 69 years]). Sixteen had alcoholic liver disease, 2 had hepatitis C, and 1 each had primary biliary cirrhosis and Wilson disease. Two patients had signs of clinically overt hepatic encephalopathy.

Eight-hour urine excretion (10:00 p.m. to 6:00 a.m.) was assayed for 6-sulfatoxymelatonin by enzyme-linked immunosorbent assay (Melatonin-Sulfat-ELISA, IBL Ges mbH, Hamburg, Germany). Routine laboratory testing was performed by using standard methods. Statistical analysis was done with the paired Student Mest or the Mann-Whitney rank-sum test.

In the 8-hour urine measurements, cirrhotic patients had a significantly decreased concentration (mean ± SE, 19.01 ± 2.76 ng/mL compared with 39.2 ± 5.41; P = 0.001) and total excretion (median, 8.28 mg [range, 0.85 to 28.1 mg] compared with 12.21 mg [range, 9.12 to 29.04 mg]; P<0 .05) of 6-sulfatoxymelatonin, compared with controls (Figure). Urine volumes were similar in the two groups. No correlation to Child class or liver function measures was seen.

These findings indicate that the elevated plasma melatonin levels seen in cirrhotic patients are at least partly due to impaired hepatic catabolism.

Petra E. Steindl, MD Peter Ferenci, MD Wolfgang Marktl, MD University of Vienna Vienna, Austria

References 1. Garfinkel D, Zisapel N. Liver cirrhosis and circadian rhythm [Letter].

Ann Intern Med. 1996;125:154. 2. Steindl PE, Finn B, Bendok B, Rothke S, Zee PC, Blei AT. Disruption

of the diurnal rhythm of plasma melatonin in cirrhosis. Ann Intern Med. 1995;123:274-7.

3. Rosenthal NE. Plasma melatonin as a measure of the human clock. J Clin Endocrinol Metab. 1991;73:225-6.



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