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tients whose prognosis is better to begin with are more likely to have a response. In the absence of evidence that allows us to make unbiased estimates of the efficacy of treatment in terms of global measures of health or mortality, a recommendation for the widespread use of antiviral drugs to treat hepatitis C seems imprudent4 and extravagant. THOMAS B. NEWMAN, M.D., M.P.H. University of California, San Francisco San Francisco, CA 94143-0560
Combination Therapy for Hepatitis C Infection To the Editor: Two studies in the November 19 issue, one by McHutchison et al.1 and one by Davis et al.,2 were supported by Schering-Plough and show that combining interferon alfa-2b with ribavirin leads to better virologic and biochemical rates of response in patients with hepatitis C. The cost to the patient of a 48-week course of this drug combination (Rebetron, Schering-Plough, Kenilworth, N.J.) is about $18,000. The side effects of an initial course of treatment are considerable: in the study by McHutchison et al., about two thirds of patients had influenza-like symptoms, and about one third each had nausea, depression, insomnia, and alopecia.1 The only death reported in the two studies was the result of suicide.2 In deciding whether the substantial cost and year-long decrement in the quality of life associated with this treatment are justified by future health benefits, patients, physicians, and payers need to know the extent to which treatment will ultimately affect clinically relevant outcomes, such as survival, liver failure, and liver cancer. A major limitation of the studies that neither the authors nor the editorialist3 mentions is that only short-term and intermediate outcomes were assessed. It is not clear to what extent, if at all, the higher rate of virologic response will translate into lower rates of cirrhosis, liver failure, liver transplantation, or death. Such a determination must be made on an intention-to-treat basis, with mortality rates compared in entire groups of patients who are randomly assigned to various treatments or to no treatment. Any other type of comparison could be biased by a selection effect, in which patients destined to do poorly cannot tolerate or have no response to antiviral drugs, whereas pa-
1. McHutchison JG, Gordon SC, Schiff ER, et al. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. N Engl J Med 1998;339:1485-92. 2. Davis GL, Esteban-Mur R, Rustgi V, et al. Interferon alfa-2b alone or in combination with ribavirin for the treatment of relapse of chronic hepatitis C. N Engl J Med 1998;339:1493-9. 3. Liang TJ. Combination therapy for hepatitis C infection. N Engl J Med 1998;339:1549-50. 4. Froom J, Froom P. “Prudence” in disease prevention. J Clin Epidemiol 1991;44:1127-30.
To the Editor: The issue that I fail to see directly addressed by McHutchison et al. and Davis et al. is the effect of this very expensive intervention on any “hard” end point, specifically overall survival or a decrease in the need for transplantation. I am aware that an improvement in biochemical markers reflects an improvement in histologic findings, but have yet to see data supporting the idea that such an approach improves the overall outcome. The logic that such a relation should exist is reasonable, but as oncologists have learned from studying chronic lymphocytic leukemia, myeloma, and even breast cancer treated with high-dose regimens, what seems to be a logical approach — aggressive and early treatment — does not always translate into any long-term benefit. Until a real benefit of this expensive and toxic therapy is demonstrated, I wonder whether patients should not continue to be treated only in clinical studies and not as a matter of standard practice. CHRISTINA M. CLAY, M.D. 741 Millbrook Ln. Haverford, PA 19041
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The authors reply: To the Editor: Our studies demonstrate that the combination of interferon alfa-2b and ribavirin is far more likely than interferon alfa-2b alone to lead to a long-term response with no detectable virus when used as initial treatment or after relapse in patients with chronic hepatitis C. A sustained virologic response is the goal of antiviral treatment, since it is not associated with late relapse and is a reliable indicator of the normalization of serum aminotransferase levels and of the reduction of hepatic inflammation, or even its disappearance, on liver biopsy.1 The likelihood of progression to fibrosis and cirrhosis depends on the severity of periportal inflammation. Indeed, a response to combination therapy results in a significant reduction in the rate of hepatic fibrosis and in regression of septal fibrosis in more than half of patients.2 Although we agree with Dr. Clay that it is logical to assume that these short-term benefits would translate into a reduction in morbidity and mortality, clinical trials have not demonstrated that survival is increased or that the rate of hepatic failure and the need for transplantation are reduced, nor would we expect them to do so. In view of the usually slow rate of progression of chronic hepatitis C, a controlled clinical study designed to show such a benefit would require hundreds or perhaps thousands of patients who were followed for many years. Such a study would be impractical, considering the probable development of better therapeutic regimens during the study period. Including a placebo group would probably be unethical, since currently available therapy is capable of eradicating infection in more than a third of patients. Although the duration of the study and enrollment requirements could be reduced by including only patients who were at high risk for progression to liver failure (e.g., those with advanced fibrosis or cirrhosis), it would still be difficult to justify withholding treatment in the control group. The National Institutes of Health is currently designing studies to test the effect on morbidity and mortality of long-term treatment with interferon to suppress the virus in patients with fibrosis or cirrhosis in whom the virus was not eradicated during the initial course of treatment. The effect of treatment on morbidity and mortality might also be better addressed in other ways, such as through modeling and cost–benefit analyses.3,4 Finally, we agree with Drs. Newman and Clay that the use of other end points can also provide meaningful information. Indeed, a response to treatment with interferon alone or in combination with ribavirin is associated with an improvement in the health-related quality of life.5,6 GARY L. DAVIS, M.D. University of Florida Gainesville, FL 32610-0214
JOHN G. MCHUTCHISON, M.D.
3. Davis GL, Albright JE, Cook SF, Rosenberg DM. Projecting the future healthcare burden from hepatitis C in the United States. Hepatology 1998; 28:390A. abstract. 4. Wong JB, Davis GL, Pauker SG. Cost-effectiveness of ribavirin and interferon alfa-2b after interferon relapse in chronic hepatitis C. Hepatology 1998;28:591A. abstract. 5. Bonkovsky HL, Woolley JM, Consensus Interferon Study Group. Reduction of health-related quality of life in chronic hepatitis C and improvement with interferon therapy. Hepatology 1999;29:264-70. 6. Ware JE, Bayliss MS, Mannocchia M, Davis GL. Health-related quality of life in chronic hepatitis C: impact of treatment and treatment response. Gastroenterology (in press).
To the Editor: Drs. Newman and Clay both raise valid questions that cannot be easily answered. I agree that the two studies addressed only the short-term end point of response to treatment — that is, elimination of the virus and improvement in aminotransferase levels and histologic findings in the liver. Indeed, combination treatment with interferon and ribavirin has not been shown to slow the rate of progression to cirrhosis, liver failure, or death. However, a study of these long-term end points would require many years of follow-up and an enormous amount of resources and would most likely have unacceptably high rates of noncompliance and withdrawal. The slow rate of progression associated with hepatitis C–related liver disease is a formidable problem in any study designed to address the long-term effects of treatment. Two lines of evidence support the beneficial effect of treatment with regard to long-term prognosis. First, a longterm follow-up study of patients with chronic non-A, non-B hepatitis (which was subsequently shown to be hepatitis C) who were treated successfully with interferon in the 1980s showed that there was no progression of liver disease, or even improvement in the condition.1 Second, several studies, including one published in 1995,2 have shown a reduced incidence of hepatocellular carcinoma among patients with chronic hepatitis C who are treated successfully with interferon. Notwithstanding the lack of long-term randomized, controlled studies, such findings support the substantial benefits of a sustained response to treatment in terms of morbidity and mortality. Although the naysayers may still argue that definitive proof is lacking, I see no reasons to withhold a reasonably effective treatment from those who are likely to benefit. As physicians, we must be sensitive to the needs of our patients in a time of change. Nevertheless, I would like to underscore the importance of limiting treatment to patients whose liver disease is most likely to progress: those with persistently elevated aminotransferase levels, viremia, and findings of fibrosis and moderate inflammation on liver biopsy. Finally, physicians and patients must carefully weigh the risks (which are clinically significant in the case of treatment with interferon alfa-2b and ribavirin), the benefits (moderate in this instance), and the cost (substantial in this instance) of any treatment option for a disease that has emerged as an important public health problem.
Scripps Clinic and Research Foundation La Jolla, CA 92037 1. Marcellin P, Boyer N, Degott C, et al. Long-term histologic and viral changes in patients with chronic hepatitis C who responded to alpha interferon. Liver 1994;14:302-7. 2. Poynard T, McHutchison J, Davis GL, et al. Impact of interferon alfa2b and ribavirin on the liver fibrosis progression in patients with chronic hepatitis C. Hepatology 1998;28:497A. abstract.
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T. JAKE LIANG, M.D. National Institutes of Health Bethesda, MD 20892-1800 1. Lau DTY, Kleiner DE, Ghany MG, Park Y, Schmid P, Hoofnagle JH. 10-Year follow-up after interferon-alpha therapy for chronic hepatitis C. Hepatology 1998;28:1121-7.
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2. Nishiguchi S, Kuroki T, Nakatani S, et al. Randomised trial of effects of interferon-alpha on incidence of hepatocellular carcinoma in chronic active hepatitis C with cirrhosis. Lancet 1995;346:1051-5.
Carotid Endarterectomy To the Editor: In his editorial on the appropriate use of carotid endarterectomy (Nov. 12 issue),1 Dr. Chassin states that “data on the rates of death or stroke within 30 days after surgery, adjusted for the severity of carotid disease and coexisting conditions, should be routinely available to physicians and patients.” It has been clear for several years that the benefit of this procedure is highly dependent on surgical risk. Although further refinement may be required, validated methods of adjusting the rates of complications on the basis of the risk factors of the patients are currently available.2 As I and several colleagues have pointed out,3 professional standards focusing on surgical risk have been promulgated since at least 1989. Yet complications are still not being widely monitored.4 Therefore, it is not surprising that we found only 19 percent of the physicians who responded to a national survey indicated that they knew the perioperative mortality rate associated with carotid endarterectomy at the hospital where they refer patients or perform the procedure, and only 15 percent responded that they knew the perioperative rate of stroke.5 Only about 50 percent of neurologists and 60 percent of vascular surgeons and neurosurgeons reported that they knew these rates. Given the clinical need for accurate information concerning surgical risk, the question is not whether these data should be collected, analyzed, and reported, but how these tasks should be accomplished. Because of the general failure of the voluntary professional guidelines that have been available for several years, uniform quality-assurance programs should be mandated. If required by the Joint Commission on Accreditation of Healthcare Organizations, appropriate procedures could be developed and instituted over a very short period.3 LARRY B. GOLDSTEIN, M.D. Duke University Medical Center Durham, NC 27710 1. Chassin MR. Appropriate use of carotid endarterectomy. N Engl J Med 1998;339:1468-71. 2. McCrory DC, Goldstein LB, Samsa GP, et al. Predicting complications of carotid endarterectomy. Stroke 1993;24:1285-91. 3. Goldstein LB, Moore WS, Robertson JT, Chaturvedi S. Complication rates for carotid endarterectomy: a call to action. Stroke 1997;28:889-90. 4. Chaturvedi S, Femino L. Are carotid endarterectomy complication rates being monitored? Neurology 1998;50:1927-8. 5. Goldstein LB, Bonito AJ, Matchar DB, et al. US national survey of physician practices for the secondary and tertiary prevention of ischemic stroke: design, service availability, and common practices. Stroke 1995;26: 1607-15.
To the Editor: Table 1 of the editorial by Dr. Chassin contains an error with respect to the results for the patients with moderate stenosis in the North American Symptomatic Endarterectomy Trial (NASCET). The column showing the rates of surgical complications implies that a lower complication rate (4.8 percent) was achieved in the European Carotid Surgery Trial (ECST) in the
group of patients with at least 60 percent stenosis than in the three NASCET groups (5.8 to 6.7 percent). Such a conclusion would be incorrect. The rate provided for ECST is for complications of major stroke and death,1 whereas the rates provided for NASCET are for complications of any stroke and death.2,3 Published data do not allow a precise comparison of the rates of perioperative complications within the first 30 days after surgery between the two trials. In NASCET, a major perioperative stroke was defined as one causing a functional deficit that persisted for at least 90 days. In ECST, a major perioperative stroke was defined as one causing symptoms that lasted longer than seven days. It is likely that the rate of any stroke or death in ECST exceeded that in NASCET and that lower rates of perioperative complications contributed to the finding of a lower degree of stenosis at which surgery becomes favored over medical therapy in NASCET than was found in ECST. JEFFREY L. SAVER, M.D. UCLA Stroke Center Los Angeles, CA 90095-1769 1. Randomised trial of endarterectomy for recently symptomatic carotid stenosis: final results of the MRC European Carotid Surgery Trial (ECST). Lancet 1998;351:1379-87. 2. North American Symptomatic Carotid Endarterectomy Trial Collaborators. Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. N Engl J Med 1991;325:445-53. 3. Barnett HJM, Taylor DW, Eliasziw M, et al. Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis. N Engl J Med 1998;339:1415-25.
To the Editor: Barnett et al. (Nov. 12 issue)1 report the results of NASCET and describe the benefits of carotid endarterectomy as compared with medical therapy in the treatment of symptomatic carotid stenosis. The results of the study are extremely important in defining the natural history of this disease, but their utility in making current decisions about treatment are limited by the obsolescence of the medical interventions used in the study. Since the creation of the NASCET protocol in 1987, the understanding of carotid disease and the medical therapeutics for its treatment have made important advances. Although antiplatelet, antihypertensive, and hypolipidemic agents remain the cornerstones of medical therapy, the most current treatment protocols differ considerably from those studied in NASCET. Patients in NASCET received primarily aspirin as their antiplatelet therapy. Combination therapy with agents such as dipyridamole and clopidogrel has since been shown to nearly double the reduction in the risk of stroke achieved with aspirin alone.2,3 Although 40 percent of the patients participating in NASCET were taking lipid-lowering medications by the end of the study, recent trials have shown that even patients with average cholesterol levels may have up to a 30 percent reduction in the risk of stroke with inhibitors of 3-hydroxy-3-methylglutaryl–coenzyme A reductase.4 Although the study reports a 10 to 15 percent prevalence of hypertension in the study population, it does not report the incidence of stroke in the patients with hypertension. The risk of stroke for a patient with aggressively controlled hypertension may have been considerably lower than the aggregate numbers reported in NASCET.5,6
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Although NASCET was designed to measure the incremental benefit of surgery by giving similar medical therapy to both the group receiving medical treatment alone and the group receiving surgical treatment, the conclusions of the study might have been different if more effective medical regimens had been used. Since surgical complications cause an early excess mortality, the lower rates of complications in the group receiving medical treatment alone tend to diminish the apparent benefits of surgical intervention. Furthermore, since medical interventions may not benefit postsurgical patients to the same degree as patients with untreated carotid disease at high risk for stroke, improvements in medical therapies would again disproportionately benefit those in the medical-treatment group. The benefit of carotid endarterectomy as compared with a course of intensive blood-pressure control, lipid-lowering therapy, and second-generation antiplatelet drugs remains open to question. JACOB S. ELKINS, M.D. University of California, San Francisco, Medical Center San Francisco, CA 94143-0119 1. Barnett HJM, Taylor DW, Eliasziw M, et al. Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis. N Engl J Med 1998;339:1415-25. 2. Diener HC, Cunha L, Forbes C, Sivenius J, Smets P, Lowenthal A. European Stroke Prevention Study. 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci 1996;143:1-13. 3. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996;348:1329-39. 4. Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996;335:1001-9. 5. Staessen JA, Fagard R, Thijs L, et al. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. Lancet 1997;350:757-64. 6. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension: final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA 1991;265:3255-64.
To the Editor: Tu and colleagues (Nov. 12 issue)1 state that a principal cause of the decline in the rates of carotid endarterectomy was the publication of a study by RAND reporting high levels of inappropriate use and that the subsequent rise was due to the publication of the findings of randomized clinical trials in which carotid endarterectomy was reported to be beneficial. This juxtaposition leaves the reader with the impression that the criteria for appropriateness used in the RAND study, which were the result of a group-consensus process, have been shown to be invalid by the results of subsequent clinical trials. In fact, the results of randomized clinical trials have supported rather than refuted the criteria developed by the RAND panel. In 1984, the RAND panel judged that carotid endarterectomy was appropriate for symptomatic patients with 50 to 69 percent stenosis and low surgical risk,2 a judgment subsequently shown to be correct by the results reported by Barnett and colleagues, also in the November 12 issue of the Journal.3 With the addition of these new data, randomized clinical trials have provided direct evidence confirming the judgments for 18 criteria rated as appropriate and 14 criteria rated as inappropriate, accounting for about one third of all operations (1302) performed as reported in the original RAND study.
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There has been no instance in which the results of a randomized clinical trial have refuted the judgment of the 1984 consensus panel. Two thirds of the patients in the original RAND studies have undergone surgery for indications that have not yet been studied in clinical trials. For these patients, consensus guidelines are still the only alternative to individual physician judgment. PAUL G. SHEKELLE, M.D., PH.D. West Los Angeles Veterans Affairs Medical Center Los Angeles, CA 90073
R.E. PARK, PH.D. RAND Santa Monica, CA 90407 1. Tu JV, Hannan EL, Anderson GM, et al. The fall and rise of carotid endarterectomy in the United States and Canada. N Engl J Med 1998;339: 1441-7. 2. Merrick NJ, Fink A, Brook RH, et al. Indications for selected medical and surgical procedures — a literature review and ratings of appropriateness: carotid endarterectomy. Santa Monica, Calif.: RAND, 1986. 3. Barnett HJM, Taylor DW, Eliasziw M, et al. Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis. N Engl J Med 1998;339:1415-25.
The authors reply: To the Editor: Dr. Goldstein agrees that risk-adjusted data on perioperative complications after carotid endarterectomy should be available to patients and physicians and suggests that the Joint Commission on Accreditation of Healthcare Organizations require hospitals to collect and report such data as part of their quality-assurance activities. Requiring public disclosure of data on complications would represent a departure from usual practice for voluntary accrediting agencies. However, other organizations (e.g., state health departments or purchaser coalitions) might serve more effectively as neutral foci for the collection, verification, and dissemination of this data. A staged process that permitted confidential use of the data in order for hospitals to make improvements for a time before the data were released to the public might make the process more palatable to hospitals. Dr. Saver is correct that ECST and NASCET used different definitions in assessing the occurrence of stroke. ECST published data on “disabling strokes” (those with a Rankin score of 3 or more at six months) and other “major strokes” (those with symptoms lasting more than seven days) but did not give data on strokes with symptoms lasting more than 24 hours but not more than seven days.1 The two major published reports on NASCET themselves used different definitions. The 1991 article reported “major strokes,” using the definition given by Dr. Saver, but the 1998 article used a different definition for “disabling stroke.”2,3 Both reported data on “any strokes” (those with symptoms lasting more than 24 hours). The published data from ECST and NASCET were not complete enough to permit exactly comparable calculations concerning either perioperative or long-term outcomes. These differences in definitions of end points are but some of the many differences between the two trials. Other major differences include the requirement by NASCET (but not by ECST) that participating centers demonstrate a perioperative complication rate of «6 percent, the exclusion by NASCET
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(but not by ECST) of patients over the age of 80 years with severe stenosis, and differences in the methods of measuring angiographic stenosis. All of these differences make direct comparisons of the rates of complications between the studies impossible to interpret. In Table 1 of my editorial, I presented the most comparable data available from the major trials. Of the many end points reported, I selected “all strokes and deaths” instead of ipsilateral stroke or disabling stroke because I believe this end point is the single most important one most physicians wish to consider. Thus, for the ECST results, strokes with symptoms lasting more than seven days are included (in both the column for absolute risk reduction and the column for surgical complications). For the NASCET results, strokes with symptoms lasting more than 24 hours are included (also in both columns). MARK R. CHASSIN, M.D., M.P.P., M.P.H. Mount Sinai School of Medicine New York, NY 10029-6574 1. Randomised trial of endarterectomy for recently symptomatic carotid stenosis: final results of the MRC European Carotid Surgery Trial (ECST). Lancet 1998;351:1379-87. 2. North American Symptomatic Carotid Endarterectomy Trial Collaborators. Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. N Engl J Med 1991;325:445-53. 3. Barnett HJM, Taylor DW, Eliasziw M, et al. Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis. N Engl J Med 1998;339:1415-25.
To the Editor: Dr. Elkins may or may not be correct when he suggests that the benefits of carotid endarterectomy would have been less than those in NASCET if current medical treatments had all been available and used throughout the trial. We presume that he refers to the patients with
