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N Engl J Med, Vol. 347, No. 2

July 11, 2002

www.nejm.org

The New England

Journal

Medicine

VOLUME 347

ULY

11, 2002

NUMBER 2

A CONTROLLED TRIAL OF ARTHROSCOPIC SURGERY FOR OSTEOARTHRITIS OF THE KNEE

J. B

RUCE

OSELEY

, M.D., K

IMBERLY

O’M

ALLEY

, P

.D., N

ANCY

J. P

ETERSEN

, P

.D., T

ERRI

J. M

ENKE

, P

.D., B

ARUCH

A. B

RODY

, P

.D., D

AVID

H. K

UYKENDALL

, P

.D., J

OHN

C. H

OLLINGSWORTH

, D

.P.H., C

AROL

M. A

SHTON

, M.D., M.P.H.,

AND

ELDA

P. W

RAY

, M.D., M.P.H.

BSTRACT

Background

Many patients report symptomatic re- lief after undergoing arthroscopy of the knee for os- teoarthritis, but it is unclear how the procedure achieves this result. We conducted a randomized, placebo-controlled trial to evaluate the efficacy of ar- throscopy for osteoarthritis of the knee.

Methods

A total of 180 patients with osteoarthritis of the knee were randomly assigned to receive arthro- scopic débridement, arthroscopic lavage, or placebo surgery. Patients in the placebo group received skin incisions and underwent a simulated débridement without insertion of the arthroscope. Patients and assessors of outcome were blinded to the treatment- group assignment. Outcomes were assessed at mul- tiple points over a 24-month period with the use of five self-reported scores — three on scales for pain and two on scales for function — and one objective test of walking and stair climbing. A total of 165 pa- tients completed the trial.

Results

At no point did either of the intervention groups report less pain or better function than the pla- cebo group. For example, mean (±SD) scores on the Knee-Specific Pain Scale (range, 0 to 100, with higher scores indicating more severe pain) were similar in the placebo, lavage, and débridement groups: 48.9±21.9, 54.8±19.8, and 51.7±22.4, respectively, at one year (P=0.14 for the comparison between placebo and la- vage; P=0.51 for the comparison between placebo and débridement) and 51.6±23.7, 53.7±23.7, and 51.4± 23.2, respectively, at two years (P=0.64 and P=0.96, respectively). Furthermore, the 95 percent confidence intervals for the differences between the placebo group and the intervention groups exclude any clin- ically meaningful difference.

Conclusions

In this controlled trial involving pa- tients with osteoarthritis of the knee, the outcomes after arthroscopic lavage or arthroscopic débridement were no better than those after a placebo procedure. (N Engl J Med 2002;347:81-8.)

From the Houston Veterans Affairs Medical Center (J.B.M., K.O., N.J.P., T.J.M., D.H.K., C.M.A., N.P.W.); the Department of Orthopedic Surgery (J.B.M.), the Department of Medicine, Section of Health Services Research (K.O., N.J.P., T.J.M., C.M.A., N.P.W.), and the Center for Medical Ethics and Health Policy (B.A.B.), Baylor College of Medicine; and International Survey Research (D.H.K.) — all in Houston; and the Laguna Honda Hos- pital, San Francisco (J.C.H.). Address reprint requests to Dr. Wray at the Section of Health Services Research, Baylor College of Medicine, 2002 Holcombe Blvd. (M.R. 152), Houston, TX 77030, or at nwray@bcm. tmc.edu.

HEN medical therapy fails to relieve the pain of osteoarthritis of the knee, arthroscopic lavage or débridement is often recommended. More than

650,000 such procedures are performed each year

at a cost of roughly $5,000 each. In uncontrolled studies of knee arthroscopy for osteoarthritis, about half the patients report relief from pain.

2-16

However, the physiological basis for the pain relief is unclear. There is no evidence that arthroscopy cures or arrests the osteoarthritis. Therefore, we conducted a random- ized, placebo-controlled trial to assess the efficacy of arthroscopic surgery of the knee in relieving pain and improving function in patients with osteoarthri- tis. Both patients and assessors of outcome were blind- ed to the treatment assignments.

METHODS

The college and hospital institutional review board approved the protocol. A data and safety monitoring board monitored the study.

Study Participants

Participants were recruited from the Houston Veterans Affairs Medical Center from October 1995 through September 1998. Patients were eligible if they were 75 years old or younger, had os- teoarthritis of the knee as defined by the American College of Rheumatology,

reported at least moderate knee pain on average (»4 on a visual-analogue scale ranging from 0 to 10) despite max- imal medical treatment for at least six months, and had not un- dergone arthroscopy of the knee during the previous two years.

The New England

Journal

Medicine

VOLUME 347

ULY

11, 2002

NUMBER 2

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N Engl J Med, Vol. 347, No. 2

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The severity of osteoarthritis in the study knee (that with the greatest pain-induced limitation of function) was assessed radio- graphically and graded on a scale of zero to four.

The scores for the three compartments were added together to generate a sever- ity grade of 0 to 12. Criteria for exclusion were a severity grade of 9 or higher, severe deformity, and serious medical problems.

All patients provided informed consent, which included writing in their chart, “On entering this study, I realize that I may receive only placebo surgery. I further realize that this means that I will not have surgery on my knee joint. This placebo surgery will not benefit my knee arthritis.” Of the 324 consecutive patients who met the criteria for inclusion, 144 (44 percent) declined to par- ticipate. Participants were younger than those who declined to participate (52.3±11.3 years vs. 55.3±12.4 years, P=0.002), were more likely to be white (62.2 percent vs. 50.7 percent, P=0.03), and had more severe arthritis (25.0 percent vs. 12.5 percent with grade 7 or 8 arthritis, P<0.001).

Randomization Process and Treatment Groups

Participants were stratified into three groups according to the severity of osteoarthritis (grade 1, 2, or 3; grade 4, 5, or 6; and grade 7 or 8). A stratified randomization process with fixed blocks of six was used. Sealed, sequentially numbered, stratum-specific envelopes containing treatment assignments were prepared and given to the research assistant. After the patient was in the oper- ating suite, the surgeon was handed the envelope. The treatment assignment was not revealed to the patient.

Participants were randomly assigned to arthroscopic débridement, arthroscopic lavage alone, or the placebo procedure. One orthope- dist performed all the operations. Patients in the débridement group or the lavage group received standard general anesthesia with endo- tracheal intubation. Patients in the placebo group received a short- acting intravenous tranquilizer and an opioid and spontaneously breathed oxygen-enriched air.

Lavage

After diagnostic arthroscopy in patients in the lavage group, the joint was lavaged with at least 10 liters of fluid. Anything that could be flushed out through arthroscopic cannulas was removed. Nor- mally, no instruments were used to mechanically débride or remove tissue. However, if a mechanically important, unstable tear in the meniscus (e.g., a displaced “bucket-handle” tear) was encountered, the torn portion was removed and the remaining meniscus was smoothed to a firm, stable rim. (There is general agreement that it is inappropriate to leave this type of meniscal tear untreat- ed.

11,13,19,20

) No other débridement was performed.

Débridement

After diagnostic arthroscopy in patients in the débridement group, the joint was lavaged with at least 10 liters of fluid, rough articular cartilage was shaved (chondroplasty was performed), loose debris was removed, all torn or degenerated meniscal fragments were trimmed, and the remaining meniscus was smoothed to a firm and stable rim. No abrasion arthroplasty or microfracture was performed. Typically, bone spurs were not removed, but any spurs from the tibial spine area that blocked full extension were shaved smooth.

Placebo Procedure

To preserve blinding in the event that patients in the placebo group did not have total amnesia, a standard arthroscopic débride- ment procedure was simulated. After the knee was prepped and draped, three 1-cm incisions were made in the skin. The surgeon asked for all instruments and manipulated the knee as if arthros- copy were being performed. Saline was splashed to simulate the sounds of lavage. No instrument entered the portals for arthros- copy. The patient was kept in the operating room for the amount of time required for a débridement. Patients spent the night after

the procedure in the hospital and were cared for by nurses who were unaware of the treatment-group assignment.

Postoperatively, there were two minor complications and no deaths. Incisional erythema developed in one patient, who was giv- en antibiotics. In a second patient, calf swelling developed in the leg that had undergone surgery; venography was negative for thrombo- sis. In no case did a complication necessitate the breaking of the randomization code.

Postoperative care was delivered according to a protocol spec- ifying that all patients should receive the same walking aids, grad- uated exercise program, and analgesics. The use of analgesics after surgery was monitored; during the two-year follow-up period, the amount used was similar in the three groups.

End Points

Study personnel who were unaware of the treatment-group as- signments performed all postoperative outcome assessments; the operating surgeon did not participate in any way. Data on end points were collected 2 weeks, 6 weeks, 3 months, 6 months, 12 months, 18 months, and 24 months after the procedure. To assess whether patients remained unaware of their treatment-group assignment, they were asked at each follow-up visit to guess which procedure they had undergone. Patients in the placebo group were no more likely than patients in the other two groups to guess that they had undergone a placebo procedure. For example, at two weeks, 13.8 percent of the patients in the placebo group guessed that they had undergone a placebo procedure, and 13.2 percent of the patients in the lavage and débridement groups guessed that they had under- gone a placebo procedure.

The primary end point was pain in the study knee 24 months after the intervention, as assessed by a 12-item self-reported Knee- Specific Pain Scale (KSPS) created for this study (see Supplemen- tary Appendix 1, available with the full text of this article at http:// www.nejm.org). Scores on this scale range from 0 to 100, with higher scores indicating more severe pain. In addition, to ensure our ability to detect any benefit, we also used five secondary efficacy end points: two additional assessments of pain and three assessments of function at all time points. Arthritis pain in general (i.e., not spe- cifically in the study knee) was assessed by means of the four-item pain subscale of the Arthritis Impact Measurement Scales (AIMS2- P).

21,22

Higher scores on this subscale indicate more severe pain. Body pain (i.e., not necessarily from arthritis and not necessarily in the knee) was assessed with the 2-item pain subscale of the Medical Outcomes Study 36-item Short-Form General Health Survey (SF- 36-P).

23,24

Higher scores on this subscale indicate less severe pain. The AIMS2-P and the SF-36-P scores were transformed into scores on a scale from 0 to 100.

Two self-reported measures of physical function were used: the 5-item walking–bending subscale from the AIMS2 (AIMS2-WB, transformed into scores on a scale from 0 to 100, with higher scores indicating more limited function

21,22

) and the 10-item phys- ical-function subscale from the SF-36 (SF-36-PF, transformed into scores on a scale from 0 to 100, with higher scores indicating better function

23,24

). As an objective measure, we devised the Physical Functioning Scale (PFS) to record the amount of time in seconds that a patient required to walk 30 m (100 ft) and to climb up and down a flight of stairs as quickly as possible. Longer times indicate poorer functioning.

All six outcome scales had good reliability. The median Cron- bach’s alpha (according to analyses of data from eight time points for all scales) exceeded 0.80. Results for all the outcome measures at all the time points that are not reported here are summarized in Supplementary Appendix 2, available with the full text of this article at http://www.nejm.org.

Statistical Analysis

Our pilot study indicated that it would be feasible to recruit 60 patients per year. The trial was designed to have 90 percent power,

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A RANDOMIZED TRIAL OF KNEE ARTHROSCOPY

N Engl J Med, Vol. 347, No. 2

July 11, 2002

www.nejm.org

with a two-sided type I error of 0.04, to detect a moderate effect size (0.55) between the placebo group and the combined arthro- scopic-treatment groups in terms of body pain as measured by the SF-36-P at two years, with an enrollment of 180 patients and 16 or fewer lost to follow-up (i.e., 164 or more completing the two- year follow-up). The primary hypothesis was that the patients in two arthroscopic-intervention groups combined would report the same amount of knee pain at two years as the patients assigned to the placebo group. All statistical tests compared the treatment groups in terms of the values at each visit rather than analyzing the changes from base line. (Scores for these changes [“change scores”] were analyzed, with results that did not differ from the results presented here.) The data and safety monitoring board re- viewed interim data 15 months and 24 months after enrollment began, using the Haybittle–Peto group-sequential method, with stopping boundaries of P=0.001 for the two interim analy- ses.

25,26

All reported P values are two-sided and have not been ad- justed for multiple comparisons.

Our prespecified analytic strategy was to test, at all time points, for the superiority of the arthroscopic procedures over the place- bo procedure. Lacking evidence of superiority, we tested for ev- idence that the arthroscopic procedures were equivalent

27-29

to the

placebo procedure by determining the extent to which the study was powered to reject the hypothesis that the arthroscopic treat- ments caused a small but clinically important improvement (the “minimal important difference”). The minimal important differ- ence for a scale is the smallest change score associated with a pa- tient’s perception of a change in health status,

but it can vary somewhat according to the method of calculation and the study sample.

31,32

Minimal important differences for each of the six study scales were calculated on the basis of the trial data by two differ- ent methods: the change ratings of patients (their scores on a sin- gle-item scale that asked patients if their condition was the same, somewhat better [or worse], or much better [or worse] than be- fore surgery) and the standard error of measurement (the SD of the instrument multiplied by the square root of one minus its re- liability coefficient).

30-32

Estimates were also obtained from the lit- erature.

31-33

For each scale, we tested the hypothesis that the place- bo procedure was equivalent to the arthroscopic procedures, using as the minimal important difference the midpoint of the range of the minimal important differences reported in the literature or calculated on the basis of our data. If the 95 percent confidence interval around the estimated size of the effect does not include the minimal important difference, one can reject the hypothesis that

*There were no significant differences among the three groups. Plus–minus values are means ±SD.

†Severity of osteoarthritis was assessed by radiography.

‡Percentages are based on the number of patients who participated in the trial.

§Scores on the Knee Society Clinical Rating Scale range from 0 to 100, with higher scores indi- cating fewer knee-related symptoms.

¶Scores for all psychological attributes, except expectations for benefit, range from 0 to 100, with higher scores indicating more of the variable (e.g., more anxiety, depression, or optimism).

¿Expectations were retrospectively assessed two weeks after the procedure. Scores range from 1 to 5, with higher scores indicating higher expectations.

ABLE

ASE

-L

INE

HARACTERISTICS

THE

ANDOMIZED

ATIENTS

HARACTERISTIC

LACEBO

ROUP

(N=60)

AVAGE

ROUP

(N=61)

ÉBRIDEMENT

ROUP

(N=59)

Age (yr) 52.0±11.1 51.2±10.5 53.6±12.2

Male sex (%) 93.3 88.5 96.6

Race (%) White 60.0 59.0 61.0 Black 31.7 31.2 22.0 Other 8.3 9.9 17.0

Severity of osteoarthritis in knee (%)† Mild 28.3 27.9 30.5 Moderate 46.7 45.9 45.8 Severe 25.0 26.2 23.7

Analgesic use (%)‡ Nonprescription 70.0 67.2 64.4 Prescription 21.7 21.3 15.3

Mean score on Knee Society Clinical Rating Scale‡§ Knee symptoms 49.4 50.2 51.4 Function 62.2 62.4 57.6

Psychological attributes¶ Anxiety 27.0±21.0 30.2±19.9 28.4±22.4 Depression 20.0±32.0 28.1±37.2 22.0±35.3 Expectations for benefit¿ 3.5±1.0 3.5±0.9 3.6±1.1 Optimism 72.6±21.0 74.5±19.4 73.7±17.1 Satisfaction with general health 39.3±25.1 43.7±22.4 46.5±24.8 Social functioning 65.5±25.6 60.3±23.9 67.6±25.2 Somatization 11.3±12.7 9.6±12.4 10.0±10.7 Stress 28.4±19.7 26.1±18.2 27.9±18.8 Vitality 54.8±21.0 52.7±19.7 57.7±19.3

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N Engl J Med, Vol. 347, No. 2

July 11, 2002

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The New England Journal of Medic ine

the arthroscopic procedures have a small but clinically important benefit.

RESULTS

A total of 180 patients underwent randomization; 60 were assigned to the placebo group, 61 to the la- vage group, and 59 to the débridement group. Base- line characteristics were similar in the three study groups (Table 1).

At no point did either arthroscopic-intervention group have greater pain relief than the placebo group (Fig. 1, Table 2, and Supplementary Appendix 2). For example, there was no difference in knee pain between the placebo group and either the lavage group or the débridement group at one year (mean [±SD] KSPS scores, 48.9±21.9, 54.8±19.8, and 51.7±22.4, re- spectively; P=0.14 for the comparison with the la- vage group, and P=0.51 for the comparison with the débridement group) or at two years (mean KSPS scores, 51.6±23.7, 53.7±23.7, and 51.4±23.2, re- spectively; P=0.64 and P=0.96, respectively). Sim- ilarly, there was no significant difference in arthritis pain between the placebo group and the lavage group or the débridement group at one or two years (Table 2).

Furthermore, at no time point did either arthro- scopic-intervention group have significantly greater improvement in function than the placebo group (Fig. 2, Table 3, and Supplementary Appendix 2). For example, there was no significant difference between the placebo group and either the lavage group or the débridement group in the self-reported ability to walk and bend at one year (mean AIMS2-WB scores, 49.4±25.5, 49.6±29.1, and 56.4±28.4, respectively; P=0.98 for the comparison with the lavage group, and P=0.19 for the comparison with the débride- ment group) or at two years (mean AIMS2-WB score, 53.8±27.5, 51.1±28.3, and 56.4±29.4, respectively; P=0.61 and P=0.64, respectively). Indeed, objective- ly measured walking and stair climbing were poorer in the débridement group than in the placebo group at two weeks (mean PFS score, 56.0±21.8 vs. 48.3± 13.4; P=0.02) and one year (mean PFS score, 52.5± 20.3 vs. 45.6±10.2; P=0.04) and showed a trend to- ward worse functioning at two years (mean PFS score, 52.6±16.4 vs. 47.7±12.0; P=0.11) (Table 3).

Lacking evidence of the superiority of the arthro- scopic treatments over the placebo procedure in re- lieving pain or improving function, we considered whether the 95 percent confidence intervals for the

Figure 1.

Mean Values (and 95 Percent Confidence Intervals) on the Knee-Specific Pain Scale. Assessments were made before the procedure and 2 weeks, 6 weeks, 3 months, 6 months, 12 months, 18 months, and 24 months after the procedure. Higher scores indicate more severe pain.

0 Before

Procedure

100

2 yr2 wk 6 wk 3 mo 6 mo 1 yr 18 mo

After Procedure

NO. AT RISK

Placebo Lavage Débridement

60 61 58

57 57 59

59 59 59

56 59 58

57 59 56

53 57 50

52 56 51

55 55 53

M ea

n K

n ee

-S p

ec if

ic P

ai n

S ca

le S

co re

Débridement Lavage Placebo

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A RANDOMIZED TRIAL OF KNEE ARTHROSCOPY

N Engl J Med, Vol. 347, No. 2

July 11, 2002

www.nejm.org

differences in outcome between each arthroscopic procedure and the placebo procedure included clin- ically important differences. The minimal important differences used for this evaluation were as follows: a difference of 13.5 points on the KSPS, 10.0 on the AIMS2-P, 11.8 on the SF-36-P, 12.8 on the AIMS2- WB, 11.3 on the SF-36-PF, and 4.5 on the PFS. At almost all time points during follow-up (72 of 84 comparisons), the confidence intervals excluded these minimal important differences.

DISCUSSION

This study provides strong evidence that arthro- scopic lavage with or without débridement is not better than and appears to be equivalent to a place- bo procedure in improving knee pain and self-report- ed function. Indeed, at some points during follow-up, objective function was significantly worse in the dé- bridement group than in the placebo group.

Arthroscopy is the most commonly performed type of orthopedic surgery, and the knee is by far the most common joint on which it is performed.

Numerous uncontrolled, retrospective case series have reported substantial pain relief after arthroscopic lavage or ar- throscopic débridement for osteoarthritis of the knee.

2-16

In the only previous double-blind, random- ized, controlled trial of knee arthroscopy of which we are aware,

patients with minimal osteoarthritis as assessed by radiography were assigned to undergo arthroscopic lavage with either 3000 ml of fluid (treat- ment) or 250 ml of fluid (control) and were followed for one year. Both the treatment and the control groups reported improvement in function at 12 months, and although the report interprets the study as having proved the efficacy of lavage, there was no statistically significant difference between the groups in terms of the primary outcome at any point during follow-up.

To explain the improvement that has been report- ed after these procedures, some have proposed that the fluid that is flushed through the knee during ar- throscopy cleanses the knee of painful debris and in- flammatory enzymes.

4,6,9,15,16,34

Others have suggest- ed that the improvement is due to the removal of flaps of articular cartilage, torn meniscal fragments, hypertrophied synovium, and loose debris.

2-14

How- ever, our study found that outcomes after arthro- scopic treatment are no better than those after a pla- cebo procedure. This lack of difference suggests that the improvement is not due to any intrinsic efficacy of the procedures. Although patients in the placebo groups of randomized trials frequently have improve- ment, it may be attributable to either the natural his- tory of the condition or some independent effect of the placebo.

Because we found no evidence that lavage or dé-

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86 · N Engl J Med, Vol. 347, No. 2 · July 11, 2002 · www.nejm.org

The New England Journal of Medic ine

bridement is superior to a placebo procedure, the question arises whether these arthroscopic procedures could have small but clinically important benefits that we missed because of our limited sample size. To eval- uate this possibility, we determined the size of the clinical benefit that the trial was able to rule out, us- ing the minimal important difference for each of our scales. Because estimates of minimal important dif- ferences based on different samples and different methods do not yield the same values, we used the midpoint of the range of available minimal impor- tant differences in order to test our hypothesis about the equivalence of the three procedures. For the great majority of comparisons, the 95 percent confidence intervals did not contain the minimal important dif- ference, indicating that there was not a clinically im- portant improvement that the study had simply failed to detect.

One surgeon performed all the procedures in this study. Consequently, his technical proficiency is crit- ical to the generalizability of our findings. Our study surgeon is board-certified, is fellowship-trained in arthroscopy and sports medicine, and has been in practice for 10 years in an academic medical center. He is currently the orthopedic surgeon for a Nation-

al Basketball Association team and was the physician for the men’s and women’s U.S. Olympic basketball teams in 1996.

The principal limitation of this study is that our participants may not be representative of all candi- dates for arthroscopic treatment of osteoarthritis of the knee. Almost all participants were men, because the study was conducted at a Veterans Affairs medical center. We do not know whether our findings may be generalized to women, although uncontrolled studies do not indicate that there are differences be- tween the sexes in responses to arthroscopic proce- dures.8,10,13 A selection bias might have been intro- duced by the fact that 44 percent of the eligible patients declined to participate in the study. We be- lieve this high rate of refusal to participate resulted from the fact that all patients knew they had a one- in-three chance of undergoing a placebo procedure. Patients who agreed to participate might have been so sure that an arthroscopic procedure would help that they were willing to take a one-in-three chance of undergoing the placebo procedure. Such patients might have had higher expectations of benefit or been more susceptible to a placebo effect than those who chose not to participate.

Figure 2. Mean Values (and 95 Percent Confidence Intervals) on the Walking–Bending Subscale of the Arthritis Impact Measurement Scales (AIMS2). Assessments were made before the procedure and 2 weeks, 6 weeks, 3 months, 6 months, 12 months, 18 months, and 24 months after the procedure. Higher scores indicate poorer functioning.

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A RANDOMIZED TRIAL OF KNEE ARTHROSCOPY

N Engl J Med, Vol. 347, No. 2 · July 11, 2002 · www.nejm.org · 87

If the efficacy of arthroscopic lavage or débride- ment in patients with osteoarthritis of the knee is no greater than that of placebo surgery, the billions of dollars spent on such procedures annually might be put to better use. This study has also shown the great potential for a placebo effect with surgery, although it is unclear whether this effect is due solely to the natural history of the condition or whether there is some independent effect. Researchers should recon- sider the best ways of testing the efficacy of surgical procedures performed purely for the improvement of symptoms. In the debate about placebo-controlled trials of surgery, the critical ethical considerations surround the choice of the placebo. Finally, health care researchers should not underestimate the place- bo effect, regardless of its mechanism.35

Supported by a grant from the Department of Veterans Affairs.

REFERENCES

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The New England Journal of Medicine Downloaded from nejm.org on January 13, 2024. For personal use only. No other uses without permission.

88 · N Engl J Med, Vol. 347, No. 2 · July 11, 2002 · www.nejm.org

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