`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`The New England
`Journal
` Medicine
`of
`
`Copyr ight © 2002 by the Massachusetts Medical Societ y
`
`VOLUME 346
`
`M
`
`A Y
`
` 9, 2002
`
`NUMBER 19
`
`IMMEDIATE REPAIR COMPARED WITH SURVEILLANCE
`OF SMALL ABDOMINAL AORTIC ANEURYSMS
`
`, M.D.,
` B. R
`, M.S., D
` R. J
`, M.D., G
` E. W
`, M.D., S
` A. L
`F
`EINKE
`ONOVAN
`OHNSON
`ARY
`ILSON
`AMUEL
`EDERLE
`RANK
`F
` N. L
`, M.D., C
` W. A
`, M.D., D
` J. B
`, M.D., P
`.D., L
` M. M
`, M.D.,
`H
`ALLARD
`AVID
`CHER
`HARLES
`ITTOOY
`RED
`OUIS
`ESSINA
` L. G
`, M.D., E
` P. C
`, M.D., W
` C. K
`, M.D.,
` D
` B
`, M.D.,
`I
`AN
`ORDON
`DMUND
`HUTE
`ILLIAM
`RUPSKI
`AND
`ENNIS
`ANDYK
`
` A
` D
`
` M
` V
` A
` C
` S
` G
`*
`FOR
`THE
`NEURYSM
`ETECTION
`AND
`ANAGEMENT
`ETERANS
`FFAIRS
`OOPERATIVE
`TUDY
`ROUP
`
`E
`
`ACH year in the United States, 9000 deaths
`result from rupture of abdominal aortic an-
`eurysms.
` Another 33,000 patients undergo
`1
`elective repair of asymptomatic abdominal
`aortic aneurysms to prevent rupture, which results in
`1400 to 2800 operative deaths.
` Because most ab-
`2,3
`dominal aortic aneurysms never rupture,
` elective re-
`4
`pair is undertaken only when the risk of rupture is
`considered high. The strongest known predictor of
`rupture is the maximal diameter of the aneurysm.
`5,6
`Elective repair has been recommended for patients
`with aneurysms of 4.0 cm or more in diameter who
` although oth-
`do not have medical contraindications,
`7
`ers have advocated the use of surveillance by means
`of imaging until the diameter reaches 5.0 cm or 6.0
`cm.
` As a result, surgery for small abdominal aortic
`8,9
`aneurysms has been considered one of the areas of
`vascular surgery that is most in need of randomized
`trials.
`10,11
`We undertook a randomized clinical trial to deter-
`mine which of two strategies resulted in a higher rate
`of survival for patients with small abdominal aortic
`aneurysms: immediate open surgical repair or surveil-
`lance with ultrasonography or computed tomography
`
`A
`BSTRACT
`Background
`Whether elective surgical repair of
`small abdominal aortic aneurysms improves survival
`remains controversial.
`Methods
`We randomly assigned patients 50 to 79
`years old with abdominal aortic aneurysms of 4.0 to
`5.4 cm in diameter who did not have high surgical risk
`to undergo immediate open surgical repair of the an-
`eurysm or to undergo surveillance by means of ul-
`trasonography or computed tomography every six
`months with repair reserved for aneurysms that be-
`came symptomatic or enlarged to 5.5 cm. Follow-up
`ranged from 3.5 to 8.0 years (mean, 4.9).
`Results
`A total of 569 patients were randomly as-
`signed to immediate repair and 567 to surveillance. By
`the end of the study, aneurysm repair had been per-
`formed in 92.6 percent of the patients in the immedi-
`ate-repair group and 61.6 percent of those in the sur-
`veillance group. The rate of death from any cause, the
`primary outcome, was not significantly different in
`the two groups (relative risk in the immediate-repair
`group as compared with the surveillance group, 1.21;
`95 percent confidence interval, 0.95 to 1.54). Trends
`in survival did not favor immediate repair in any of the
`prespecified subgroups defined by age or diameter
`of aneurysm at entry. These findings were obtained
`despite a low total operative mortality of 2.7 percent
`in the immediate-repair group. There was also no re-
`duction in the rate of death related to abdominal aor-
`tic aneurysm in the immediate-repair group (3.0 per-
`cent) as compared with the surveillance group (2.6
`percent). Eleven patients in the surveillance group had
`rupture of abdominal aortic aneurysms (0.6 percent
`per year), resulting in seven deaths. The rate of hospi-
`talization related to abdominal aortic aneurysm was
`39 percent lower in the surveillance group.
`Conclusions
`Survival is not improved by elective
`repair of abdominal aortic aneurysms smaller than
`5.5 cm, even when operative mortality is low. (N Engl
`J Med 2002;346:1437-44.)
`Copyright © 2002 Massachusetts Medical Society.
`
`From the Veterans Affairs Medical Centers in Minneapolis (F.A.L.,
`D.B.R., E.P.C.), Long Beach, Calif. (S.E.W., I.L.G.), West Haven, Conn.
`(G.R.J.), Hines, Ill. (F.N.L.), Madison, Wis. (C.W.A.), San Francisco
`(L.M.M.), Denver (W.C.K.), and Tampa, Fla. (D.B.); and the Baylor Health
`Care System, Dallas (D.J.B.). Address reprint requests to Dr. Lederle at the
`Department of Medicine (III-0), Veterans Affairs Medical Center, Minne-
`apolis, MN 55417, or at frank.lederle@med.va.gov.
`Other authors (all at Veterans Affairs Medical Centers) were Steven J.
`Busuttil, M.D., Cleveland; Gary W. Barone, M.D., Little Rock, Ark.; Steven
`Sparks, M.D., San Diego, Calif.; Linda M. Graham, M.D., Ann Arbor, Mich.;
`Joseph H. Rapp, M.D., San Francisco; Michel S. Makaroun, M.D., Pitts-
`burgh; Gregory L. Moneta, M.D., Portland, Oreg.; Robert A. Cambria,
`M.D., Milwaukee; Raymond G. Makhoul, M.D., Richmond, Va.; Darwin
`Eton, M.D., Miami; Howard J. Ansel, M.D., Minneapolis; and Julie A.
`Freischlag, M.D., Los Angeles.
`*Other participants in the study group are listed in the Appendix.
`
`N Engl J Med, Vol. 346, No. 19
`
`·
`
`May 9, 2002
`
`·
`
`www.nejm.org
`
`·
`
`1437
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org at THE OHIO STATE UNIV on May 8, 2022. For personal use only. No other uses without permission.
`
` Copyright © 2002 Massachusetts Medical Society. All rights reserved.
`
`TMT 2093
`Medtronic v. TMT
`IPR2021-01532
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`The New England Journal of Medicine
`
`(CT) with repair reserved for aneurysms that enlarged
`or became symptomatic.
`
`METHODS
`
`Study Design
`Details of the study methods have been published previously.
`12
`The study was approved by the human research committees of the
`coordinating center and each participating center.
`Patients were identified through referral and an ultrasonograph-
`ic screening program that has been described previously.
` Eligible
`13,14
`patients were 50 to 79 years of age and had abdominal aortic an-
`eurysms that measured 4.0 to 5.4 cm in diameter by CT within
`12 weeks before randomization. Patients were ineligible if they
`had previously undergone aortic surgery or if they had evidence
`of rupture of the aneurysm; an expansion of the aneurysm of 1.0 cm
`or more in the past year or 0.7 cm or more in the past six months;
`suprarenal or juxtarenal aortic aneurysm (defined by an anticipated
`need for reimplantation of a main renal artery); a known thoracic
`aortic aneurysm of 4.0 cm or more in diameter; a probable need
`for aortic surgery within six months, other than repair of the abdom-
`inal aneurysm; severe heart, lung, or liver disease
`; a serum cre-
`12
`atinine concentration of 2.5 mg per deciliter or higher; a history
`of a major surgical procedure or angioplasty within the previous
`three months; expected survival of less than five years; severe debil-
`itation; an inability to give informed consent; or a high likelihood
`of noncompliance with the protocol. The vascular surgery team
`at each participating center agreed to invite all eligible patients to
`enroll.
`
`Randomization and Management
`Randomization was designed with equal probability of assign-
`ment to each of the two groups by means of a computer-generated
`random-number code and was tamper-proof, blocked, and strat-
`ified according to medical center. Assignments were made over the
`telephone by the coordinating center after eligibility had been ver-
`ified; patients’ treatment assignments could not be concealed, but
`aggregate outcome data were not revealed to patients and investi-
`gators during the study.
`In the immediate-repair group, standard open repair with inter-
`position of a synthetic graft was to be performed within six weeks
`after randomization. In the surveillance group, patients were fol-
`lowed without repair until the aneurysm reached at least 5.5 cm
`in diameter or enlarged by at least 0.7 cm in six months or at least
`1.0 cm in one year, or until symptoms developed that were attrib-
`uted to the aneurysm by the attending vascular surgeon. When
`one of these criteria was met, open repair was to be carried out
`within six weeks if the patient remained a candidate for surgery.
`Clinicians at the participating centers used their usual methods for
`preoperative evaluation, perioperative management, and the per-
`formance of surgery. All patients were to have follow-up visits ev-
`ery six months throughout the study. Patients in the surveillance
`group who had unrepaired aneurysms underwent ultrasonography
`or CT at these visits.
`
`Imaging
`CT measurements were used to determine the diameter of the
`aneurysm for the purpose of randomization or for assessment of the
`need for elective repair in patients in the surveillance group. Ultra-
`sonography was used for most follow-up imaging in patients in the
`surveillance group so that exposure to radiation would be mini-
`mized. Once the diameter of an aneurysm had been measured as
`5.3 cm or greater, CT was used for subsequent follow-up imaging.
`We also attempted to obtain CT scans for all surviving patients at
`the end of the study.
`The diameter of the aneurysm was defined as the maximal exter-
`nal cross-sectional measurement in any plane but perpendicular
`
`to any bend in the vessel. CT scans obtained to determine the di-
`ameter of the aneurysm for enrollment purposes or to assess the
`need for repair in patients in the surveillance group were read at a
`central laboratory by an experienced CT radiologist. Measurements
`were made on hard copies of CT scans by interpolation from the dis-
`play scale with the use of calipers and a magnifying glass. The vari-
`ability in measurements determined by the same reader in the cen-
` The
`tral laboratory was 0.2 cm or less in 63 of 70 cases studied.
`15
`measurements of abdominal aortic aneurysms that were determined
`by the central laboratory averaged 0.1 cm larger than local readings
`of CT scans, probably because the central laboratory searched more
`meticulously for the maximal diameter.
`15
`
`Outcomes
`The primary outcome measure was the rate of death from any
`cause. The secondary outcome was the rate of death related to ab-
`dominal aortic aneurysm, defined as death caused directly or indi-
`rectly by rupture or repair, preoperative evaluation, late graft failure
`or complication, or abdominal aortic aneurysm or pseudoaneurysm
`after grafting or any death occurring within 30 days after aneurysm
`repair (including reoperations) or within 30 days after randomiza-
`tion in patients in the surveillance group (none of which occurred).
`We attempted to obtain autopsies whenever possible, particularly in
`the case of unexplained deaths. An outcomes committee that was
`blinded to the treatment-group assignment determined the cause
`of death and whether the death was related to the abdominal aortic
`aneurysm. An independent monitoring board analyzed the study
`events at six-month intervals with the use of a group sequential stop-
`ping boundary.
`16
`
`Statistical Analysis
`The study began in 1992 with a planned enrollment of 1350 pa-
`tients over a period of four years and an additional three years of
`follow-up; it was calculated that this sample would provide 85 per-
`cent power to detect a 25 percent difference in mortality rates at a
`two-tailed significance level of 0.05, assuming an annual mortality
`rate of 8 percent with the inferior strategy. Because enrollment pro-
`gressed more slowly than expected and fewer deaths occurred than
`anticipated, an additional year of enrollment and follow-up were
`added.
`Patients were not excluded after randomization, and the primary
`analysis was conducted according to the intention-to-treat principle.
`Cumulative survival curves were generated by the product-limit
`method, and differences between the treatment groups were eval-
`uated by the log-rank test. Estimates of relative risk (expressed as the
`risk in the immediate-repair group as compared with that in the sur-
`veillance group) and 95 percent confidence intervals were calculated
`with the use of the Cox proportional-hazards model. P values are
`two-tailed and were obtained with chi-square tests or t-tests. All data
`were entered twice and checked by computer algorithms.
`
`RESULTS
`
`Study Patients
`Ultrasonography was performed on 126,196 vet-
`erans in the study screening program,
` of whom 2662
`14
`had abdominal aortic aneurysms and were considered
`for randomization. With the addition of referred pa-
`tients, a total of 5038 patients with aneurysms were
`considered for randomization, of whom 1466 (29 per-
`cent) declined to undergo evaluation, 2311 (46 per-
`cent) were excluded, 125 (2 percent) were evaluated
`and found eligible but declined to undergo random-
`ization, and 1136 (23 percent) underwent randomiza-
`tion. The principal reasons for exclusion were an an-
`
`1438
`
`·
`
`N Engl J Med, Vol. 346, No. 19
`
`·
`
`May 9, 2002
`
`·
`
`www.nejm.org
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org at THE OHIO STATE UNIV on May 8, 2022. For personal use only. No other uses without permission.
`
` Copyright © 2002 Massachusetts Medical Society. All rights reserved.
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`IMMEDIATE REPAIR COMPARED WITH SURVEILL ANCE OF SMALL ABDOMINAL AORTIC ANEURYSMS
`
`aneurysm repair; 72.1 percent of these repairs were
`performed by six weeks after randomization, as spec-
`ified in the protocol (Fig. 1 and Table 2). In the sur-
`veillance group, 61.6 percent had undergone repair by
`the end of the study; in 9.0 percent, the procedures
`were performed despite the fact that the aneurysms
`did not meet the study criteria for repair. Two patients
`in the immediate-repair group and one in the surveil-
`lance group underwent endovascular repair, and in one
`of these cases conversion to open repair was required.
`No patient in the surveillance group underwent repair
`solely because of a rapid rate of expansion of the an-
`eurysm. As expected, the rate of repairs among the
`patients in the surveillance group increased with the
`diameter of the aneurysm at randomization. Four years
`after randomization, 27 percent of aneurysms that had
`measured 4.0 to 4.4 cm at randomization had been
`repaired, as compared with 53 percent of those that
`had measured 4.5 to 4.9 cm and 81 percent of those
`that had measured 5.0 to 5.4 cm. The proportion of
`follow-up visits completed was 85.3 percent in the im-
`mediate-repair group and 87.0 percent in the surveil-
`lance group (P=0.02).
`
`Mortality
`Vital status and aneurysm-repair status were known
`for all patients at the end of the study on July 31, 2000.
`There was no significant difference between the two
`
`Immediate-repair group
`
`Surveillance group
`
`0
`
`1
`
`2
`
`5
`4
`3
`Year of Study
`
`Off-protocol
`
`6
`
`7
`
`8
`
`100
`
`90
`
`80
`
`70
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`
`Aneurysms Repaired (%)
`
`Patients with
`
`Figure 1.
` Cumulative Rate of Repair of Abdominal Aortic Aneu-
`rysm, According to Treatment Group.
`Data for patients who died were not censored; the percentages
`are of the original cohorts. “Off-protocol” repairs are those of
`aneurysms that did not meet the study criteria for repair in pa-
`tients in the surveillance group. The vertical dashed line at six
`weeks represents the protocol deadline for repair in the imme-
`diate-repair group.
`
`eurysm diameter outside of the eligible range (as
`measured on a CT scan by the central laboratory),
`severe heart or lung disease, and a judgment that the
`patient was unlikely to adhere to the protocol. Only
`one patient was excluded because of a rapid rate of
`expansion of the aneurysm.
`Base-line characteristics of the patients are summa-
`rized in Table 1. Most patients were male, white, and
`had smoked — characteristics that reflect the demo-
`graphic characteristics of the population of veterans
`and represent known risk factors for abdominal aortic
` The two groups did not differ signif-
`aneurysm.
`13,14
`icantly at base line, except for a small difference in the
`serum creatinine level.
`
`Follow-up and Repair
`The mean duration of follow-up was 4.9 years. In
`the immediate-repair group, 92.6 percent underwent
`
`T
`
`ABLE
`
` 1.
`
`C
`
` P
`
`
`ATIENTS
`THE
`OF
`HARACTERISTICS
` R
`.*
`OF
`ANDOMIZATION
`
`
`
`AT
`
`
`
`THE
`
` T
`
`IME
`
`
`
`C
`HARACTERISTIC
`
`Age (yr)
`Male sex (%)
`White race (%)
`Weight (kg)
`Smoking (%)
`Ever smoked†
`Current smoking
`Medical conditions (%)
`Coronary disease
`Cerebrovascular disease
`Hypertension
`Diabetes
`Chronic obstructive lung disease
`Use of a beta-blocker
`Blood pressure (mm Hg)
`Systolic
`Diastolic
` (liters)
`FEV
`1
`Serum creatinine (mg/dl)‡
`Cholesterol (mg/dl)
`Total
`LDL
`HDL
`Abdominal aortic aneurysm
`Diameter (cm)
`Family history (%)
`
`-R
`I
`EPAIR
`MMEDIATE
`G
`ROUP
`(N=569)
`
`S
`URVEILLANCE
`G
`ROUP
`(N=567)
`
`68.4±5.9
`98.8
`94.6
`86.9±14.4
`
`67.8±6.1
`99.6
`93.5
`86.7±14.5
`
`94.2
`41.4
`
`43.6
`12.0
`57.8
`9.7
`23.0
`16.9
`
`94.2
`36.9
`
`40.2
`12.7
`54.9
`9.9
`21.2
`14.8
`
`140.1±18.0
`79.5±10.9
`2.5±0.6
`1.2±0.3
`
`212.8±39.8
`138.2±37.1
`39.1±13.5
`
`4.7±0.4
`14.2
`
`139.7±17.4
`79.2±10.0
`2.6±0.6
`1.1±0.3
`
`212.5±40.4
`137.1±34.8
`40.2±21.8
`
`4.7±0.4
`11.5
`
`*Plus–minus values are means ±SD. All differences between the groups
` denotes the forced
`were nonsignificant unless otherwise indicated. FEV
`1
`expiratory volume in one second, LDL low-density lipoprotein, and HDL
`high-density lipoprotein.
`†Ever smoked is defined as having smoked more than 100 cigarettes over
`the patient’s lifetime.
`‡P=0.02 for the comparison between groups.
`
`N Engl J Med, Vol. 346, No. 19
`
`·
`
`May 9, 2002
`
`·
`
`www.nejm.org
`
`·
`
`1439
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org at THE OHIO STATE UNIV on May 8, 2022. For personal use only. No other uses without permission.
`
` Copyright © 2002 Massachusetts Medical Society. All rights reserved.
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`The New England Journal of Medicine
`
`T
`
`ABLE
`
` 2.
`
` O
`
`UTCOMES
`
`
`
`AMONG
`
` P
`
`ATIENTS
`
`
`
`WITH
`
` A
`
`BDOMINAL
`
` A
`
`ORTIC
`
` A
`
`NEURYSM
`
`.*
`
`V
`ARIABLE
`
`Death
`Total — no. (%)
`According to diameter of aneurysm —
`no./no. in subgroup (%)
`4.0–4.4 cm
`4.5–4.9 cm
`5.0–5.4 cm
`According to age — no./no. in sub-
`group (%)
`50–59 yr
`60–69 yr
`70–79 yr
`AAA-related — no. (%)
`Thoracic aortic aneurysm–related — no. (%)
`Other sudden death — no. (%)
`Rupture of AAA — no. (%)
`Repair of AAA (ruptured and unruptured)
`— no. (%)
`Other AAA-related hospitalization —
`no. of hospitalizations‡
`Status of surviving patients at end of study
`Unrepaired AAA — no. (%)
`Repaired AAA
`Exit CT performed — no. (%)
`Proximal AAA »4.0 cm — no.
`Iliac-artery aneurysm »2.5 cm — no.
`Any aneurysm — no. (%)§
`No CT available — no. (%)
`
`-
`I
`MMEDIATE
`R
` G
`EPAIR
`ROUP
`(N=569)
`
`S
`URVEILLANCE
`G
`ROUP
`(N=567)
`
` R
`R
`ISK
`ELATIVE
`(95% CI)
`
`143 (25.1)
`
`122 (21.5)
`
`1.21 (0.95–1.54)†
`
`37/174 (21.3)
`46/205 (22.4)
`60/190 (31.6)
`
`32/197 (16.2)
`33/188 (17.6)
`57/182 (31.3)
`
`1.48 (0.92–2.38)
`1.27 (0.81–1.99)
`1.02 (0.71–1.47)
`
`1.02 (0.38–2.73)
`1.34 (0.93–1.93)
`1.10 (0.78–1.55)
`1.15 (0.58–2.31)
`
`1.00 (0.56–1.77)
`
`8/47 (17.0)
`61/251 (24.3)
`74/271 (27.3)
`17 (3.0)
`2 (0.4)
`23 (4.0)
`2 (0.4)
`527 (92.6)
`
`8/51 (15.7)
`55/279 (19.7)
`59/237 (24.9)
`15 (2.6)
`0
`24 (4.2)
`11 (1.9)
`349 (61.6)
`
`255
`
`129
`
`31 (5.4)
`
`328 (57.6)
`19 (3.3)
`27 (4.7)
`77 (13.5)
`67 (11.8)
`
`155 (27.3)
`
`242 (42.7)
`17 (3.0)
`13 (2.3)
`185 (32.6)
`48 (8.5)
`
`*CI denotes confidence interval, AAA abdominal aortic aneurysm, and CT computed tomography.
`†After adjustment for clinical characteristics at the time of randomization that were significant independent predictors
`of death according to forward stepwise regression analysis, the relative risk of death was 1.15 (95 percent confidence in-
`terval, 0.90 to 1.47). The significant independent predictors of death (in decreasing order of the variance they explained)
`were a higher serum creatinine level, a lower weight, a diagnosis of chronic obstructive lung disease, a larger AAA diam-
`eter, a lower forced expiratory volume in one second, a diagnosis of diabetes, and nonuse of a beta-blocker.
`‡Data include hospitalizations for complications of AAA repair shown in Table 3.
`§Data are for unrepaired aneurysms and clinically important residual or recurrent aneurysms after repair.
`
`groups in the primary outcome of the rate of death
`from any cause (relative risk, 1.21 for repair vs. surveil-
`lance; 95 percent confidence interval, 0.95 to 1.54)
`(Fig. 2 and Table 2). Survival trends did not favor
`immediate repair in any of the prespecified subgroups
`defined according to age or diameter of aneurysm at
`randomization, and there was no significant interac-
`tion with respect to mortality between treatment
`group and either age or diameter of aneurysm at ran-
`domization. The results were similar after adjustment
`for base-line clinical variables that were significant in-
`dependent predictors of death (adjusted relative risk,
`1.15; 95 percent confidence interval, 0.90 to 1.47)
`(Table 2).
`
`Rupture of Aneurysms
`The rate of death related to abdominal aortic aneu-
`rysm was not reduced by immediate repair (Table 2).
`
`Eleven ruptures of abdominal aortic aneurysms oc-
`curred in the surveillance group, a rate of 0.6 percent
`per year of follow-up of unrepaired aneurysms. Of
`these ruptures, two were incidental findings at the time
`of elective repair (one described as a hole in the aortic
`wall covered by a thin layer of connective tissue, the
`other as a hole plugged by thrombus), and seven re-
`sulted in death. Nine of the 11 diagnoses of rupture
`were confirmed at the time of surgery, another had a
`characteristic clinical presentation and was associated
`with findings on CT scanning after embalming that
`were consistent with rupture, and the last had only a
`characteristic clinical presentation. The two patients
`in the immediate-repair group who had ruptures of
`abdominal aortic aneurysms included one with an in-
`cidental rupture (also described as a hole in the aortic
`wall covered by a thin layer of connective tissue) de-
`tected at the time of elective repair and one who died
`
`1440
`
`·
`
`N Engl J Med, Vol. 346, No. 19
`
`·
`
`May 9, 2002
`
`·
`
`www.nejm.org
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org at THE OHIO STATE UNIV on May 8, 2022. For personal use only. No other uses without permission.
`
` Copyright © 2002 Massachusetts Medical Society. All rights reserved.
`
`

`

`IMMEDIATE REPAIR COMPARED WITH SURVEILL ANCE OF SMALL ABDOMINAL AORTIC ANEURYSMS
`
`Surveillance group
`
`Immediate-repair group
`
`0
`
`1
`
`2
`
`5
`4
`3
`Year of Study
`
`6
`
`7
`
`8
`
`1.0
`
`0.9
`
`0.8
`
`0.7
`
`0.6
`
`0.5
`
`0.4
`
`0.3
`
`0.2
`
`0.1
`
`0.0
`
`Cumulative Survival
`
`NO. AT RISK
`Surveillance
`Immediate repair
`
`567
`569
`
`552
`545
`
`530
`526
`
`513
`502
`
`393
`383
`
`274
`264
`
`183
`172
`
`76
`67
`
`Figure 2. Cumulative Survival According to Treatment Group.
`
`after the repair of a contained rupture proximal to a
`previous repair. Thoracic aortic aneurysm caused
`two deaths in the immediate-repair group, one from
`the rupture of a thoracic aneurysm after the repair
`of an abdominal aortic aneurysm and the other after
`elective repair of a thoracic aneurysm. In addition to
`operative deaths and those caused by rupture, there
`were 24 sudden deaths in the surveillance group and
`23 in the immediate-repair group, suggesting that
`there was not a large number of undiagnosed rup-
`tures of aneurysms in the surveillance group. In ad-
`dition to those listed in Table 2, two other deaths in
`the immediate-repair group could be considered to
`be aneurysm-related: a sudden death at home two
`months after an aneurysm repair that was complicat-
`ed by postoperative ventricular tachycardia and a death
`following repair of a ventral hernia resulting from an-
`eurysm repair.
`In 20 patients in the surveillance group, repair was
`performed because of pain suggestive of rupture but
`no rupture was found at the time of surgery (a presen-
`tation known to herald imminent rupture17). Although
`these aneurysms were repaired because of pain, 10 of
`them were measured on CT scans by the central lab-
`oratory as 5.5 cm or more in diameter, and another
`6 were measured as that large by the local laboratory
`but the CT scans had not been read centrally at the
`
`time of surgery. Three other patients in the surveil-
`lance group had incidental repair of an aneurysm dur-
`ing aortoiliac surgery for symptomatic occlusive dis-
`ease (resulting in one of the operative deaths); in two
`of these patients, the diameter of the aneurysm had
`been measured by the local laboratory as 5.5 cm or
`greater before surgery, but there was no reading from
`the central laboratory before surgery.
`
`Enlargement of Aneurysms
`The median rate of increase in the diameter of an-
`eurysms in the surveillance group, according to the
`first and last CT readings by the central laboratory
`(or the first and last ultrasonographic readings in pa-
`tients with fewer than two CT readings by the central
`laboratory), was 0.32 cm per year (interquartile range,
`0.16 to 0.42 cm; mean follow-up time, 3.0 years). The
`only significant univariate predictors of an increased
`rate of enlargement were a larger initial diameter and
`the absence of diabetes.
`
`Complications of Repair
`The operative mortality associated with the repair of
`unruptured abdominal aortic aneurysms was 2.0 per-
`cent at 30 days; when in-hospital mortality beyond
`30 days was included, the rate was 2.4 percent. An ad-
`ditional 1.5 percent of the patients required reoper-
`
`N Engl J Med, Vol. 346, No. 19 · May 9, 2002 · www.nejm.org · 1441
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org at THE OHIO STATE UNIV on May 8, 2022. For personal use only. No other uses without permission.
`
` Copyright © 2002 Massachusetts Medical Society. All rights reserved.
`
`

`

`The New England Journal of Medicine
`
`ation because of complications. The results of repair
`of unruptured abdominal aortic aneurysms according
`to treatment group are presented in Table 3. The op-
`erative mortality and the rate of reoperation were not
`higher in the surveillance group, but there were more
`myocardial infarctions. In two patients in the imme-
`diate-repair group, laparotomy was performed, but the
`first attempt at repair of the aneurysm was aborted,
`and the surgery had to be completed at a later date;
`in two patients in the surveillance group, laparotomy
`was performed, but the repair of the aneurysm was
`aborted because metastatic cancer was found.
`As expected, given the greater number of repairs of
`abdominal aortic aneurysms performed in the imme-
`diate-repair group, there were also more rehospitaliza-
`tions because of postoperative complications (Table 3).
`The total number of hospitalizations related to abdom-
`inal aortic aneurysms (both for repair and for other
`reasons including preoperative evaluation, canceled re-
`pairs, postoperative complications, and ruptures with-
`out repair) was 39 percent lower in the surveillance
`group than in the immediate-repair group (Table 2).
`The number of patients surviving with aneurysms
`at the end of the study is also shown in Table 2. These
`data include patients with unrepaired abdominal aortic
`
`TABLE 3. COMPLICATIONS OF REPAIR
`OF UNRUPTURED ABDOMINAL AORTIC ANEURYSMS.*
`
`VARIABLE
`
`Operative death
`Within 30 days
`Within 30 days or during
`hospitalization
`Major complication with no
`operative death
`Reoperation required
`Myocardial infarction†
`Amputation
`Paraplegia
`Stroke
`Pulmonary embolism
`Dialysis
`Any complication‡
`Late graft failure§
`Rehospitalization for com-
`plications
`
`IMMEDIATE-
`REPAIR GROUP
`(N=526)
`
`SURVEILLANCE
`GROUP
`(N=340)
`
`no. (%)
`
`11 (2.1)
`14 (2.7)
`
`6 (1.8)
`7 (2.1)
`
`9 (1.7)
`5 (1.0)
`2 (0.4)
`0
`3 (0.6)
`4 (0.8)
`1 (0.2)
`275 (52.3)
`2 (0.4)
`108 (20.5)
`
`4 (1.2)
`13 (3.8)
`2 (0.6)
`2 (0.6)
`2 (0.6)
`1 (0.3)
`2 (0.6)
`193 (56.8)
`1 (0.3)
`56 (16.5)
`
`*Differences between groups were not significant unless
`otherwise indicated.
`†P=0.004 for the comparison between groups.
`‡Complications have been described elsewhere.12
`§All three late graft failures were fatal aortoenteric fistulas.
`
`aneurysms and those with clinically important resid-
`ual or recurrent aneurysms after repair (defined as an
`abdominal aortic aneurysm of at least 4.0 cm in diam-
`eter proximal to the graft or an iliac-artery aneurysm
`of at least 2.5 cm in diameter).
`
`DISCUSSION
`As compared with surveillance by CT or ultraso-
`nography, a strategy of immediate repair did not im-
`prove the rate of survival among patients with low
`surgical risk who had abdominal aortic aneurysms of
`4.0 to 5.4 cm in diameter. The confidence interval ex-
`cludes a benefit of more than 5 percent from imme-
`diate repair. These findings were obtained despite a low
`operative mortality rate. The nonsignificant survival
`trends did not favor immediate repair in any of the pre-
`specified subgroups defined according to age or diam-
`eter of aneurysm at entry.
`We did not find an increase in operative mortality or
`the need for reoperation when elective repair was de-
`layed until the diameter of the aneurysm was 5.5 cm,
`as had been previously predicted,18 but more myocar-
`dial infarctions occurred. The low mortality associated
`with repair of unruptured aneurysms in our study may
`be attributed both to the skill of the surgical teams
`and to our criteria for inclusion, which selected for
`patients who did not have high surgical risk and were
`therefore presumably most likely to benefit from elec-
`tive repair.
`Our results confirm and extend those of the only
`other randomized trial of surgery for small abdominal
`aortic aneurysms, the United Kingdom Small Aneu-
`rysm Trial, which also found no benefit from repair of
`aneurysms less than 5.5 cm in diameter.19 The con-
`fidence intervals in that study did not exclude a 25 per-
`cent reduction in mortality with immediate repair, and
`the operative mortality in the immediate-repair group
`in that study was a relatively high 5.8 percent. These
`factors left some experts unconvinced of the conclu-
`sions drawn by the study investigators, and several sub-
`sequent editorials endorsed immediate repair of ab-
`dominal aortic aneurysms smaller than 5.5 cm if the
`operative mortality was likely to be less than 5.8 per-
`cent.20,21 Our findings indicate that there is unlikely to
`be a survival benefit associated with the elective repair
`of abdominal aortic aneurysms smaller than 5.5 cm,
`even when there is low mortality associated with the
`procedure.
`The most likely reason that immediate repair was
`not beneficial in our study was that the rate of rup-
`ture was low (0.6 percent per year). This rate of rup-
`ture, although consistent with those reported in pre-
`vious population-based studies,5,6 was obtained with
`the aid of an active surveillance program in which pa-
`tients were urged to return for scheduled imaging
`studies at six-month intervals. Whether the results of
`
`1442 · N Engl J Med, Vol. 346, No. 19 · May 9, 2002 · www.nejm.org
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org at THE OHIO STATE UNIV on May 8, 2022. For personal use only. No other uses without permission.
`
` Copyright © 2002 Massachusetts Medical Society. All rights reserved.
`
`

`

`IMMEDIATE REPAIR COMPARED WITH SURVEILL ANCE OF SMALL ABDOMINAL AORTIC ANEURYSMS
`
`our trial would apply to practice settings with less rig-
`orous surveillance programs is not known. Our finding
`that diabetes was associated with slower enlargement
`of aneurysms is consistent with our previous observa-
`tion that diabetes is associated with a reduced prev-
`alence of aneurysm,13,14 but the reasons for this asso-
`ciation remain unknown.
`A limitation of our study is that the subjects were
`almost all men. Although this imbalance reflects the
`predominance of men among veterans, it also reflects
`the demographic characteristics of persons with ab-
`dominal aortic aneurysm, which is four times as prev-
`alent in men as in women.22 Women accounted for
`only 17 percent of the study population in the United
`Kingdom Small Aneurysm Trial, which was conduct-
`ed in a general population. As compared with men,
`women with abdominal aortic aneurysm are older and
`appear to have a higher risk of rupture,23 higher rup-
`ture-related mortality,24 and higher mortality after
`elective repair,25,26 so the results of these trials may not
`be applicable to women.
`Another limitation of our study is the duration of
`follow-up. The larger number of aneurysms that re-
`mained unrepaired in the patients in the surveillance
`group at the end of the study could ultimately lead to
`increased mortality, but no trend in this direction has
`yet been observed.
`The question raised at the end of the report of the
`United Kingdom Small Aneurysm Trial19 regarding
`whether the optimal diameter for repair mi