ALIF Paper

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SPINE Volume 29, Number 2, pp 113–122
©2004, Lippincott Williams & Wilkins, Inc.
A Prospective, Randomized Controlled Clinical Trial of
Anterior Lumbar Interbody Fusion Using a Titanium
Cylindrical Threaded Fusion Device
Rick C. Sasso, MD,* Scott H. Kitchel, MD,† and Edgar G. Dawson, MD‡
Study Design. A prospective, randomized, controlled
clinical trial comparing a cylindrical threaded titanium
cage to a femoral ring allograft control for anterior lumbar
interbody fusion.
Objective. To compare these two implants with regard
to arthrodesis. Secondary outcome measures included
pain relief, neurological status, and general health status.
Summary of Background Data. Anterior lumbar interbody fusion is a well-accepted procedure using trapezoidal femoral ring allografts or cylindrical titanium cages.
Clinical and biomechanical studies evaluating these two
distinct constructs are numerous; however, no prospective, randomized study comparing them has been done.
Methods. A multicenter trial of 140 patients: 78 were
randomized to the cylindrical threaded titanium cage device treatment arm and 62 patients randomized into the
control group. All had autogenous iliac crest bone graft
packed into the device. All patients had a single-level
stand-alone anterior lumbar interbody fusion at either the
L4–L5 or L5–S1 interspace for symptomatic degenerative
disc disease. Radiographic fusion data were collected as
well as multiple types of outcome data, including pain/
disability scores, neurologic status, and overall health.
Results. At 12 months, 97% of the cylindrical threaded
titanium cage device group and 40% of the control group
demonstrated radiographic fusion. At 24 months, 97% of
the cylindrical threaded titanium cage group and 52% of
the control group showed radiographic fusion. These fusion rate differences are statistically significant (P 
0.001). The Oswestry and neurologic scores were not significantly different between groups.
Discussion. This is the first prospective, randomized,
multicenter clinical trial that compares fusion cage results
to control data.
Conclusion. Cylindrical threaded titanium cages have
a higher fusion rate, comparable improvements in clinical
outcome (Oswestry, Low Back Pain Questionnaire, SF-
36), and fewer secondary supplemental fixation procedures compared to the femoral ring allograft control. [Key
words: anterior lumbar interbody fusion, Interbody fusion
cage, prospective trial, femoral ring allograft, INTER FIX
Threaded Fusion Device] Spine 2004;29:113–122
The use of interbody fusion cages has increased markedly over the past 5 years, and it is now estimated that
5,000 cages are implanted monthly in the United States.
1
It has been shown that interbody cages effectively achieve
fusion
2–5
and that the use of interbody cages can be cost
effective.
6,7
Further, it has been shown that achieving
successful fusion correlates with better clinical outcomes.
7
While several prospective studies have been undertaken on different interbody fusion devices,
2–4
none
of these studies has been designed as a prospective, randomized, multicenter clinical trial that compares fusion
cage results to control data.
The INTER FIX Threaded Fusion Device was developed by Medtronic Sofamor Danek for use in spinal fusion procedures in skeletally mature patients with degenerative disc disease. The device is also indicated for use in
patients with no more than Grade 1 lumbar spondylolisthesis or retrolisthesis at a single level. INTER FIX device
implants are to be used with autogenous bone graft and
implanted via an open anterior approach. The following
study was conducted as a prospective, randomized, multicenter study to determine the safety and effectiveness of
the INTER FIX device in the treatment of patients with
symptomatic lumbar degenerative disc disease.
History. The INTER FIX device has been distributed in
Europe since 1995 and has been marketed in at least 20
countries. The U.S. Food & Drug Administration approved the Premarket Approval application for the INTER FIX device on May 14, 1999. This approval covers
the use of the device with autologous bone graft in spinal
fusion procedures via the open anterior approach for
patients with degenerative disc disease at one level from
L2–S1, including those with Grade 1 or less spondylolisthesis or retrolisthesis.
Device Design and Preclinical Testing. The INTER FIX
device is a hollow, threaded cylinder with a removable
end cap (Figure 1). The device was originally approved
for 18 sizes with diameters from 12 mm to 20 mm and
lengths from 20 mm to 29 mm with end cap components.
Subsequently, 8 additional size devices, with 22- or
24-mm diameters, have received a marketing clearance
from the Food & Drug Administration. The information
presented and the results of the clinical trial, however,
From the *Indiana Spine Group, Indianapolis, Indiana; †Eugene, Oregon; and ‡Los Angeles, California.
Acknowledgment date: June 5, 2002. First revision date: September 12,
2002. Acceptance date: March 28, 2003.
The device(s)/drug(s) is/are FDA-approved or approved by corresponding national agency for this indication.
Corporate/Industry funds were received in support of this work. Although one or more of the author(s) has/have received or will receive
benefits for personal or professional use from a commercial party related directly or indirectly to the subject of this manuscript, benefits
will be directly solely to a research fund, foundation, educational institution, or other nonprofit organization which the author(s) has/have
been associated.
Address correspondence to Rick C. Sasso, MD, Indiana Spine Group,
8402 Harcourt Rd., Suite 400, Indianapolis, IN 46260; E-mail:
rsasso@on-net.net
113are based on the 18 original sizes that were used in the
clinical trial. The end caps provide strength while reducing metal volume and increasing the space available for
autograft. Each cylinder component has a 30° included
angle self-tapping V-thread over the entire outer surface
of the implant and a 45° chamfer at the ends to facilitate
insertion into the prepared intervertebral cavity. Each
cylinder component has multiple through-holes that are
to be placed cephalad and caudad and multiple small
transverse holes to enhance vascularization of the graft
within the device. The INTER FIX device is manufactured from titanium alloy (Ti-6Al-4V).
Biomechanical laboratory testing to characterize the
mechanical properties of the INTER FIX device included
static compression testing, cyclic fatigue testing, and stability testing, which was comprised of stiffness testing,
insertion torque, and push-out testing. The INTER FIX
device failed at an average compression load of 79,797 N
without breakage and cyclic load testing of 5 million
cycles of compression loads ranging from 880 N to 9,600
N without failure. Using a combined loading (compression, bending moment, and shear) test fixture that enhanced simulation of a dynamically loaded spine, breakage did not occur at 5 million cycles at a maximum
bending moment of 135 N-m, which is a substantially
greater load than the bending moment of 33 N-m that
the motion segment can resist before sustaining damage.
In another “combined” loading mechanical test, which
also attempted to replicate the complex lumbar loading
situation via a compression shear apparatus, the INTER
FIX device has a strength of 30,570 N and 4,000 N in
static and fatigue (5  10
6
cycles) loading situations,
respectively. This compares favorably with estimate
maximum in vivo loads of 2,200 N and 1,400 N, respectively. Based on these data, the INTER FIX device appears to provide a significant safety factor over the complex in vivo loading situation.
15
Clinical Trial. The purpose of this clinical trial is to
determine the safety and efficacy of the INTER FIX device for treatment of symptomatic degenerative disc disease and to compare it with a completely biologic femoral ring allograft implant (Figure 2).
Methods
A prospective, randomized, multicenter clinical trial of the INTER FIX device was conducted in the United States to determine the safety and effectiveness of the anterior spinal use of the
INTER FIX device in the treatment of patients with symptomatic degenerative disc disease. A total of 140 patients were
entered into the study at 13 study sites. The following is the list
of investigators participating in the prospective, randomized
study:
● Avi Bernstein, MD, Park Ridge, IL
● Gary Michelson, MD, Los Angeles, CA
● Courtney Brown, MD, Lakewood, CO
● Robert Pashman, MD, Los Angeles, CA
● Craig Callewart, MD, Dallas, TX
● Richard Salib, MD, Minneapolis, MN
● Guy Danielson, MD, Tyler, TX
● Rick Sasso, MD, Indianapolis, IN
● Edgar Dawson, MD, Los Angeles, CA
● Robert Watkins, MD, Los Angeles, CA
● Alexander Hadjipavlou, MD, Galveston, TX
● Douglas Weiland, MD, Clearwater, FL
● Scott Kitchel, MD, Eugene, OR
Seventy-eight patients were randomized to the INTER FIX
device treatment arm (Figure 3), and 62 patients were randomFigure 1. INTER FIX Threaded Fusion Device.
Figure 2. Femoral ring allograft.
114 Spine • Volume 29 • Number 2 • 2004ized to the control group (Figure 4). Investigational patients
were treated with the INTER FIX device filled with autogenous
bone derived from the iliac crest. Control patients were treated
with femoral ring allograft also filled with iliac crest-derived
autogenous bone. All patients underwent an anterior surgical
approach for a single-level interbody fusion. Patients had at
least 6 months of nonoperative treatment before surgical intervention, including physical therapy, medications, braces, chiropractic care, bed rest, spinal injections, or exercise programs.
The clinical trial was designed as an equivalence trial, to determine if the INTER FIX device outcomes are no worse than
those of the control, according to methods described by Blackwelder.
10
Patients enrolled in the study had symptomatic degenerative disc disease diagnosed by symptoms of intractable
leg and/or back pain with positive diagnostic imaging findings.
In addition, patients had to exhibit spinal instability as defined
by 4 mm of translation or 5° of angulation on flexion–
extension radiographs, have single-level symptomatic involvement from L2–S1, and have no greater than Grade 1 spondylolisthesis. The positive diagnostic imaging findings for
patients enrolled in the study, as noted by intractable leg and/or
back pain in the presence of instability, included at least one of
the following: 1) herniated nucleus pulposus as documented by
MRI, CT, or myelographic techniques, 2) collapse of disc space
of 2 mm as determined by anteroposterior and lateral radiographs, 3) scarring and/or thickening of the anulus fibrosis,
ligamentum flavum, and/or facet joint capsule, 4) osteophyte
formation on the vertebral endplates, 5) osteophyte formation
or hypertrophy of the facet joint, or 6) disc disruption manifested by resorption and narrowing of the disc space. Specifi-
cally excluded from the clinical trial were patients who had a
previous anterior interbody fusion procedure at the involved
spinal level; had osteopenia, osteoporosis, or osteomalacia; or
required bone growth stimulation. Contraindications to use of
INTER FIX device use were active infection at the operative site
or patients with an allergy to titanium or titanium alloy. No
posterior instrumentation could be present at the surgical
level.The primary outcome variable tested in this study was
fusion. Other outcome measures included pain relief, neurologic status, and general health status. All radiographs were
interpreted by an independent board-certified radiologist, and
patients completed subjective data surveys independently. Demographic information of the patients in the clinical trial is
presented in Table 1. The demographic characteristics of both
treatment groups were similar.Each patient had to agree to
participate in the research protocol and each was assigned by
random selection, with neither surgeon nor patient knowing
whether they would receive a cage or an allograft until after the
consent was signed.
Surgical Procedure. Preoperative planning required the identification of which intervertebral disc to operate on followed by
selecting the proper size construct by using templates which
were designed for use with plain radiographs, CT, or MRI
scans. Care was taken to match the scale of magnification on
the radiographic study.
Figure 3. Lateral radiograph of INTER FIX.
Figure 4. Lateral radiograph of femoral ring allograft 3 months
postoperative.
Clinical Trial of ALIF • Sasso et al 115The INTER FIX device was implanted through an anterior
spinal approach, either transperitoneal or retroperitoneal. The
amount of great vessel release and retraction was limited to that
required for insertion of the instruments and constructs. Both
double barrel outer sleeve and single barrel outer sleeve methods of implant placement were available. Two cages are inserted in the disc space. The double barrel procedure is presented here.
A standard block discectomy is recommended. The centering pin should be used to fluoroscopically confirm the midline
of the disc. Measurement of the available space for the selected
device size was carried out using the blunt proximal end of the
double barrel outer sleeve and compared with the preoperative
radiographic template. While holding the double barrel, the
necessary width of the discectomy was identified and marked.
Disc material was removed from the defined space with a scalpel, rongeur, or curette. The procedure proceeded with sizespecific instrumentation for the appropriate diameter INTER
FIX device.
Distraction shafts were placed to distract the vertebral bodies before vertebral reaming. The double barrel outer sleeve is
firmly seated into the disc space replacing the distractor. An
appropriate size reamer is selected, depth stop adjusted, and
disc space prepared. Several passes of the reamer should be
undertaken. Any remaining intradiscal disc, bone, or anular
material is removed with the rongeur.
The INTER FIX device is filled with autogenous bone using
a bone press. The end cap is affixed and the device is placed in
the corresponding inserter. The device is then advanced into
place, checking depth with lateral fluoroscopy. The optimal
position of the INTER FIX device is slightly countersunk from
the anterior surface and within the lateral margins of the vertebral bodies. Two INTER FIX devices should be implanted
side by side at the surgical level. The long axis of the INTER
FIX device should be in the anteroposterior direction.
Standard wound closure was then carried out. No other
fixation was used in patients in this study. Ambulation was
initiated when tolerated usually on the day of surgery. A corset
or thoracic lumbosacral orthosis was sometimes used after surgery for immobilization.
The surgical technique for the control was the surgeon’s
standard method of anterior spinal implantation of the femoral
ring allograft. A block discectomy of the entire disc and preparation of the endplates with complete removal of the cartilage
while preserving the subchondral bone was done. The femoral
ring allograft was cut with an oscillating saw to exactly match
the interspace in distraction. The intramedullary canal of the
trapezoidal ring was packed with autogenous iliac crest cancellous bone. As with the INTER FIX device, no other fixation
was used in patients in the study. The same postoperative regimen was also recommended for the control device.
Patients were evaluated before surgery, perioperatively, and
after surgery at 3, 6, 12, and 24 months following surgery. The
protocol also stipulated that patients had to be evaluated biennially until the last patient had reached his/her 24-month evaluation. Therefore, 48-month data are available for some of the
patients. Evaluations included the assessment of fusion at the
involved level, pain/disability status, neurologic status, and
general health status. The results have since been updated as of
May 2000, with data on all available patients in the randomized study. Also, additional data on patients who have been
evaluated at 48 months after surgery are included. The inclusion of the 48-month results is for information purposes; however, because of the partial information, these data will not be
discussed. It is noteworthy that the 48-month results are consistent with those at 12 and 24 months postoperative. Approximately one third of all the patients in the randomized group
have reached this time point.
Results
Fusion
Fusion was determined using anteroposterior, lateral,
and flexion–extension radiographs that were interpreted
by an independent board-certified radiologist at 6, 12,
and 24 months after surgery. Arthrodesis was based on
the spinal level showing evidence of bridging trabecular
bone, translational stability (3 mm), angular motion
stability (5°), and the absence of radiolucent lines
around more than 50% of the implant(s). Patients requiring secondary surgeries resulting from nonunions
were considered as having failed fusions and were included in the fusion calculations. Fusion data are presented in Table 2. At 12 months, 96.7% of the INTER
FIX device group and 40.4% of the control group demonstrated radiographic fusion. At 24 months, 97.0% of
the INTER FIX group and 51.9% of the control group
showed radiographic fusion. The data demonstrates that
the INTER FIX device is not only no worse than the
Table 1. Demographic Information
INTER FIX Device Control
Age (yr) (mean [range]) N  77
41.0 [18–64]
N  62
41.2 [27–59]
Weight (lb)
(mean [range])
N  77
170.5 [100–270]
N  62
172.8 [109–250]
Height (in.)
(mean [range])
N  76
66.6 [60–75]
N  62
67.9 [60–74]
Sex [frequency (%)]
Male 30 (39.0) 33 (53.2)
Female 47 (61.0) 29 (46.8)
Tobacco used
[frequency (%)]
Yes 23 (29.9) 20 (32.3)
No 54 (70.1) 42 (67.7)
Workers’ Compensation
[frequency (%)]
Yes 32 (42.1) 22 (35.5)
No 44 (57.9) 40 (64.5)
Taking preoperative
medication for pain
[frequency (%)]
Yes 59 (76.6) 46 (74.2)
No 18 (23.4) 16 (25.8)
Previous back surgery
[frequency (%)]
Yes 32 (41.6) 27 (43.6)
No 45 (58.4) 35 (56.5)
Table 2. Successful Fusion Rates (%) at 6, 12, 24, and 48
Months
Treatment Group 6 Months 12 Months 24 Months 48 Months
INTER FIX
device
95.0 (38/40) 96.7 (58/60) 97.0 (64/66) 92.0 (23/25)
Control 10.9 (6/55) 40.4 (21/52) 51.9 (27/52) 42.1 (8/19)
116 Spine • Volume 29 • Number 2 • 2004control (  0.01) but that the INTER FIX device fusion
rates were superior to the control rates at 6, 12, and 24
months (P  0.001) (Figure 5).
Pain/Disability
Pain and the disability resulting from pain were assessed
using the Oswestry Low Back Pain Disability QuestionFigure 5. A: Preoperative sagittal T2-weighted MRI with degeneration of the L5–S1 disc and a normal L4–L5 disc. B: Discogram with
morphologic abnormality of the L5–S1 disc and a large posterior anular tear. The L4–L5 disc is anatomically normal. Exact concordant
10/10 pain was reproduced at L5–S1. The L4–L5 injection caused no pain. C: Postoperative lateral radiograph with INTER FIX cages in good
position. D: Intraoperative picture of the two cages implanted at the L5–S1 interspace. E: Coronal CT scan 1 year postoperative. Bone has
grown through and around the cages.
Clinical Trial of ALIF • Sasso et al 117naire. This questionnaire was administered before surgery and at each postoperative visit. The Oswestry Questionnaire evaluates the patient’s response to 10 questions
that focus on pain, personal care, lifting, walking, sitting,
standing, sleeping, sex life, social life, and ability to
travel. Responses range from zero to five, and the lower
numerical score represents a better pain and disability
status with regard to each variable. The total score is
determined by summing the scores to individual questions and dividing that total by the maximum possible
total score to yield a percentage score. A lower score is
characteristic of less pain and disability. Mean Oswestry
Questionnaire scores are presented in Table 3. The mean
overall scores significantly improved in all groups compared with the preoperative scores (P  0.001). The
INTER FIX device group showed improvement from a
mean preoperative value of 51.1 to a mean value of 33.7
at 6 months, 32.9 at 12 months, and 29.5 at 24 months.
The control group preoperative mean value was 52.7,
falling to 38.4 at 6 months, 34.4 at 12 months, and 31.5
at 24 months. There was no statistical difference between
the treatment groups.
Neurologic Evaluation
All patients in the clinical trial underwent neurologic
evaluation before surgery and after surgery at every follow-up visit. The neurologic assessment tool addressed
motor function, sensory, reflexes, and degree of straight
leg raising producing pain. An algorithm was developed
to transform the detailed scores for each parameter into
an overall classification representing maintenance or improvement in neurologic status at a given postoperative
time as compared with their preoperative neurologic status. Overall neurologic status maintenance or improvement is based on demonstrating maintenance or improvement in at least three of the four categories. Table 4
shows the distributions of patients in the treatment
groups having a maintenance or improvement in neurologic condition following surgery. Overall values for the
INTER FIX device group were 97.2% at 6 months,
100% at 12 months, and 97.0% at 24 months. The control group overall values were 98.3% at 6 months,
100.0% at 12 months, and 95.6% at 24 months. There
were no statistically significant differences between the
randomized INTER FIX device group and the control
group at these time periods (P  0.05).
General Health Status
The general health status of all study patients was assessed using the Medical Outcomes Study 36-item Short
Form Health Survey (SF-36). Patients completed this
self-administered test before surgery and at each postoperative visit. The test consists of 36 questions involving
eight subscales of health status: physical function, rolephysical, pain index, general health perception, vitality,
social function, role-emotional, and mental health.
These eight subscales can be summarized further into
two measures pertaining to physical health (PCS) and
mental health (MCS). The PCS is based primarily on the
physical functioning, role-physical, bodily pain, and general health scales. The MCS is based on the vitality, social
function, role-emotional, and mental health scales.
Higher numbers represent increasing improvement. Table 5 presents the mean PCS and MCS results for the two
treatment groups. All the postoperative scores were
higher than the preoperative scores indicating improvement. The INTER FIX device group showed mean score
improvement in PCS scores of preoperative value of 28.3
to 35.3 at 6 months, 37.9 at 12 months, and 39.8 at 24
months. Mean MCS scores improved from a preoperative value of 42.2 to 24-month value of 46.8. Control
mean values of PCS and MCS at preoperative, 6-, 12-,
and 24-month follow-up were 28.5/41.9, 36.4/47.1,
37.0/46.9, and 37.3/51.0, respectively. There were no
statistically significant differences at any time period between the investigational and control groups in the mean
change in PCS and MCS scores postoperative compared
with the preoperative value (P  0.05).
Adverse Effects
Table 6 presents the nature and frequency of adverse
events through the latest evaluation of the patients. The
most common and serious adverse effects were intraoperative vascular, neurologic injuries or spinal events,
such as disc herniation or foraminal stenosis. A total of 9
(11.5%) intraoperative vascular events occurred in patients in the INTER FIX device group and 2 (3.2%) vascular intraoperative injuries occurred in the control
group. In the INTER FIX device group, 14 (17.9%) neurologic events occurred compared with 16 (25.8%) neurologic events in the control group. Spinal events occurred in 11 (14.1%) of the INTER FIX device group
and 4 (6.5%) in the control group. Sacroiliac pain occurred in 7 (8.9%) of the INTER FIX device treatment
group and 3 (4.8%) of the control group while 4 (5.1%)
of the INTER FIX device group had back pain compared
with 14 (22.5%) of the control group. In the INTER FIX
device group, 5 (6.4%) had incisional pain, as did 8
(12.9%) of the control group. While there were no occurrences of implant displacement or loosening or implant breakage in the INTER FIX device group, there
were 6 (9.7%) and 5 (8.1%), respectively, in the control
group. There was only one death in the study of a patient
in the control group (1.6%) that resulted from cardiac
arrest and was not associated with the implant. None of
the adverse event rates for the INTER FIX device group
was statistically higher than those for the control group.
The rates of implant breakage, implant loosening/
displacement, back pain, and other pain in the control
group were statistically higher (P  0.05) than those for
the INTER FIX device group.
Some of these adverse events led to surgical interventions subsequent to clinical trial surgery. These surgeries
were classified as revision, removal, supplemental fixation, and reoperation. The definitions for these classifi-
cations are as follows:
118 Spine • Volume 29 • Number 2 • 2004● Revision—A procedure that adjusts or in any way
modifies the original implant configuration (e.g., adjusting position of original configuration, removal
with replacement of component, adding a fixation
screw to the bone graft).
● Removal—A procedure that removes one or more
components of the original implant configuration
without replacement of any components.
● Supplemental fixation—A procedure in which additional instrumentation not approved as part of the
protocol is placed.
● Reoperation—A procedure that involves any surgical procedure that does not remove, modify, or add
any components.
These results are summarized in Table 7. The INTER
FIX device group had a significantly fewer number of
supplemental fixations compared with the control group
(P  0.003).
Discussion
Although several interbody fusion devices are currently
marketed, none of these cages has been subjected to the
rigors of a prospective, randomized, multicenter clinical
trial until now. This clinical trial of the INTER FIX
Threaded Fusion Cage is therefore a landmark study,
which demonstrates the superior results of increased fusion rates using the INTER FIX device compared with
the control of treatment involving a femoral allograft
ring filled with autogenous bone.
Rapoff et al
8
studied the stability of the spine following INTER FIX device implantation. The biomechanical
testing included the effects of the device on spinal stiffness and the implant insertion torque and push-out properties. Stiffness testing was performed using lumbar calf
spines evaluating stiffness in flexion– extension, axial
torsion, axial loading, and lateral bending using the intact spine as a baseline. Results showed that the spines
instrumented with the INTER FIX device were stiffer
than intact spines and spines with resected posterior elements in flexion, extension, and overall. The overall stiffness testing results were comparable to SpineTech’s BAK
device. The INTER FIX device instrumented spines were
significantly stiffer in extension. Insertion torque and
push-out testing using human cadaveric spines were performed on both the INTER FIX and BAK devices. Results for the two devices were similar and the INTER FIX
device was found to be resistant to migration and
push-out.
Sandhu et al
9
reported on the use of the INTER FIX
device for single-level anterior lumbar interbody fusion
procedures in sheep comparing this to iliac crest dowels
and interbody decortication. Six-month evaluation, including manual palpation of fusion site and histology,
showed 100% fusion to palpation and 37% complete
fusion by histologic evaluation in the INTER FIX group.
Radiographic evaluation, which included measurement
of interbody distraction and angulation, was carried out
at 2, 4, and 6 months after surgery. The INTER FIX
device maintained disc space height over time. The iliac
crest dowel group also had a 100% fusion rate but demonstrated more collapse of the interbody space at
follow-up.
Prospective, multicenter randomized clinical trials are
the gold standard of scientific studies. While these studies
are required for pharmaceutical testing, they are rarely
done in a surgical setting.
11,12
The lack of prospective,
randomized orthopedic studies and prevalence of poor
study designs and analysis is reported throughout the
orthopedic literature.
13,14
The prospective, randomized
clinical trial design limits bias, although it does not completely eliminate it in the surgical setting because of surgeon familiarity with specific techniques and proceTable 3. Mean Oswestry Pain/Disability Scores
Treatment Group Preoperative 6 Months 12 Months 24 Months 48 Months
INTER FIX device 51.1 (N  77 33.7 (N  73 32.9 (N  66 29.5 (N  69 23.7 (N  29
Control 52.7 (N  60 38.4 (N  57 34.4 (N  53 31.5 (N  48 14.8 (N  15
Table 4. Neurological Maintenance or Improvement Rates (%) at 6, 12, 24, and 48 Months
Treatment Group Motor Function Sensory Reflexes SLR Overall
6 months
INTER FIX device 100.0 (72/72) 95.8 (69/72) 88.9 (64/72) 96.7 (59/61) 97.2 (70/72)
Control 100.0 (58/58) 100.00 (58/58) 93.1 (54/58) 98.0 (49/50) 98.3 (57/58)
12 months
INTER FIX device 100.0 (66/66) 98.5 (65/66) 93.9 (62/66) 96.3 (52/54) 100.0 (66/66)
Control 100.0 (52/52) 98.1 (52/53) 92.5 (49/53) 97.9 (47/48) 100.0 (52/52)
24 months
INTER FIX device 100.0 (67/67) 98.5 (66/67) 88.1 (59/67) 93.3 (56/60) 97.0 (64/66)
Control 97.8 (44/45) 91.1 (41/45) 95.6 (43/45) 93.0 (40/43) 95.6 (43/45)
48 months
INTER FIX device 100.0 (27/27) 92.6 (25/27) 85.2 (23/27) 100.0 (27/27) 100.0 (27/27)
Control 100.0 (14/14) 92.9 (13/14) 92.9 (13/14) 100.0 (14/14) 100.0 (14/14)
Clinical Trial of ALIF • Sasso et al 119dures.
11
In this clinical trial, however, all surgeons
participating were competent and familiar with both the
investigational and control procedures, thereby minimizing any bias that could result from surgical technique
variations. Because this was a multicenter study, surgical
bias in terms of reproducibility was also minimized.
There were other important design features of this
clinical trial, including the use of the independent boardcertified radiologist for interpretation of postoperative
films. This served to eliminate bias and standardize the
interpreted results. A very specific definition of fusion
was utilized, requiring that evidence of bridging trabecular bone, translational stability (3 mm), and angular
motion stability ( 5°) be present, and the absence of
radiolucent lines around 50% of the implant(s) be evident for fusion to be considered to have occurred. Finally, the patients themselves supplied the subjective
data via the Oswestry Disability Scale and the SF-36,
keeping these data free of the clinician’s interpretation
and bias. All these factors further support the validity of
this clinical trial.
One of the more difficult areas to evaluate in any lumbar fusion study is the subjective measure of patient outcome. Two measures were used in this study to measure
patient improvement, the Oswestry Low Back Pain
Questionnaire and the SF-36. Using both these measures,
patients had improvement when the INTER FIX device
was used compared with preoperative values. The mean
INTER FIX results were also better initially and at 3, 6,
12, and 24 months than the results from the control
group for both the Oswestry and SF-36 measurements.
There were no statistically significant differences between the control and experimental groups in regards to
Oswestry, SF-36, or neurologic scores. The improvement
seen in both groups is likely more a function of the approach itself (anterior lumbar interbody fusion) rather
than what material or device was implanted or whether
fusion actually occurred. Although fusion indexes are
not inconsequential, many factors are associated with
patient satisfaction. Exposure and soft tissue factors are
especially important in patient satisfaction outcomes.
Traditionally, an anterior approach is correlated with a
better outcome despite a lower fusion rate compared
with a more soft tissue destructive posterolateral exposure. Fraser
16
found that better outcomes are obtained
after anterior interbody fusion than after posterolateral
fusion with internal fixation despite a higher fusion rate
in the latter group.
The INTER FIX device was found to be not only statistically equivalent to, but better than, the femoral ring
allograft for interbody fusion in rate of fusion. Improvement in terms of clinical outcomes was demonstrated
through use of the Oswestry Low Back Pain Questionnaire and the SF-36. There were no statistically signifi-
cant differences in specific adverse event rates that favored the control group. However, the INTER FIX
device group had statistically fewer secondary supplemental fixation procedures. Although there is no statisTable 5. Mean PCS and MCS Scores at 6, 12, 24, and 48 Months
Treatment Group
Preoperative 6 Months 12 Months 24 Months 48 Months
PCS MCS PCS MCS PCS MCS PCS MCS PCS MCS
INTER FIX device 28.3 N77 42.2 N77 35.3 N71 46.5 N71 37.9 N66 46.3 N66 39.8 N68 46.8 N68 41.8 N29 48.8 N29
Control 28.5 N61 41.9 N61 36.4 N55 47.1 N55 37.0 N53 46.9 N53 37.3 N48 51.0 N48 47.8 N15 51.9 N15
Table 6. Adverse Effects
Complication
Total Adverse Events
INTER FIX Device
[no. (% of 78)]
Control
[no. (% of 62)]
Vascular intraoperative 9 (11.5) 2 (3.2)
Sacroiliac pain 7 (8.9) 3 (4.8)
Neurological 14 (17.9) 16 (25.8)
Back pain 4 (5.1) 14 (22.5)†
Incisional 5 (6.4) 8 (12.9)
Spinal event 11 (14.1) 4 (6.5)
Urological 2 (2.6) 2 (3.2)
Other 7 (9.0) 5 (8.1)
Other pain 6 (9.7)†
Gastrointestinal 5 (6.4) 5 (8.1)
Retrograde ejaculation 1 (1.3)
Respiratory 6 (7.7) 1 (1.6)
Leg pain 2 (2.6)
Trauma 1 (1.3)
Peritoneal 3 (3.8)
Vascular postoperative 1 (1.3) 2 (3.2)
Bone fracture 2 (2.6)
Implant displacement/
loosening
6 (9.7)†
Graft site pain 1 (1.6)
Nonunion* 1 (1.3)
Nonunion (outcome
pending)
1 (1.3) 3 (4.8)
Meningitis 1 (1.6)
Implant breakage 5 (8.1)†
Death 1 (1.6)
* Did not result in second surgery; nonunions that did result in second surgeries appear in Table 7.
† P  0.05.
Table 7. Secondary Surgical Procedures
INTER FIX Device (N  77)
[no. (%)]
Control (N  62)
[no. (%)]
Revisions 2 (2.6) 3 (4.8)
Removals 1 (1.3) 0 (0.0)
Supplemental fixations 6 (7.8) 17 (27.4)*
Reoperations 12 (15.6) 11 (17.7)
* P  0.05.
120 Spine • Volume 29 • Number 2 • 2004tically significant difference between the two groups in regards to intraoperative vascular injury and other
intraoperative problems, the number of patients in this
study may be too small to detect a difference if indeed it
does exist. The authors are currently looking at this issue
with a much larger cohort. Intraoperative complications of
anterior lumbar interbody fusion through a mini-open retroperitoneal approach using either cylindrical or trapezoidal implants are being compared for future publication.
The results of this prospective randomized study indicate that the INTER FIX device is safe and effective for
use in interbody fusion as an improved alternative to
femoral ring allograft.
Key Points
● Stand-alone anterior titanium cylindrical threaded
interbody fusion cages have a higher fusion rate than
stand-alone anterior femoral ring allograft.
● Improvements in clinical outcome were similar
in both groups.
● Intraoperative complications were higher in the
cylindrical threaded cage group compared with the
trapezoidal femoral ring control cohort but did not
reach statistical significance.
References
1. McAfee PC. Interbody fusion cages in reconstructive operations on the spine.
J Bone Joint Surg Am. 1999;81:859–880.
2. Ray CD. Threaded titanium cages for lumbar interbody fusions. Spine. 1997;
22:667–680.
3. Kuslich SD, Ulstrom CL, Griffith SL, et al. The Bagby and Kuslich method
of lumbar interbody fusion, history, techniques, and 2-year follow-up:
results of a United States prospective, multicenter trial. Spine. 1998;23:
1267–1279.
4. Hacker RJ. Comparison of interbody fusion approaches for disabling low
back pain. Spine. 1997;22:660–666.
5. Weiner BK, Fraser RD. Spine update: lumbar interbody cages. Spine. 1998;
23:634–640.
6. Ray CD. Threaded fusion cages for lumbar interbody fusions: an economic
comparison with 360° fusions. Spine. 1997;22:681–685.
7. Vamvanij V, Fredrickson BE, Thorpe JM, et al. Surgical treatment of internal
disc disruption: an outcome study of four fusion techniques. J Spinal Disord.
1998;11:375–382.
8. Rapoff AJ, Ghanayem AJ, Zdeblick TA. Biomechanical comparison of posterior lumbar interbody fusion cages. Spine. 1997;22:2375–2379.
9. Sandhu HS, et al. Distractive properties of a threaded interbody fusion device: an in vivo model. Spine. 1996;21:1201–1210.
10. Blackwelder WC. Proving the null hypothesis in clinical trials. Control Clin
Trials. 1982;3:345–353.
11. Keller RB, Rudicel SA, Liang MH. Outcomes research in orthopaedics. In:
Schafer M, ed. Instructional Course Lectures, vol. 43, Chicago: AAOS,
1994:599–612.
12. Van Vleet JD. Prospective multicenter clinical trials in orthopedics, special
concerns and challenges. In: Witkin KB, ed. Clinical Evaluation of Medical
Devices: Principles and Case Studies, Totawa, NJ: Humana Press, 1997:
103–164.
13. Gartland JJ. Orthopaedic clinical research: deficiencies in experimental design and determinations of outcome. J Bone Joint Surg Am. 1988;70:1357–
1364.
14. Gross M. A critique of the methodologies used in clinical studies of hip-joint
arthroplasty published in the English language orthopaedic literature. J Bone
Joint Surg Am. 1988;70:1364–1371.
15. INTER FIX PMA #P970015. Attachment VI.A, vol. 5. 1997:01–05.
16. Fraser RD. Interbody, posterior, and combined lumbar fusions. Spine. 1995;
20(suppl):167–177.
Point of View
H. Randal Woodward, MD
This article meets the “gold standard” for scientific studies, as it is prospective, randomized, and multicentered.
The field of clinical spinal research is difficult in part
because of the many variables present. This study attempted to limit the variables by using strict inclusion
criteria and evaluating only one variable, the merit of
cylindrical metal implants compared with cortical ring
implants. The goal of the study appears to have been
achieved by showing that the fusion rate and the clinical
outcomes using cylindrical metal implants are at least as
good as or better than those obtained with cortical ring
implants.
Interpretation of the results, however, raises the question of why the clinical outcomes are similar in the face
of fewer apparently solid fusions in the control group
(cortical rings). If the objective of surgery is to relieve
pain by elimination of motion, higher fusion rates should
result in better clinical outcomes.
1
The authors quote
Fraser,
2
implying that the anterior approach may be responsible for a better outcome than can be achieved with
the posterolateral approach. In this paper, however, the
same anterior approach was used in both study groups.
A closer look at the adverse events reported of “back
pain” and “other pain” in the control group may be
reflective of the greater number of failed unions in the
cortical ring group. This factor may not be well represented in the Oswestry or SF-36 scores. Another possible
explanation may be that despite the radiographic appearance, there may have been larger numbers of nonunions in the cylindrical metal implant group. If, indeed,
the number of solid fusions were similar in both groups;
the clinical outcomes being similar would make sense.
From the Nebraska Spine Center, Omaha, Nebraska.
The device(s)/drug(s) is/are FDA-approved or approved by corresponding national agency for this indication.
No funds were received in support of this work. No benefits in any
form have been or will be received from a commercial party related
directly or indirectly to the subject of this manuscript.
Address correspondence to H. Randal Woodward, MD, Nebraska
Spine Center, 11819 Miracle Hills Drive, Omaha, NE 68154; E-mail:
hrwoodward@nebraskaspinecenter.com
Clinical Trial of ALIF • Sasso et al 121Determination of solid fusion is often very difficult
using presently available radiographic technology. The
authors correctly used the present standard for assessment of fusion, using evidence of bridging bone, radiolucent lines, and motion studies. The fundamental difficulties with these methods are further compounded by the
variable of bone implants compared with metal implants. The radiographic assessment can be improved
using more accurate methods such as high resolution CT
scans with reconstructions (as in Figure 5E). Even this
technique is not foolproof, I would urge that future prospective studies hold to this higher standard, especially
for those whose primary outcome variable is fusion.
References
1. Vamvanij V, Fredrickson BE, Thorpe JM, et al. Surgical treatment of internal
disc disruption: an outcome study of four fusion techniques. J Spinal Disord.
1998;11:375–382.
2. Fraser, R. Interbody, anterior and combined lumbar fusions. Spine. 1995;
20(suppl):167–177.
122 Spine • Volume 29 • Number 2 • 2004