An improved process for development and testing of vena caval filters: The percutaneous steel Greenfield filter

An improved process for development testing of vena caval filters: The percutaneous steel Greenfield filter Lazar J. Greenfield, Ann

Arbor,

Mich.,

MD, Mary C. Proctor, and

Natick,

MS, and Keith R. Roberts,

and

BS,

Mass.

Background. The purpose of this study was to develop a reduced profile stainless steel Greenfield filter with an over-the-wire delivery system and to compare its pev$ownance with the existing Food and Drug Administration-approved Greenfield jilters. In addition, we wanted to standardize a system for evaluating filter prototypes. Methods. Percutaneous stainless steel Jilters with various hook configurations were evaluated for efficacy and safety in four in vitro modules designed to reproduce potential liabilities experimentally. Animal studies to assess thrombus capture and resolution, jilter stability, migration, and hemodynamics were completed in 4 dogs and 38 sheep. Results. Mathematical modeling suggested that hook angle was the most relevant factor in improving resistance to migration. Prototypes that varied with respect to hook length and angle were evaluated in both the in vitro testing unit and in sheep. The stainless steel filter with two downward directed hooks provided clot capture comparable with the current Greenfield filter, maintenance of few, and resistance to fatigue and corrosion while providing signaficant resistance to migration and penetration (p 4 0.05). Conclusions. The percutaneous stainless steel Greenfield jilter with the alternating hook design provides a reduced profile device that can be placed over a wire to improve positioning. The use of a standardized testing system reduced both the time and cost of bringing this new device to the market. (Surgery 1997;121:50-7.) of Surgery,

From the Department Scientific Corporation,

UniversiQ Mass.

Natick,

of Michigan,

1972 THE GREENFIELD vena caval filter has been used safely and effectively to prevent pulmonary embolism. Two models are currently approved for marketing by the FDA; the original 24F stainless steel filter (SGF), designed for operative insertion, and the newer, percutaneously inserted 12F titanium device (TGF-MH) (Fig. 1). Although the two differ slightly in design, they share the same low incidence of recurrent pulmonary embolism (3% to 5%) and high rate of long-term caval patency (96%).le3 Because we had achieved percutaneous insertion with the TGF-MH, we were interested in developing a delivery system that would allow for placement over a guide wire, as was possible with the SGF. One advantage of using a guide wire system is SINCE

Supported Accepted

in part by a grant for publication

Reprint requests: Lax University of Michigan, MI 48109-0346. Copyright

SURGERY

Boston

J. Greenfield, 2101 Taubman

0 1997 by Mosby-Year

0039.6060/97/$5.00tO

50

from

Scientific

Corporation.

May 1, 1996.

Book,

11/56/74679

MD, Department of Surgery, Center/Box 0346, Am Arbor, Inc.

Ann

Arbor,

Mich.,

and the Boston

improved accessibility from the left femoral vein, which traditionally has been difficult with the TGF system because of the angle at which the iliac vein joins the vena cava. In addition, having the guide wire in place at the time of discharge improves centering of the carrier system and reduces the incidence of limb asymmetry occasionally seen with the TGF when the carrier abuts the wall of the vena cava. While designing this device we developed a research plan designed to decrease the time required to bring a model from concept to market. Computer-generated mathematical models were used to identify design characteristics associated with filter performance. Standardized in vitro tests were then developed to allow early decisions regarding the performance of prototype filters. The designs with the highest probability of success then underwent experimental in vivo studies before initiation of clinical trials. The result of these efforts is the 12F percutaneous stainless steel Greenfield filter with alternating hook design (SGF-AH), which combines the advantages of the over-the-wire delivery system of the original 24F filter with the reduced profile of the titanium system. The

sl4?Y Volume

Greenfield, Proctor, Roberts 51 121,

Number

1

Fig. 1. The currently marketed Greenfield hook and percutaneous titanium Greenfield

filters. Standard 24F stainless steel filter (right) with standard filter (lefti with modified, recurved hook.

effects of the changes in apical design and the hook arrangements are the basis of this report.

MATERIAL

AND METHODS

The percutaneous stainless steel filter is produced from the same 316L stainless steel wire used in the original Greenfield filter (SGF) and retains its conical design (Fig. 2). The major change involved modification of the limb/apex attachment. The nose bead is now welded, as opposed to swaged, and the limb angle of entry at the nose bead was reduced from 1’7.5” to O”, resulting in a reduction of the device profile and an increase in the overall length. Three major hook prototypes were evaluated: the standard hook (SH), the modified hook (MH), and the alternating hook (AH). There were three variations of the modified hook and two variations of the alternating hook. These devices were evaluated with respect to their abilities to improve caval fixation and reduce the incidence of caval penetration. These changes effectively eliminated the problems of distal migration (i.e., caudal movement with respect to the initial position of the filter) and caval wall penetration while allowing for an over-the-wire delivery system of reduced profile. Mathematical modeling. The earliest percutaneous stainless steel filter prototypes (SH and MH) were found to lack adequate futation in the vena cava as a result of the increased flexibility needed to allow them to be folded into the smaller delivery capsule. This problem was addressed by developing a mathematical model to identify those factors associated with filter stability. A randomized factorial design was used to evaluate the ability of a filter to resist displacement forces. Sixteen

Fig. 2. Newly approved percutaneous steel Greenfield filter. Numbering from the left-most lateral leg, hooks on legs 1 and 4 point downward, whereas legs 2,3,5, and 6 have an upward bend to improve fixation. This pattern is referred to as alternating hooks.

52

Greenfield,

Proctor,

Rob&s January

Table

I. In vitro models Test

used in filter

evaluation

on the Embolic

Capture

Unit

Embolic capture

To determine ability of caval filter to trap experimental emboli of 5xlOmm

Caval wall displacement

To determine ability of filter to resist migration

ECU with cadaveric or silicone rubber cava of 22 and 28 mm;* 10 emboli released to challenge the filter Filters are positioned within 22 and 28 mm silicone rubber cavas and are exposed to series of lateral compressions of caval wall

Infrafilter

To determine pressures generated below a filter in response to loading with experimental emboli

Filters positioned in the ECU flow circuit and challenged with 1 to 8 gm of experimental embolic loading?

To determine ability of filter to resist migration after impact of given mass over fixed distance:

Filters positioned in inverted position and tubes of 2.3, 5, and 13 gm are delivered from

Momentum

pressure

20 mm

above

1997

(ECU)

Procedure

Purpose

SUPY

Outcome Number of escaped emboli is recorded and compared with currently marketed filter Distance that the device migrates during course of 12 challenges delivered over its length is measured and compared with rates for currently marketed filters Pressure generated at fixed distance below filter is recorded 1 and 5 minutes after delivery and compared with pressures generated below marketed filters Distance the filter moves in response to impact is recorded and compared with distance moved by marketed filters

*The ECU is run at flow rate of 2 l/min. Specific gravity of perfusate and density of emboli are maintained in same ratio of that of emboli to blood. iFour grams of emboli are equivalent to loading 70% of volume of filter. At this level, flow begins to be compromised with cone-shaped filter. :This test was designed to recreate impact on filter when struck by an embolus. It does not attempt to replicate physiologic conditions but is used simply as a means of comparing performances of devices.

trials were conducted with filters suspended in 20 mm latex tubes and submitted to sufficient force to move the filter 3 inches distally at a compression rate of 5 inches per minute. The results from these independent trials were entered into a mathematical modeling program titled ECHIP (ECHIP, Inc., Hockessin, DE) that develops regression models that relate the dependent and independent variables, allowing identification of those independent variables that are significant. The effects of various hook widths, heights, and angles and the interactions of these variables were evaluated. On the basis of the results from the ECHIP program, filter prototypes were developed that incorporated those combinations of hook length (0.035 and 0.05 inches) and hook angle (80” and 85”) most likely to improve stability. Further modeling was performed to evaluate hook interaction with a cylindrical cava in an attempt to evaluate penetration and movement (Carda; Adra Systems; Version 7.2, 1985). In vitro testing. During the initial development phase, standardized tests of the radial force exerted by the filter limbs on the vena caval wall, the stability of the filter base measurement in the face of prolonged compression at high temperatures (creep), and fatigue

testing after exposure to a corrosive environment were conducted. The methods for conducting these tests have been reported elsewhere.4 The performance of the percutaneous steel filter was compared with that of the standard filter. The devices were manufactured from the same material but under different manufacturing processes. The null hypothesis stated that the performance of the percutaneous steel filter would not differ from the performance of the standard filter. Next we studied the design of the filter hook. Evaluating prototypical filters in animals is an expensive and time-consuming process. To address this problem we developed four in vitro tests to compare the performance of prototypical filters with that of the currently available devices. The end points of the testing included resistance to downward movement in response to impact from a falling weight, resistance to movement in response to caval wall displacement, embolic trapping ability, and infrafilter pressure in response to embolic loading. An extracorporeal pump circuit, the Embolic Capture Unit (ECU), was used in our previous work5 and modified to conduct the new in vitro tests (Fig. 3). The procedures used with this circuit including embo-

Green$eld,

Surgev Volume 121, Number 1

Table II. Results of ECHIP analysis of effect of filter hook variables on resistance to distal movement p Value Independent variables Hook height Hook angle Hook flare angle Interaction of variables Hook width/flare angle Hook height/flare angle Hook angle/flare angle %tatistically

significant

when corrected

for multiple

Proctor, Roberts

33

Delivery chute

0.045 <0.03” 0.038 0.047 0.045 0.051 comparisons.

lit capture, caval wall displacement, infrafilter pressure, and impact momentum are detailed in Table I. Performance standards were established through testing of all models of the Greenfield filter by using both synthetic and cadavervena cavas. Performance was ranked and validated against results from both clinical experience with the marketed TGF-MH and SGF and earlier animal tests. Animal studies. Three major prototypes of the percutaneous stainless steel filter were studied in animals. In all cases procedures for placement and evaluation of the filters conformed with the standards approved by the Committee on the Use and Care of Animals at the University of Michigan. The first series evaluated the 12F steel filter with standard hooks (SGF-SH) in four dogs and eight sheep. Dogs were used so comparisons with the original SGF could be made, and sheep were used to achieve a more realistic caval size. The results were reported in a previous publication.” The device behaved similarly to the earliest titanium filter, exhibiting insufficient lateral force of the limbs to secure fixation allowing distal migration, angulation, and caval penetration. After modification of the hook, the next series compared the SGF-MH with the standard filters with respect to caval fixation before endothelialization. Six filters were placed in three animals through the right femoral vein, one infrarenal and one suprarenal. Emboli were formed in the filter carrier system by adding oxidized cellulose to the blood retained within the introducer sheath, forming an embolus 15 cm long and 4 mm in diameter. Five minutes after the oxidized cellulose was introduced, the thrombus was released into the iliac vein. The filter was observed under fluoroscopy during passage of the embolus to determine whether it was sufficiently fixed to the vena cava to withstand the embolic impact. Cavograms were obtained 15 minutes after embolization, and the sheep were then killed. The vena cavas and filters were examined for stability of filter fixation to the caval wall. Next, a 30-day randomized controlled trial was con-

- Inverted filter

Fig. 3. The Embolic

Capture Unit used to conduct studies of filter prototypes, thus reducing the need for preliminary animal studies. Filter is inverted for testing resistance to momentum.

ducted in 15 sheep to determine the optimal modified hook and angle design. Acute and chronic stability of three variants of the SGF-MH were evaluated in both the, infrarenal and suprarenal vena cavas. The filters differed with respect to hook length (0.035 versus 0.05 inches) and hook angle (SO” versus 85”). After deployment, anteroposterior and lateral postplacement radiographs were obtained. Studies were repeated at ‘I and 30 days after placement. Animals were killed and underwent necropsy. Before removal of each vena cava we recorded the number of hook points, hooks, and filter limbs penetrating the caval wall. The cava was removed, and the surrounding tissues were examined for evidence of penetration. The extent of migration, change in filter base diameter, and the incidence of caval penetration were determined from the radiographs at each follow-up. All radiographs were corrected for magnification.

by using

All measurements

digital

calipers

were

done

to limit

by the

systematic

same

error.

reader

The

54

Greenfield,

Proctor, Roberts Januay

RADIAL

SuvY 1997

FORCE VS. VENA CAVA DIAMETER SIMULATED STORAGE

2 0

Vena Cava

* SGF data

Fig. 4. Graph of interaction rable performances.

Width

(mm)

unavailable

between

caval diameter

null hypothesis of no difference among designs was evaluated. Further modification of the filter consisted of reversing the direction of two of the hooks (SGF-AH). The fourth animal study was conducted with this device. The purpose was to evaluate early fmation in the face of embolic loading and clot resolution during the acute and chronic periods. The experimental intervention was conducted as described above. Animals were imaged 72 hours after placement, recovered, and returned to a farm, one half for 6 months and the rest for 12 months. They were returned for anteroposterior and lateral radiographs, vena cavograms, and necropsy. The resolution of the thrombus was graded radiographically, and the caval wall was examined for evidence of a histologic inflammatory response. The purpose of the final study was to determine whether the SGF-AH provided superior fixation when compared with the filters with unidirectional hooks. The trial design was identical to the third study. Data were combined with that from the study of the SGF-MH prototypes. The behavior of the filters with respect to migration, change in filter base diameter, and penetration was then compared. Finally, we submitted caval tissue for histologic study to characterize the filter hook-

and radial force for TGF and SGF-AH shows compa-

caval wall interaction in hook configuration

to determine whether the change resulted in caval wall injury.

RESULTS Mathematical modeling. Results from the ECHIP analysis (Table II) indicated that the amount of force necessary to move the filter distally increased as a function of increasing the angle of the hook. In addition, increasing the hook width and the interaction of hook width/hook height and hook width/hook angle also improved resistance to distal movement (p < 0.05). This analysis suggested that performance of the filter with respect to resistance to distal migration could be improved by increasing the angle of the hook alongwith the hook height and flare angle (Table II). These findings were supported by results from the CADRA model, which identified hook angle and width as strongly associated. On the basis of the ECHIP analysis, filter prototypes differing with respect to hook angle, orientation, and height were developed. Because the objective was to maintain a 12F delivery system, only modifications of the hook that could be delivered with this system were considered. The resulting prototypes were tested in the in vitro system. In vitro testing. Material in vitro testing was done be-

suF-9 Volume

Greenfield, 121,

Number

Table III. Animal Device

studies

of percutaneous

of animals

No.

No.

stainless

steel Greenfield

of jltm

SGF-SH*

8 sheep 4 dogs

8 6

SGF-MHt

5 sheep

10

SGF-MH

3 sheep

6

SGF-MH

15 sheep

30

SGF-AH::

2 sheep

2

SGF-AH

5 sheep

10

Assess filter resolution

temperature

on

the

radial

the

SGF

(n = 20)

and

percutaneous

to a simulated

steel

physiologic

stability

and

clot

One half of filters penetrated cava and migrated, small amount of oxycell thrombus in apex of filter Five of 10 filters migrated from 3-9 mm, 3 of 10 penetrated vena cava, 5 of 10 increased filter base diameter by 6 mm or more All emboli were trapped within filters, 6 of 6 filters remained well fixed in vena cava No significant difference among prototypes with respect to migration, mean prototype migration from 3-7 mm; no significant difference among prototypes with respect to change in base diameter; increased caval penetration in prototype with hook length of 0.05 inches; 14 of 30 with minimal asymmetry All emboli captured by filters; 2 of 2 filters remained well fixed to cava; all filters clear at 6-mo cavogram Mean migration, 1 mm; mean increase in filter base, 2.1 mm; mean penetration score comparable with SGF-MH, 0.035 inches; 1 of 10 with minimal asymmetry

Assess acute clot trapping ability and stability of filter with embolic challenge Assess migration, penetration, and change in filter base diameter of 3 prototype SGF-MH filters with variable hook angle and length

Assess acute clot trapping ability and stability of filter with embolic challenge and long-term clot resolution Assess migration, penetration, and change in filter base diameter and symmetry of alternating hook design

force

of

the

SGF-AH and the TGF-MH was studied and found to be comparable; results indicated 5.0 and 4.5 gm of radial force, respectively, were exerted. The final set of material studies involved determining the fatigue life of the percutaneous steel filter when subjected to a simulated physiologically corrosive environment. Comparison of after exposure

55

Outcome

Assess migration, penetration, and change in filter base diameter

fore use of the mathematical model and revealed that design and material changes to the percutaneous steel filter had not affected its performance characteristics compared with the original SGF and titanium Greenfield filters. The device exhibited a radial force at a caval diameter of 21 mm that was nearly identical to the SGF and only slightly greater than the TGF-MH (Fig. 4). In a second set of studies the effect of prolonged compresat high

Roberts

filter

Purpose

*12F stainless steel filter with six upward directed hooks. t12F stainless steel filter with six upward directed 80” recumed hooks. $12F stainless steel filter with four upward directed 80” recurred hooks and two recurred

sion

Proctor,

1

filters

(n = 20)

corrosive

en-

downward

vironment ference.

directed

hooks

failed to reject the null hypothesis These

same

devices

then

underwent

of no difone

mil-

lion cycles of fatigue testing without failure. Table I summarizes the testing each filter prototype was subjected to in the ECU. Migration of the percutaneous stainless steel filter remained a problem. The prototypes differed with respect to angle, length, and orientation of the hooks. The design that showed the greatest resistance to migration was the SGF-AH, which had six hooks with a length of 0.035 inches, two ofwhich were oriented downward, whereas the other four were directed upward. Compared with the SGF-MH, the mean movement was 5.19 mm versus 14.9 mm (p < 0.00001). When all of the prototypes were grouped by hook orientation, a significant difference existed between those with an alternating orientation versus those with upward directed hooks (p = 0.0004). When the ef-

56

Greenfield,

Proctor, Roberts January

Fig. 5. Transverse section through

a wire void with myointimal

feet of the number of alternating hooks (3 up/3 down versus 4 up/2 down) was compared, the 4/2 configuration was statistically superior (p < 0.01). We failed to reject the null hypothesis of no difference between the SGF-AH and the marketed Greenfield filters with respect to the ability to capture thrombi in the ECU that were 5 x 10 mm (p> 0.05). Finally, we compared the pressure generated below the three types of Greenfield filters when they were filled with 1 to 8 gm of experimental emboli composed of chicken fat. Four grams of emboli occluded 70% of the filter; at that point the conical geometry of the Greenfield filter loses its advantage in preventing caval stenosis or occlusion. The null hypothesis of no difference in the infrafilter pressure could not be rejected when the three types of Greenfield filters were compared (p = 0.07). This series of tests failed to show a difference in function among the SGF-AH, SGF, and TGF-MH with respect to the ability of the filter to trap emboli and to maintain flow when filled with thrombus to 70% of its volume. In addition, SGF-AH was superior to all of the prototypes with respect to resistance to caval migration. Animal studies. A total of 72 percutaneous stainless steel filters were placed in 42 animals (38 sheep and 4 dogs). In all cases the device performed well as a filter, but the first two iterations, the SGF-SH and the SGF-MH, had a higher degree of migration than that associated with the SGF and the TGF-MH. Table III lists each of the animal trials, their purposes, and their outcomes. The results of these studies correlated well with the in vitro models and predicted the outcomes from the Investigational New Device (IND) clinical study. Gross examination of the histologic samples from two sheep obtained 1 year after implant of the SGF-AH indicated excellent incorporation of all limbs. There was

tissue filling

SW&F9 1997

the area beyond the wire.

no evidence of thrombus within the filter. Light microscopy indicated normal myointimal encapsulation despite some disruption of the media (Fig. 5). Results from the immunochemistry assays revealed a positive factor VIII test, indicating myointimal endothelial coverage; the HHF-35 was strongly positive, which is associated with proliferating myointimal smooth muscle cells. The final design, the SGF-AH, was found to meet or exceed the performance of the marketed Greenfield filters. It was taken into clinical trials during 1994 and, after successful completion of the clinical study, was approved for marketing by the Food and Drug Administration in June 1995.

DISCUSSION Although there are no established standards for preclinical testing of vena caval filters, a well-designed research and development plan should include mathematical models and both in vitro and in vivo studies. If well planned, this combination should provide the most cost-effective and expeditious approach to approval of an improved device. In addition, a balanced research plan that uses validated modeling and in vitro testing will conserve scarce animal resources by limiting the number of necessary in vivo studies. In fact, this has not always occurred. The consequences have been unfortunate for some patients, especially in countries that grant approval without adequate long-term testing. We have even seen examples in our own country of filters released under a 510 K (a Food and Drug Administration marketing application) that appeared comparable to the Greenfield filter to which each was compared but were shown to be inferior when monitored during an extended period.’ During a time when biomedical research funds are being severely limited, industrial sponsors are establish-

Surgery Volume

Greenfield, 121, Number

Proctor, Roberts 37

1

ing working relationships with. academic investigators to develop and evaluate new technology. The SGF-AH is an excellent example of such a collaboration. The joint efforts of the bioengineers of the Medi-Tech division of Boston Scientific Corporation and the Greenfield Vascular Research Laboratory led to an expedited development and evaluation process. If the standardized in vitro tests and mathematical modeling capabilities had been in place at the initiation of this study, we could have begun clinical trials at least 18 months earlier and reduced the number of animals by 20, which would have resulted in a savings of nearly $100,000 in preapproval testing. The mathematical modeling identified characteristics of filter design associated with stability. The standardized in vitro testing system allowed the evaluation of multiple prototypes in a short period of time, preventing delays from following blind alleys. The in vivo studies provided confirmation of the data obtained from the modeling and in vitro studies and allowed investigation of the histologic effects of the device on the vena cava, as well as any thrombogenic effects of material or design changes. We were able to significantly reduce the design phase and the number of animal

studies, thus allowing ample time to study the long-term performance in the sheep model. The result was a new vena caval filter that offers the traditional safety and efficacy associated with the Greenfield filter in addition to the ease of insertion associated with a reduced profile, over-the-wire delivery system. REFFXENCES 1, Greenfield LJ, Proctor the titanium Greenfield

MC, Cho KJ, et al. Extended evaluation of vena caval filter. JVasc Surg 1994;20:458-

65. 2. Greenfield

LJ, Michna

B. Twelve-year

Greenfield 3. Greenfield

vena caval filter. Surgery 1988;104:706-12. LJ, Cho KJ, Proctor MC, et al. Results of a multicenter

study of the modified

hook

titanium

1991;14:253-7. 4. Greenfield LJ, Savin M. Comparison

clinical

Greenfield

neous raphy.

Greenfield LJ, Tauscher

stainless Surgery

with the

filter. JVasc

of titanium

steel Greenfield vena caval filters. Surgery 5. Greenfield LJ, Proctor MC. Experimental asymmetric 6. Greenfield

experience

and

Surg

stainless

1989;106:820-8. embolic capture

by

filters. J Vast Surg 1992;16:436-44. J, Marx V. Evaluation of a new percuta-

steel Greenfield 1991;109:722-9.

7. Crochet DP, Stora 0, Ferry term results of a prospective

filter by intravascular

ultrasonog-

D, et al. Vena Tech-LGM filter: longstudy. Radiology 1993;188:857-60.