23 Biodegradable Stents

Biodegradable Stents

Takafumi Tsuji, ^MD , Hideo Tamai, MD , and Keiji Igaki, PhD

C

ONTENTS

T

^HE

R

^{OLE OF}

S

^{TENTS IN}

P

ERCUTANEOUS

C

^ORONARY

I

NTERVENTION

H

ISTORY OF THE

B

IODEGRADABLE

S

^TENT

H

ISTORY OF THE

I

^GAKI

–T

^AMAI

S

^TENT

A

PPLICATION OF THE

I

GAKI

–T

AMAI

S

TENT TO

H

UMAN

C

ORONARY

A

RTERIES

T

IME

-C

OURSE OF

IVUS F

INDINGS

A

FTER

I

MPLANTATION OF THE

I

GAKI

–T

AMAI

S

TENT

C

ONCLUSIONS

R

EFERENCES

23

THE ROLE OF STENTS IN PERCUTANEOUS CORONARY INTERVENTION

Percutaneous coronary intervention (PCI) is indispensable in the treatment of ischemic heart disease. In the early days of conventional balloon angioplasty, acute coronary occlusion as a result of coronary dissection or vessel recoil was observed immediately after PCI, and initial results were not satisfactory. Moreover, the long- term restenosis rate was 30–40%, and the recurrence of angina was a problem. In order to solve these problems, Sigwart et al. (1) developed a metallic stent, which was used clinically for the first time in 1986. As this pioneering work, the use of stents has become routine in the practice of PCI. Metallic stents are very effective in the preven- tion of acute coronary occlusion by coronary dissection or recoil of a vessel.

Furthermore, the results of large clinical trials, such as STRESS and BENESTENT, suggested that metallic stents are also effective in the prevention of chronic restenosis (2,3). Despite the success that has been achieved with metallic stents, there are also some important limitations. There is a risk of subacute thrombosis (SAT) until endothe- lial cells cover the surface of the metallic stent. Although the frequency of SAT has been lowered by the use of antiplatelet agents, such as ticlopidine, for at least 1 mo after stent implantation, SAT has not been completely eliminated. Moreover, in-stent restenosis in a complicated coronary lesion poses a significant clinical problem especially

From: Contemporary Cardiology: Essentials of Restenosis: For the Interventional Cardiologist Edited by: H. J. Duckers, E. G. Nabel, and P. W. Serruys © Humana Press Inc., Totowa, NJ

369

370 Part IV / Therapy of Restenosis

with the expanding use of PCI to treat ischemic heart disease. Stents are thought to be required for about 12 mo to prevent lumen narrowing in response to chronic vessel remodeling. As metallic stents remain permanently implanted, there is concern about the deleterious effects of stents on the coronary vessels that may take several years to develop. Furthermore, metallic stents may serve as an obstacle for the treatment of in- stent restenosis.

HISTORY OF THE BIODEGRADABLE STENT

Although stents made from biodegradable polymers, have been proposed for many years in order to overcome the limitations of metallic stents, progress in this area has been slow and biodegradable stents have not achieved widespread acceptance. Stack et al. (4) of Duke University developed the first biodegradable stent in the early 1980s.

After these investigators tested several polymer materials, they produced a polymer stent made from poly-

L

-lactic acid (PLLA), and implanted the PLLA stents in the femoral artery of 11 dogs. Although in-stent occlusion was observed in one animal within 18 mo, stent thrombosis and neointimal hyperplasia were rarely observed in the other animals. Subsequently, many studies on the polymer stent were performed, and research that questioned the biocompatibility of PLLA was presented as the joint effort of three prominent institutions from 1992 to 1996 (5). Although biocompatibility of PLLA material was already widely accepted in orthopedic procedures at that time (6–9), biocompatibility of PLLA for the coronary arteries was regarded as problematic.

Thereafter, polymer stents were developed using various materials with results that were not as good as metallic stents and thus, polymer stents were never used clinically.

HISTORY OF THE IGAKI–TAMAI STENT

Initially, Tamai et al. selected polyglycolic acid (PGA) as a material for the polymer stent. PGA is a polymer that is hydrolyzed in the body and biodegraded within 3 mo, and the clinical utility of this material had already been demonstrated in applications, such as biodegradable sutures. The thread of PGA was woven in the shape of a mesh, and the PGA polymer stent was produced. A PGA stent was successfully implanted in dog coro- nary arteries for the first time in 1993, and in pig coronary arteries in 1994. In the study of dog coronary arteries, a PGA stent was implanted in the left anterior descending artery in 25 dogs, and coronary angiography (CAG) and pathological observation were per- formed up to 24 wk later. Thrombus occlusion of the stent was not observed in the coro- nary angiograms, and percent diameter stenosis (%DS) reached a maximum of 26% by the fourth week of follow-up. There was mild neointimal hyperplasia and a very slight foreign body reaction in the postmortem pathological examination.

Moreover, in the animals with 24 wk of follow-up, biodegradation of the stent strut was complete and inflammation was not observed. In contrast to these results, in the pig coronary arteries the PGA stent produced advanced stenosis and was insufficient as a stent. It is thought that pig coronary arteries have a restenosis response that is closer to human coronary arteries than dog coronary arteries. Therefore, it was decided to continue research using pig coronary arteries. As the peak of in-stent restenosis occurs within 6 mo in human coronary arteries, the stent material was changed to PLLA and additional stents were implanted in pig coronary arteries. PLLA is a polymer, which is hydrolyzed in the body and biodegraded within 24 mo. Although the mechanical

23_Igaki 6/15/07 5:08 PM Page 370

strength of the biodegradable polymer stent is weakened as hydrolysis progresses, the mechanical strength of the PLLA stent is maintained for 12 mo after implantation.

Initially, the PLLA polymer stent was woven from the thread of PLLA in the shape of a mesh and implanted in pig coronary arteries. The results were not satisfactory because neointimal hyperplasia was very high, peaking by the fourth week.

Histological examinations at the site of restenosis showed that neointimal hyperpla- sia was proportional to the degree of injury to the vessel wall, and it was thought that the cause of restenosis was vessel injury at the time of stent implantation. Subsequent to this work, a PLLA self-expanding coil stent (Igaki–Tamai stent, Fig. 1) was devel- oped and research was resumed using pig coronary arteries (10). Fourteen Igaki–Tamai stents and nine Palmaz-Schatz stents were implanted in pig coronary arteries and serial CAG was performed. In the sixth week, there was no significant difference in minimal lumen diameter (MLD) (2.18 ± 0.84 mm vs 2.30 ± 0.58 mm, p = 0.82) and %DS (24.2

± 19.8% vs 15.9 ± 15.6%, p = 0.49) between Igaki–Tamai stents and Palmaz–Schatz stents. The histological findings in pigs with the Igaki–Tamai stent showed that the lumen was large and there was mild neointimal hyperplasia in the second, sixth, and sixteenth week (Fig. 2).

APPLICATION OF THE IGAKI–TAMAI STENT TO HUMAN CORONARY ARTERIES

The Igaki–Tamai stent is a self-expanding biodegradable polymer stent made from

the thread of PLLA with a zigzag helical coil design. The thickness of the stent strut is

0.017 mm (0.007 in.), and the stent length is 12 mm. The stent is mounted on a balloon

with a covered sheath and implanted at the lesion site by balloon expansion. Clinical

application of the Igaki–Tamai stent was carried out for the first time following approval

of the Ethics Committee of the hospital and written informed consent in September

1998. Ultimately, 84 PLLA stents were implanted in 63 lesions in 50 patients through

Fig. 1. The Igaki–Tamai stent is a self-expanding biodegradable polymer stent made from the thread of PLLA with the zigzag helical coil design.

April 2000 (11). CAG (Fig. 3) and intravascular ultrasound (IVUS) (Figs. 4 and 5) were performed before and immediately after the procedure. Additional assessment by quantitative CAG and intracoronary ultrasound was performed 1 d, 3 mo, 6 mo, and 12 mo after the procedure. Aspirin (81 mg/d) and ticlopidine (200 mg/d) were administered as antiplatelet therapy for at least 1 mo after stent implantation.

Although stent implantation was successful in all cases, there was SAT in one case, and thus the in-hospital success rate was 98%. No other thrombotic occlusions were observed over 12 mo of follow-up. Major adverse cardiac events were evaluated and the major adverse cardiac events-free survival rate including target lesion revascularization was 84.2%. In the analysis by quantitative CAG, the reference diameter was 2.95 ± 0.46 mm

372 Part IV / Therapy of Restenosis

Fig. 2. The histological findings after implantation of the Igaki–Tamai stent in pig coronary arteries.

Findings are shown at 2, 4, and 16 wk after implantation.

Fig. 3. Representative case. Coronary angiograms are displayed of the proximal right coronary artery in a 62-yr-old male. Angiograms are shown before the procedure, immediately after the procedure, and at 3, 6, 12, and 24 mo later.

23_Igaki 6/15/07 5:08 PM Page 372

Fig. 4. Representative case. IVUS images of the proximal right contrary artery in a 62-yr-old male. Images are shown before the procedure, immediately after the procedure, and at 3, 6, 12, and 24 mo later.

Fig. 5. Restenosis and TLR rates.

and the lesion length was 13.5 ± 5.7 mm. MLD before the procedure was 0.91 ± 0.39 mm,

and the DS was 69 ± 13% MLD was 1.76 ± 0.74 mm and 2.16 ± 0.52 mm at 6 and 12 mo

after the procedure, respectively. The DS was 38 ± 22% and 29 ± 13% at 6 and 12 mo,

respectively. The restenosis rate was 20 and 17%, and the target lesion revascularization

rate was 11 and 13% at 6 and 12 mo, respectively. These results are equivalent to those

achieved with conventional metallic stents (Tables 1 and 2).

TIME-COURSE OF IVUS FINDINGS AFTER IMPLANTATION OF THE IGAKI–TAMAI STENT

IVUS images of the Igaki–Tamai stents after implantation were similar to IVUS images of conventional metallic stents; there was high-echo contrast accompanied by multiple reflections where the stent struts made contact with the vessel wall. IVUS images 6 mo after implantation revealed neointimal hyperplasia inside the stent, but the stent struts still showed high-echo contrast. In the 19 patients that had serial IVUS through 24 mo of follow-up, the vessel area (VA) was 16.3 mm

²

, the stent area (SA) was 6.8 mm

²

, the lumen area (LA) was 4.7 mm

²

, the plaque + media area (P + M) was 9.5 mm

²

, and the neointimal area (NI) was 2.1 mm

²

at 6 mo. At 12 mo of follow-up, the VA was 15.6 mm

²

, the SA was 6.8 mm

²

, the LA was 5.3 mm

²

, the P + M was 8.7 mm

²

, and the NI was 1.5 mm

²

. At 24 mo, the stent struts were difficult to distinguish with IVUS suggesting that the majority of the stent had biodegraded. A paired t-test showed that there were no significant changes in the VA and SA from 6 to 12 mo. However, the LA showed a tendency to expand (p = 0.060), and the P + M area and NI area were reduced significantly (p = 0.011 and p = 0.021, respectively) from 6 to 12 mo. These results indicate that the neointima was decreased by the time the stent biodegraded and suggest that biodegradation of the stent did not cause new neointimal hyperplasia. There was no reduction of the VA because of remodeling; the lumen was maintained, and the reduction of the intensity of the stent accompanying biodegradation did not have a neg- ative influence on the lumen area.

374 Part IV / Therapy of Restenosis

Table 2 One-Year Results

Death : 0

QMI : 1/50

^a

(2%)

CABG : 0

Stent thrombosis :1/50

^a

(2%)

Re-PCI

6 mo : 6/50 (12%)

12 mo : 7/50 (14%)

MACE-free rate (Kaplan-Meier) : 84.2%

aSame patient.

Table 1 In-hospital Results Initial success

Procedure success : 84/84 (100%) Lesion success : 63/63 (100%) Clinical success : 49/50 (98%) Complications

Death : 0

QMI : 1/50

^a

(2%)

Energent CABG : 0

Re-PCI : 1/50

^a

(2%)

Bleeding : 0

aSame patient.

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CONCLUSIONS

The Igaki–Tamai stent is a biodegradable polymer stent made from PLLA and has been shown to function adequately as a coronary stent. Recently, drug-eluting stents, which are coated with drugs, such as sirolimus (12) and paclitaxel (13), have received a great deal of attention for their potential ability to prevent restenosis. The drug- eluting stent has a polymer coating attached to the metallic stent and the drug is con- tained in the polymer coating. As the Igaki–Tamai stent is made up entirely of polymer, this stent can hold more amount of drug than the polymer-coated metallic stent. Therefore, further prevention of restenosis can be expected with the develop- ment of a drug-eluting Igaki–Tamai stent. Additional research will be required to determine if biodegradable polymer stents can produce a dramatic improvement in the clinical results of PCI.

REFERENCES

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WB Saunders, Philadelphia, PA, 1994, pp. 787–802.

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7. Schakenraad JM, et al. Enzyme activity toward poly (L-lactic acid) implants. J Biomed Mater Res 1990;24:529–545.

8. Bos RRM, et al. Resorbable poly (L-lactide) plates and screws for the fixation of zygomatic frac- tures. J Oral Maxillofac Surg 1987;45:751–753.

9. Suganuma J, et al. Biological response of intramedullary bone to poly-L-lactic acid. J Appl Biomat 1993;4:13–27.

10. Tamai H, et al. A biodegradable poly-L-lactic acid coronary stent in the porcine coronary artery.

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12. Regar E, et al. Angiographic findings of the multicenter Randomized Study With the Sirolimus- Eluting Bx Velocity Balloon-Expandable Stent (RAVEL): sirolimus-eluting stents inhibit restenosis irrespective of the vessel size. Circulation 2002;106:1949–1956.

13. Liistro F, et al. First clinical experience with a paclitaxel derivate-eluting polymer stent system implantation for in-stent restenosis: immediate and long-term clinical and angiographic outcome.

Circulation 2002;105:1883–1886.