Services on Demand
- Cited by SciELO
- Access statistics
Print version ISSN 0066-782X
Arq. Bras. Cardiol. vol.84 no.3 São Paulo Mar. 2005
Cristiana Marques de Araujo; Gustavo Adolfo
B. Rando; Maria Fernanda Z. Mauro; Salvador A. B. Cristóvão; Isaac
S. Moscoso Sanchez; Adnan Ali Salman; João B. de Oliveira Neto; José
São Paulo, SP - Brazil
Hospital Beneficência Portuguesa de São Paulo
OBJECTIVE: The excellent results obtained
with sirolimus (rapamicin)-eluting stents for preventing restenosis have motivated
the evaluation of other substances with that property. Batimastat is a highly
effective metalloproteinase enzyme blocker, with the potential to reduce the
degradation of extracellular matrix and to inhibit the migration of smooth muscle
cells, with the consequent capacity to control coronary restenosis.
METHODS: From October 2001 to April 2002, 34 patients were prospectively selected with de novo lesions in a native coronary artery >50% and < 100%, which could be treated with stents of 3 to 4 mm in diameter and 18 mm in length. The primary outcome of the study was to assess the occurrence of major cardiovascular events (death of cardiac origin, acute myocardial infarction, and the need for revascularizing the target vessel) by the 30th day and fourth month; the secondary outcome of the study was to assess the rate of coronary restenosis 4 months after implantation and subacute thrombosis by the 30th day.
RESULTS: The success rate of the procedure was 97.1%. The primary outcome occurred in 2.9% and 27.2% of the patients by the 30th day and fourth month, respectively. The binary restenosis rate on angiography was 39.3%. No episode of subacute thrombosis occurred. The comparative analysis between groups with and without restenosis showed no significant difference between both, except for late luminal loss, which was greater in G-I.
CONCLUSION: Batimastat-eluting stents had a good safety profile; however, they were not effective in controlling coronary restenosis.
Key words: restenosis, coronary stent, coronary angioplasty
Coronary stents have proved to be better than balloon catheters, because they provide greater safety to the procedure, greater immediate luminal gain, and a smaller rate of restenosis 1,2. Despite these benefits, the incidence of coronary restenosis remains elevated, being > 30% in certain groups of patients 3-6.
The mechanisms involved in the appearance of restenosis are as follows: negative remodeling of the vessel, local formation of thrombus, neointimal proliferation, and excessive production of extracellular matrix 7-9.
An alteration in collagen metabolism has been shown to be probably involved in the restenosis process 10. The metalloproteinase enzyme (MP), which has the capacity to degrade collagen and other proteins, such as elastin and proteoglycans 11, facilitating the migration of smooth muscle cells, has an increased activity after injury with a balloon catheter 12-14. Thus, batimastat (BB94), a nonspecific inhibitor of that enzyme, is potentially useful in controlling coronary restenosis.
This study assessed the clinical and angiographic results of batimastat-eluting coronary stents in the treatment of coronary artery disease.
The stents used in this study were composed of stainless steel and coated with a phosphorylcholine polymer (PC) of the BiodivYsio Drug Delivery (DD) PC-Stent system of Biocompatibles, immersed in a solution containing batimastat at the dosage of 2.0 mg per mm of stent. The PC's coating has the capacity to absorb approximately 30 mg of the drug, a dose that proved effective in studies with animal models. In vitro studies have estimated the period of batimastat release at 24 days (T100%), while in vivo studies have estimated it at 28 days (T99%). The use of batimastat-eluting stents showed no evidence of systemic events in a 6-month follow-up in rats and rabbits receiving the drug intraperitoneally and undergoing balloon angioplasty.
The study protocol was approved by the committee on ethics in research, and all patients signed a written informed consent.
This study prospectively selected patients older than 18 years diagnosed with stable or unstable angina or documented silent ischemia, who had de novo lesions < 18 mm in length in a native coronary artery, and stenosis > 50% and < 100% in vessels whose diameters ranged from 3 to 4 mm. The left ventricular ejection fraction should be > 30%.
The exclusion criteria were as follows: life expectancy < 9 months; need for great surgical intervention during the 6 months studied; acute myocardial infarction within the preceding 30 days; serum creatinine values > 2.0 mg/dL; platelet count < 100,000 cells/mm3; insulin-dependent or noninsulin-dependent diabetic patients; restenotic lesions; lesions in saphenous or aorto-ostial bypass grafts; contraindications for the use of recommended medications; and, finally, patients who had participated in another investigational study with drugs or devices in the preceding 30 days.
The patients were medicated with 200 mg of acetylsalicylic acid and 75 mg of clopidogrel or 250 mg ticlopidine twice a day, initiated 3 days before the procedure. Aspirin was indefinitely maintained, and clopidogrel or ticlopidine was maintained for 3 months.
Initial laboratory assessment included the following measurements: hemoglobin, hematocrit, leukocytes, sodium, potassium, urea, creatinine, GOT, GPT, CK-MB. The 12-lead ECG was performed 24 hours before and every 8 hours after the procedure.
In the hemodynamic laboratory, after placement of the arterial introducer, heparin was administered aiming at maintaining ACT between 250 and 300 seconds. Nitroglycerin was injected intracoronarily at the dosage of 50 to 200 mg, and 2 orthogonal projections where the lesion to be treated was better visualized were filmed.
Stents were implanted after lesion predilation with a balloon catheter. Eleven-, 15-, and 18-mm-long and 3.0-, 3.5-, and 4.0-mm-diameter stents were used. We tried to maintain a balloon/artery ratio of 1:1.
The hemodynamic parameters analyzed by the investigators with digital quantitative angiography performed in a Phillips H 5000 device before and after stent implantation were as follows: minimum luminal diameter, reference diameter, percentage of stenosis, and late luminal loss. Success of the procedure was defined as a residual lesion < 10% and normal coronary flow obtainment (TIMI III).
After the procedure, the introducer was withdrawn when ACT was < 180 seconds. CK-MB measurements were taken every 8 hours. GP IIbIIIa inhibitor was not used.
Assessment of patients after 1 and 4 months included: anamnesis, physical examination, ECG, hemogram, and serum measurements of Na+, K+, urea, creatinine, GOT, and GPT.
Control coronary angiography was performed, on average, 4±1 months after stent implantation. Restenosis was considered a vessel lumen obstruction > 50%.
The primary outcome of the study was to assess the occurrence of major cardiac events (death of cardiac origin, acute myocardial infarction, and the need for revascularization of the target vessel) by the 30th day and the fourth month. Acute myocardial infarction was defined as "Q" when CKMB levels increased more than 2.5 times its normal value, and new Q waves appeared in at least 2 contiguous leads on an electrocardiogram. The acute myocardial infarction was defined as "non Q" when only the enzymatic elevation was observed.
The secondary outcomes included binary restenosis by the fourth month (stenosis > 50% of the luminal diameter) and incidence of subacute thrombosis of the stent by the 30th day.
The continuous variables were expressed as mean and standard deviation and analyzed by using the Student t test. The categorical variables were expressed as percentages and compared by using the Fisher exact test. The significance level of P<0.05 was adopted.
From October 2001 to April 2002, 34 patients underwent batimastat-eluting stent implantation. Their basic clinical characteristics are shown in table I.
The procedure was successful in 33 (97.1%) patients. In one patient, progression of the stent was not possible due to marked tortuosity of the coronary artery. As the stent could not be implanted in the lesion, the patient was excluded from the study.
One (2.9%) patient had non-Q acute myocardial infarction in the in-hospital phase. Primary outcome of eligible patients on the fourth month was 27.2%, due exclusively to the need for revascularization of the target vessel. The major adverse cardiac events are shown in table II.
Subacute thrombosis of the stent was observed neither by the 30th day, nor after 4 months. Binary restenosis by the fourth month was observed in 13 of the 33 (39.3%) eligible patients.
Because of the high restenosis rate found, and in an attempt to identify a possible determining factor, the patients were divided into 2 groups as follows: G-I, patients with restenosis; and G-II, patients with no restenosis. However, the comparative analysis showed no differences between both groups regarding the major clinical and angiographic variables associated with the restenosis process (tab. III).
The results of digital quantitative angiography, including late luminal loss (LLL), defined as the difference between the minimum luminal diameter (MLD) immediately after stent implantation and MLD in the fourth month, are listed in table IV. Significant differences were observed only in the LLL, which were greater in G-I.
Despite the use of stents, coronary restenosis has been the limiting factor of the percutaneous coronary revascularization success in the long run 1,2.
Some techniques, such as brachytherapy 15, rotational and directional atherectomy, and excimer laser 16-18, have been used to control restenosis, but with limited results.
Restenosis after stent implantation occurs as a result of the proliferation and migration of smooth muscle cells (SMC) to the vascular lumen and the excessive production of extracellular matrix19-22. The metalloproteinase (MP) enzymes involved in migration of the SMC and that belong to the group of proteinases may be subdivided into 3 classes: collagenoses, stromelysines, and gelatinases. Those enzymes can degrade the components of the extracellular matrix, including collagen, and the glycoprotein membrane, therefore, facilitating the migration of smooth muscle cells 23.
Batimastat is a low-molecular-weight mimetic peptide containing a hydroxamate group responsible by chelation of the zinc atom in the active site of the metalloproteinases, therefore inhibiting the action of that enzyme. It was initially used as an oncologic drug 24.
Studies with animals have shown that batimastat was effective in preventing both negative arterial remodeling and late luminal loss after balloon catheter angioplasty 25-27.
In this study, the use of batimastat-eluting stents proved to be safe; neither thrombosis of the stent, nor any detectable deleterious effect of the drug was observed. However, control neither of angiographic restenosis (38.2%), nor of the need for new revascularization (27.2%), was observed in the fourth month. Analysis of the subgroups of patients with and without restenosis showed no significant differences when comparing the clinical and angiographic variables.
Our results are in accordance with those of the unpublished European prospective nonrandomized multicentric study, Brillant I (batimastat anti-restenosis trial utilizing the BiodivYsio local drug delivery PC stent), which selected 173 patients with de novo lesions in native coronary arteries. Thirty days after implantation, 2 (1.2%) patients had non-Q acute myocardial infarction related to the procedure, and the 6-month angiographic control showed a binary restenosis rate of 25%.
Recent randomized studies 28-32 using sirolimus (rapamicin)- and paclitaxel-eluting stents, whose action mechanism differs from that of batimastat, had extremely favorable results, with a significant decrease in the restenosis rate and in the need for revascularization of the target lesion. The angiographic analysis and intracoronary ultrasound in one of those studies showed sustained suppression of neointimal proliferation one year after implantation33. Those findings have shown that drug-eluting stents are a safe and effective form of treatment, with the potential to change coronary artery disease therapy in the future.
Other drugs, such as stradiol34,35, tacrolimus36, and everolimus37, have been investigated with good initial results, and they may soon be available for daily use, enlarging the treatment options and contributing to reduce the cost of the procedure.
In conclusion, our results showed that batimastat-eluting stents, at the recommended dosage and with the release kinetic used, were not effective in inhibiting coronary restenosis; it even showed greater rates than those reported in the SOPHOS study 38, in which the BiodivYsio stent was used without drug elution.
1. Serruys PW, de Jaegere P, Kiemeneij F et at. A comparison of balloon-expandable-stent implantation with balloon angioplasty in patients with coronary artery disease. N Engl J Med 1994; 331:489-495. [ Links ]
2. Fischman DL, Leon MB, Baim DS et al. A randomized comparison of coronary stent placement and balloon angioplasty in the treatment of coronary artery disease. N Engl J Med 1994; 331:496-501. [ Links ]
3. Elezi S, Kastrati A, Neumann FJ et al. Vessel size and long-term outcome after coronary stent placement. Circulation 1998; 98:1875-80. [ Links ]
4. Ho KKL, Senerchia C, Rodrigues O, Chauhan MS, Kuntz RE. Predictors of angiographic restenosis after stenting: pooled analysis of 1197 patients with protocol-mandated angiographic follow-up from 5 randomized stent trials. Circulation 1998; 98:Suppl I:I-362 (abstract). [ Links ]
5. Kobayashi Y, De Gregorio J, Kobayashi N et al. Stented segment length as an independent predictor of restenosis. J Am Coll Cardiol 1999; 34:651-9. [ Links ]
6. Abizaid A, Kornowski R, Mintz GS et al. The influence of diabetes mellitus on acute and late clinical outcomes following coronary stent implantation. J Am Coll Cardiol 1998; 32:584-9. [ Links ]
7. Casscells W. Migration of smooth muscle cells: Critical events in restenosis. Circulation 1993; 86:723-9. [ Links ]
8. Aronson D, Bloomgarden Z, Rayfield EJ. Potencial mechanisms promoting restenosis in diabetic patients. J Am Coll Cardiol 1996; 27:528-35. [ Links ]
9. Shi Y, Pienick M, Fard A et al. Adventitial remodeling after coronary arterial injury. Circulation 1996; 93:340-8. [ Links ]
10. Strauss BH, Robinson R, Balchelor WB et al. In vivo collagen turnover following experimental balloon angioplasty injury and the role of matrix metalloproteinases. Cir Res 1996;79:541-50. [ Links ]
11. Dollery CM, McEwan JR, Henney AM. Matrix metaloproteinases and cardiovascular disease. Cir Res 1995; 77:863-8. [ Links ]
12. Bendeck MP, Zempo N, Clowes AW et al. Smooth muscle cell migration and matrix metaloproteinase expression after arterial injury in the rat. Circ Res 1994;75:539-45. [ Links ]
13. Zempo N, Kenagy RD, Au YP et al. Matrix metaloproteinases of vascular wall cells are increased in balloon-injured rat carotid artery. J Vasc Surg 1994;20:209-17. [ Links ]
14. Southgate KM, Fisher M, Banning AP et al. Up regulation of basement membrane degrading metaloproteinase secretion after balloon injury of pig carotid arteries. Cir Res 1996;79:1177-87. [ Links ]
15. Teirstein PS, Massullo V, Jani S et al. Catheter-based radiotherapy to inhibit restenosis after coronary stenting. N Engl J Med 1997;336:1697-703. [ Links ]
16. Mehran R, Dangas G, Mintz GS et al. Treatment of in-stent restenosis with excimer laser versus rotational atherectomy: comparative mechanisms and results. Circulation 2000;101:2484-9. [ Links ]
17. Topol EJ, Leya F, Pinkerton CA et al. A comparison of directional atherectomy with coronary angioplasty in patients with coronary artery disease. N Engl J Med 1993;329:221-7. [ Links ]
18. Gruberg L, Waksman R, Satler LF et al: Novel approaches for the prevention of restenosis. Expert Opin Investig Drugs 2000;9:2555-78. [ Links ]
19. Schwarts RS. Pathophysiology of restenosis: interaction of thrombosis, hyperplasia, and/or remodeling. Am J Cardiol 1998;81:14E-17E. [ Links ]
20. Santoian EC, King SB III: Intravascular stents, intimal proliferation and restenosis. J Am Coll Cardiol 1992;19:877-79. [ Links ]
21. Virmani R, Farb A. Pathology of in-stent restenosis. Curr Opin Lipidol 1999;10: 499-506. [ Links ]
22. Raines EW. The extracellular matrix can regulate vascular cell migration, proliferation and survival: relationshions to vascular disease. Int J Exp Pathol 2000;81:173-82. [ Links ]
23. Brown Pd. Ongoing trials with matrix metalloproteinase inhibitors. Expert Opin Investig Drugs 2000;9:2167-77. [ Links ]
24. Topper JN. Genes, matrix and restenosis. Arterioscler Thromb Vasc Biol 2000; 20:2173-182. [ Links ]
25. Jiang H, Wen G. Batimastat. J Current Opinion in Oncologic, Endocrine & Metabolic Investigational Drugs 1999;1:525-35. [ Links ]
26. De Smet BJ, De Kleijn D, Hanemaaijer R et al. Metalloproteinase inhibition reduces constritive arterial remodeling after balloon angioplasty: a study in he atherosclerotic Yucatan micropig. Circulation 2000;101:2962-67. [ Links ]
27. Sierevogel MJ, Pasterkamp G, Velema EV et al. Oral matrix metalloproteinase inhibition and arterial remodeling after balloon dilation, an intravascular ultrasound study in the pig. Circulation 2001;103:302-7. [ Links ]
28. Morice CM, Serruys PW, Sousa E et al. A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization. N Engl J Med 2002; 346: 1773-1780. [ Links ]
29. Moses JW, Leon MB, Popma JJ et al. Sirolimus-Eluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med 2003; 349:1315-23. [ Links ]
30. Schofer J, Schlüter M, Gershick AH et al. Sirolimus-eluting stents for treatment of patients with long atherosclerotic lesions in small coronary arteries: double-blind, randomized controlled trials (E-SIRIUS). Lancet 2003;362:1093-9. [ Links ]
31. Grube E, Silber S, Hauptmann KE et al. TAXUS I Six and twelve-month results from a randomized, double-blind trial on a slow-release paclitaxel-eluting stent for de novo coronary lesions. Circulation 2003;107:38-42. [ Links ]
32. Tanabe K, Serruys PW, Grube E et al. TAXUS III Trial In-stent restenosis treated with stent-based delivery of paclitaxel incorporated in a slow-release polymer formulation. Circulation 2003;107:559-64. [ Links ]
33. Sousa JE, Costa MA, Abizaid AC et al. Sustained suppession of neointimal proliferation by sirolimus-eluting stents. One year angiographic and intravascular ultrasound follow-up. Circulation 2001;104:2007-2011. [ Links ]
34. Souza JE, Abizaid A, Abzaid AS et al. Estradiol-Eluting BiodivYsio Stent to prevent restenosis: a pilot feasibility and safety study. Am J Cardiol 2002; 90 (Suppl.6A): 6-7H. [ Links ]
35. Abizaid A, Leon MB, Souza JE et al. First human experience with the 17-beta-estradiol-eluting stent (Easter-Trial). JACC 2004;43:000-00. [ Links ]
36. Trabattoni D, Antoniucci D, Fabiochi R et al. First clinical experience with the Tacrolimus-Eluting Janus Carostent in de novo coronary arteries: the Jupiter I study. Am J Cardiol 2003; 92 (Suppl.6A): 60L. [ Links ]
37. Costa RA, Lansky AJ, Mehran R et al. Everolimus-Eluting Stent for the treatment of de novo coronary lesions: B-Angiographic follow-up of the FUTURE trial. Am J Cardiol 2003; 92 (Suppl.6A): 61L. [ Links ]
38. JL Boland, A Colombo, Mangione JA et al. Multicenter evaluation of the phosphorylcholine-coated biodivYsio stent in short de novo coronary lesions: The SOPHOS study. International Journal of Cardiovascular Interventions 2000;3:215-25. [ Links ]
José Armando Mangione
Rua Comendador Elias Jafet, 415
São Paulo, SP, Brazil
Received for publication: 01/22/2004
Accepted for publication: 03/24/2004
English version by Stela Maris Costalonga