This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by von Essen, R. Articles by Weidinger, G. Search for Related Content PubMed PubMed Citation Articles by von Essen, R. Articles by Weidinger, G.

(Circulation. 1997;96:1482-1487.)
© 1997 American Heart Association, Inc.

Articles

Effects of Octreotide Treatment on Restenosis After Coronary Angioplasty

Results of the VERAS Study

Rainer von Essen, MD; Ralf Ostermaier, MD; Eberhard Grube, MD; Wolfgang Mäurer, MD; Ulrich Tebbe, MD; Raimund Erbel, MD; Michael Roth, MD; Werner Oel, MD; Joachim Brom, PhD; Gottfried Weidinger, PhD; ; for the VERAS Investigators

From Stiftsklinik Augustinum (R. von E., R.O., M.R., W.O.), München; Krankenhaus Siegburg (E.G.); Klinikum Bayreuth (W.M.); Klinikum Lippe-Detmold (U.T.); Universitätsklinikum Essen (R.E.); and Sandoz (J.B., G.W.), Nürnberg, Germany.

Correspondence to Rainer von Essen, MD, Klinik für Innere Medizin, Stiftsklinik Augustinum, Wolkerweg 16, 81375 München, Germany.

	Abstract

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
Background The VERAS study (VErringerung der Re- stenoserate nach Angioplastie durch ein Somatostatin-analogon [Prevention of Restenosis Following Angioplasty With a Somatostatin Analogue]) was a placebo-controlled trial to evaluate the effects of octreotide for the prevention of restenosis after coronary angioplasty. Octreotide is a somatostatin analogue with antiproliferative properties on smooth muscle cell growth in vitro that limits myointimal thickening of arteries in balloon injury models.

Methods and Results Patients received either octreotide or placebo, starting 1 hour before angioplasty and continued for 3 weeks. The minimal luminal diameters before and after angioplasty and at 6-month follow-up were analyzed with a digital quantitative algorithm. Of the initial 274 patients recruited, 217 (108 in the octreotide group and 109 in the placebo group) could be analyzed after a complete 6-month evaluation: the minimal luminal diameters were 1.67±0.57 mm in the oc-treotide-treated group and 1.66±0.64 mm in the placebo group (two-paired P=.70), and the relative losses were 0.16±0.22 and 0.13±0.21 (two-paired P=.27). The restenosis rates were also identical in both treatment groups: final diameter stenosis 50% (34.3% versus 33.9%, two-paired P=1.0), loss of 50% of the initial gain (34.3% versus 33.9%, two-paired P=1.0), and absolute reduction of minimal luminal diameter >0.72 mm (29.6% versus 24.8%, two-paired P=.45). Likewise, there was no difference with regard to the incidence of clinical events (death, myocardial infarction, bypass operations, reintervention). Octreotide was well tolerated, with the exception of gastrointestinal side effects, which were three times more common than in the placebo group.

Conclusions Octreotide did not reduce the angiographically determined restenosis rate or the incidence of major clinical events after coronary angioplasty.

Key Words: angioplasty • restenosis • octreotide

	Introduction

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
Recurrence of stenosis after PTCA is the major limitation of its long-term success.¹ Restenosis varies in most series from 30% to 50% and occurs predominantly within the first 6 months. The pathophysiological mechanisms of restenosis are complex, but experimental and clinical data strongly suggest intimal hyperplasia as a key mechanism. Vascular injuries induced by the balloon dilation initiate the intimal proliferation of SMCs via the release of growth factors.^{2 3 4} The most important mediators of SMC proliferation are PDGF, IGF-1, bFGF, EGF, TGF-ß, and angiotensin II.^{5 6} The receptors of all these growth factors share the common feature of a tyrosine kinase domain.⁷ Binding results in activation of the tyrosine kinase with subsequent autophosphorylation of the receptor inducing the mitogenic response of the cell.⁸ Deactivation of these growth factor receptors involves specific tyrosine phosphatases.^{9 10} The growth-inhibitory peptide somatostatin as well as its long-acting analogues octreotide and angiopeptin have been found to stimulate tyrosine phosphatase activities and dephosphorylate growth factor receptors correlating with their inhibitory effect on the growth of normal and tumor cells, including SMCs.^{11 12} In addition to this local effect, octreotide has a systemic antiproliferative property demonstrated by the inhibition of the growth hormone/IGF-1 axis. IGF-1, which seems to be a crucial factor for SMC proliferation, is inactivated by multiple binding proteins in plasma. Octreotide and angiopeptin stimulate these regulatory binding proteins, resulting in reduced IGF-1 activity.^{13 14} Octreotide as well as angiopeptin inhibits the proliferation of cultured human coronary artery SMCs and reduces neointimal thickening after balloon injury in various animal models.^{15 16 17 18 19}

The impact of octreotide on restenosis in patients with angioplasty has not been tested; therefore, the purpose of the VERAS trial was to determine whether systemic therapy with octreotide for 3 weeks initiated before coronary angioplasty would decrease the extent or the incidence of restenosis assessed by QCA after 6 months.

	Methods

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
Study Population
All consecutive patients scheduled for PTCA with an angiographically documented significant stenosis in one or more epicardial coronary arteries were eligible for this study in seven centers (see "Appendix"). Between September 1993 and December 1994, 274 patients who met the inclusion and exclusion criteria listed below were recruited. The study was approved by the institutional ethics committees and was carried out according to the Declaration of Helsinki; all patients gave written informed consent.

Criteria for Inclusion in the Study
Patients between 21 and 75 years with angiographically proven, significant coronary artery disease (stenosis 50% luminal diameter) amenable to PTCA could participate. Patients with their first restenosis after PTCA could be included. Patients with severe congestive heart failure (ejection fraction <40%), a myocardial infarction within the previous 2 weeks, or another major illness were excluded from the study. Other criteria for exclusion were the inability to follow the protocol, previous CABG, a history of gastrointestinal bleeding within the past 3 months, a history of a cerebrovascular incident, insulin-dependent diabetes mellitus, and hypersensitivity to octreotide. Women of child-bearing potential and participants of other trials within the past 8 weeks were also excluded.

Randomization and Treatment Protocol
Patients were randomly assigned to receive subcutaneous injections of 500 µg octreotide or placebo every 8 hours for 3 weeks. The first injection had to be given 1 hour before the PTCA; 274 patients formed the intention-to-treat population. Of these, PTCA was not possible or not successful (eg, guide wire could not be passed or bail-out stent implantation) in 15 patients. Nineteen patients discontinued treatment because of (mainly gastrointestinal) adverse events, 11 patients withdrew their informed consent, and 4 patients refused the angiographic follow-up. For 8 patients, evaluation by QCA was not possible. Therefore, completed clinical and angiographic follow-up could be obtained in 217 patients.

Concomitant therapy consisted of aspirin, nitrates, ß-blockers, calcium antagonists, ACE inhibitors, and lipid-lowering drugs if indicated. Heparin was not allowed in addition to the dose specified during the PTCA procedure.

Follow-up Protocol
Routine follow-up angiography was performed at 6 months; when symptoms recurred within the follow-up period, coronary angiography was carried out earlier (when no definite restenosis was present and the follow-up time was <5 months, the patient was asked to undergo another coronary angiogram at 7 months). The compliance was judged by counting the remaining ampoules, inspection of injection sites, and questioning.

PTCA Procedure
A bolus of 10 000 U heparin was given initially, and an additional bolus of 5000 U was administered if the procedure took >60 minutes. Choice of balloon type, inflation duration, and pressure was left to the operator. Nitroglycerin (0.3 mg IC) was given before imaging. Three coronary angiograms were obtained and compared immediately before and after PTCA and after the follow-up procedure at 6 months (including a baseline and follow-up left ventricular angiogram). PTCA was considered successful if the reduction in the percentage of vessel diameter stenosis was 20%, the post-PTCA percentage of vessel diameter stenosis was <50%, and no severe complications related to angioplasty occurred. The angiographic views of the patients were documented and kept constant.

Angiographic Analysis and Predefined Criteria for Restenosis
Stenosis was measured in two (right coronary artery) or six (left coronary artery) near-orthogonal views after intracoronary administration of nitrates. Whenever possible, end-diastolic frames were analyzed, and the views were chosen that showed the stenosis best. The clinically most relevant lesion was defined as the "target lesion" after the initial diagnostic angiography and before randomization at the discretion of the investigator; only the target lesion was considered in the analysis described below.

Angiographic analysis was performed in the QCA core laboratory in a blinded fashion by means of a digital quantitative algorithm (QANSAD). This centerline method is described in detail elsewhere.²⁰ After the original calibration, the x-ray tube patient distance was used for standardization. The edge contour of the segment of interest was automatically detected and measurements of the most stenotic diameter (MLD) were made; then, the prestenotic and poststenotic segments were defined and measured, and percent stenosis was calculated for each view.

Restenosis was defined as^{1 21} final percentage of vessel diameter stenosis 50%, loss of 50% of the gain in the percentage of vessel diameter stenosis achieved at PTCA, and absolute loss of >0.72 mm of MLD.

The morphology of the stenosis was classified according to American College of Cardiology/American Heart Association classification of lesion type.

End Points
The primary end point of this study was the within-patient change in MLD related to the interpolated reference diameter as determined by QCA after PTCA and at follow-up. The following calculations were performed: relative gain, MLD_post-PTCA minus MLD_pre-PTCA/reference diameter; net gain index, MLD_follow-up minus MLD_pre-PTCA/reference diameter; and relative loss, MLD_post-PTCA minus MLD_follow-up/reference diameter.

Secondary end points were the restenosis rate according to the three definitions mentioned above as well as the incidence of clinical events such as death, myocardial infarction, CABG, or repeat PTCA.

Statistical Analysis
The required sample size was calculated to achieve a statistical significant difference with respect to the reduction of relative loss values from 0.11±0.15 (mean±SD) in the control group to 0.05±0.15 (mean±SD) with octreotide medication (two-sided test with =0.05 and ß=0.20). For safety/tolerability analysis, all randomized patients were included who received at least one dose of medication and had at least one post-baseline safety evaluation. For efficacy analysis, intention-to-treat and per-protocol populations were defined: the intention-to-treat population comprised randomized patients who received at least one dose of medication, and the per-protocol population consisted of all randomized patients who completed the planned duration of treatment; had valid baseline, post-PTCA, and repeat angiographies; and did not violate the protocol in any way liable to influence efficacy outcome. Continuous variables were compared by the U test (Wilcoxon-Mann-Whitney), qualitative variables were analyzed by the ² test; and Fisher's exact test was used to compare restenosis rates between both treatment groups.

	Results

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
The baseline clinical and angiographic characteristics of the 274 randomized patients (137 patients in each group) are summarized in Tables 1 and 2. All baseline characteristics were evenly distributed, so the two treatment groups were absolutely comparable.

View this table: [in this window] [in a new window]   Table 1. Demographic and Clinical Characteristics of the Total Patient Population

View this table: [in this window] [in a new window]   Table 2. Angiographic Characteristics of the Total Patient Population

Before angioplasty, the percentage of stenosis of the vessel to be dilated was 67.8±11.6% (MLD, 1.01±0.48 mm) for patients treated with octreotide (n=108 patients with angiographic follow-up) and 68.1±13.2% (MLD, 0.94±0.41 mm) for patients in the placebo group (n=109). Immediately after PTCA, the percentages were 30.4±11.9% (MLD, 2.15±0.54 mm) and 31.6±12.1% (MLD, 2.04±0.51 mm), respectively. At 6-month follow-up, the percentage of residual stenosis was 44.0±16.1% (MLD, 1.68±0.58 mm) in the octreotide-treated group and 42.5±18.6% (MLD, 1.66±0.64 mm) in the placebo-treated group (Figure). Therefore, no difference in vessel stenosis between the two groups was demonstrated. The interpolated reference diameters were 3.06±0.66 mm before PTCA and 3.12±0.67 mm after PTCA for patients in the octreotide group and 2.97±0.67 and 2.98±0.58 mm, respectively, for patients in the placebo group. At follow-up, the interpolated reference diameters shifted slightly to 2.99±0.68 and 2.88±0.66 mm, respectively.

View larger version (28K): [in this window] [in a new window]   Figure 1. MLD (in mm; top) and respective percent stenosis (bottom) of the dilated vessels before PTCA, after PTCA, and at follow-up at 6 months (mean±SD). Black bars indicate octreotide group (n=108); gray bars, placebo group (n=109).

Relative gain, relative loss, and net gain index are presented in Table 3; there were no statistically significant differences between the octreotide and the placebo group. Restenosis per patient was defined according to the three different criteria listed above. Restenosis at follow-up defined as final percent stenosis 50% occurred in 34.3% in the octreotide group and 33.9% in the placebo group. Likewise, on the basis of the second definition (loss of 50% of initial gain), the restenosis rates were 34.3% versus 33.9%, respectively. On the basis of the third definition (absolute loss of >0.72 mm), the restenosis rates were 29.6% versus 24.8% (Table 4). All differences were not significant, and there was a good correlation among all three criteria used.

View this table: [in this window] [in a new window]   Table 3. Angiographic Findings at Follow-up

View this table: [in this window] [in a new window]   Table 4. Restenosis Rates According to Three Definitions

Table 5 summarizes the incidence of major clinical events during the follow-up period of 6 months. Primary clinical end points were death, myocardial infarction, CABG, and repeat intervention. Reinterventions were considered only when their need was based on clinical symptoms and premature angiographic evaluation; the necessity for reintervention obtained as a result of routine angiography at 6 months was not considered. The distribution of these events was nearly identical between the two groups. As expected, repeat PTCA was the most frequent event. One patient died because of an allergic reaction to contrast media application during repeat angiography, so there was no relation to drug administration.

View this table: [in this window] [in a new window]   Table 5. Incidence of Clinical Events During the Follow-up Period of 6 Months

Side effects (Table 6) were mainly gastroenterological, as expected: 57 patients in the octreotide group complained of diarrhea (compared with 19 in the placebo group), 15 versus 10 of nausea, 8 versus 2 of vomiting, 8 versus 6 of bloating, and 16 versus 10 of pain (especially abdominal pain); steatorrhea was noticed in 9 patients versus 0. Interestingly, only three infections occurred in the octreotide-treated group versus nine in the placebo-treated group. Other signs and symptoms were equally distributed and rare. Angina pectoris complaints are also listed in the table, reflecting the major clinical events mentioned above.

View this table: [in this window] [in a new window]   Table 6. Side Effects

	Discussion

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
Basic Considerations for Octreotide Treatment
The high rate of restenosis has remained an obstacle to overcome. It has been shown that the reduction in the risk factors for atherosclerosis, like hypercholesterolemia, hypertension, or smoking, does not decrease the incidence of restenosis. And, despite encouraging theoretical and experimental evidence, numerous studies to prevent or reduce restenosis with antiplatelet and antithrombotic agents, lipid-lowering drugs, fish oils, calcium antagonists, and ACE inhibitors have not shown unequivocal beneficial effects.²²

At the start of the VERAS study, SMC proliferation as the response to injury was considered the main culprit for the narrowing of the vessel lumen, and it was hypothesized that octreotide prevents myointimal thickening after vessel injury by systemic and local inhibition of growth factor effects. In in vitro experiments, oc-treotide inhibited IGF-1– and bFGF-induced proliferation of human coronary artery SMCs in a dose-dependent manner; PDGF-stimulated cultures were only minimally affected by octreotide. No effect on SMC migration was observed.¹⁷ Additionally, octreotide reduced neointimal thickening after balloon injury of femoral arteries in rats. This effect of octreotide correlated with a decrease in local IGF-1 mRNA levels as well as decreased activation of transcription factors.^{18 19}

First clinical approaches with a somatostatin analogue were reported for angiopeptin.^{23 24 25} However, due to the inconsistent results of three clinical trials, it was the purpose of the VERAS trial to determine the effect of high-dose octreotide to prevent or reduce restenosis in a large clinical trial. With respect to adverse events, gastrointestinal side effects occurred predominantly as expected.²⁶ These side effects (especially diarrhea) could be treated effectively with pancreatic enzyme preparations.

Discrepancy Between Experimental Data and Angiographic and Clinical Outcome
VERAS does not show any effect of octreotide on the angiographically determined restenosis rate or the incidence of clinical events. Several explanations may account for this apparent failure. With respect to the method of QCA, differences between the individual centers were eliminated by central evaluation of the cine films using state-of-the-art QCA equipment. Additionally, the angiographic characteristics before angioplasty were identical between both treatment groups. The high dosage of octreotide might still have been too low, and it may be possible that a second study with local application of octreotide via a catheter would be successful. On the other hand, the pretreatment period might have been too short to effectively reduce the IGF-1 level; however, the application regimen was sufficient to inhibit the growth factor–induced proliferation of SMCs on the level of signal transduction. Species differences in the biological response to vascular injury and in animal models of restenosis and different protocol designs for experimental and clinical studies may well explain the different outcomes in the treatment of restenosis.

The strategies aimed at blocking selectively biological mediators by octreotide could be limited by the multiplicity of mediators and their mutual interference, the plurality of cell surface receptors, and intracellular signaling mechanisms. Furthermore, it was recently discussed that restenosis is related not only to the formation of new intimal mass but also to remodeling processes.^{27 28} Even beneficial effects of vascular SMC proliferation and reendothelialization as part of an essential reparative process are hypothesized.^{29 30} Therefore, the inhibition of growth factors via stimulation of tyrosine phosphatase activity by octreotide seems insufficient for the prevention of restenosis in patients after PTCA.

A major and perhaps successful approach to prevent the development of restenosis is by blocking the platelet glycoprotein IIb/IIIa inhibiting platelet aggregation. The monoclonal antibody c7E3 has been shown to reduce major ischemic complications in high-risk patients after angioplasty by 23%.³¹ Furthermore, the EPILOG trial was prematurely stopped because of positive findings at the first interim analysis.³² This study also included low-risk patients; the incidence of bleeding events was the same in the treatment and placebo groups because of weight-adjusted heparin administration. An angiographic analysis of restenosis is pending. Trapidil, a PDGF antagonist, has also been shown to be effective in reducing the restenosis rate after angioplasty (24.2% in the trapidil group versus 39.7% in the aspirin group); however, clinical events were similar in both groups.³³ Whether trapidil or glycoprotein IIb/IIIa receptor blockers maintain the very promising first findings remain to be seen.

As a matter of fact, therapy with antiproliferative agents otherwise has been disappointing insofar as agents that are effective in vitro and in animal models did not have impressive clinical success. Again, in vivo veritas was proved by the VERAS trial (J. Madri).

	Selected Abbreviations and Acronyms

 

bFGF = basic fibroblast growth factor CABG = coronary artery bypass graft surgery EGF = epidermal growth factor IGF-1 = insulin-like growth factor–1 MLD = minimal luminal diameter PDGF = platelet-derived growth factor PTCA = percutaneous transluminal coronary angioplasty QCA = quantitative coronary angiography SMC = smooth muscle cell TGF-ß = transforming growth factor-ß VERAS = VErringerung der Restenoserate nach Angioplastie durch ein Somatostatin-analogon (Prevention of Restenosis Following Angioplasty With a Somatostatin Analogue)

	Appendix 1

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
VERAS Study Group
Coordinating Center
Stiftsklinik Augustinum, München (R. von Essen, MD, principal investigator).

Angiographic Core Laboratory
W. Oel, MD; and M. Hanke-Dubois, RN, Stiftsklinik Augustinum, München.

Participating Clinics and Investigators
The following institutions and investigators participated in VERAS. The number of patients enrolled at each center is given in parentheses: Stiftsklinik Augustinum, München (76): R. von Essen, MD (principal investigator); M. Roth, MD; R. Ostermaier, MD; R. von der Ropp; MD; F. Saathoff, MD; K. Unger, MD; J.-E. Kasulke, MD; Krankenhaus Siegburg (76): E. Grube, MD (main investigator); U. Hausen, RN; N. Cattelaens, MD; U. Gerckens, MD; D. Schiftah, RN; Klinikum Bayreuth (44): W. Mäurer, MD (main investigator); K. Hofmann, RN; J. Hornig, MD; B. Bender, MD; Klinikum Lippe-Detmold (32): U. Tebbe, MD (main investigator); J. Carlsson, MD; S. Miketic, MD; L. Obergassel, MD; A. Kuhn, MD; Universitätsklinikum Essen (25): R. Erbel, MD (main investigator); J. Ge, MD; D. Baumgart, MD; M. Haude, MD; Elisabeth-Krankenhaus Essen (9): G. Sabin, MD (main investigator); G. Szurawitzki, MD; M. Tekiyeh, MD; A. Treeger, MD; Franz-Volhard-Klinik, Freie Universität Berlin, Berlin-Buch (7): D. Gulba, MD (main investigator), H. Kleiner, MD. Rudolf-Virchow-Klinik; and Freie Universität Berlin (5): W. Rutsch, MD (main investigator).

Data Coordinating and Analysis
H. Kaiser, PhD; and H. Bachmann, PhD (Sandoz, Nürnberg).

Project Coordination
J. Brom, PhD; G. Weidinger, PhD; and R. Ross, Head Monitoring Group (Sandoz, Nürnberg).

	Acknowledgments

 
We gratefully thank Isolde Brenner for assistance in the preparation of the manuscript.

Received December 10, 1996; revision received March 24, 1997; accepted March 30, 1997.

	References

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 

1. Serruys PW, Luijten HE, Beatt KJ, Geuskens R, de Feyter PJ, van den Brand M, Reiber JHC, ten Katen HJ, van Es GA, Hugenholtz PG. Incidence of restenosis after successful coronary angioplasty: a time-related phenomenon: a quantitative angiographic study in 342 consecutive patients at 1, 2, 3, and 4 months. Circulation. 1988;77:361-371.[Abstract/Free Full Text]
   
2. Liu MW, Roubin GS, King SB III. Restenosis after coronary angioplasty: potential biologic determinants and role of intimal hyperplasia. Circulation. 1989;79:1374-1387.[Abstract/Free Full Text]
   
3. Jackson CL, Schwartz SM. Pharmacology of smooth muscle cell replication. Hypertension. 1992;20:713-736.[Abstract/Free Full Text]
   
4. Libby P, Schwartz D, Brogi E, Tanaka H, Clinton SK. A cascade model for restenosis: a special case of atherosclerosis progression. Circulation. 1992;86(suppl III):III-47-III-52.
   
5. Epstein SE, Speir E, Unger EF, Guzman RJ, Finkel T. The basis of molecular strategies for treating coronary restenosis after angioplasty. J Am Coll Cardiol. 1994;23:1278-1288.[Abstract]
   
6. Nikol S, Huehns TY, Höfling B. Molecular biology and post-angioplasty restenosis. Atherosclerosis. 1996;123:17-31.[Medline] [Order article via Infotrieve]
   
7. Yarden Y, Ullrich A. Growth factor receptor tyrosine kinases. Annu Rev Biochem. 1988;57:443-478.[Medline] [Order article via Infotrieve]
   
8. Cohen P. Signal integration at the level of protein kinases, protein phosphatases and their substrates. Trends Biochem Sci. 1992;17:408-413.[Medline] [Order article via Infotrieve]
   
9. Pallen CJ, Tan YH, Guy GR. Protein phosphatases in cell signalling. Curr Opin Cell Biol. 1992;4:1000-1007.[Medline] [Order article via Infotrieve]
   
10. Lau KH, Baylink DJ. Phosphotyrosyl protein phosphatases: potential regulators of cell proliferation and differentiation. Crit Rev Oncol. 1993;4:451-471.
    
11. Colas B, Cambillau C, Buscail L, Zeggari M, Esteve JP, Lautre V, Thomas F, Vaysse N, Susini C. Stimulation of a membrane tyrosine phosphatase activity by somatostatin analogues in rat pancreatic acinar cells. Eur J Biochem. 1992;207:1017-1024.[Medline] [Order article via Infotrieve]
    
12. Buscail L, Delesque N, Esteve J-P, Saint-Laurent N, Prats H, Clerc P, Robberecht P, Bell GI, Liebow C, Schally AV, Vaysse N, Susini C. Stimulation of tyrosine phosphatase and inhibition of cell proliferation by somatostatin analogues: mediation by human somatostatin receptor subtypes SSTR1 and SSTR2. Proc Natl Acad Sci U S A. 1994;91:2315-2319.[Abstract/Free Full Text]
    
13. Ezzat S, Ren S-G, Braunstein GD, Melmed S. Octreotide stimulates insulin-like growth factor-binding protein-1: a potential pituitary-independent mechanism for drug action. J Clin Endocrinol Metab. 1992;75:1459-1463.[Abstract]
    
14. Wolthers T, Grøfte T, Flyvbjerg A, Frystyk J, Vilstrup H, Ørskov H, Foegh M. Lanreotide, a somatostatin analogue, dose dependently stimulates insulin-like growth factor binding protein I. J Clin Endocrinol Metab. 1994;78:141-144.[Abstract]
    
15. Lundergan C, Foegh ML, Vargas R, Eufemio M, Bormes GW, Kot PA, Ramwell PW. Inhibition of myointimal proliferation of the rat carotid artery by the peptides, angiopeptin and BIM 23034. Atherosclerosis. 1989;80:49-55.[Medline] [Order article via Infotrieve]
    
16. Santoian EC, Schneider JE, Gravanis MB, Foegh M, Tarazona N, Cipolla GD, King SB III. Angiopeptin inhibits intimal hyperplasia after angioplasty in porcine coronary arteries. Circulation. 1993;88:11-14.[Abstract/Free Full Text]
    
17. Grant MB, Wargovich TJ, Ellis EA, Caballero S, Mansour M, Pepine CJ. Localization of insulin-like growth factor I and inhibition of coronary smooth muscle cell growth by somatostatin analogues in human coronary smooth muscle cells: a potential treatment for restenosis? Circulation. 1994;89:1511-1517.[Abstract/Free Full Text]
    
18. Yumi K, Fagin JA, Dimayuga P, Yano J, Forrester JS, Cercek B. Somatostatin analogue octreotide decreases arterial IGF-1 gene expression and neointimal thickening after injury. Clin Res. 1994;42:15A. Abstract.
    
19. Yamashita M, Dimayuga P, Zhu J, Yano J, Kaul S, Shah PK, Regnstrom J, Nilsson J, Cercek B. Effect of somatostatin analog octreotide on AP-1 and nuclear factor-B activation and cell proliferation after balloon injury. J Invest Med. 1996;44(suppl 1):101A. Abstract.
    
20. Beier J, Oswald H, Fleck E. Edge detection for coronary angiograms: error correction and impact of derivatives. IEEE Comp Soc Press. 1992;513-516.
    
21. Bairati I, Roy L, Meyer F. Double-blind, randomized, controlled trial of fish oil supplements in prevention of recurrence of stenosis after coronary angioplasty. Circulation. 1992;85:950-956.[Abstract/Free Full Text]
    
22. Herrman J-PR, Hermans WRM, Vos J, Serruys PW. Pharmacological approaches to the prevention of restenosis following angioplasty: the search for the holy grail? Drugs. 1993;46:18-52(pt I), 249-262(pt II).[Medline] [Order article via Infotrieve]
    
23. Eriksen UH, Amtorp O, Bagger JP, Emanuelsson H, Foegh M, Henningsen P, Saunamäki K, Schaeffer M, Thayssen P, Orskov H, Kuntz RE, Popma JJ. Randomized double-blind Scandinavian trial of angiopeptin versus placebo for the prevention of clinical events and restenosis after coronary balloon angioplasty. Am Heart J. 1995;130:1-8.[Medline] [Order article via Infotrieve]
    
24. Emanuelsson H, Beatt KJ, Bagger J-P, Balcon R, Heikkilä J, Piessens J, Schaeffer M, Suryapranata H, Foegh M, for the European Angiopeptin Study Group. Long-term effects of angiopeptin treatment in coronary angioplasty: reduction of clinical events but not angiographic restenosis. Circulation. 1995;91:1689-1696.[Abstract/Free Full Text]
    
25. Kent KM, Williams DO, Cassagneau B, Broderick T, Chapekis A, Simpfen-dorfer C, Cote G, Bates E, Tauscher G, Kuntz RE, Popma JJ, Foegh M. Double blind, controlled trial of the effect of angiopeptin on coronary restenosis following balloon angioplasty. Circulation. 1993;88(suppl I):I-506, Abstract.
    
26. Lamberts SW, van der Lely A-J, de Herder WW, Hofland LJ. Octreotide. N Engl J Med. 1996;334:246-254.[Free Full Text]
    
27. Glagov S. Intimal hyperplasia, vascular modeling, and the restenosis problem. Circulation. 1994;89:2888-2891.[Free Full Text]
    
28. Schwartz SM. How vessels narrow. Z Kardiol. 1995;84(suppl 4):129-135.
    
29. Asahara T, Bauters C, Pastore C, Kearney M, Rossow S, Bunting S, Ferrara N, Symes JF, Isner JM. Local delivery of vascular endothelial growth factor accelerates reendothelialization and attenuates intimal hyperplasia in balloon-injured rat carotid artery. Circulation. 1995;91:2793-2801.[Abstract/Free Full Text]
    
30. Weissberg PL, Clesham GJ, Bennett MR. Is vascular smooth muscle cell proliferation beneficial? Lancet. 1996;347:305-307.[Medline] [Order article via Infotrieve]
    
31. Topol EJ. Prevention of cardiovascular ischemic complications with new platelet glycoprotein IIb/IIIa inhibitors. Am Heart J. 1995;130(suppl):666-672.
    
32. Ferguson JJ III. EPILOG and CAPTURE trials halted because of positive interim results. Circulation. 1996;93:637.[Free Full Text]
    
33. Maresta A, Balducelli M, Cantini L, Casari A, Chioin R, Fabbri M, Fontanelli A, Monici Preti PA, Repetto S, De Servi S, Varani E for the STARC Investigators. Trapidil (triazolopyrimidine), a platelet-derived growth factor antagonist, reduces restenosis after percutaneous transluminal coronary angioplasty. Circulation. 1994;90:2710-2715.[Abstract/Free Full Text]
    

This article has been cited by other articles:

				P. Delafontaine, Y.-H. Song, and Y. Li Expression, Regulation, and Function of IGF-1, IGF-1R, and IGF-1 Binding Proteins in Blood Vessels Arterioscler. Thromb. Vasc. Biol., March 1, 2004; 24(3): 435 - 444. [Abstract] [Full Text]

				J. Frystyk, T. Ledet, N. Moller, A. Flyvbjerg, and H. Orskov Cardiovascular Disease and Insulin-Like Growth Factor I Circulation, August 20, 2002; 106(8): 893 - 895. [Full Text] [PDF]

				W. R. P. Agema, J. W. Jukema, S. N. Pimstone, and J. J. P. Kastelein Genetic aspects of restenosis after percutaneous coronary interventions;towards more tailored therapy Eur. Heart J., November 2, 2001; 22(22): 2058 - 2074. [PDF]

				A. Bayes-Genis, C. A. Conover, and R. S. Schwartz The Insulin-Like Growth Factor Axis : A Review of Atherosclerosis and Restenosis Circ. Res., February 4, 2000; 86(2): 125 - 130. [Abstract] [Full Text] [PDF]

				A. Tiran, R. A. Tio, J. M. Ossewaarde, B. Tiran, P. den Heijer, T. H. The, and M. M. Wilders-Truschnig Coronary Angioplasty Induces Rise in Chlamydia pneumoniae-Specific Antibodies J. Clin. Microbiol., April 1, 1999; 37(4): 1013 - 1017. [Abstract] [Full Text]

				S. KHARE, U. KUMAR, R. SASI, L. PUEBLA, L. CALDERON, K. LEMSTROM, P. HAYRY, and A. Y. C. PATEL Differential regulation of somatostatin receptor types 1-5 in rat aorta after angioplasty FASEB J, February 1, 1999; 13(2): 387 - 394. [Abstract] [Full Text]

This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by von Essen, R. Articles by Weidinger, G. Search for Related Content PubMed PubMed Citation Articles by von Essen, R. Articles by Weidinger, G.