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(Circulation. 1995;91:1689-1696.)
© 1995 American Heart Association, Inc.

Articles

Long-term Effects of Angiopeptin Treatment in Coronary Angioplasty

Reduction of Clinical Events but Not Angiographic Restenosis

Håkan Emanuelsson, MD, PhD; Kevin J. Beatt, MD, PhD; Jens-Peder Bagger, MD, PhD; Raphael Balcon, MD, PhD; Juhani Heikkilä, MD, PhD; Jan Piessens, MD, PhD; Marc Schaeffer, BSc; Harry Suryapranata, MD, PhD; Marie Foegh, MD, DSc; for the European Angiopeptin Study Group

From Sahlgrenska University Hospital (H.E.), Göteborg, Sweden; Charing X Westminster Hospital (K.J.B.), London; Skejby Hospital (J.-P.B.), Aarhus, Denmark; National Heart and Chest Hospital (R.B.), London; Helsinki (Finland) University Hospital (J.H.); University Ziekenhuizen (J.P.), Leuven, Belgium; The American University (M.S.), Washington, DC; Hospital de Wezenland (H.S.), Zwolle, the Netherlands; and Georgetown University and the Henri Beaufour Institute, USA, Inc. (M.F.), Washington, DC.

Correspondence to Håkan Emanuelsson, MD, Division of Cardiology, Sahlgrenska University Hospital, S-413 45 Göteborg, Sweden.

	Abstract

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Background Angiopeptin is a cyclic octapeptide analogue of somatostatin that has been shown to limit myointimal thickening of arteries in balloon injury models and to restore the vasodilating response to acetylcholine. A randomized, double-blind placebo controlled trial was conducted to assess the effect of angiopeptin in restenosis prevention after percutaneous transluminal coronary angioplasty (PTCA).

Methods and Results Patients received a continuous infusion of either placebo or angiopeptin subcutaneously 6 to 24 hours before PTCA and for 4 days after PTCA (3 mg per 24 hours before PTCA followed by 6 mg per 24 hours after PTCA and for the remaining period). A 1.5-mg bolus dose of placebo or angiopeptin was given at PTCA. Aspirin (acetylsalicylic acid, 150 mg/d) was administered throughout the study period. Coronary angiograms obtained before and after PTCA and at 6-month follow-up were subjected to computerized quantification. Clinical follow-up was performed after 12 months. Primary clinical end points were death, myocardial infarction, coronary artery bypass surgery, or repeat PTCA. In total, 553 patients with 742 lesions were randomized. Clinical follow-up was available for all 553 patients. Angiopeptin decreased the clinical events during 12 months of follow-up from 36.4% in the placebo-treated group to 28.4% in the angiopeptin-treated patients (P=.046). Quantitative angiography after PTCA and at follow-up was available in 423 of 455 patients who underwent successful PTCA. The minimal lumen diameter at follow-up was 1.52±0.64 mm in the angiopeptin-treated group compared with 1.52±0.64 mm in the placebo-treated patients (P=.96). The late losses were 0.31±0.59 and 0.30±0.62 mm (P=.81) and the restenosis rates (>50% diameter stenosis at follow-up) were 36% and 37% (P=.85) in the angiopeptin- and placebo-treated groups, respectively.

Conclusions In this study, angiopeptin significantly decreased the incidence of clinical events, principally the rate of revascularization procedures. In contrast, no significant effect was seen on angiographic variables.

Key Words: growth substances • angina • angioplasty • coronary disease

	Introduction

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While various factors such as dissection, thrombus formation, and recoil may affect early results after percutaneous transluminal coronary angioplasty (PTCA), late clinical outcome is thought to be related to vascular smooth muscle cell proliferation and matrix formation, resulting in renarrowing of the lumen of the dilated vessel. This sequence of events constitutes a significant clinical problem and occurs in 30% to 40% of all patients treated.^{1 2 3 4 5} Cellular growth is regulated in part by interaction of the cell with proteins and polypeptides in serum. Insulin-like growth factor (IGF-1) has been identified as an important serum and tissue component responsible for cell proliferation in various tissues, including the vascular wall.^{6 7} The growth-promoting effect of IGF-1 is potentiated by platelet-derived growth factor (PDGF).^{8 9} In addition, fibroblast growth factor increases the binding of IGF-1 to smooth muscle cells, promoting the growth stimulation of IGF-1.^{8 9 10} Angiopeptin, a cyclic octapeptide analogue of somatostatin, prevents an increase in IGF-1 in the vascular wall after balloon injury.¹¹ Furthermore, angiopeptin inhibits myointimal thickening in balloon-injury models in several animal species at doses similar to those used in PTCA studies in patients.^{12 13 14 15}

Recently, two double-blind controlled PTCA studies were performed with angiopeptin. In a pilot study in five centers, in which 112 total patients were treated with either placebo or 750 µg/d angiopeptin, the clinical event rate by intention-to-treat analysis at 12 months was lower in the angiopeptin-treated group (25%, compared with 34% in the placebo-treated group), but this difference was not statistically significant.¹⁶ However, a significantly lower angiographic restenosis rate at 6 months was seen in the angiopeptin-treated group (12% versus 40%). In that trial, angiopeptin was administered as in the present study, namely as a continuous subcutaneous infusion for 5 days. In a larger multicenter study of 1246 patients, in which angiopeptin was administered as subcutaneous injections twice per day, there were no statistically significant effects on clinical events or quantitative coronary angiography at follow-up, possibly due to a suboptimal daily dosing regimen.¹⁷ The aim of the present investigation was to evaluate whether the beneficial results of the first pilot study could be confirmed in a larger patient population by use of continuous infusion of angiopeptin. Since data from clinical studies have shown that higher doses of angiopeptin are well tolerated,¹⁷ 6 mg/d angiopeptin was given in the present study.

	Methods

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Between October 1991 and November 1992, all patients who were scheduled for angioplasty were considered for inclusion at 18 participating centers (see "Appendix"). Eligibility criteria included a patient history compatible with myocardial ischemia and at least one significant coronary stenosis (>50% in diameter). During this study period, 553 patients were randomized to double-blind administration of either angiopeptin or placebo. Active drug was given as a continuous infusion 6 to 24 hours before PTCA (3 mg SC) and a bolus dose of 1.5 mg just before PTCA; the drug was infused at a rate of 6 mg per 24 hours SC on the day of and for 3 days after PTCA. All patients were given a dose of 150 mg aspirin (acetylsalicylic acid) each day throughout the study period. Patients were treated with ß-blockers, calcium antagonists, angiotension-converting enzyme inhibitors, or long-acting nitrates at the discretion of the investigators. Trial medication was supplied by Henri Beaufour Institute, USA (Washington, DC). Patients were excluded from participation in the study if they had had a recent myocardial infarction (within 4 weeks), severe congestive heart failure, or conditions that precluded follow-up angiography.

The study was approved by the ethics committee at each study center, and written informed consent was obtained from every patient.

Angioplasty Procedure and Follow-up
Balloon angioplasty was performed at each study center according to standard procedures. Selective coronary angiography was performed before PTCA, after PTCA, and at 6 months' follow-up, or earlier if symptoms occurred. Angiograms were recorded to meet the standards for quantitative coronary angiography. Each lesion was viewed in at least two angiographic projections. To achieve maximal vasodilation, each angiogram was preceded by intracoronary injection of 125 to 250 µg nitroglycerin. Angiograms were reviewed at a central angiographic core laboratory and analyzed with an automatic edge-detection algorithm.¹⁸ Acute gain (minimal lumen diameter [MLD] after PTCA minus MLD before PTCA), late loss (MLD after PTCA minus MLD at follow-up) and loss index (late loss divided by acute gain) were calculated from these measurements.

Preprocedural lesion morphology was graded by use of standardized qualitative criteria for eccentricity, length, contour, presence of thrombus, ostial location, angulation, tortuosity, and total occlusion.¹⁹ The presence of postprocedural thrombus or coronary dissection was also recorded according to previously defined criteria.^{20 21}

Patients were seen in the outpatient clinic 1 week and 6 months after the procedure for a physical examination, laboratory tests, and an ECG. In addition, at 3, 9, and 12 months, a telephone interview was performed to record clinical events.

End Points
Clinical outcome was analyzed by inclusion of all study patients (intention-to-treat analysis). The primary clinical outcome end point was freedom from major clinical events (death, myocardial infarction, bypass surgery, or repeat coronary angioplasty hierarchical) during the follow-up period. End points were defined as follows: death: all deaths were considered cardiac death; myocardial infarction: the presence of at least two of the following: (1) occlusion of a previously patent coronary artery, (2) prolonged chest pain (30 minutes), (3) serial enzyme pattern typical for myocardial infarction with at least one cardiac enzyme raised to more than twice the local upper limit for normal, or (4) development of a new Q wave; bypass surgery: emergency or elective coronary bypass surgery involving at least one of the previously dilated lesions; and repeat angioplasty: repeat angioplasty involving at least one of the previously dilated lesions. The decision to perform repeat intervention or bypass surgery was blinded to treatment and based on findings at follow-up angiography in combination with clinical symptoms and the features of myocardial ischemia on ECG or by myocardial scintigraphy.

Angiographic end points were obtained in all patients who had an angiographic follow-up with an analyzable angiogram. The primary angiographic end point was to assess the effect of angiopeptin over placebo on the late angiographic outcome (restenosis) after balloon angioplasty. Restenosis was defined as stenosis of >50% in diameter at angiographic follow-up. Secondary angiographic end points included changes in percent diameter stenosis, follow-up MLD, and late loss.

Statistical Analysis
In the present study, the values for continuous data are expressed as mean±SD, whereas categorical data are reflected by frequencies and corresponding percentages. The differences for continuous data were evaluated by Student's t test, and categorical data were tested by ² test. Event-free survival rates were estimated by the Kaplan-Meier method, and a log-rank test was used to detect difference between groups.

	Results

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The demographic, clinical, and angiographic characteristics of the 553 randomized patients (278 treated with angiopeptin, 275 with placebo) with 742 total lesions (378 treated with angiopeptin, 364 with placebo) are displayed in Tables 1 and 2. There were no significant baseline differences between groups except for a lower prevalence of bifurcation lesions in the angiopeptin-treated group (14% versus 22%; P=.01). Table 3 shows the flow chart of patients in the study. PTCA was unsuccessful or not performed as planned in 98 patients (44 treated with angiopeptin, 54 with placebo). Emergency bypass surgery or stent implantation was necessary in 24 patients (12 treated with angiopeptin, 12 with placebo), and elective surgery was necessary in 13 (3 treated with angiopeptin, 10 with placebo). Twenty-five patients with unsuccessful PTCA (13 treated with angiopeptin, 12 with placebo) were treated medically. In addition, 4 patients (all treated with placebo) who had a "successful" procedure by visual assessment were excluded on the basis of an inadequate angiographic result by quantitative analysis.

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

View this table: [in this window] [in a new window]   Table 2. Preprocedural and Postprocedural Lesion Morphology in Patients Undergoing Successful Percutaneous Transluminal Coronary Angioplasty

View this table: [in this window] [in a new window]   Table 3. Patient Flow for 6-Month Angiographic Follow-up and 12-Month Clinical Follow-up

Taking into account patients who refused follow-up angiography or had a technically inadequate film (20 treated with angiopeptin, 7 with placebo), 423 patients with 538 total lesions were used for final angiographic analysis. Clinical follow-up, on the other hand, was obtained in all 553 patients.

Success rates for all attempted cases as assessed visually were 89.7% for angiopeptin-treated patients versus 87.7% for placebo-treated patients. The magnitude of lumen improvement was similar in both treatment groups, and no difference was noted in postprocedural lumen diameter (P=.70) or postprocedural percent stenosis (P=.97) (see Table 4).

View this table: [in this window] [in a new window]   Table 4. Angiographic Findings of Patients Undergoing Successful Angioplasty

Late Clinical and Angiographic Results
A primary clinical end point occurred in 28.4% of angiopeptin-treated patients and in 36.4% of placebo-treated patients during the 12-month follow-up period (P=.046). The relative risk for the angiopeptin group was 0.78, with a 95% confidence interval of 0.61 to 1.00 (Table 5). Patient-based analysis of the clinical end points revealed target-vessel PTCA to be the most frequently occurring event (n=108; 14.7% in the angiopeptin-treated group versus 20.7% in the placebo-treated group; P=.03). Coronary artery bypass surgery was performed in 29 patients (10.4%) in the angiopeptin-treated group and in 27 (9.8%) in the placebo-treated group (P=.81). The mortality rates during the 12-month follow-up period were 1.4% and 1.8% (P=.54) in the angiopeptin- and placebo-treated groups, respectively. Myocardial infarction occurred in 1.8% of the angiopeptin-treated patients versus 4.0% of the placebo-treated patients (P=.18) during the follow-up period. Fig 1 shows the cumulative event-free survival rates for the primary clinical end points over time in both groups. Fig 1 (top) shows the event-free survival rate, including target-vessel revascularization, death, and myocardial infarction, whereas Fig 1 (bottom) includes all revascularizations in addition to death and infarction. There were more adverse reactions in the angiopeptin-treated group than in the placebo-treated group. The most frequent adverse experiences were gastrointestinal disturbances (Table 6).

View this table: [in this window] [in a new window]   Table 5. Incidence of Clinical Events at 12 Months (Hierarchical)

View larger version (11K): [in this window] [in a new window]   Figure 1. Graphs showing proportion of patients who survived without events at 12 months (no death, myocardial infarction, or target vessel revascularization) (top). Bottom graph also includes patients who underwent non–target vessel revascularization procedures. All patients included (n = 553). Note that the y axis is from 0.55 to 1.05.

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

Table 4 summarizes the quantitative coronary angiographic findings. The minimal lumen diameter at follow-up was 1.52±0.64 mm in the angiopeptin-treated group, compared with 1.52±0.64 mm in the placebo-treated group (P=.96). The percent stenosis was also similar (45±21% versus 45±20%, P=.70). The restenosis rates (>50% diameter stenosis) were 36% versus 37% in the angiopeptin- and placebo-treated groups, respectively (P=.85). The late loss was 0.31±0.59 mm in the angiopeptin-treated group and 0.30±0.62 mm in the placebo-treated group (P=.81). The cumulative frequency-distribution curve of percent diameter stenosis at follow-up is shown in Fig 2.

View larger version (16K): [in this window] [in a new window]   Figure 2. Graph showing cumulative frequency distribution of percent diameter stenosis at follow-up.

A significant correlation was found between restenosis rates and length of angiopeptin pretreatment (P<.05). A longer pretreatment period resulted in a higher rate of angiographic success.

	Discussion

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Rationale for Angiopeptin Treatment
Angiopeptin is hypothesized to prevent myointimal thickening after vessel injury mainly by inhibition of secretion of growth factors involved in smooth muscle cell proliferation. In addition, the intercellular signal transduction induced by growth factors whose receptors contain an intracellular tyrosine kinase may be inhibited.²² These growth factors include IGF-1, PDGF, epidermal growth factor, and basic fibroblast growth factor (bFGF). IGF-1 is a crucial progression factor for smooth muscle cell proliferation. PDGF and bFGF increase IGF-1 receptors on smooth muscle cells, and this increase in IGF-1 receptors is needed for the mitogenic effect of IGF-1 on smooth muscle cell proliferation.¹⁰ Balloon injury of arteries causes an increase in IGF-1 and mRNA for IGF-1 in the vascular wall.^{7 11} This increase in IGF-1 after balloon injury in rabbits is prevented by administration of 20 µg · kg^-1 · d^-1 angiopeptin.¹¹ A further mechanism may be dephosphorylation of the phosphorylated tyrosine kinase by angiopeptin-induced activation of a membrane-bound phosphatase.²⁰

Data are also available from morphometric studies of the coronary arteries of pigs,¹² the aorta and iliac arteries of rabbits¹³ and in the aorta¹⁵ and carotid arteries of rats.¹⁴ In rabbits, in vivo administration of 2, 20, and 200 µg · kg^-1 · d^-1 angiopeptin inhibited myointimal thickening.²³ The lack of a dose-response curve in vivo for myointimal thickening is in contrast to the in vitro dose-response curves obtained in explants of pig coronary arteries²⁴ and rat carotid arteries.²⁵

Postponing treatment for 8 hours after balloon injury decreases the efficacy of angiopeptin, and a delay of 18 hours completely abolishes the inhibitory effect of angiopeptin on myointimal hyperplasia.¹³ In contrast, total duration of treatment seems to play a minor role; 2 days of treatment with angiopeptin showed the same inhibition of myointimal thickening as obtained after 5 and 21 days of treatment.¹³

Previous Double-Blind Randomized Trials
In one study,¹⁶ 112 patients were randomized to continuous infusion of angiopeptin (750 µg/d SC) or placebo infusion given the day before balloon angioplasty and for 4 days thereafter. A bolus dose of 375 µg angiopeptin or placebo was administered just before the procedure. Follow-up of clinical events was performed 12 months later, and follow-up angiography was performed 6 months after the procedure. The clinical event rate was reduced at 12 months from 34% in the placebo-treated group to 25% in the angiopeptin-treated group. Owing to the small number of patients in this pilot study, this 26% difference did not reach statistical significance. By use of a binary angiographic end point (>50% diameter stenosis), restenosis was significantly reduced in lesions treated with angiopeptin (12%, versus 40% in the placebo-treated patients; P=.005). Late lumen loss was also reduced (0.12±0.46 mm in the angiotensin-treated group versus 0.52±0.64 mm in the placebo-treated group, P=.003), and, consequently, repeat revascularization was required less frequently in angiopeptin-treated patients (11% versus 32% in the placebo-treated group; P=.027).

These promising findings were not corroborated in a large study comprising 1246 patients, in which angiopeptin was administered as two subcutaneous injections per day instead of as a continuous subcutaneous infusion.¹⁷ In this trial, patients taking three different dosages (5, 20, and 80 µg · kg^-1 · d^-1 SC BID) of angiopeptin were compared with placebo-treated patients. No statistically significant effect could be demonstrated in the angiographic or clinical parameters with any of the dosages of angiopeptin, although a lower clinical event rate was seen in all three angiopeptin-treated groups compared with the placebo-treated group. One possible explanation for the discrepancy between these two studies might be the short half-life of angiopeptin (90 minutes): Given this half-life, two subcutaneous injections per day might be insufficient, and sustained plasma levels may be needed for longer periods than provided by the two daily injections. In addition, patients were not pretreated with angiopeptin for any substantial period in this study.

Dosage and Duration of Treatment
In animal models, no close dose-response relation has been found with angiopeptin, which has had the same efficacy on myointimal thickening at dosages ranging from 2 to 200 µg · kg^-1 · d^-1. In the first clinical, randomized angiopeptin trial (pilot study) for restenosis prevention,¹⁶ a medium dose (10 µg · kg^-1 · d^-1) was chosen primarily for patient safety. At the start of the present trial, pharmacodynamic properties of angiopeptin in humans were insufficiently known, but it was decided that this trial would use a higher dose than the first study. Due to these circumstances and insufficient knowledge regarding dosage and efficacy in vivo, the finding was not unexpected that the increase in the dosage of angiopeptin did not enhance the efficacy of the treatment from that seen in the pilot study of 112 patients who were treated with a dosage that was eight times lower.¹⁶

Another crucial question is the length of the treatment period before balloon dilatation. In animal models, lack of pretreatment has been shown to result in loss of therapeutic efficacy.¹³ The reason for this may be that the decline in IGF-1 after treatment with angiopeptin occurs over several days, in part owing to the long half-life of IGF-1. This is consistent with findings from previous human studies. In the first study with a positive outcome,¹⁶ pretreatment duration was 24 hours, whereas in a study with a negative result,¹⁷ the first injection was given shortly before balloon angioplasty. In the present study, a significant correlation was found between the restenosis rate and the length of pretreatment. Thus, 24-hour pretreatment may be considered preferable, given previous experiences with animals and humans.

Discrepancy Between Clinical and Angiographic Results
The biological process that occurs after coronary angioplasty is myointimal hyperplasia, and it was therefore not unexpected that repeat PTCA was the most common clinical event in this trial. It has been generally assumed that an improvement in clinical outcome after PTCA treatment would be related to prevention of the recurrence of stenosis in the treated vessel. The difference in the clinical event rates between the treatment groups was mainly due to a reduction in PTCA. This discrepancy between clinical and angiographic variables may seem inconsistent and contradictory. However, there could be several potential explanations for these results. In this study, standardization of the angiographic procedure was exercised as previously described.²⁶ The analysis was performed in a dedicated core laboratory according to current standards, and the participating study centers practiced quality control. On the other hand, the limitations of quantitative coronary angiography must be emphasized, in particular, the difficulties of using the technique to accurately represent three-dimensional morphology of the lesion. There is a possibility that the lack of difference in angiographic restenosis to some extent reflects the inherent inability of angiography to detect small differences in minimal lumen diameters.²⁷ Intravascular ultrasound imaging might have been a more appropriate method for evaluation of stenosis severity in the present study. It has recently been demonstrated that intravascular ultrasound imaging assessed the presence and severity of coronary lesions more accurately than did coronary angiography.²⁸

Another possible explanation may be that although angiopeptin did not affect the angiographic results, it could affect the regeneration process after balloon dilatation in a way that could beneficially influence function and remodeling of the vessel. A recent experimental study in rabbits showed that the balloon-injured aorta from rabbits receiving angiopeptin by continuous infusion for 2 weeks responded to acetylcholine with vasodilation. This was not the case for the placebo-treated animals.²⁹ These data suggest that improvement of neoendothelial function after angiopeptin treatment may beneficially affect the physiological role of the treated vessel. This effect is not necessarily related to the degree of myointimal proliferation and may not be reflected by morphological methods, eg, coronary angiography.

Finally, one reason for the lower incidence of clinical events after angiopeptin without concomitant angiographic changes might be a beneficial extracoronary effect of angiopeptin. However, no such effects have yet been documented in humans, and given the short treatment period in this study, this mechanism seems less likely.

Since 13 angiopeptin-treated patients (versus only 2 in the placebo-treated group) refused follow-up angiography, it could be argued that performing additional angiograms in the angiopeptin-treated group might have stimulated more repeat revascularizations. However, this seems unlikely for several reasons. Repeat angioplasty was clinically driven either by angina or by a positive exercise tolerance test. Furthermore, patients who did not return for angiographic follow-up were likely to be free of clinical symptoms. Coronary angiography in these patients thus would have increased the difference in clinical events between the treatment groups.

Conclusions
This study demonstrated that when angiopeptin treatment was started 6 to 24 hours before PTCA, it significantly decreased the incidence of clinical events. On the other hand, no significant effect on angiographic variables was seen. There could be various explanations for these findings, such as the method of quantitative coronary angiography not being sensitive enough to detect small differences between the two treatment groups or hitherto unrecognized mechanisms of action for angiopeptin. In future studies with angiopeptin, the pretreatment period should be at least 24 hours. A lower dose than was used in the present study may be equally effective. Intravascular ultrasound imaging, a diagnostic method complementary to quantitative coronary angiography, may assist in the evaluation of morphological changes in the coronary arteries.

European Angiopeptin Study Group: Study Coordinator: Håkan Emanuelsson; Steering Committee: Jens Peder Bagger, Raphael Balcon, William E. Battle, Kevin J. Beatt, Håkan Emanuelsson, Marie Foegh, and Merete Holm Bentzen.

Participating Clinics and Investigators: Belgium: Universitaire Ziekenhuizen Gasthuisberg, Leuven: J. Piessens (Principal Investigator), W. Desmet, and Ivan De Scheerder. Denmark: Gentofte Hospital; Hellerup: O. Amtorp (Principal Investigator); Skejby Hospital, Aarhus: J.P. Bagger (Principal Investigator); Rigshospitalet, Copenhagen: K. Saunamäki (Principal Investigator) and R. Steffensen; and Odense University Hospital: P. Thayssen (Principal Investigator) and P.E. Andersen. Finland: Helsinki University Central Hospital: J. Heikkilä (Principal Investigator) and K.S. Virtanen. Germany: Waldkrankenhaus St Marien, Erlangen: E. Lang (Principal Investigator) and H. Beyer. The Netherlands: Hospital de Weezenlanden, Zwolle: H. Suryapranata (Principal Investigator), J. Hoorntje, F. Zijlstra, and M.-J. de Boer. Norway: Haukeland Sykehus, Bergen: H. Vik-Mo (Principal Investigator) and K.-J. Kuiper. Sweden: Sahlgrenska Hospital, Göteborg: H. Emanuelsson, (Principal Investigator), P. Hårdhammar, Lars Lönn, and P. Albertsson; Lasarettet in Lund: S. Persson (Principal Investigator) and U. Albrechtsson; and Karolinska Hospital, Stockholm: M. Aasa (Principal Investigator) and B. Svane. United Kingdom: London Chest Hospital: R. Balcon (Principal Investigator); St Mary's Hospital, London: R.A. Foale (Principal Investigator) and J. Shahi; Guy's Hospital, London: G. Jackson (Principal Investigator), G.E. Sowton, and B. Mishra; Leeds General Infirmary: J. McLenachan (Principal Investigator); St Mary's Hospital Medical School, London: D.J. Sheridan (Principal Investigator) and D. O'Gorman; and Chelsea and Westminster Hospital, London: R. Sutton (Principal Investigator). United States: Henri Beaufour Institute, USA, Inc, Washington, DC: M. Foegh and W. Battle.

Quantitative Angiographic Core Laboratory: Chelsea and Westminster Hospital, London, UK: K.J. Beatt and T. Huehns.

Data Coordinating and Analysis Centers: IPSEN ApS, Copenhagen, Denmark; IPSEN International, London, UK.

Statistician: Marc Schaeffer, American University, Washington, DC.

Received August 1, 1994; revision received October 24, 1994; accepted October 31, 1994.

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