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(Circulation. 1997;95:83-89.)
© 1997 American Heart Association, Inc.

Articles

Effect of the Direct Nitric Oxide Donors Linsidomine and Molsidomine on Angiographic Restenosis After Coronary Balloon Angioplasty

The ACCORD Study

Jean-Marc Lablanche, MD; Gilles Grollier, MD; Jean-Rene Lusson, MD; Jean-Pierre Bassand, MD; Gerard Drobinski, MD; Bernard Bertrand, MD; Salvatore Battaglia, MD; Bernard Desveaux, MD; Yves Juilliere, MD; Jean-Michel Juliard, MD; Jean-Philippe Metzger, MD; Pierre Coste, MD; Jean-Claude Quiret, MD; Jean-Luc Dubois-Rande, MD; Pierre Dominique Crochet, MD; Brice Letac, MD; Jacques Boschat, MD; Patrice Virot, MD; Gerard Finet, MD; Herve Le Breton, MD; Bernard Livarek, MD; Florence Leclercq, MD; Thierry Beard, MD; Thierry Giraud, MD; Eugene P. McFadden, MRCPI; Michel E. Bertrand, MD

the Centre Hospitalier Regional et Universitaire, Hopital Cardiologique, Lille, France (J.-M.L., E.P.M., M.E.B.); Hopital Cote de Nacre, Caen (G.G.); Hopital Gabriel Montpied, Clermont Ferrand (J.-R.L.); Hopital Saint-Jacques, Besancon (J.-P.B.); Groupe Hospitalier Pitie-Salpetriere, Paris (G.D.); Centre Hospitalier Regional et Universitaire, Grenoble (B.B.); Hopital Broussais, Paris (S.B.); Hopital Trousseau, Tours (B.D.); Hopital de Brabois, Vandoeuvre (Y.J.); Hopital Bichat, Paris (J.-M.J.); Groupe Hospitalier Necker-Enfants Malades, Paris (J.-P.M.); Hopitaux de Haut Leveque, Pessac (P.C.); Groupe Hospitalier Sud, Amiens (J.-C.Q.); Centre Hospitalier Henri Mondor, Creteil (J.-L.D.-R.); Hopital Nord, Nantes (P.D.C.); Hopital Charles Nicolle, Rouen (B.L.); Hopital Morvan, Brest (J.B.); Hopital Universitaire Dupuytren, Limoges (P.V.); Hopital Louis Pradel, Lyon (G.F.); Hopital Hotel-Dieu, Rennes (H.L.B.); Hopital Andre Mignot, Le Chesnay (B.L.); Hopital Arnaud de Villeneuve, Montpellier (F.L.); Hopital Purpan, Toulouse (T.B.); and Laboratoires Hoechst, Paris La Defense (T.G.).

	Abstract

Top Abstract Introduction Methods Results Discussion Appendix References

 
Background Nitric oxide (NO) donors, in addition to their vasodilator effect, decrease platelet aggregation and inhibit vascular smooth muscle cell proliferation. These actions could have beneficial effects on restenosis after coronary balloon angioplasty.

Methods and Results In a prospective multicenter, randomized trial, 700 stable coronary patients scheduled for angioplasty received direct NO donors (infusion of linsidomine followed by oral molsidomine) or oral diltiazem. Treatment was started before angioplasty and continued until 12 to 24 hours before follow-up angiography at 6 months. The primary study end point was minimal lumen diameter, assessed by quantitative coronary angiography, 6 months after balloon angioplasty. Clinical variables were well matched in both groups. However, despite intracoronary administration of isosorbide dinitrate, the reference diameter in the NO donor group was significantly greater than in the diltiazem group on the preangioplasty, postangioplasty, and follow-up angiograms. Pretreatment with an NO donor was associated with a modest improvement in the immediate angiographic result compared with pretreatment with diltiazem (minimum luminal diameter, 1.94 versus 1.81 mm; P=.001); this improvement was maintained at the 6-month angiographic follow-up (minimal lumen diameter, 1.54 versus 1.38 mm; P=.007). The extent of late luminal narrowing did not differ significantly between groups (loss index in the NO donor and diltiazam groups, 0.35±0.78 and 0.46±0.74, respectively; P=.103). Restenosis, defined as a binary variable (50% stenosis), occurred less often in the NO donor group (38.0% versus 46.5%; P=.026). Combined major clinical events (death, nonfatal myocardial infarction, and coronary revascularization) were similar in the two groups (32.2% versus 32.4%).

Conclusions Treatment with linsidomine and molsidomine was associated with a modest improvement in the long-term angiographic result after angioplasty but had no effect on clinical outcome. The improved angiographic result related predominantly to a better immediate procedural result, because late luminal loss did not differ significantly between groups.

Key Words: endothelium-derived factors • sydnonimines • angioplasty • restenosis

	Introduction

Top Abstract Introduction Methods Results Discussion Appendix References

 
Coronary balloon angioplasty is associated with a high (30% to 70%) rate of restenosis that detracts from its clinical value in the treatment of coronary artery disease.^{1 2} To date, despite the performance of many well-designed clinical trials, no pharmacological agent tested has been convincingly demonstrated to reduce restenosis.

Over the last decade, the pivotal role of endothelium in the regulation of vascular tone has been demonstrated in experimental and clinical studies. Endothelium-derived relaxing factor has been identified as NO.³ More recently, additional roles for NO donors in the control of smooth muscle cell proliferation and inhibition of platelet adhesion and thrombus formation after angioplasty have been identified.^{4 5 6} The aim of the ACCORD study was to study the effect of molsidomine and linsidomine (SIN-1), which act by direct liberation of NO into the bloodstream, on restenosis after coronary balloon angioplasty.

	Methods

Top Abstract Introduction Methods Results Discussion Appendix References

 
Patient Selection and Recruitment
The coordinating center and the angiographic core laboratory were located at the Hopital Cardiologique, Lille, France. The 22 participating hospitals and the principal investigators are listed in the "Appendix." The study protocol was approved by the Ethical Committee of the University of Lille.

Eligible patients were those (70 years of age) with angina and/or objective evidence of myocardial ischemia who were referred for balloon angioplasty of a significant (by visual assessment) stenosis. Patients with recent myocardial infarction (<3 weeks), recent unstable angina (pain within 8 days), severe left ventricular dysfunction (ejection fraction <35%), systolic pressure <100 mm Hg, or a contraindication to aspirin therapy were excluded. Other exclusion criteria were restenosis lesions, left main coronary lesions, graft lesions, or totally occluded lesions (TIMI perfusion grade of 0 or 1).⁷

Patient Randomization
Randomization was performed by computer terminals (Minitel, France Telecom) installed in each center by a private company (Medyal) that was completely independent from the study sponsors and investigators. Randomization was stratified according to center and the type of vessel disease (single vessel or multivessel). The randomization center assigned the number of the randomization package to be used for each patient. This was the first number available within the appropriate stratum of the randomization plan. This randomization plan removed any possibility of substitution of patients.

Treatment Protocol
The active treatment group received a continuous infusion of linsidomine (1 mg/h IV) that was started between 3 and 18 hours before the procedure. Because of the hypotensive effects of linsidomine that allow easy identification of the drug, treatment administration was not blinded. Blood pressure was measured 10 minutes after initiation of treatment, and the dose of linsidomine was decreased by increments of 0.2 mg/h if mean arterial pressure decreased by >10%. The infusion was continued for 24 hours after the procedure, with blood pressure monitored every 4 hours. Two hours before the end of the infusion, molsidomine (4 mg orally) was given and continued at a dose of 4 mg three times daily until follow-up angiography. The control group received diltiazem 60 mg three times daily. The first dose of diltiazem was given at least 3 hours before the procedure, and treatment was continued until the follow-up angiography. Diltiazem was chosen because it is widely used in France in patients after coronary angioplasty. It has previously been shown to have no effect on the occurrence of restenosis.^{8 9} Both groups received aspirin (250 mg daily), started before the procedure and continued for 6 months, and similar intravenous heparin therapy during angioplasty. Heparin (10 000 IU) was administered at the start of the procedure, with an additional bolus (5000 IU) after each hour of the procedure. The duration and dose of heparin after the procedure were left to the discretion of the local investigator. During follow-up, administration of long-acting nitrates, calcium antagonists (other than diltiazem administered by protocol), oral anticoagulants, or ACE inhibitors was forbidden, as was the use of any antiplatelet agent other than aspirin.

Angioplasty Procedure and Angiographic Analysis
Angioplasty was performed at each center in accordance with local practice. The patient remained in the study if the procedure was judged to be successful by the investigator (residual stenosis visually estimated as <50% without major complication). Coronary angiography was performed before, immediately after, and between 4 and 6 months after angioplasty. Follow-up angiography was performed earlier if there was a clinical indication. If a follow-up angiogram performed sooner than 4 months after angioplasty did not demonstrate restenosis, the patient was encouraged to return for another angiography at 6 months.

Isosorbide dinitrate (2 mg) was injected into the coronary artery before each angiogram and in both groups in an attempt to standardize vasomotor tone. The angiograms were recorded on standard 35-mm film. Three views of the stenosis were obtained at the time of angioplasty and were recorded on a worksheet to allow them to be duplicated exactly at the time of follow-up angiography. An attempt was made to obtain two orthogonal views for each lesion.

At the end of the study, films were sent to the core laboratory at the University of Lille for qualitative and quantitative analysis. Angiographic analysis was performed without knowledge of treatment allocation or clinical data. Quantitative analysis was performed on sequential angiograms filmed in the same projection. The frames were selected by the cardiologist who performed the quantitative analysis from the projection in which the stenosis appeared most severe just before angioplasty. Quantitative analysis was performed with the Computer Assisted Evaluation of Stenosis and Restenosis system, a computerized automatic analysis system that has been fully described elsewhere.¹⁰

Clinical and Angiographic End Points
The primary end point was angiographic restenosis defined as a residual stenosis of <50% stenosis after angioplasty that became 50% at the 6-month follow-up. For this end point, it was calculated that a sample size of 313 patients per group was required to demonstrate a reduction in restenosis of between 20% and 30% (allowing for a two-tailed error of 0.05 and a ß error of 0.20). To allow for incomplete angiographic follow-up (estimated lost-to-follow-up rate of 10%), it was initially decided to include 700 patients. However, during the course of the study, several groups demonstrated that restenosis was best analyzed as a continuous variable with a normal distribution.^{11 12} To increase the power of the study to detect a treatment effect, an additional end point, the net gain in MLD at the dilated site (see definition below), was added before the results were analyzed. The other angiographic end point was percent stenosis at follow-up angiography, which was expressed as a continuous variable. Secondary end points were the occurrence of death, nonfatal target lesion myocardial infarction, and coronary artery bypass grafting or repeated angioplasty. Target lesion myocardial infarction was defined clinically at the participating site.

Definitions
Acute gain was defined as the difference between the MLD at the dilated site just before and immediately after the procedure. Late loss was defined as the MLD at the dilated site immediately after the procedure minus the MLD at the dilated site 6 months after angioplasty. Net gain was defined as the MLD at the dilated site 6 months after angioplasty minus the MLD at the dilated site just before angioplasty. The loss index, defined as the ratio of late loss to acute gain,¹³ was also calculated. As part of a post hoc statistical analysis, the loss index was recalculated as the slope of the regression between late loss and acute gain for each treatment group. The balloon-artery ratio was defined as the nominal size of the balloon used divided by the reference diameter of the dilated vessel. Immediate recoil was defined as the largest nominal balloon size minus the MLD after angioplasty divided by the largest nominal balloon size.

Statistical Analysis
The statistical analysis was performed by the Biometric Unit of Laboratoires Hoechst with SAS software (version 6.04, SAS Institute). All tests were two-tailed, and values of P<.05 were considered significant. Three populations were defined: (1) patients who had initial angioplasty (intention-to-treat population), (2) patients who had follow-up angiographies that could be analyzed by the continuous MLD approach (first per-protocol population), and (3) patients who had follow-up angiographies that could be analyzed by the categorical restenosis approach (second per-protocol population).

The baseline characteristics were compared between the two groups by use of the t test, ² test, or Fisher's exact test as appropriate. Clinical events related to the procedure and those occurring during follow-up were compared with the Mantel-Haenszel test on ordered categories. When more than one clinical event occurred per patient, the most severe event was used for the analysis, with the following decreasing order of severity: death, nonfatal myocardial infarction, coronary artery bypass grafting, and target-vessel repeated angioplasty. The MLD, the changes in MLD, and percent stenosis (acute gain, late loss, and net gain) were compared between groups by t tests. Univariate ANOVA was performed to test the correlation between the changes in MLD (late loss and net gain) and the following variables: treatment allocation, center, sex, age, presence of at least one complex angiographic characteristic (angulation of >45°, eccentric lesion, overhanging edge, filling defect before angioplasty, irregular border, tandem, stenosis >10 mm long, calcification, ostial lesion, lesion located at a bifurcation, and proximal tortuosity), presence of dissection after angioplasty, history of hypercholesterolemia, recent myocardial infarction (<3 months), unstable angina, diabetes, and duration of treatment before angioplasty. Multivariate statistical analysis with the step-down regression procedure was performed with variables almost significantly (P<.10) correlated with net gain or late loss in MLD to obtain ultimate risk factors for restenosis. The categorical restenosis rates were compared between the two groups with the ² test. Adjustment for factors remaining significant in the multivariate model was performed to test the true difference of restenosis rate between the two treatment groups by use of the Cochran-Mantel-Haenszel test and logistic regression. The odds ratio and its 95% confidence interval were calculated. Additional post hoc analyses of covariance, with adjustment for balloon size, and logistic regression (with the Wald test) for the reference diameter were performed to determine whether balloon size or reference diameter had any effect on the observed outcomes.

	Results

Top Abstract Introduction Methods Results Discussion Appendix References

 
Baseline Characteristics and Procedural Outcome
Between January 1990 and October 1992, 723 patients were randomized in the study; 23 were excluded before angioplasty for the following reasons: withdrawal of informed consent (3 patients), adverse events (2), inclusion errors (17), and protocol violation recognized by the investigator (1). Thus, 700 patients (350 in each group) underwent angioplasty and constitute the intention-to-treat population. Table 1 details the baseline patient characteristics. In the 48 hours after angioplasty, 47 patients (23 in the NO donor group and 24 in the diltiazem group) were excluded because of complicated or uncomplicated failure (42 patients) or performance of repeated angioplasty (4) or because treatment forbidden by protocol was administered (1). Therefore, 653 patients were eligible for angiographic follow-up, which was actually performed in 579 patients (88.7%). A follow-up angiogram was not performed or was not considered in the angiographic analysis (angiography <4 months that did not demonstrate restenosis without a subsequent 6-month angiography) in 74 patients: 40 patients refused; 29 were withdrawn from the study because of side effects, complications, or intercurrent illness; 3 were excluded because repeated angiography performed before 4 months did not show restenosis; and in 2 patients, follow-up was not performed because the angioplasty film was accidentally destroyed. After angiographic follow-up, 59 patients were excluded by the steering committee for the following reasons. For 33 patients, the core angiographic laboratory was unable to perform accurate measurements on one or more film sequences because of the quality of the film, no view of the empty catheter was filmed, or the size of the catheter used was not recorded. For 11 patients, the dilated lesion was either a total occlusion (TIMI grade 0 or 1) or a nonsignificant stenosis (<40%). These assessments were based on the report from the angiographic core laboratory. The patients were judged by the steering committee to be errors of inclusion. Four other patients were excluded because the inclusion criteria had been violated: myocardial infarction within 15 days of angioplasty (2 patients) and unstable angina within 7 days of angioplasty (2 patients). Two patients were excluded because the duration of pretreatment before PTCA was <3 hours. Nine patients were excluded because they had received drug treatment that was forbidden by protocol. Thus, 520 patients had angiograms suitable for analysis; 48 patients considered primary successes (stenosis visually <50%) by the investigator were found to have a residual stenosis >50% by the angiographic core laboratory. Thus, these 48 patients were not evaluable for the classification of restenosis as a categorical variable (<50% stenosis after PTCA with >50% stenosis at follow-up) because they had a residual >50% stenosis after PTCA.

View this table: [in this window] [in a new window]   Table 1. Baseline Clinical Characteristics (Intention-to-Treat Population)

In summary, 520 patients had three angiograms suitable for analysis; this group is defined as the first per-protocol population. There were 255 patients with 292 dilated lesions in the diltiazem group and 265 patients with 305 dilated lesions in the NO donor group. Finally, 472 patients were suitable for the categorical restenosis analysis (second per-protocol population).

Safety
Apart from hypotension and headaches, which were more frequent in the NO donor group within 48 hours after angioplasty (21 and 10 patients, respectively, versus 5 and 0 patients in the diltiazem group), the incidence of side effects and the number of dropouts as a result of adverse events were similar between the two treatment groups (13 and 10, respectively).

Angiographic Restenosis
Table 2 details the main angiographic and procedural characteristics of the first per-protocol population. Duration of treatment before angioplasty was longer (18.1±24.1 hours) in the diltiazem group than in the NO donor group (8.8±5.7 hours). The duration of follow-up was similar in both groups. Compliance with oral treatment was similar between the two groups. There were no between-group differences in the location of the dilated site or angiographic characteristics of the lesions before angioplasty. Major procedural variables, such as the total duration and the number of inflations or the occurrence of dissection after angioplasty, also were similar between groups. The total dose of heparin administered during (NO donor group, 10 700±2440 IU; diltiazem group, 10 860±2410 IU; P=.46) or after (NO donor group, 21 590±6270 IU; diltiazem group, 21 850±6550 IU; P=.66) the procedure did not differ significantly between groups. Although the nominal balloon size was slightly larger (+0.08 mm) in the NO donor group, the mean balloon-to-artery ratio was the same in both groups. Table 3 and the Figure give the major results of the quantitative coronary angiographic analysis. Despite the systematic use of intracoronary isosorbide dinitrate in both groups, the mean reference diameter was greater in the NO donor group than in the diltiazem group before angioplasty. The mean MLD did not differ significantly between groups before angioplasty. Immediately after angioplasty, the mean MLD in the NO donor group was greater than in the diltiazem group (0.13 mm; P=.001), with a significant difference in acute gain (0.10 mm; P=.017). At follow-up, MLD remained greater in the NO donor group (0.16 mm; P=.007), with a significant difference in net gain (0.13 mm; P=.026). Late loss, loss index, and the slope of the regression between late loss and acute gain did not differ significantly between groups. The post hoc analysis, after adjustment for a possible effect of balloon size on outcome, is presented in Table 4. This analysis demonstrated an identical superior (P=.01) acute gain in the NO donor group (+0.10 mm). The net gain at 6 months was again greater in the NO donor group (P=.06). With the categorical approach, the restenosis rate in the NO donor group (primary efficacy variable) was 38.0% compared with 46.5% in the diltiazem group (uncorrected P=.062). Multivariate analysis identified three factors independently correlated with changes in MLD: center, treatment allocation, and history of hypercholesterolemia. After adjustment for center and a history of hypercholesterolemia, the difference in restenosis rate between the two groups was significant (P=.026). After further adjustment for the reference diameter, the equivalent value was P=.036.

View this table: [in this window] [in a new window]   Table 2. Angiographic and Procedural Characteristics (Per-Protocol Population)

View this table: [in this window] [in a new window]   Table 3. Quantitative Angiographic Data (Per-Protocol Population)

View larger version (24K): [in this window] [in a new window]   Figure 1. Cumulative frequency distribution curves of the MLD at the dilated site, before PTCA, immediately after PTCA, and at follow-up (F-up). There was no difference in the baseline distribution between the NO donor group (continuous line) and the diltiazem group (dotted line). Immediately after angioplasty, the MLD in the linsidomine group was significantly larger (P=.001) than in the diltiazem group. At follow-up, the MLD remained larger (P=.007) in the NO donor group.

View this table: [in this window] [in a new window]   Table 4. Post Hoc Analysis With Adjustment for Balloon Size

Clinical Outcome
Clinical follow-up was not available for 5 patients in the NO donor group and 4 patients in the diltiazem group. At 6 months, a total of 108 patients in the NO donor group and 101 patients in the diltiazem group had undergone revascularization with PTCA and/or coronary angiography bypass graft surgery. Table 5 lists the event rates in the two populations. The combined rate of major events was similar in both groups: 32.2% in the NO donor group and 32.4% in the diltiazem group.

View this table: [in this window] [in a new window]   Table 5. Procedural Complications and Clinical Events in Rank Order of Severity During Follow-up in the Intention-to-Treat Population

	Discussion

Top Abstract Introduction Methods Results Discussion Appendix References

 
The major finding of this study was that treatment with the direct NO donors—intravenous linsidomine started before angioplasty and continued for 24 hours after the procedure, followed by oral molsidomine for 6 months—was associated with a modest increase in MLD compared with a control group treated with oral diltiazem that also started before angioplasty and continued for 6 months. The improved angiographic outcome was due to a better immediate result in the NO donor group that was maintained during follow-up. The improvement in immediate angiographic outcome was not associated with an increase in periprocedural complications. Six-month clinical outcome was similar in both groups.

Restenosis After Balloon Angioplasty
Restenosis is the major limitation of balloon coronary angioplasty. Attempts to prevent restenosis with pharmacological agents have, to date, been unsuccessful.² New mechanical tools have also been developed to tackle restenosis.^{12 13} Directional atherectomy produced no improvement in restenosis but an increase in periprocedural complications.¹⁴ Intracoronary stent implantation is the only therapy shown to have a beneficial effect on restenosis.¹⁵ Use of a monoclonal antibody directed against platelet receptors in high-risk angioplasty is associated with an improved clinical outcome at 6 months at the expense of an increased risk of bleeding.¹⁶ However, the effects on angiographic restenosis are unknown.

Endothelium and Restenosis
Endothelial injury after balloon angioplasty is ubiquitous and facilitates adhesion and aggregation of platelets at the site of denudation. The subsequent release of growth-promoting substances by platelets and other cells, such as monocytes and macrophages, stimulates smooth muscle cell proliferation and migration, thus initiating the cascade of events that results in neointimal proliferation, a marked proliferative response occurring when endothelial denudation is extensive.¹⁷ The central role of endothelium in the control of vascular tone is well established.¹⁸ NO has been identified as one of the relaxant factors synthesized and released by normal endothelium.³ NO may theoretically interact with the process of restenosis at several levels. First, NO has an inhibitory effect on platelet adhesion,⁶ platelet aggregation,¹⁹ and leukocyte adhesion.²⁰ Second, NO reduces the synthesis of DNA in smooth muscle cells and has an inhibitory effect on smooth muscle cell proliferation.^{4 5} Third, NO is a direct scavenger of superoxide anions.²¹ Finally, NO has a beneficial effect on arterial remodeling.²² It has been shown in animal models that when endothelium regenerates after injury, the neoendothelium has an impaired capacity to synthesize and/or release endothelium-derived relaxing factors.²³ When L-arginine, the physiological precursor of NO, was administered to animals before endothelial denudation, neointimal thickening was significantly reduced compared with that observed in control animals that did not receive L-arginine.²⁴

NO Donors
Linsidomine and molsidomine are members of the sydnonimine antianginal class of drugs. Sydnonimines were developed in Japan and were initially used as antihypertensive agents.^{25 26} Subsequently, molsidomine was approved in several European countries as an antianginal drug. Linsidomine is derived from molsidomine by hydrolysis and decarboxylation. The novel feature of this group of compounds is the sydnonimine ring, a mesoionic heterocycle that opens independently of enzymatic activity and gives rise to a direct NO-releasing molecule.²⁷ Linsidomine is suitable only for parenteral administration, whereas molsidomine is active when administered orally.^{28 29} SIN-lA is the active metabolite of both drugs and releases NO by spontaneous degradation.³⁰ Thus, the mechanisms of action of these drugs contrast with that of the nitrates, which act through an enzyme system attached to the surface of the cell membrane.³¹ In fact, in nitrate-tolerant human coronary arteries, the responsiveness to linsidomine is maintained.³² Angiographic studies have shown that linsidomine is a potent dilator of human epicardial coronary arteries.³³ Linsidomine and molsidomine are well tolerated; there are no reports of clinically significant methemoglobinemia.

Present Study
The present study demonstrated that pretreatment with linsidomine was associated with a better immediate result after balloon angioplasty than pretreatment with diltiazem. The larger acute gain (+0.13 mm) in the NO donor group was maintained at 6 months (+0.16 mm). Indeed, the angiographic benefit (difference in MLD) at follow-up in the NO donor group compared with the control group was of the same order of magnitude as the benefit obtained by implantation of an intracoronary stent (0.09 mm) in the recently reported Belgian Netherlands Stent Study.¹⁵

The quantitative angiographic analysis shows that the improved long-term angiographic outcome in the NO donor group was related primarily to a better immediate angiographic result. The mechanisms responsible for the better angiographic result are probably related to the potent vasodilator effects of linsidomine. The reference diameter in the group pretreated with linsidomine was slightly but significantly greater than that in the group pretreated with diltiazem. This difference occurred despite the systematic intracoronary administration of isosorbide dinitrate immediately before angioplasty in both groups. The dose used (2 mg) was similar to that used in other restenosis prevention trials. It is unlikely that the difference in reference diameter resulted from a randomization bias. All other clinical and angiographic baseline characteristics were well matched in both groups. Furthermore, the anatomic distribution of the dilated segments was similar in the two groups. As a consequence of the larger reference diameter, the absolute balloon size was slightly but significantly larger in the linsidomine group. The ratio between the diameter of the balloon and the diameter of the adjacent angiographically normal vessel was the same in both groups, demonstrating that the larger balloon size in the linsidomine group was not the result of systematic oversizing in this group. Furthermore, post hoc subgroup analyses stratifying for balloon diameter and correcting for the difference in reference diameter between groups confirmed the existence of a treatment effect that was independent of balloon size or reference diameter. The acute gain (0.13 mm) cannot be accounted for solely by the difference in balloon size (0.08 mm). The enhanced vasodilation produced by linsidomine that leads to an improved arterial compliance may also have contributed. This possibility is supported by the facts that the immediate elastic recoil was significantly less in the linsidomine group than in the diltiazem group and that the observed acute gain after adjustment for balloon size remained significantly greater in the NO donor group. Previous angiographic studies have shown that the late loss in MLD after angioplasty is directly correlated to the acute gain in diameter resulting from angioplasty.^{13 34} It was an intriguing finding in the present study that although the immediate gain was greater in the linsidomine group, the late loss did not differ significantly between groups.

In summary, the better long-term angiographic result is probably related to the use of a larger balloon, reflecting the larger preprocedural reference diameter associated with pretreatment by linsidomine, and to a significantly lesser degree of immediate elastic recoil. Both mechanisms contributed to the achievement of a better acute result that was maintained at follow-up. Finally, when this study was designed, the available evidence suggested that diltiazem had no effect on the occurrence of restenosis^{8 9} ; a recent meta-analysis suggests that calcium antagonists may have a beneficial effect on the occurrence of restenosis; thus, the use of diltiazem in the control group could potentially have led to an underestimation of the effect of NO donors on angiographic restenosis.³⁵ Despite the better long-term angiographic result, there was no difference in clinical end points between the groups. The rate of late revascularization was the same (28%) in both groups. It is difficult, however, to evaluate in an unbiased fashion the clinical benefit of a given treatment in a study that requires repeated angiography to define the primary end point. In clinical practice, symptom status and noninvasive tests generally guide the decision to perform repeat angiography. In restenosis prevention trials, the additional knowledge of coronary anatomy may affect subsequent management. Furthermore, the power of the study was insufficient to determine whether treatment was associated with long-term clinical benefit.

Study Limitations
This study was not conducted in a double-blind fashion. Therefore, although the statistical analyses suggest that deliberate oversizing of the balloon did not occur in the NO donor group, such a possibility cannot be excluded. Second, the power of the study was insufficient to determine whether NO donor treatment was associated with a reduction in clinical events. Third, the angiographic benefit at follow-up was demonstrated on angiograms performed soon after discontinuation of treatment in the two groups; thus, we cannot exclude with certainty that a vasodilator effect of molsidomine or diltiazem was present at the time of angiography.

Conclusions
This study demonstrates that pretreatment with intravenous linsidomine, a direct NO donor, followed by oral molsidomine is associated with a modest improvement in long-term angiographic outcome after balloon angioplasty compared with treatment with diltiazem. This long-term angiographic benefit resulted from a better immediate angiographic result that was not associated with an increase in periprocedural complications or more extensive late loss in luminal diameter.

	Selected Abbreviations and Acronyms

 

ACCORD = Angioplastie Coronaire Corvasal Diltiazem MLD = minimal luminal diameter NO = nitric oxide PTCA = percutaneous transluminal coronary angioplasty TIMI = Thrombolysis in Myocardial Infarction

	Acknowledgments

 
This work was supported by a grant from Laboratoires Hoechst, France.

	Footnotes

 
Reprint requests to Jean-Marc Lablanche, Service de Cardiologie B et Hemodynamique, Hopital Cardiologique, CHRU de Lille, 59037 Lille, France.

	Appendix

Top Abstract Introduction Methods Results Discussion Appendix References

 
In addition to the study authors, the following investigators participated in the ACCORD trial.

Study coordinator: J.-M. Lablanche.

Steering Committee: M.E. Bertrand, B. Dupuis, H. Allain, and J.-M. Lablanche.

Angiography core laboratory: E.P. McFadden, C. Bauters, J.-M. Lablanche, and M.E. Bertrand, Hopital Cardiologique, Lille, France.

Study monitors: T. Giraud, H. Kolsky, P. Lendresse, and J.C. Reglier, Laboratoires Hoechst, Paris.

Statistical analysis: M. Kabir, J.C. Lemarie, and M.-D. Riou, Laboratoires Hoechst, Paris.

Investigators: Hopital Cote de Nacre, Caen: P. Tessier and J.C. Potier; Hopital Gabriel Montpied, Clermont-Ferrand: Jean Cassagnes and P. Barraud; Hopital Saint-Jacques, Besancon: F. Schiele and N. Meneveau; Groupe Hospitalier Pitie-Salpetriere, Paris: G. Montalescot; CHRU, Grenoble: J. Machecourt; Hopital Broussais, Paris: J.-L. Guermonprez; Hopital Trousseau, Tours: L. Quilliet and L. Maillard; Hopital de Brabois, Vandoeuvre: N. Danchin, F. Cherrier; Hopital Bichat, Paris: P.G. Steg and D. Himbert; Groupe Hospitalier Necker-Enfants Malades, Paris: A. Vacheron and C. Le Feuvre; Hopitaux de Haut-Leveque, Pessac: P. Dos Santos and P. Besse; Groupe Hospitalier Sud, Amiens: P. Avinee; Centre Hospitalier Henri Mondor, Creteil: A. Castaigne and E. Aptecar; Hopital Nord, Nantes: O. Bar; Hopital Charles Nicolle, Rouen: R. Koning and B. Baala; Hopital Morvan, Brest: M. Gilard and P. Cornec; Hopital Universitaire Dupuytren, Limoges: J.J. Doumeix and J. Bensaid; Hopital Louis Pradel, Lyon: J. Beaune and X. Andre-Fouet; Hopital Hotel-Dieu, Rennes: C. Leclerc and J.C. Pony; Hopital Andre Mignot, Le Chesnay: J.-P. Normand; Hopital Arnaud de Villeneuve, Montpellier: R. Grolleau; Hopital Purpan, Toulouse: D. Carrie and P. Bernadet.

Received May 1, 1996; revision received August 9, 1996; accepted August 19, 1996.

	References

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