Walter R.M. Hermans

Does the new angiotensin converting enzyme inhibitor cilazapril prevent restenosis after percutaneous transluminal coronary angioplasty? Results of the MERCATOR study: a multicenter, randomized, double-blind placebo-controlled trial

BACKGROUND Cilazapril is a novel angiotensin converting enzyme inhibitor with antiproliferative effects in the rat model after balloon injury. METHODS AND RESULTS We conducted a randomized, double-blind placebo-controlled trial to assess the effect of cilazapril in angiographic restenosis prevention after percutaneous transluminal coronary angioplasty (PTCA). Patients received cilazapril 2.5 mg in the evening after successful PTCA and 5 mg b.i.d. for 6 months or matched placebo. In addition, all patients received aspirin for 6 months. Coronary angiograms before PTCA, after PTCA, and at 6-month follow-up were quantitatively analyzed. In 94% of 735 recruited patients, PTCA was successful and all inclusion and exclusion criteria were met. For the per-protocol analysis, quantitative angiography after PTCA and at follow-up was available in 595 patients who complied with the treatment regimen (309 control, 286 cilazapril). The mean difference in minimal coronary lumen diameter between post-PTCA and follow-up angiogram (primary end point) was -0.29 +/- 0.49 mm in the control group and -0.27 +/- 0.51 mm in the cilazapril group. Clinical events during 6-month follow-up, analyzed on an intention-to-treat basis, were ranked according to the most serious clinical event ranging from death (control, two; cilazapril, three), nonfatal myocardial infarction (control, eight; cilazapril, 5), coronary revascularization (control, 51; cilazapril, 53), or recurrent angina requiring medical therapy (control, 67; cilazapril, 68) to none of the above (control, 224; cilazapril, 212). There were no significant differences in ranking. CONCLUSIONS Long-term angiotensin converting enzyme inhibition with cilazapril in a dose of 5 mg b.i.d. does not prevent restenosis and does not favorably influence the overall clinical outcome after PTCA.

Pharmacological approaches to the prevention of restenosis following angioplasty. The search for the Holy Grail? (part II)

SummaryLuminal renarrowing after balloon angioplasty still hampers the long term vessel patency in a substantial percentage of patients. Morphologically, the restenotic lesion comprises hyperplasia of intimai tissue, which is mainly characterised by proliferation of smooth muscle cells of the synthetic type with abundant extracellular matrix production, chiefly composed of proteoglycans. Unravelling the underlying pathophysiological process enables more specific intervention in basic interactions and cell responses. Critical events in the development of restenotic tissue are platelet aggregation and thrombus formation, while the release of several mediators promotes proliferation and migration of various cell types. All of these steps give access for a diversity of pharmacological interventions. With this in mind, antithrombotic, antiplatelet, antiproliferative, antiinflammatory, calcium channel blocking and lipid-lowering drugs have been investigated in the prevention of restenosis.Part II of this article reviews newer approaches, such as antibodies to growth factors, gene transfer and antisense oligonucleotides.

Luminal narrowing after percutaneous transluminal coronary angioplasty. A study of clinical, procedural, and lesional factors related to long-term angiographic outcome. Coronary Artery Restenosis Prevention on Repeated Thromboxane Antagonism (CARPORT) Study Group.

BACKGROUND The renarrowing process after successful percutaneous transluminal coronary angioplasty (PTCA) is now believed to be caused by a response-to-injury vessel wall reaction. The magnitude of this process can be assessed by the change in minimal lumen diameter (MLD) at follow-up angiography. The aim of the present study was to find independent patient-related, lesion-related, and procedure-related risk factors for this luminal narrowing process. A model that accurately predicts the amount of luminal narrowing could be an aid in patient or lesion selection for the procedure, and it could improve assessment of medium-term (6 months) prognosis. Modification or control of the identified risk factors could reduce overall restenosis rates, and it could assist in the selection of patients at risk for a large loss in lumen diameter. This population could then constitute the target population for pharmacological intervention studies. METHODS AND RESULTS Quantitative angiography was performed on 666 successfully dilated lesions at angioplasty and at 6-month follow-up. Multivariate linear regression analysis was performed to obtain variables with an independent contribution to the prediction of the absolute change in minimal lumen diameter. Diabetes mellitus, duration of angina < 2.3 months, gain in MLD at angioplasty, pre-PTCA MLD, lesion length > or = 6.8 mm, and thrombus after PTCA were independently predictive of change in MLD. Overall prediction of the model was poor, however, percentage-correct classification for a predicted change between -0.1 to -0.4 mm was approximately 10%. Lesions showing no change or regression (change > -0.1 mm) and lesions showing large progression (< or = -0.4 mm) were more predictable (correct classification, 59.5% and 49.7%, respectively). CONCLUSIONS Renarrowing after successful PTCA as determined with contrast angiography is a process that cannot be accurately predicted by simple clinical, morphological, and lesion characteristics.

Quantitative angiographic assessment of elastic recoil after percutaneous transluminal coronary angioplasty

Little is known about the elastic behavior of the coronary vessel wall directly after percutaneous transluminal coronary angioplasty (PTCA). Minimal luminal cross-sectional areas of 151 successfully dilated lesions were studied in 136 patients during balloon inflation and directly after withdrawal of the balloon. The circumvent geometric assumptions about the shape of the stenosis after PTCA, a videodensitometric analysis technique was used for the assessment of vascular cross-sectional areas. Elastic recoil was defined as the difference between balloon cross-sectional area of the largest balloon used at the highest pressure and minimal luminal cross-sectional area after PTCA. Mean balloon cross-sectional area was 5.2 +/- 1.6 mm2 with a mean minimal cross-sectional area of 2.8 +/- 1.4 mm2 immediately after inflation. Oversizing of the balloon (balloon artery ratio greater than 1) led to more recoil (0.8 +/- 0.3 vs 0.6 +/- 0.3 mm, p less than 0.001), suggestive of an elastic phenomenon. A difference in recoil of the 3 main coronary branches was observed: left anterior descending artery 2.7 +/- 1.3 mm2, circumflex artery 2.3 +/- 1.2 mm2 and right coronary artery 1.9 +/- 1.5 mm2 (p less than 0.025). The difference was still statistically significant if adjusted for reference area. Thus, nearly 50% of the theoretically achievable cross-sectional area (i.e., balloon cross-sectional area) is lost shortly after balloon deflation.

Lumen narrowing after percutaneous transluminal coronary balloon angioplasty follows a near gaussian distribution: A quantitative angiographic study in 1,445 successfully dilated lesions

To determine whether significant angiographic narrowing and restenosis after successful coronary balloon angioplasty is a specific disease entity occurring in a subset of dilated lesions or whether it is the tail end of a gaussian distributed phenomenon, 1,445 successfully dilated lesions were studied before and after coronary angioplasty and at 6-month follow-up study. The original cohort consisted of 1,353 patients of whom 1,232 underwent repeat angiography with quantitative analysis (follow-up rate 91.2%). Quantitative angiography was carried out off-line in a central core laboratory with an automated edge detection technique. Analyses were performed by analysts not involved with patient care. Distributions of minimal lumen diameter before angioplasty (1.03 +/- 0.37 mm), after angioplasty (1.78 +/- 0.36 mm) and at 6-month follow-up study (1.50 +/- 0.57 mm) as well as the percent diameter stenosis at 6-month follow-up study (44 +/- 19%) were assessed. The change in minimal lumen diameter from the post-angioplasty angiogram to the follow-up angiogram was also determined (-0.28 +/- 0.52 mm). Seventy lesions progressed toward total occlusion at follow-up. All observed distributions approximately followed a normal or gaussian distribution. Therefore, restenosis can be viewed as the tail end of an approximately gaussian distributed phenomenon, with some lesions crossing a more or less arbitrary cutoff point, rather than as a separate disease entity occurring in some lesions but not in others.

Prevention of restenosis after percutaneous transluminal coronary angioplasty: the search for a "magic bullet".

Percutaneous transluminal coronary angioplasty (PTCA) is an accepted treatment for providing relief of angina pectoris in patients with single-and multivessel disease. Increased experience and advances in technology have resulted in a high primary success rate (90 % to 95 % ) and a lower complication rate (4 % to 5 % ). Despite the therapeutic success of coronary angioplasty, the exact mechanisms of dilatation remain speculative and involve multiple processes including stretching of the vessel at the site of the dilatation and disruption and fissuring of the plaque.’ Angiographic renarrowing at the site of PTCA, frequently accompanied by recurrence of symptoms of angina, is a common phenomenon (30 % ) and has a negative bearing on the long-term results of PTCA. This usually occurs within the first 6 months after PTCA.“, ” Although many of the risk factors for restenosis have been identified (Table 1),4-25 most of these are difficult to influence. Until now we have not found a technical or pharmacologic cure, and we are unable to predict which patients or vessel segments will have restenosis. The reason why a clinically significant restenosis occurs in only a minority of the dilated vessels (30%) remains an enigma. Although the typical restenotic lesion differs from the usual atherosclerotic plaque in architecture and lipid content, both contain smooth muscle cells and fibrous tissue,P6. 27 and it is even likely that the factors responsible for restenosis are similar to those that effect de novo atherosclerosis. In some cases of “restenosis” it is conceivable that it is caused by progression of the preexisting atherosclerotic plaque. An important step in the restenosis process is activation of the hemostatic system with platelet adhesion, platelet aggregation, and fibrin formation. This is followed by smooth muscle cell proliferation, which is mediated by growth factors produced by cellular constituents in the blood and damaged vessel wa11.2”~2g Each of these steps could be sites of intervention that might halt the restenosis process. The drugs that could reduce or prevent restenosis in the animal model are listed in Table II. Some of these have been investigated in prospective randomized angioplasty trials and although efficacy has not been demonstrated, they continue to be used and prescribed in daily routine. In this review we will concentrate on the drugs (Fig. 1) that have been tested to prevent restenosis in the animal model (Table III) and in postangioplasty patients (Table IV). Animal models are of limited value in restenosis research because it is impossible to create arterial stenoses in animals (e.g., pigs, rabbits, or dogs) that resemble human coronary artery disease (Table V). Most models use an inflated balloon to “injure” the intimal and medial layers of the vessel wall, although infused air has also been used. Some investigators have performed experiments in iliac or carotid arteries rather than in coronary arteries; others have fed the animals an atherogenic diet for brief periods of time to induce an “atherosclerotic lesion.” Several studies in animals have examined the degree of platelet deposition after arterial injury to test the hypothesis that platelet aggregation and platelet-derived substances are responsible for the restenosis process.2g-“’ Other studies use angiographic or histologic findings in damaged arteries to assess restenosis (Table IV). Recently a model of human restenosis

Therapeutic dissection after successful coronary balloon angioplasty: No influence on restenosis or on clinical outcome in 693 patients☆

OBJECTIVES The objective of this study was to examine the relation between an angiographically visible coronary dissection immediately after successful coronary balloon angioplasty and a subsequent restenosis and long-term clinical outcome. BACKGROUND The study population comprised all 693 patients who participated in the MERCATOR trial (randomized, double-blind, placebo-controlled restenosis prevention trial of cilazapril, 5 mg two times a day). METHODS Cineangiographic films were processed and analyzed at a central angiographic core laboratory, without knowledge of clinical data, with use of an automated interpolated edge detection technique. Dissection was judged according to the National Heart, Lung, and Blood Institute classification. Angiographic follow-up was obtained in 94% of patients with 778 lesions. Two approaches were used to assess the restenosis phenomenon: 1) categoric, using the traditional cutoff criterion of greater than 50% diameter stenosis at follow-up, and 2) continuous, defined as absolute change in minimal lumen diameter (mm) between the postcoronary angioplasty and follow-up, adjusted for the vessel size (relative loss). Clinical outcome was ranked according to the most serious adverse clinical event per patient during the 6-month follow-up period, ranging from death, nonfatal myocardial infarction, coronary revascularization and recurrent angina requiring medical therapy to none of these. RESULTS Dissection was present in 247 (32%) of the 778 dilated lesions. The restenosis rate was 29% in lesions with and 30% in lesions without dissection (relative risk 0.97; 95% confidence interval 0.77 to 1.23). The relative loss in both groups was 0.10 (mean difference 0; 95% confidence interval -0.03 to 0.03). Clinical outcome ranged from death in 4 patients (0.9%) without dissection and 1 patient (0.4%) with dissection; nonfatal myocardial infarction in 4 (0.9%) without and 8 (3.2%) with dissection; coronary revascularization in 73 (16.6%) without and 32 (12.7%) with dissection; recurrent angina requiring medical therapy in 88 (20%) without and 47 (18.7%) with dissection to no serious adverse event in 272 (61.7%) without and 114 (65.1%) with dissection. CONCLUSIONS These data indicate that a successfully dilated coronary lesion with an angiographically visible dissection is no more likely to develop restenosis, and is not associated with a worse clinical outcome, at 6-month follow-up than is a dilated lesion without visible dissection on the post-balloon angioplasty angiogram.

Regional differences in elastic recoil after percutaneous transluminal coronary angioplasty: A quantitative angiographic study

The immediate result of percutaneous transluminal coronary angioplasty is influenced by both plastic and elastic changes of the vessel wall. To evaluate the amount of elastic recoil after coronary balloon angioplasty, the minimal luminal cross-sectional area of the largest balloon used at highest inflation pressure was compared with the minimal luminal vessel cross-sectional area directly after final balloon deflation in 607 lesions (526 patients). Elastic recoil was defined as the difference between balloon cross-sectional area and minimal luminal cross-sectional area of the dilated coronary segment immediately after balloon withdrawal. A videodensitometric analysis technique was used to avoid geometric assumptions on stenosis morphology directly after angioplasty. Mean balloon cross-sectional area was 5.3 +/- 1.6 mm2 and minimal luminal cross-sectional area after angioplasty was 2.8 +/- 1.4 mm2. Reference areas before and after angioplasty did not differ (6.0 +/- 2.6 and 6.2 +/- 2.6 mm2, respectively). Univariate analysis revealed that asymmetric lesions, lesions located in less angulated parts of the artery and lesions with a low plaque content showed more elastic recoil. Lesions located in distal parts of the coronary tree were also associated with more elastic recoil probably related to relative balloon oversizing in these distal lesions.

Usefulness of quantitative and qualitative angiographic lesion morphology, and clinical characteristics in predicting major adverse cardiac events during and after native coronary balloon angioplasty

Major, adverse cardiac events (death, myocardial infarction, bypass surgery and reintervention) occur in 4 to 7% of all patients undergoing coronary balloon angioplasty. Prospectively collected clinical data, and angiographic quantitative and qualitative lesion morphologic assessment and procedural factors were examined to determine whether the occurrence of these events could be predicted. Of 1,442 patients undergoing balloon angioplasty for native primary coronary disease in 2 European multicenter trials, 69 had major, adverse cardiac procedural or in-hospital complications after > or = 1 balloon inflation and were randomly matched with patients who completed an uncomplicated in-hospital course after successful angioplasty. No quantitative angiographic variable was associated with major adverse cardiac events in univariate and multivariate analyses. Univariate analysis showed that major adverse cardiac events were associated with the following preprocedural variables: (1) unstable angina (odds ratio [OR] 3.11; p < 0.0001), (2) type C lesion (OR 2.53; p < 0.004), (3) lesion location at a bend > 45 degrees (OR 2.34; p < 0.004), and (4) stenosis located in the middle segment of the artery dilated (OR 1.88; p < 0.03); and with the following postprocedural variable: angiographically visible dissection (OR 5.39; p < 0.0001). Multivariate logistic analysis was performed to identify variables independently correlated with the occurrence of major adverse cardiac events. The preprocedural multivariate model entered unstable angina (OR 3.77; p < 0.0003), lesions located at a bend > 45 degrees (OR 2.87; p < 0.0005), and stenosis located in the middle portion of the artery dilated (OR 1.95; p < 0.04).(ABSTRACT TRUNCATED AT 250 WORDS)

Restenosis after directional coronary atherectomy and balloon angioplasty: comparative analysis based on matched lesions.

OBJECTIVES Late lumen narrowing after directional coronary atherectomy was assessed by quantitative coronary angiography and compared with that after balloon angioplasty. BACKGROUND Directional coronary atherectomy has been introduced as an alternative technique for balloon angioplasty and may reduce the incidence of restenosis. METHODS A prospectively collected consecutive series of 87 native coronary artery lesions successfully treated with atherectomy were matched with 87 coronary artery lesions selected from a consecutive series of lesions that had been successfully dilated by balloon angioplasty. Late angiographic analysis was performed in 158 lesions. The net gain index represents the ultimate gain in minimal lumen diameter at follow-up study, normalized for the vessel size. This index is the result of the relative gain attained during the procedure (the ratio of the change in minimal lumen diameter and reference diameter) and the relative loss observed during the follow-up period (the ratio of the change in minimal lumen diameter during the follow-up period and the reference diameter). RESULTS Matching for clinical and angiographic variables resulted in two comparable groups with similar baseline stenosis characteristics. Atherectomy resulted in a more pronounced increase in minimal lumen diameter than did balloon angioplasty (mean +/- SD 1.17 +/- 0.29 to 2.44 +/- 0.42 mm vs. 1.21 +/- 0.38 to 2.00 +/- 0.36 mm, p < 0.001). However, this favorable immediate result was subsequently lost during late angiographic follow-up, so that the minimal lumen diameter at follow-up and the net gain index did not differ significantly between the two groups (1.76 +/- 0.62 vs. 1.77 +/- 0.59 mm, p = 0.93, and 0.18 +/- 0.19 vs. 0.17 +/- 0.17, p = 0.70). Consequently, the relative gain and relative loss were higher in the atherectomy group. For both techniques, the relative gain was linearly related to the relative loss but the slope of the regression line was steeper for atherectomy, suggesting that the relative loss in the atherectomy group is proportionally even larger for a given relative gain compared with that in the angioplasty group. CONCLUSIONS In matched groups of patients, atherectomy induces a greater initial gain in minimal lumen diameter than does balloon angioplasty. However, the vascular wall injury induced by the device is of a different nature (debulking vs. dilating) that leads to more relative loss over the follow-up period in the atherectomy group.