The CAIRP (CAndesartan for In-stent Restenosis Prevention)<br />
Trial — A Multicenter Study of AT1-Receptor Blocker Therapy<br />
in Coro

Stent implantation revolutionized interventional cardiology. Stent development required improved antiplatelet therapy and new materials.^1–3 Nonetheless, intimal hyperplasia resulting in in-stent restenosis (ISR) occurs in a significant number of patients. Despite several promising therapeutic approaches using beta-emitting probes or the release of substances from coated stent surfaces, a solution to the ISR problem remains unsatisfactory.^4,5 Recently, polymer-regulated paclitaxel and sirolimus delivery at the site of arterial injury was shown to reduce, but not eliminate, ISR.^6–12 Angiotensin II (Ang II) is an important vasoactive peptide contributing to ISR. Ang II is generated locally in the vessel wall and has a direct trophic influence on vascular smooth muscle cells ( VSMC).¹³ Ang II AT₁ receptors mediate the Ang II-related growth and inflammatory signals.^14,15
A T1-receptor blocking drugs are widely used to treat hypertension and heart failure.¹⁶ To date, three clinical trials have evaluated the effect of AT_1-receptor blockers on ISR. The Valsartan for Prevention of Restenosis after Stenting (VAL-PREST) and Valsartan versus ACE inhibition after bare-metal stent implantation (VALVACE) trials showed a significantly reduced ISR rate in patients receiving 80 mg of valsartan compared to placebo¹⁷ or angiotensin-converting enzyme (ACE) inhibitors,¹⁸ respectively. By contrast, the intimal hyperplasia inhibition by new angiotensin II receptor antagonist (ISHIN) trial failed to show a significant difference in ISR rates in patients treated with 8 mg/day of candesartan compared to placebo.¹⁹ To investigate this issue further, we performed a randomized, controlled trial.

Methods
This study was designed to investigate the effects of AT_1- receptor blockade with candesartan cilexetil compared to placebo in angiographically documented ISR over 6 months in patients with coronary heart disease undergoing coronary stenting. The ethics committee of the Charité Medical Faculty, in Berlin, Germany, approved the study, and written informed consent was obtained from all patients.
We recruited patients with angina pectoris and/or objective signs of ischemia (exercise electrocardiogram [ECG]/thallium scintigraphy) accompanied by coronary stenosis (> 50% reduction in diameter on visual estimation). They were scheduled for revascularization by means of balloon angioplasty with subsequent stent implantation. Inclusion criteria were suitability for interventional revascularization and written informed consent to participate in the study. Major exclusion criteria were acute myocardial infarction < 14 days before enrollment, indication for surgical treatment for coronary heart disease, bypass stenosis after aorto-coronary bypass operation, severe cardiac insufficiency (NYHA Class IV), known allergic reaction to ACE inhibitors or AT_1-receptor blockers, markedly impaired renal or hepatic function, and severe concomitant diseases such as malignancy. In addition, patients were excluded if their blood pressure was > 140/85 mmHg at one of three independent measurements, despite antihypertensive medication. Before enrollment and randomization, eligibility was confirmed by means of a general medical history including cardiovascular medical history and cardiovascular risk factors, and by general physical examination, resting and exercise ECG and general laboratory tests.
At least 1 day before stent implantation, patients were randomized to candesartan cilexetil or placebo. The target dose of candesartan cilexetil was 16 mg (2 tablets daily). Concomitant medication was acetylsalicylic acid (ASA) as long-term therapy and an adenosine diphosphate antagonist for 4 weeks for the prevention of early stent thrombosis. Apart from excluding other AT_1-blockers, no restrictions were placed on the prescription of other cardiac medications such as betablockers, diuretics or ACE inhibitors. In the event of a marked drop in blood pressure (> 12 mmHg systolic and/or 8 mmHg diastolic) during administration of the study drug, any concomitant antihypertensive medication was adjusted. If the patient did not take concomitant antihypertensive medication, the study medication was reduced to 8 mg of candesartan cilexetil (or 1 placebo tablet) daily.
Stent implantation was performed utilizing standard methods at least 24 hours after starting the study. Patients returned to the hospital 4 and 12 weeks after implantation for an outpatient visit to evaluate any adverse event. Six months after stent implantation, repeat coronary angiography, including quantitative coronary angiography (QCA) and intravascular ultrasound (IVUS) in one-third of the patients, were performed to investigate ISR. In addition, a complete clinical examination was performed, including exercise ECG or myocardial scintigraphy as on the first visit.
Quantitative coronary angiography. Diagnostic, periprocedural and follow-up angiography at baseline and after 6 months was performed in standardized projections. The angiographic data were digitalized, collected and centrally analyzed by an independent investigator in the core laboratory at Charité. All technical data (projections, position of the image intensifier, magnification factors, French size of the catheter, medication, contrast medium) were reported in detail. Angiography was performed before and directly after stenting and was repeated after 6 months. All angiograms had to meet appropriate standards for quantitative angiographic imaging. Before the intervention and at the end of the procedure, the target vessel was imaged in identical projections (orthogonal where possible) and at magnifications (> 2 for the right coronary artery [RCA] or > 3 for the left circumflex artery [LCX] and the left anterior descending artery [LAD]) that appeared suitable for a QCA analysis (CAAS II, Pie Medical System, Maastricht, Netherlands). It was recommended that large-lumen guide (7 Fr) catheters should be used, in order to achieve optimal contrast. Before the planned intervention, after stent implantation and during the follow-up examination, nitrates (i.e., 0.2 mg nitroglycerin) were injected prior to the angiographic imaging for QCA analysis. General technical aspects of coronary angiography have been reported elsewhere.²⁰
Intravascular ultrasound examination. At 6 months, one-third of patients underwent IVUS in addition to coronary angiography to determine the plaque and neointimal volume. The ultrasound examination was performed after the coronary angiography. After motorized retraction at 0.5 mm/second without ECG triggering, the images obtained were recorded on CD. Before the start of the examination, the picture quality was precisely adjusted, particularly in the close-up range. The image section was selected to ensure that the circumference of the vessel was clearly visible. The cross-sectional area and the maximal and minimal stent diameters were measured.²¹
Statistical analysis. For all quantitative variables, we determined the minimum, maximum, median and 1st and 3rd quartiles, and calculated the mean and standard deviation. The primary target parameter was the in-stent minimal lumen diameter (MLD) 6 months after implantation.
With 100 patients per group and a type-I error of 5%, differences in the expected values for the primary target parameters of 0.4 standard deviations can be demonstrated with a power of 90%. For binary incidences with these case numbers, odds ratios of 3 to below 2 can be demonstrated on the 5% level, with a power of 80%.
In accordance with the randomization and the case numbers of 100 patients per group, it was assumed that the distributions of the MLDs between the two groups after stent implantation was identical, apart from incidental deviations. Therefore, the MLDs 6 months after stent implantation were directly compared with each other, and the baseline values were not taken into account as covariables. As the MLDs were normally distributed in each group, t-tests for unmatched samples were used to compare the expected values; the 95% confidence interval for each group was calculated as an effect measure of the difference in the expected values. The observed difference was considered statistically significant if the calculated test size was greater than or equal to the 0.975 fractile of the respective distribution function of the test statistic (two-tailed test evaluation on the 5% level).
Secondary variables (restenosis rate, plaque area, incidence of major adverse cardiac events) were presented as descriptive statistics only, and p-values for these variables were considered exploratory.

Results

We enrolled 206 patients at 6 investigational centers. Candesartan was given to 107, while 99 received placebo. In each treatment group, 1 patient withdrew consent prior to receiving the drug. Forty-seven patients (28 patients in the Candesartan Group, and 19 in the Placebo Group) discontinued treatment during the study. Adverse events were reported in 14 candesartan patients and 9 placebo patients. Two candesartan patients and 4 placebo patients were lost to follow up. Eleven candesartan patients and 9 placebo patients left the study for other reasons. Demographic variables are shown in Table 1. The baseline demographics, characteristics and risk factors did not differ.

The mean MLDs at baseline before stent implantation, at baseline after stenting and after 6 months of treatment, as well as the mean change in each treatment group evaluated by QCA, are presented in Table 2. Mean MLDs after 6 months of treatment are shown in Figure 1. After 6 months of treatment, the mean MLD was 1.57 mm (confidence level [CL]: 1.45–1.69 mm) in the Candesartan Group and 1.48 mm (CL: 1.34–1.62 mm) in the Placebo Group. The mean difference between the two treatment groups was 0.090 mm (CL: - 0.092–0.2725), with a standard deviation of 0.595; this difference was not statistically significant (p = 0.33). In an exploratory analysis, the MLDs after 6 months that corresponded to the patients’ minimal MLDs after stent implementation, were analyzed. The mean corresponding MLDs (cMLDs) at baseline after stent implantation and after 6 months’ treatment were calculated. After 6 months, the mean cMLD was 1.56 mm (CL: 1.44–1.68 mm) in the Candesartan Group and 1.40 mm (CL: 1.28–1.53 mm) in the Placebo Group, as shown in Figure 2. The mean difference between the two groups was 0.16 mm (CL: -0.011–0.3315). This difference was not statistically significant (p = 0.066), but there was a trend toward larger cMLDs at follow up for the Candesartan Group.

In an additional analysis, the patients were stratified into two groups (target vessel diameter < 2.75 mm and ≥ 2.75 mm) according to the corresponding reference lumen diameter (defined in the same way as the cMLD) after stenting. After 6 months’ treatment, candesartantreated patients with small vessels showed a larger mean cMLD (1.39 mm) than those receiving placebo (1.18 mm). In vessels with a reference lumen diameter < 2.75 mm, there was a statistically significant advantage (mean treatment difference 0.21 mm) in favor of candesartan (p = 0.022), as shown in Figure 3. In vessels ≥ 2.75 mm, there was no significant difference between the two groups. The mean cMLD was 1.75 mm in the Candesartan Group and 1.80 mm in the Placebo Group, and the difference between treatments was -0.05 mm. In addition, the MLD was evaluated by IVUS in 25 candesartan-treated and 20 placebo-treated patients. There was no statistically significant difference in MLD in any location between the treatment groups.
The restenosis rate (defined as a decrease in MLD ≥ 50% from baseline after stent implantation) after 6 months was 30.6% for the patients treated with candesartan, and 28.4% for the placebo-treated patients; there was no significant difference in restenosis rates between the two treatment groups. In those patients who underwent IVUS at 6 months, a mean cross-sectional plaque area of 69.3% (standard deviation [SD] ± 5.9%) was observed in the candesartan-treated patients (n = 25), compared with 70.0% (SD ± 7.3%) in the placebo-treated patients (n = 20).

Adverse events are reported in Table 3. In the Candesartan Group, 27 patients (29.3%) experienced major adverse events (mainly repeat target vessel revascularization due to restenosis) compared with 30 patients (33.3%) in the Placebo Group. There were no statistically significant differences between the candesartan and placebo groups.

Discussion
We were unable to show that therapy with an AT_1- receptor blocker improves the outcome after PCI with bare-metal stents in all stented blood vessels. However, we found a positive effect of AT_1-receptor blocker therapy when we examined a patient subgroup with smaller vessel diameters. Small vessels have a higher ISR rate than large vessels. Small vessels are therefore highly desirable clinical targets, particularly because restenoses in small vessels are difficult to treat.
The data from our multicenter trial are not in agreement with those reported by the VALPREST and VALVACE investigators.^17,19 A benefit of AT_1- receptor blocker therapy was shown In the VALPREST trial, but only patients with more complex stenoses (type B1/C) were included in this study. The results could also have been confounded by the distribution of diabetic patients in the treatment and placebo groups. Diabetes was more common in the treatment group in that study. In the VALVACE trial, only patients with acute coronary syndromes benefited from the AT_1-receptor blocker treatment. However, the study compared valsartan to ACE inhibitor treatment. Both groups received anti-Ang II-treatment in that study. The ISHIN trial was confounded by a relatively low candesartan dose. A simple tablet treatment to decrease ISR, particularly in small vessels, would be of great clinical utility. Brachytherapy proved to be cumbersome and unsatisfactory for various reasons. Drug-eluting stents^6–12 are limited by in-stent thrombosis, which is not necessarily common, but can be devastating when it occurs.^22,23
The candesartan-related effect in our study was modest. It is possible that the dose required to provide vascular protection is higher than that needed to block the hemodynamic actions of Ang II.²⁷ This explanation is underscored by the fact that reductions in neointimal proliferation are concentration-dependent.^28,29 In addition, a foreign body reaction with multinucleated giant cells may occur in reaction to stenting.30 How such reactions are to be minimized is unclear. Furthermore, pretreatment with an AT_1- receptor blocker might be necessary for efficacy.^31–35 Although we could not show a significant reduction in ISR rates, there was a trend toward larger cMLDs at follow up for the Candesartan Group when comparing the cMLD at baseline after stenting and after 6 months’ treatment. When patients were stratified into two groups (< 2.75 mm/≥ 2.75 mm) according to the cMLD after stenting, we demonstrated a significant advantage in the Candesartan Group for patients with smaller vessels.
Study limitations. Our study necessarily has limitations. Even though our trial was multicentered, the total number of patients was relatively small. According to our results and previously published data, some subgroups showed a benefit with AT_1-receptor blocker therapy. The number of patients in the present study makes it difficult to obtain more significant data on subgroups. Finally, more detailed information about neointimal proliferation could not be gained due to the limited number of IVUS examinations. Nevertheless, our findings underscore the potential benefit of AT_1-receptor blocker therapy for certain subgroups after bare-metal stenting. Studies combining the use of drug-eluting stents and AT_1-receptor blockers for small coronary arteries should provide additional information on such benefits.
Acknowledgements. The authors wish to thank Drs. S. Gerbaulet, H. Olthoff and O. Weingärtner for their help with patient recruitment and follow up. Prof. Dr. Berger, of the University of Hamburg, Germany, performed the statistical analysis. Although he retired over two years ago, he was very kind to support us with further advice. AstraZeneca (Wedel, Germany) supplied the randomized medication and study monitoring.

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