Cilostazol reduces restenosis after carotid artery stenting
Article Outline
Background
Although carotid artery stenting (CAS) has been proposed as an alternative to carotid endarterectomy in cerebral revascularization, restenosis remains an unsolved issue. Cilostazol is a unique antiplatelet drug that has vasodilatory effects and inhibits smooth muscle cell proliferation. We investigated whether cilostazol reduces restenosis after CAS.
Methods
A database of 113 consecutive CAS procedures between April 2002 and December 2007 was assessed retrospectively. All patients received aspirin (100 mg/d) and another antiplatelet drug such as cilostazol (200 mg/d), ticlopidine (200 mg/d), or clopidogrel (75 mg/d) at least 3 days before CAS. Two antiplatelet drugs were continued for 2 to 3 months after CAS and reduced to one thereafter. Patients were evaluated at 3 and 6 months and at 6-month intervals thereafter with duplex ultrasound (DUS) imaging. Angiography was used for confirmation when stenosis was suspected as >50% with DUS imaging.
Results
We were able to monitor 97 patients for a 12-month period. The overall combined rate of stroke, myocardial infarction, and death was 3.1% at 30 days and 4.1% at 1 year. In-stent recurrent stenosis was documented in 11 patients (11%); in 10 patients (9.7%), this occurred ≤12 months of CAS. In-stent restenosis was significantly reduced in the cilostazol (+) group (0% vs 15.7% [11 of 70], P = .03). Patient characteristics were similar between the cilostazol (+) and cilostazol (–) groups.
Conclusions
Although this study was retrospective and nonrandomized, the results suggest that cilostazol administration improves long-term patency after CAS due to its inhibitory effect on smooth muscle cell growth.
Carotid artery stenting (CAS) is being used widely to treat severe carotid obstructive disease and is now accepted as a less invasive technique that provides an alternative for some patients, particularly those with significant comorbidities.1, 2, 3, 4, 5 Although distal embolism decreased with the use of the embolization protection device (EPD), up to 10% of patients develop >50% stenosis as determined by angiography or carotid duplex ultrasound (DUS) scanning, and this problem is not yet solved.3, 6, 7, 8 The rate approaches 20% in some patient subgroups, such as women and the elderly.7
These series of studies placed aspirin, ticlopidine, or clopidogrel as the current standard of antiplatelet drugs. Cilostazol, a cyclic adenosine monophosphate phosphodiesterase inhibitor, has multiple actions, including vasodilation and inhibition of platelet aggregation.9, 10, 11 Cilostazol is widely used as an antiplatelet drug in Japan. Several small trials reported that cilostazol use after endovascular treatment for peripheral artery and coronary artery diseases has a low rate of in-stent restenosis.12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 However, it is not known whether a preventive effect of cilostazol on restenosis is similarly recognized after CAS. Accordingly, the present study was undertaken to determine whether cilostazol is effective in preventing restenosis after CAS compared with other antiplatelet drugs.
Methods
Study design and patient sample
A retrospective study was conducted of patients who had undergone CAS between April 2002 and December 2007. Carotid DUS scans performed before the stenting procedure documented high-grade carotid stenosis in all patients. High-risk patients for carotid endarterectomy (CEA) with symptomatic carotid stenosis of ≥50% and asymptomatic carotid stenosis of ≥80% were considered for the stenting protocol. Procedural indications, clinical, laboratory, antiplatelet drugs, techniques, treatment outcomes, and the postoperative course were analyzed.
Eligibility for CAS was further determined on the basis of criteria established at a consensus conference,23 including:
During this period, 106 patients underwent 113 CAS procedures, and we were able to monitor 97 patients for 12 months. These included 83 men and 14 women with a mean age of 69.9 ± 7.2 years. Of these, 61 patients (62.9%) had symptomatic stenosis and 36 (37.1%) had asymptomatic lesions. Indications for CAS included recurrent stenosis after previous CEA in 5 (5.1%), high-risk cardiac comorbidity in 26 (26.8%), high-risk pulmonary comorbidity in 1 (1.0%), high carotid bifurcation in 30 (30.9%), and previous ipsilateral cervical radiation therapy in 8 (8.2%). Clinical characteristics are presented in Table I.
Table I. Patient characteristics
| Variable | No. (%) or |
|---|---|
| mean ± SD | |
| Patients, total | 97 (100) |
| Age, y | 69.6±7.2 |
| Male sex | 83(85.6) |
| Type of lesion | |
| Asymptomatic carotid stenosis | 36(37.1) |
| Symptomatic carotid stenosis | 61(62.9) |
| Stroke | 38(39.2) |
| Transient ischemic attack | 16(16.5) |
| Amaurosis fugax | 7(7.2) |
| Severity of stenosis, % | 82.9±9.5 |
| Comorbidities | |
| Coronary artery disease | 32(33.0) |
| History of myocardial infarction | 18(18.6) |
| Smoking | 70(72.2) |
| Hypertension | 78(80.4) |
| Diabetes | 29(29.9) |
| COPD | 1(1.0) |
| Hypercholesterolemia | 49(50.5) |
| Renal insufficiency | 7(7.2) |
| Peripheral artery disease | 8(8.2) |
| CAS indications | |
| High-risk cardiac comorbidity | 26(26.8) |
| High carotid bifurcation | 30(30.9) |
| High-risk pulmonary comorbidity | 1(1.0) |
| History of neck irradiation | 8(8.2) |
| Stenosis after CEA | 5(5.1) |
CAS protocol
A neurologist independent from the study examined all patients before each procedure to determine neurologic status. DUS scanning was also performed in all cases. Patients treated electively received aspirin (100 mg/d) and another antiplatelet agent such as clopidogrel (75 mg/d), ticlopidine (200 mg/d), or cilostazol (200 mg/d) for at least 3 days before the intervention. Patients electively received aspirin and thienopyridine (ticlopidine or clopidogrel). Clopidogrel was approved in Japan by the Pharmaceutical Affairs Law after December 2006, so patients received ticlopidine before then, and clopidogrel was added after December 2006. Patients with peripheral artery disease or coronary artery disease received cilostazol or thienopyridine, or both, before CAS. This combination of antiplatelet drugs was continued from the protocol for cardiovascular medicine.
Standard monitoring techniques were used during CAS, including intra-arterial pressure monitoring, oximetry, and continuous electrocardiography. During the procedure, the patient's neurologic status was continuously monitored by verbal command.
Standard retrograde access was achieved through the common femoral artery under local anesthesia with 1% lidocaine. An 8F vascular sheath was inserted. Heparin was administered to achieve an activated clotting time of >300 seconds.
An 8F guiding catheter was navigated into the common carotid artery. Carotid angiogram and intracranial injections were performed. A 0.018-inch guidewire system with EPD was then manipulated to cross the internal carotid lesion. For patients with high-grade stenosis that was nearly occluded or with thrombosis, procedures were performed using the reversed-flow system.
After the activation of the EPD system, a coaxial angioplasty balloon was used to predilate the carotid lesion if necessary. Next, a self-expanding carotid stent was deployed across the internal carotid stenosis. Postdilation was performed if necessary. On completion, ipsilateral cervical and intracranial carotid angiography was performed to assess technical success and to exclude distal cerebral embolization.
Patients were monitored in an intensive care unit overnight and were discharged 3 or 4 days later. A clinical examination and DUS scanning were performed before discharge to confirm stent patency and position. One antiplatelet drug was prescribed to be taken for life and another to be terminated after 2 or 3 months. Life-long aspirin therapy was prescribed. In patients with peripheral artery disease or coronary artery disease, cilostazol or thienopyridine, or both, was added before CAS. This combination of antiplatelet drugs was continued from the protocol for cardiovascular medicine. After CAS, this combination was continued for life.
Follow-up protocol and criteria for restenosis assessment
All patients were scheduled for follow-up at the hospital's outpatient clinic at 1, 3, 6, 9, and 12 months after the procedure and every 6 months thereafter. During these routine postoperative visits, the surgeon and the independent neurologist examined each patient, and carotid DUS scans were performed at 3 and 6 months and at 6-month intervals thereafter.
The velocity criteria used to evaluate carotid artery stenosis were modifications of the Japanese Academy of Neurosonology Guidelines for Neurosonology and were validated in our hospital. Peak systolic velocity >150 cm/s correlated with >50% stenosis.24 In addition, luminal reductions on grayscale images and color flow disturbances were further evaluated. In-stent restenosis identified by DUS scanning was further verified by carotid angiography, and stenosis was measured geometrically on the basis of the North American Symptomatic Carotid Endarterectomy Trial (NASCET) criteria.25 When >50% restenosis was recognized, carotid angioplasty and possible stenting were subsequently performed.
Statistical analysis
Clinical variables that may be associated with restenosis after CAS were analyzed. Continuous data are shown as mean ± standard deviation (SD). The unpaired t test was used to compare continuous variables between the groups. The χ2 test or Fisher's exact test was used to compare ratios. Statistical significance was defined as a P < .05.
Results
CAS outcomes at 30 days and 1 year
All lesions were accessed, and the procedures were performed successfully, for a technical success rate of 100%. Mean stenosis treated was 82.9% ± 9.5%, and the mean residual stenosis after treatment was 5.2% ± 0.5%. Wallstents (Boston Scientific, Natick, Mass) were deployed in 71 procedures (73.2%), Precise (Cordis, Miami, Fla) in 8 (8.2%), Protage (eV3, Plymouth, Minn) in 2 (2.1%), Xpert (Abbott Vascular, Redwood City, Calif) in 1 (1.0%), and SMARTeR stent (Cordis) in 15 (15.5%). All stenting procedures were performed with EPDs, including the PercuSurge Guardwire device (Medtronic, Minneapolis Minn) in 82 (84.5%), AngioGuard XP (Cordis) in 7 (7.2%), and a reversed-flow system in 7 (7.2%).
The overall 30-day stroke, myocardial infarction, and death rate was 3.1% (n = 3). Each of the three strokes was minor (2 ipsilateral minor strokes and 1 contralateral stroke). Postoperative DUS scanning was performed ≤1 week after CAS. No in-stent restenosis, carotid dissections, or thromboses were documented. During the 1-year follow-up, one patient sustained a myocardial infarction. The overall 1-year outcome for stroke, myocardial infarction, and death was 4.1%.
Long-term follow-up and in-stent restenosis
Nine patients were lost to follow-up, which was a mean of 28.6 ± 13.3 months (range, 12-67 months). In-stent restenosis, confirmed by DUS scanning and angiography, was detected in 11 of 97 carotid arteries (11.3%) within a mean of 8.9 ± 3.0 months (range, 5-16 months). Mean restenosis was 55.5% ± 7.2%, and mean peak systolic velocity was 200.8 ± 75.1 cm/s. All patients with recurrent stenosis were asymptomatic. Patients were a mean age of 69.3 ± 16.2 years, and there were 10 men and one woman. A comparison of patient characteristics, clinical symptoms, CAS indications, CAS devices, and CAS technique among the patients with in-stent restenosis and without in-stent restenosis found no significant difference (Table II).
Table II. Comparison of patients with and without in-stent restenosis
| Variable | No ISR | ISR (≥50%) | P |
|---|---|---|---|
| (n = 86) | (n = 11) | ||
| Age, mean ± SD, y | 69.7±7.2 | 69.3±7.9 | .93 |
| Male sex, % | 84.8 | 90.1 | .93 |
| Type of lesion, % | |||
| Asymptomatic carotid stenosis | 38.4 | 27.3 | .70 |
| Symptomatic carotid stenosis | 61.6 | 72.7 | .70 |
| Stroke | 38.4 | 45.5 | .90 |
| Transient ischemic attack | 16.2 | 18.1 | .79 |
| Amaurosis fugax | 7.0 | 9.1 | .72 |
| Severity of stenosis, mean ± SD, % | 82.5±9.9 | 85.8±5.2 | .10 |
| Comorbidities, % | |||
| Coronary artery disease | 32.5 | 36.4 | .93 |
| History of myocardial infarction | 18.6 | 18.2 | .71 |
| Smoking | 70.9 | 81.8 | .69 |
| Hypertension | 82.6 | 63.6 | .28 |
| Diabetes | 30.2 | 27.3 | .88 |
| Chronic obstructive pulmonary disease | 1.2 | 0 | .22 |
| Hypercholesterolemia | 51.2 | 45.5 | .97 |
| Renal insufficiency | 8.1 | 0 | .72 |
| Peripheral artery disease | 8.1 | 9.1 | .64 |
| Carotid artery stenting indications, % | |||
| High-risk cardiac comorbidity | 26.7 | 27.3 | .75 |
| High carotid bifurcation | 30.2 | 36.4 | .95 |
| High-risk pulmonary comorbidity | 1.2 | 0 | .22 |
| History of neck irradiation | 8.1 | 9.1 | .64 |
| Stenosis after carotid endarterectomy | 5.8 | 0 | .92 |
| Stents, % | |||
| Wallstent | 74.4 | 63.6 | .69 |
| Precise | 8.1 | 9.1 | .64 |
| SMARTeR | 14.0 | 27.3 | .48 |
| Xpert | 1.2 | 0 | .22 |
| Protage | 2.3 | 0 | .54 |
| Embolization protectin device, % | |||
| PercuSurge Guardwire | 83.7 | 90.9 | .86 |
| AngioGuard | 7.0 | 9.1 | .72 |
| Navi balloon | 1.2 | 0 | .22 |
| Reversed-flow system | 8.1 | 0 | .72 |
| Preballoon dilatation, % | 97.7 | 100 | .54 |
| Postballoon dilatation, % | 80.2 | 72.7 | .85 |
| Residual stenosis post-op, mean ± SD, % | 4.8±5.2 | 8.9±8.0 | .21 |
Two patients did not want repeat treatment and were monitored with serial clinical evaluation and DUS scanning at 3- to 6-month intervals. Nine of 11 patients underwent endovascular reintervention, consisting of repeat balloon angioplasty in five and repeat angioplasty and secondary stenting in four. Technical success was achieved in all patients, and the mean carotid artery stenosis decreased from 54.6% to 11% after reintervention. No procedurally related complications were noted after in-stent restenosis intervention. All patients who underwent reintervention have remained recurrence-free during median follow-up periods of 20.6 months.
Antiplatelet therapy after CAS and in-stent restenosis
Antiplatelet drugs that were continued for 1 year after CAS are presented in Table III. The combinations of antiplatelet agents were aspirin, 28; ticlopidine, 3; clopidogrel, 10; cilostazol, 1; aspirin and ticlopidine, 23; aspirin and clopidogrel, 6; aspirin and cilostazol, 19; cilostazol and clopidogrel, 3; aspirin and ticlopidine and cilostazol, 1; and aspirin and clopidogrel and cilostazol, 3.
Table III. Antiplatelet drugs used in 97 patients after carotid artery stenting for 1 year
| Drug | No. | Overall stroke, MI, and death | Restenosis | |
|---|---|---|---|---|
| At 30 days | At 1 year | |||
| (n = 3) | (n = 4) | (n = 11) | ||
| Aspirin (+), No. (%) | 80 | 2(2.5) | 3(3.8) | 8(10.0) |
| Aspirin (–), No. (%) | 17 | 1(5.9) | 1(5.9) | 3(17.6) |
| Cilostazol (+), No. (%) | 27 | 1(3.7) | 1(3.7) | 0(0)a |
| Cilostazol (–), No. (%) | 70 | 2(2.9) | 3(4.3) | 11(15.7) |
| Ticlopidine (+), No. (%) | 27 | 0(0) | 1(3.7) | 7(25.9)b |
| Ticlopidine (–), No. (%) | 70 | 3(4.3) | 3(4.3) | 4(5.7) |
| Clopidogrel (+), No. (%) | 22 | 2(9.1) | 2(9.1) | 3(13.6) |
| Clopidogrel (–), No. (%) | 75 | 1(1.3) | 2(2.7) | 8(10.7) |
aP = .03; |
bP = .01. |
No significant differences were noted in overall 30-day and 1-year stroke, myocardial infarction, and death among patients in each drug group. Patients in the cilostazol (+) group had 0% incidences of restenosis compared with 15.7% for patients without cilostazol (P = .03). The restenosis rate was 25.9% in patients who took ticlopidine compared with 5.7% in patients without ticlopidine (P = .01). Patient, lesion characteristics, and CAS technique did not differ between the cilostazol (+) and cilostazol (–) groups. Use of additional drugs was similar between the groups, except that ticlopidine was used more frequently in the cilostazol (–) group than in the cilostazol (+) group.
Discussion
The incidence of postprocedural in-stent restenosis is 1% to 50% in published reports.1, 3, 26, 27, 28 The reported rate of in-stent restenosis depends on the definition of recurrent stenosis, duration of follow-up, and the methods of diagnosis. Although most of these reports were based on short follow-up periods, several authors more recently presented findings after periods of longer follow-up. Setacci et al29 reported a 3.6% incidence of high-grade restenosis (>80%) during a 21-month follow-up period with more than 372 carotid stents. Similarly, Chakhtoura et al26 reported an 8% high-grade restenosis rate during their 18-month follow-up of 50 CAS procedures. Our study, likewise, demonstrated an 11.3% moderate-grade (>50%) in-stent restenosis rate during a mean 28.6-month follow-up period.
Cilostazol, a phosphodiesterase 3 inhibitor, has antiplatelet action, vasodilatory effects, and inhibits smooth muscle cell proliferation.10, 11, 30, 31 Cilostazol reportedly increases the cyclic adenosine monophosphate phosphodiesterase level in vascular smooth muscle cells, resulting in upregulation of the antioncogenes p53 and p21 and hepatocyte growth factor.32 Because the increase in p53 protein blocks cell cycle progression and induces apoptosis in vascular smooth muscle cells, these mechanisms have an antiproliferative effect.33 Furthermore, hepatocyte growth factor stimulates re-endothelialization after vascular injury, inhibits abnormal vascular smooth muscle cell growth, and improves endothelial function.34
Because neointimal hyperplasia is a major cause of recurrent stenosis after CAS, these actions may possibly explain the beneficial effect of cilostazol on reducing the in-stent restenosis rate. Cilostazol also inhibits P-selectin-mediated leukocyte activation, platelet-leukocyte interaction, and subsequent Mac-I-mediated leukocyte activation.35 Because inhibition of these actions is thought to reduce neointimal thickening after vascular injury, this mechanism may also be important in the reduction of restenosis after CAS.
Earlier studies have indicated that cilostazol improves symptoms and increases walking distance in patients with peripheral artery disease with intermittent claudication.12 Recent studies have shown that cilostazol reduces restenosis and target lesion revascularization after percutaneous transluminal angioplasty in patients with peripheral artery disease.13, 14, 15 Consequently, cilostazol is a class 1 drug for patients with peripheral artery disease according to American Heart Association guidelines.36
Several studies have also shown that cilostazol has the potential to reduce restenosis compared with aspirin after balloon angioplasty, stent implantation, and directional coronary atherectomy.16, 17, 18, 19, 20 Douglas et al12 reported that cilostazol was effective on restenosis after coronary artery stenting compared with placebo. Tanabe et al21 reported on the effect of cilostazol on restenosis after coronary angioplasty and stenting compared with coronary artery stenting with ticlopidine.
In the study presented here, cilostazol was as effective as other antiplatelet drugs in preventing periprocedual and 1-year complications after CAS, as evidenced by the lack of any significant differences in vascular events observed at the 30-day and 1-year follow-up visits. Furthermore, cilostazol was more effective in reducing restenosis after stent implantation than the other antiplatelet drugs. The inhibitory effect of cilostazol on restenosis may not be due to its antiplatelet effects but is possibly due to its direct inhibition of smooth muscle cell growth.
This study was a nonrandomized, retrospective at a single-center trial, and there were few numbers. A large-scale, prospective, multicenter study should be undertaken to verify these preliminary conclusions.
Conclusion
Cilostazol may have the potential to reduce the rate of restenosis after CAS due to its inhibitory effect on smooth muscle cell growth.
Author contributions
References
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Competition of interest: none.
The editors and reviewers of this article have no relevant financial relationships to disclose per the JVS policy that requires reviewers to decline review of any manuscript for which they may have a competition of interest.
PII: S0741-5214(09)01681-4
doi:10.1016/j.jvs.2009.08.040
© 2010 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.
