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Head and neck
REVIEW
Drug eluting stents versus bare metal stents for the treatment of extracranial vertebral artery disease: a meta-analysis Vivek H Tank,1 Ritam Ghosh,2 Vikas Gupta,3 Nakul Sheth,2 Shariyah Gordon,2 Wenzhen He,2 Steven F Modica,2 Charles J Prestigiacomo,2 Chirag D Gandhi2 1
Texas Institute for Neurological Disorders (TIND), Sherman, Texas, USA 2 Department of Neurological Surgery, Rutgers New Jersey Medical School, Newark, New Jersey, USA 3 Department of Neurology, University of Missouri, Columbia, Missouri, USA Correspondence to Dr Vivek H Tank, Texas Institute for Neurological Disorders, 321 North Highland Avenue, Suite 200, Sherman, TX 75092, USA; [email protected] Received 3 May 2015 Revised 22 June 2015 Accepted 25 June 2015
ABSTRACT Background While a growing number of reports offer evidence for the potential of drug eluting stents (DES) in treating atherosclerotic stenosis of the extracranial vertebral artery, their efficacy when compared with bare metal stents (BMS) is uncertain due to the lack of a large prospective randomized trial. Methods A search strategy using the terms ‘stents’, ‘drug-eluting stents’, ‘atherosclerosis’, ‘vertebral artery’, and ‘vertebrobasilar insufficiency’ was employed through Medline. Five studies met the criteria for a comparative meta-analysis. The technical/clinical success, periprocedural complications, target vessel revascularization (TVR), rates of restenosis, recurrent symptoms, and overall survival were compared. Results There was no significant difference in the technical success (OR=1.528, p=0.622), clinical success (OR=1.917, p=0.274), and periprocedural complications (OR=0.741, p=0.614) between the two groups. An OR of 0.388 for no restenosis in the BMS to DES arms ( p=0.001) indicated a significantly higher restenosis rate in the BMS group relative to the DES group (33.57% vs 15.49%). When compared with the DES group, the BMS group had a significantly higher rate of recurrent symptoms (2.76% vs 11.26%; OR=3.319, p=0.011) and TVR (4.83% vs 19.21%; OR=4.099, p=0.001). Conclusions A significantly lower rate of restenosis, recurrent symptoms, and TVR was noted in the DES group compared with the BMS group.
INTRODUCTION
To cite: Tank VH, Ghosh R, Gupta V, et al. J NeuroIntervent Surg Published Online First: [please include Day Month Year] doi:10.1136/ neurintsurg-2015-011697
Posterior circulation strokes carry a high rate of morbidity and mortality due to the vital structures that receive blood supply from the vertebrobasilar system. It is estimated that, of the approximately 700 000 strokes occurring annually, 20% of these affect the posterior circulation.1 Furthermore, between 9% and 20% of these cerebrovascular ischemic events occur as a result of vertebral artery stenosis (VAS). The mortality associated with vertebrobasilar circulation stroke is as high as 30%, and patients experiencing vertebrobasilar transient ischemic attacks (TIAs) have a 25–35% risk of stroke within 5 years.2 The vertebral artery is the second most common area of stenosis after the carotid bifurcation, with the stenosis most frequently occurring near the origin (V0) and proximal area of the vessel (V1). The etiology of the stenosis is similar to stenosis in the anterior circulation—namely, hypertension,
smoking, hyperlipidemia, etc. However, more frequently it is the result of artery–artery embolism from the heart, aorta, or a proximal vessel such as the subclavian artery (figure 1).3 When VAS occurs, symptoms include dizziness, syncope, diplopia, hemiparesis, leg weakness, and possible cerebellar dysfunction. Due to frequently present collateral circulation from the contralateral vertebral artery, treatment is usually only necessary for bilateral stenosis, severe stenosis of the dominant vertebral artery, or severe ipsilateral stenosis with vertebrobasilar insufficiency (VBI).4 Treatment starts with a regimen of antiplatelet agents such as aspirin or clopidogrel, or anticoagulant agents such as warfarin. However, when symptoms are persistent, either surgical or endovascular options need to be explored. Traditionally, open surgical vascular procedures which include endarterectomy, surgical bypass, and carotid–vertebral transposition have been shown to be technically feasible in this region.1 However, a great deal of experience is needed to perform these procedures and they have also been associated with considerable postoperative complications, such as Horner’s syndrome and lymphocele.5 Furthermore, the mortality associated with some surgeries has been reported to be as high as 20%.3 Since the 1980s, endovascular approaches to VAS have been gaining popularity due to the lower rates of complications as well as high technical success.1 The two most common forms of endovascular surgery are angioplasty and stenting. Balloon angioplasty, while maintaining high technical success, can be associated with poor outcomes due to the angioarchitecture of the vertebral artery, primarily in the ostium. Due to a high level of elastin and smooth muscle in the tunica media, there is a considerable risk of elastic recoil, vessel dissection, and restenosis.6 As an alternative, endovascular stenting has been shown to have excellent immediate results and low periprocedural complications. The two main forms of stents are bare metal stents (BMS) and drug eluting stents (DES). BMS, which are older and more commonly used, have been found to have high levels of in-stent restenosis (ISR) (figure 2).6 7 ISR rates range from 10–67% and can be attributed to stent fracture as well as neointimal hyperplasia, which is the thickening of the tunica intima of the blood vessel resulting from a surgical procedure or injury. This is due to the aforementioned anatomical features of the vertebral artery,
Tank VH, et al. J NeuroIntervent Surg 2015;0:1–5. doi:10.1136/neurintsurg-2015-011697
1
Downloaded from http://jnis.bmj.com/ on July 21, 2015 - Published by group.bmj.com
Head and neck Figure 1 (A) V1–V3 are the extracranial segments of the vertebral artery. (B) Schematic of stenosis at the ostium. (C) Tortuous nature of ostium and V1 segment may place mechanical strain on stents.
as well as the tortuous nature of the ostium and V1 segments, which places great mechanical strain on the stents.6 These complications with BMS lead to high rates of target vessel revascularization (TVR), which is defined by a repeat intervention of the target vessel driven by recurrent clinical symptoms with a >70% stenosis.8
To combat these complications, DES coated with a variety of substances such as sirolimus and paclitaxel have been used with increased efficacy in the coronary arteries. The immunosuppressant and immunomodulatory drugs released by the stents reduce the risk of ISR by limiting macrophage accumulation and smooth muscle cell proliferation around the stent (figure 3).6
Figure 2 Treatment with bare metal stents. (A) Left subclavian arteriography shows severe stenosis at the vertebral artery ostium. (B) Post-stenting angiography shows sufficient dilation of the lesion. (C) A dilated coronary balloon-expandable stent is seen on a simple radiograph immediately after treatment. (D) Follow-up angiography at 4 months after stent placement shows in-stent restenosis (arrow). (E) Deformity of the stent is seen on a simple radiograph during follow-up at 4 months (arrow). 2
Tank VH, et al. J NeuroIntervent Surg 2015;0:1–5. doi:10.1136/neurintsurg-2015-011697
Downloaded from http://jnis.bmj.com/ on July 21, 2015 - Published by group.bmj.com
Head and neck However, there has not been extensive research comparing BMS and DES in the clinical treatment of VAS. Therefore, this meta-analysis was undertaken to compare BMS and DES in terms of clinical success, technical success, mortality, perioperative complications, recurrent symptoms, and TVR.8
MATERIALS AND METHODS A Medline search was performed using the terms ‘stents’, ‘drug-eluting stents’, ‘atherosclerosis’, ‘vertebral artery’, and ‘vertebrobasilar insufficiency’. The criteria were that the studies were published within the last 5–7 years, looked specifically at BMS and DES, and were testing for similar outcome measures of interest. Five studies met the criteria for a comparative meta-analysis.8–12 The BMS were either made of cobalt chromium or stainless steel, while the DES were either coated with sirolimus or paclitaxel. The technical and clinical success, periprocedural complications, TVR, rates of restenosis, and recurrent symptoms and overall survival were compared between the BMS and DES groups. Technical success was defined by resolving stenosis to between 20% and 30%, while clinical success was defined by technical success as well as a resolution of symptoms. Finally, the recurrent symptoms studied included TIAs, stroke, or VBI. Outcome measures were calculated using the Mantel– Haenszel method with fixed effect models. Heterogeneity among studies was analyzed as well. Sensitivity analysis was then performed with subgroup fixed effect model to solve the heterogeneity among studies. If all attempts were tried and the statistical heterogeneity was found to be a part of the variability of the selected sample trials other than the effect of differences among the groups of patients, the pooled data were then analyzed with random effect models. In case of significant heterogeneity, random effect models were used and heterogeneity between the studies was assessed with the Q statistic.
Table 1
Overview of studies included
Author
Total patients
Bare metal stents placed
Drug eluting stents placed
Akins et al11 Ogilvy et al9 Qureshi et al12 Raghuram et al10 Song et al8
12 50 12* 24† 206
7 35 3 15 94
5 15 10 13 112
*One patient required two stents for one lesion. †Four patients received bilateral stents.
While calculating OR, as some events had a number of 0, to be able to calculate the OR the name of the parameter was changed. For example, when calculating the OR for total death in BMS versus DES, the total survival rate was calculated rather than the death rate.
RESULTS The data were first compiled from the eligible studies which are listed in table 1. The mean values of the outcome parameters that were analyzed are shown in table 2, while the meta-analysis results are shown in table 3. The mean pretreatment stenosis was 83.8±4.2% in the DES group (n=156) and 80.12±2.7% in the BMS group (n=148); this difference was not significant. The rates of technical success, clinical success, and periprocedural complications were 98.78%, 95.77%, and 1.94%, respectively, for the DES group versus 100%, 97.96%, and 2.96%, respectively, for the BMS group. However, there was no significant difference in the technical success (OR=1.528, p=0.622), clinical success (OR=1.917, p=0.274), or periprocedural complications (OR=0.741, p=0.614) between the two cohorts.
Figure 3 Treatment with short balloon-expandable drug eluting stents. (A) Preprocedural angiograph shows significant vertebral ostial stenosis. (B) Postprocedural angiograph shows sufficient dilation of the lesion. (C) Follow-up at 5 months shows no intimal hyperplasia.
Tank VH, et al. J NeuroIntervent Surg 2015;0:1–5. doi:10.1136/neurintsurg-2015-011697
3
Downloaded from http://jnis.bmj.com/ on July 21, 2015 - Published by group.bmj.com
Head and neck Table 2 Mean value of outcome parameters reported in eligible studies Outcome parameters Technical success Clinical success Periprocedural complication rate (
Head and neck
REVIEW
Drug eluting stents versus bare metal stents for the treatment of extracranial vertebral artery disease: a meta-analysis Vivek H Tank,1 Ritam Ghosh,2 Vikas Gupta,3 Nakul Sheth,2 Shariyah Gordon,2 Wenzhen He,2 Steven F Modica,2 Charles J Prestigiacomo,2 Chirag D Gandhi2 1
Texas Institute for Neurological Disorders (TIND), Sherman, Texas, USA 2 Department of Neurological Surgery, Rutgers New Jersey Medical School, Newark, New Jersey, USA 3 Department of Neurology, University of Missouri, Columbia, Missouri, USA Correspondence to Dr Vivek H Tank, Texas Institute for Neurological Disorders, 321 North Highland Avenue, Suite 200, Sherman, TX 75092, USA; [email protected] Received 3 May 2015 Revised 22 June 2015 Accepted 25 June 2015
ABSTRACT Background While a growing number of reports offer evidence for the potential of drug eluting stents (DES) in treating atherosclerotic stenosis of the extracranial vertebral artery, their efficacy when compared with bare metal stents (BMS) is uncertain due to the lack of a large prospective randomized trial. Methods A search strategy using the terms ‘stents’, ‘drug-eluting stents’, ‘atherosclerosis’, ‘vertebral artery’, and ‘vertebrobasilar insufficiency’ was employed through Medline. Five studies met the criteria for a comparative meta-analysis. The technical/clinical success, periprocedural complications, target vessel revascularization (TVR), rates of restenosis, recurrent symptoms, and overall survival were compared. Results There was no significant difference in the technical success (OR=1.528, p=0.622), clinical success (OR=1.917, p=0.274), and periprocedural complications (OR=0.741, p=0.614) between the two groups. An OR of 0.388 for no restenosis in the BMS to DES arms ( p=0.001) indicated a significantly higher restenosis rate in the BMS group relative to the DES group (33.57% vs 15.49%). When compared with the DES group, the BMS group had a significantly higher rate of recurrent symptoms (2.76% vs 11.26%; OR=3.319, p=0.011) and TVR (4.83% vs 19.21%; OR=4.099, p=0.001). Conclusions A significantly lower rate of restenosis, recurrent symptoms, and TVR was noted in the DES group compared with the BMS group.
INTRODUCTION
To cite: Tank VH, Ghosh R, Gupta V, et al. J NeuroIntervent Surg Published Online First: [please include Day Month Year] doi:10.1136/ neurintsurg-2015-011697
Posterior circulation strokes carry a high rate of morbidity and mortality due to the vital structures that receive blood supply from the vertebrobasilar system. It is estimated that, of the approximately 700 000 strokes occurring annually, 20% of these affect the posterior circulation.1 Furthermore, between 9% and 20% of these cerebrovascular ischemic events occur as a result of vertebral artery stenosis (VAS). The mortality associated with vertebrobasilar circulation stroke is as high as 30%, and patients experiencing vertebrobasilar transient ischemic attacks (TIAs) have a 25–35% risk of stroke within 5 years.2 The vertebral artery is the second most common area of stenosis after the carotid bifurcation, with the stenosis most frequently occurring near the origin (V0) and proximal area of the vessel (V1). The etiology of the stenosis is similar to stenosis in the anterior circulation—namely, hypertension,
smoking, hyperlipidemia, etc. However, more frequently it is the result of artery–artery embolism from the heart, aorta, or a proximal vessel such as the subclavian artery (figure 1).3 When VAS occurs, symptoms include dizziness, syncope, diplopia, hemiparesis, leg weakness, and possible cerebellar dysfunction. Due to frequently present collateral circulation from the contralateral vertebral artery, treatment is usually only necessary for bilateral stenosis, severe stenosis of the dominant vertebral artery, or severe ipsilateral stenosis with vertebrobasilar insufficiency (VBI).4 Treatment starts with a regimen of antiplatelet agents such as aspirin or clopidogrel, or anticoagulant agents such as warfarin. However, when symptoms are persistent, either surgical or endovascular options need to be explored. Traditionally, open surgical vascular procedures which include endarterectomy, surgical bypass, and carotid–vertebral transposition have been shown to be technically feasible in this region.1 However, a great deal of experience is needed to perform these procedures and they have also been associated with considerable postoperative complications, such as Horner’s syndrome and lymphocele.5 Furthermore, the mortality associated with some surgeries has been reported to be as high as 20%.3 Since the 1980s, endovascular approaches to VAS have been gaining popularity due to the lower rates of complications as well as high technical success.1 The two most common forms of endovascular surgery are angioplasty and stenting. Balloon angioplasty, while maintaining high technical success, can be associated with poor outcomes due to the angioarchitecture of the vertebral artery, primarily in the ostium. Due to a high level of elastin and smooth muscle in the tunica media, there is a considerable risk of elastic recoil, vessel dissection, and restenosis.6 As an alternative, endovascular stenting has been shown to have excellent immediate results and low periprocedural complications. The two main forms of stents are bare metal stents (BMS) and drug eluting stents (DES). BMS, which are older and more commonly used, have been found to have high levels of in-stent restenosis (ISR) (figure 2).6 7 ISR rates range from 10–67% and can be attributed to stent fracture as well as neointimal hyperplasia, which is the thickening of the tunica intima of the blood vessel resulting from a surgical procedure or injury. This is due to the aforementioned anatomical features of the vertebral artery,
Tank VH, et al. J NeuroIntervent Surg 2015;0:1–5. doi:10.1136/neurintsurg-2015-011697
1
Downloaded from http://jnis.bmj.com/ on July 21, 2015 - Published by group.bmj.com
Head and neck Figure 1 (A) V1–V3 are the extracranial segments of the vertebral artery. (B) Schematic of stenosis at the ostium. (C) Tortuous nature of ostium and V1 segment may place mechanical strain on stents.
as well as the tortuous nature of the ostium and V1 segments, which places great mechanical strain on the stents.6 These complications with BMS lead to high rates of target vessel revascularization (TVR), which is defined by a repeat intervention of the target vessel driven by recurrent clinical symptoms with a >70% stenosis.8
To combat these complications, DES coated with a variety of substances such as sirolimus and paclitaxel have been used with increased efficacy in the coronary arteries. The immunosuppressant and immunomodulatory drugs released by the stents reduce the risk of ISR by limiting macrophage accumulation and smooth muscle cell proliferation around the stent (figure 3).6
Figure 2 Treatment with bare metal stents. (A) Left subclavian arteriography shows severe stenosis at the vertebral artery ostium. (B) Post-stenting angiography shows sufficient dilation of the lesion. (C) A dilated coronary balloon-expandable stent is seen on a simple radiograph immediately after treatment. (D) Follow-up angiography at 4 months after stent placement shows in-stent restenosis (arrow). (E) Deformity of the stent is seen on a simple radiograph during follow-up at 4 months (arrow). 2
Tank VH, et al. J NeuroIntervent Surg 2015;0:1–5. doi:10.1136/neurintsurg-2015-011697
Downloaded from http://jnis.bmj.com/ on July 21, 2015 - Published by group.bmj.com
Head and neck However, there has not been extensive research comparing BMS and DES in the clinical treatment of VAS. Therefore, this meta-analysis was undertaken to compare BMS and DES in terms of clinical success, technical success, mortality, perioperative complications, recurrent symptoms, and TVR.8
MATERIALS AND METHODS A Medline search was performed using the terms ‘stents’, ‘drug-eluting stents’, ‘atherosclerosis’, ‘vertebral artery’, and ‘vertebrobasilar insufficiency’. The criteria were that the studies were published within the last 5–7 years, looked specifically at BMS and DES, and were testing for similar outcome measures of interest. Five studies met the criteria for a comparative meta-analysis.8–12 The BMS were either made of cobalt chromium or stainless steel, while the DES were either coated with sirolimus or paclitaxel. The technical and clinical success, periprocedural complications, TVR, rates of restenosis, and recurrent symptoms and overall survival were compared between the BMS and DES groups. Technical success was defined by resolving stenosis to between 20% and 30%, while clinical success was defined by technical success as well as a resolution of symptoms. Finally, the recurrent symptoms studied included TIAs, stroke, or VBI. Outcome measures were calculated using the Mantel– Haenszel method with fixed effect models. Heterogeneity among studies was analyzed as well. Sensitivity analysis was then performed with subgroup fixed effect model to solve the heterogeneity among studies. If all attempts were tried and the statistical heterogeneity was found to be a part of the variability of the selected sample trials other than the effect of differences among the groups of patients, the pooled data were then analyzed with random effect models. In case of significant heterogeneity, random effect models were used and heterogeneity between the studies was assessed with the Q statistic.
Table 1
Overview of studies included
Author
Total patients
Bare metal stents placed
Drug eluting stents placed
Akins et al11 Ogilvy et al9 Qureshi et al12 Raghuram et al10 Song et al8
12 50 12* 24† 206
7 35 3 15 94
5 15 10 13 112
*One patient required two stents for one lesion. †Four patients received bilateral stents.
While calculating OR, as some events had a number of 0, to be able to calculate the OR the name of the parameter was changed. For example, when calculating the OR for total death in BMS versus DES, the total survival rate was calculated rather than the death rate.
RESULTS The data were first compiled from the eligible studies which are listed in table 1. The mean values of the outcome parameters that were analyzed are shown in table 2, while the meta-analysis results are shown in table 3. The mean pretreatment stenosis was 83.8±4.2% in the DES group (n=156) and 80.12±2.7% in the BMS group (n=148); this difference was not significant. The rates of technical success, clinical success, and periprocedural complications were 98.78%, 95.77%, and 1.94%, respectively, for the DES group versus 100%, 97.96%, and 2.96%, respectively, for the BMS group. However, there was no significant difference in the technical success (OR=1.528, p=0.622), clinical success (OR=1.917, p=0.274), or periprocedural complications (OR=0.741, p=0.614) between the two cohorts.
Figure 3 Treatment with short balloon-expandable drug eluting stents. (A) Preprocedural angiograph shows significant vertebral ostial stenosis. (B) Postprocedural angiograph shows sufficient dilation of the lesion. (C) Follow-up at 5 months shows no intimal hyperplasia.
Tank VH, et al. J NeuroIntervent Surg 2015;0:1–5. doi:10.1136/neurintsurg-2015-011697
3
Downloaded from http://jnis.bmj.com/ on July 21, 2015 - Published by group.bmj.com
Head and neck Table 2 Mean value of outcome parameters reported in eligible studies Outcome parameters Technical success Clinical success Periprocedural complication rate (
