Predictors of Restenosis After Coronary Stenting
Predictors of Restenosis After Coronary Stenting
In the current analysis we reported the incidence and predictors of angiographic restenosis in more than 10 000 patients with coronary artery disease treated with stent implantation at two centres over a 12 year period. The dataset analysed represents the largest population of patients with angiographic surveillance since the introduction of PCI. The salient findings are: (1) intervention with first generation DES is an independent predictor of lower rates of restenosis as compared with BMS; (2) intervention with second generation DES predicts less restenosis in comparison with first generation DES or second generation DES: small vessel size, longer stented length, complex lesion morphology, presence of diabetes mellitus, and history of bypass surgery are the most important predictors of angiographic restenosis.
Angiographic restenosis is usually defined as a binary measure being adjudicated in the presence of ≥50% lumen diameter stenosis at follow-up angiography, typically 6–9 months after intervention. Although the cut-off percentage diameter stenosis may be considered arbitrary, a significant body of evidence supports its robustness in the assessment of the efficacy of coronary stents. The introduction of DES therapy represented an important milestone in coronary intervention, significantly lowering both clinical and angiographic restenosis as compared with bare metal stenting. Indeed, the improved clinical outcomes seen with DES facilitated the expansion of percutaneous intervention to increasingly complex patient and lesion populations. However, as rates of restenosis increase with disease complexity, the absolute number of patients presenting with restenosis remains considerable and the identification of predictive factors is an issue of broad clinical importance. Moreover, although second generation DES now represent the dominant devices in clinical use, the impact of second generation DES on predictors of restenosis remains unclear.
A number of previous studies, based on relatively small patient cohorts, investigated the determinants of angiographic restenosis in patients undergoing coronary stenting. Following BMS implantation, the strongest predictors of restenosis were small vessel size, long lesion and long stented length, and presence of diabetes mellitus. In the DES era, the strongest predictors of restenosis were found to be small vessel size, long stented segments, final percentage of diameter stenosis, and the different antirestenotic potency of DES. Some studies also identified diabetes mellitus, in-stent restenosis and ostial lesion location as important predictive factors.
The present study assessed predictors of restenosis in the largest population undergoing coronary stenting and follow-up angiography since the introduction of PCI. We studied a broadly inclusive patient population treated with BMS, first generation DES and second generation DES. In addition we focused on angiographically proven restenosis as this likely represents the most objective parameter of efficacy after stent implantation, without the risk of bias associated with adjudication of clinical restenosis.
Our data confirm that across the spectrum of patients undergoing coronary stenting, small vessel size and long segment stenting continue to be strong predictors of restenosis, irrespective of the type of stent. Indeed, vessel size remains the factor most closely correlated with restenosis. Conceptually this is easy to understand: at an individual patient level, for any given degree of neointimal overgrowth after stenting the probability that the resultant diameter stenosis exceeds 50% is a straightforward function of vessel size and residual stenosis post-stenting. Although this association holds true regardless of stent type, by virtue of higher absolute suppression of neointimal hyperplasia, DES remain the most efficacious treatment modality for small vessel disease. Previous studies with BMS found the length of stented lesion strongly correlated with restenosis, although the relation between lesion length and restenosis after DES has been clear. The present dataset study underlines that total stented length remains a strong independent predictor of restenosis after both BMS and DES.
Left main stenting appears protective against restenosis in the univariate analysis, probably by virtue of a larger vessel diameter. After adjustment for other covariates (such as vessel size), left main stenting predicts higher restenosis risk, mainly due to lesion complexity (ie, bifurcation). Further investigation of the impact of left main stenting on restenosis is certainly warranted.
It is also notable that diabetes mellitus remains an important independent predictor of restenosis across the entire population enrolled in our study. Whether or not the high efficacy of DES attenuates or even eliminates the propensity of patients with diabetes to restenosis has remained a topic of some debate. Divergent definitions of diabetes and small sample sizes available for previous analyses may have had an impact on the true effect of this comorbidity in patients undergoing coronary stenting. However, the present large scale analysis confirms the importance of diabetes as a risk factor for restenosis after coronary stenting. Nevertheless, it might be observed that in the subgroup of patients treated with first generation DES, the presence of diabetes mellitus did not predict restenosis risk. Although the value of this finding in the setting of multiple comparisons may be debateable, the observation is consistent with previous data.
The current dataset also confirms that prior coronary bypass surgery remains a predictor of restenosis after stent implantation. This is in keeping with data from previous studies. The reason for this observation remains poorly defined. It is conceivable that this finding reflects the fact that these patients are likely to have more aggressive or advanced atherosclerotic disease, which confers reduced efficacy after percutaneous intervention.
We find that predictors of binary restenosis are similar across the spectrum of stent devices. However, we also demonstrate that intervention with first generation DES is a strong independent predictor of lower rates of restenosis as compared with BMS, and that intervention with second generation DES is a predictor of less restenosis in comparison with first generation DES. This supports observations from large scale meta-analysis of randomised trials and confirms the impact of device development on antirestenotic efficacy with sequential improvement from BMS to first generation DES to second generation DES.
The current analysis has some limitations. First, adjudication of restenosis was based on the percentage diameter of lumen renarrowing at surveillance angiography. As such, information on vessel wall morphology and restenotic tissue characterisation was not available. Secondly, angiographic follow-up was missing in 22.5% of patients. While these data are deemed 'missing not at random', it is a consistent feature of all large angiographic follow-up studies. Moreover the validity of such data has been shown to be high when rates of angiographic follow-up approach 80% and numerous studies have shown that angiographic surrogates are robust markers of device efficacy. These considerations notwithstanding, a possible selection bias, due to higher frequency of patients with recurrence of symptoms undergoing angiography, cannot be excluded. Thirdly, this study lacks a randomised design with stent selection based only on the period specific availability of the devices. As such, the findings in relation to comparative efficacy of different stent generations should be interpreted with caution. Fourthly, the grouping of stents as bare metal, first generation and second generation efficacy is necessarily arbitrary and cannot fully capture differences between different BMS or DES platforms. Finally, when analysing the predictive variables among BMS, first generation and second generation DES subgroups, the impact of errors introduced by multiple testing should be considered.
Discussion
In the current analysis we reported the incidence and predictors of angiographic restenosis in more than 10 000 patients with coronary artery disease treated with stent implantation at two centres over a 12 year period. The dataset analysed represents the largest population of patients with angiographic surveillance since the introduction of PCI. The salient findings are: (1) intervention with first generation DES is an independent predictor of lower rates of restenosis as compared with BMS; (2) intervention with second generation DES predicts less restenosis in comparison with first generation DES or second generation DES: small vessel size, longer stented length, complex lesion morphology, presence of diabetes mellitus, and history of bypass surgery are the most important predictors of angiographic restenosis.
Angiographic restenosis is usually defined as a binary measure being adjudicated in the presence of ≥50% lumen diameter stenosis at follow-up angiography, typically 6–9 months after intervention. Although the cut-off percentage diameter stenosis may be considered arbitrary, a significant body of evidence supports its robustness in the assessment of the efficacy of coronary stents. The introduction of DES therapy represented an important milestone in coronary intervention, significantly lowering both clinical and angiographic restenosis as compared with bare metal stenting. Indeed, the improved clinical outcomes seen with DES facilitated the expansion of percutaneous intervention to increasingly complex patient and lesion populations. However, as rates of restenosis increase with disease complexity, the absolute number of patients presenting with restenosis remains considerable and the identification of predictive factors is an issue of broad clinical importance. Moreover, although second generation DES now represent the dominant devices in clinical use, the impact of second generation DES on predictors of restenosis remains unclear.
A number of previous studies, based on relatively small patient cohorts, investigated the determinants of angiographic restenosis in patients undergoing coronary stenting. Following BMS implantation, the strongest predictors of restenosis were small vessel size, long lesion and long stented length, and presence of diabetes mellitus. In the DES era, the strongest predictors of restenosis were found to be small vessel size, long stented segments, final percentage of diameter stenosis, and the different antirestenotic potency of DES. Some studies also identified diabetes mellitus, in-stent restenosis and ostial lesion location as important predictive factors.
The present study assessed predictors of restenosis in the largest population undergoing coronary stenting and follow-up angiography since the introduction of PCI. We studied a broadly inclusive patient population treated with BMS, first generation DES and second generation DES. In addition we focused on angiographically proven restenosis as this likely represents the most objective parameter of efficacy after stent implantation, without the risk of bias associated with adjudication of clinical restenosis.
Our data confirm that across the spectrum of patients undergoing coronary stenting, small vessel size and long segment stenting continue to be strong predictors of restenosis, irrespective of the type of stent. Indeed, vessel size remains the factor most closely correlated with restenosis. Conceptually this is easy to understand: at an individual patient level, for any given degree of neointimal overgrowth after stenting the probability that the resultant diameter stenosis exceeds 50% is a straightforward function of vessel size and residual stenosis post-stenting. Although this association holds true regardless of stent type, by virtue of higher absolute suppression of neointimal hyperplasia, DES remain the most efficacious treatment modality for small vessel disease. Previous studies with BMS found the length of stented lesion strongly correlated with restenosis, although the relation between lesion length and restenosis after DES has been clear. The present dataset study underlines that total stented length remains a strong independent predictor of restenosis after both BMS and DES.
Left main stenting appears protective against restenosis in the univariate analysis, probably by virtue of a larger vessel diameter. After adjustment for other covariates (such as vessel size), left main stenting predicts higher restenosis risk, mainly due to lesion complexity (ie, bifurcation). Further investigation of the impact of left main stenting on restenosis is certainly warranted.
It is also notable that diabetes mellitus remains an important independent predictor of restenosis across the entire population enrolled in our study. Whether or not the high efficacy of DES attenuates or even eliminates the propensity of patients with diabetes to restenosis has remained a topic of some debate. Divergent definitions of diabetes and small sample sizes available for previous analyses may have had an impact on the true effect of this comorbidity in patients undergoing coronary stenting. However, the present large scale analysis confirms the importance of diabetes as a risk factor for restenosis after coronary stenting. Nevertheless, it might be observed that in the subgroup of patients treated with first generation DES, the presence of diabetes mellitus did not predict restenosis risk. Although the value of this finding in the setting of multiple comparisons may be debateable, the observation is consistent with previous data.
The current dataset also confirms that prior coronary bypass surgery remains a predictor of restenosis after stent implantation. This is in keeping with data from previous studies. The reason for this observation remains poorly defined. It is conceivable that this finding reflects the fact that these patients are likely to have more aggressive or advanced atherosclerotic disease, which confers reduced efficacy after percutaneous intervention.
We find that predictors of binary restenosis are similar across the spectrum of stent devices. However, we also demonstrate that intervention with first generation DES is a strong independent predictor of lower rates of restenosis as compared with BMS, and that intervention with second generation DES is a predictor of less restenosis in comparison with first generation DES. This supports observations from large scale meta-analysis of randomised trials and confirms the impact of device development on antirestenotic efficacy with sequential improvement from BMS to first generation DES to second generation DES.
Study Limitations
The current analysis has some limitations. First, adjudication of restenosis was based on the percentage diameter of lumen renarrowing at surveillance angiography. As such, information on vessel wall morphology and restenotic tissue characterisation was not available. Secondly, angiographic follow-up was missing in 22.5% of patients. While these data are deemed 'missing not at random', it is a consistent feature of all large angiographic follow-up studies. Moreover the validity of such data has been shown to be high when rates of angiographic follow-up approach 80% and numerous studies have shown that angiographic surrogates are robust markers of device efficacy. These considerations notwithstanding, a possible selection bias, due to higher frequency of patients with recurrence of symptoms undergoing angiography, cannot be excluded. Thirdly, this study lacks a randomised design with stent selection based only on the period specific availability of the devices. As such, the findings in relation to comparative efficacy of different stent generations should be interpreted with caution. Fourthly, the grouping of stents as bare metal, first generation and second generation efficacy is necessarily arbitrary and cannot fully capture differences between different BMS or DES platforms. Finally, when analysing the predictive variables among BMS, first generation and second generation DES subgroups, the impact of errors introduced by multiple testing should be considered.