Outcomes With Various Stents in Diabetic Patients
Outcomes With Various Stents in Diabetic Patients
In patients with diabetes all drug eluting stents are highly efficacious at reducing the risk of target vessel revascularisation without increases in any adverse safety outcomes, including very late stent thrombosis, when compared with bare metal stents. There were significant differences among types of drug eluting stent for efficacy and safety, such that everolimus eluting stents were the most efficacious and safe.
Coronary artery disease is a major cause of morbidity and mortality in patients with diabetes. Compared with patients without diabetes, those with diabetes have had worse outcomes with percutaneous transluminal coronary angioplasty, bare metal stents, and drug eluting stents. They have smaller calibre vessels, diffuse disease that often progresses rapidly, a greater burden of atherosclerotic disease, and exaggerated neointimal hyperplasia, all of which increase the likelihood of the need for repeat revascularisation. In addition, glycosylation of vascular collagen and elastin is thought to result in more diffuse pattern of restenosis. Though use of drug eluting stents has considerably reduced the risk of restenosis, this still remains a major limitation in patients with diabetes. Stents differ in the amount of neointimal hyperplasia (as measured by late lumen loss), with bare metal stents having the highest followed by zotarolimus eluting stents, paclitaxel eluting stents, sirolimus eluting stents/everolimus eluting stents (in order of decreasing late lumen loss), probably accounting for differences in relative efficacy and safety. In the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial of patients with stable ischaemic heart disease, a strategy of revascularisation with optimal medical treatment did not reduce the risk of death or myocardial infarction compared with optimal medical treatment alone. In BARI 2D only 30% of patients received a drug eluting stent. In our analysis, the point estimate for sirolimus eluting stents (rate ratio 0.71, 95% credibility interval 0.49 to 1.05) and everolimus eluting stents (0.52, 0.21 to 1.09) favoured these stents compared with bare metal stents for myocardial infarction. In addition, there was an 80% probability that everolimus eluting stents had the lowest rates of myocardial infarction of all stents including bare metal stents (probability of only 0.5% of having the lowest rate). We therefore do not know if the results of trials of revascularisation versus medical treatment would have changed with the use of newer generation stents.
There have been inconsistent results of clinical outcomes among various drug eluting stents as well as when drug eluting stents are compared with bare metal stents in patients with diabetes.
Drug Eluting Stents Versus Bare Metal Stents. A pooled patient level meta-analysis of four trials comparing sirolimus eluting stents with bare metal stents suggested an increased risk of mortality with sirolimus eluting stents in the subgroup with diabetes. This analysis, however, included only 428 patients with diabetes. Our analysis with a 25-fold greater sample size failed to show any important safety concerns with any of the currently used drug eluting stents compared with bare metal stents. These observations are consistent with those of Stettler and colleagues and extend the finding to newer generation drug eluting stents.
Sirolimus Eluting Stents Versus Paclitaxel Eluting Stents. Earlier studies and analyses comparing sirolimus eluting stents and paclitaxel eluting stents in patients with diabetes had discordant conclusions, with subgroup analyses/pooled analyses from patients with diabetes enrolled in randomised controlled trials and several registry studies suggesting that a paclitaxel eluting stent (Taxol) might perform similarly to a sirolimus eluting stent (limus), with other studies showing superiority of sirolimus eluting stents. While the limitations of earlier studies were mainly the small sample size of the cohort with diabetes, dedicated randomised controlled trials in patients with diabetes have shown superiority of sirolimus eluting stents compared with paclitaxel eluting stents. In the Drug-Eluting Stent in patients with DIABETES mellitus (DES-DIABETES) trial, sirolimus eluting stents were associated with reduction in restenosis and major adverse cardiac outcomes during up to two years of follow-up. At four years, however, there was no difference in the outcomes between the two stents. The collaborative network meta-analysis by Stettler and colleagues, which included 3852 patients with diabetes, showed no difference between sirolimus eluting stents and paclitaxel eluting stents for the efficacy (hazard ratio 0.76 (95% confidence interval 0.53 to 1.05) for target lesion revascularisation) and safety outcomes. The point estimate for target lesion revascularisation, however, favoured sirolimus eluting stents. Our analysis, with close to three times the sample size of the previous analysis, showed similar trend for the outcome of target vessel revascularisation (0.81, 95% credibility interval 0.65 to 1.01) but superiority of sirolimus eluting stents over paclitaxel eluting stents (0.73, 0.55 to 0.95) for the outcome of target lesion revascularisation and are consistent with head-to-head trials of sirolimus eluting stents versus paclitaxel eluting stents, in which sirolimus eluting stents have consistently been associated with lower late lumen loss. In addition, in a randomised trial of sirolimus eluting stents versus paclitaxel eluting stents in the same patient with multiple lesions, sirolimus eluting stents fared significantly better with lower late lumen loss.
Everolimus Eluting Stents Versus Paclitaxel Eluting Stents. A pooled analysis from the SPIRIT and COMPARE trials showed an interaction between diabetes mellitus and stent type on clinical outcomes. In patients without diabetes mellitus, everolimus eluting stents resulted in two year reductions in death, myocardial infarction, stent thrombosis, and target lesion revascularisation, whereas no significant differences in safety or efficacy outcomes were found in patients with diabetes. This study had only 1869 patients with diabetes. The point estimates favoured everolimus eluting stents, though the confidence intervals were wide (odds ratio 0.87 (95% confidence interval 0.55 to 1.40) for myocardial infarction, 0.90 (0.59 to 1.37) for target lesion revascularisation, and 0.80 (0.39 to 1.67) for stent thrombosis). Our analysis, with larger sample size, showed a significant benefit of everolimus eluting stents over paclitaxel eluting stents for target vessel revascularisation and target lesion revascularisation (rate ratio 0.68 (95% credibility interval 0.44 to 0.95) and 0.60 (0.33 to 0.93), respectively). In addition, probability analyses showed that there was an 87%, 81%, and 62% probability that everolimus eluting stents had the lowest rates of target vessel revascularisation, myocardial infarction, and any stent thrombosis, respectively, but these probability rates were low for paclitaxel eluting stents (probability of 0.3%, 2.1%, 4.5%, respectively).
Zotarolimus Eluting Stents. In our analyses, zotarolimus eluting stents were associated with a higher rate of repeat revascularisation (compared with sirolimus eluting stents or everolimus eluting stents) and higher rate of myocardial infarction (compared with sirolimus eluting stents/paclitaxel eluting stents or everolimus eluting stents). The credibility interval around the estimates for zotarolimus eluting stent were wide, suggesting less precision and confidence in the estimates, and is probably because of limited published data on the use of zotarolimus eluting stents in patients with diabetes. In the diabetes subgroup analysis from the Danish Organization for Clinical Trials with Clinical Outcome (SORT OUT) III trial, zotarolimus eluting stents were associated with a fourfold increase in the risk of a major cardiac event (18.3% v 4.8%; P<0.001), an eightfold increase in myocardial infarction (4.7% v 0.6%; P=0.049), an fivefold increase in target vessel revascularisation (14.2% v 3.0%; P=0.001), and an 11-fold increase in target lesion revascularisation (12.4% v 1.2%; P=0.002), with trends for worse definite stent thrombosis (1.8% v 0.0%) compared with sirolimus eluting stents. In patients with diabetes, given their extensive atherosclerosis and smaller reference vessel diameters, an increased late loss (such as that observed with zotarolimus eluting stents) might lead to an increase in restenosis, with a lesser margin for “tolerated late loss”. In our sensitivity analysis, inclusion of the only two published randomised trials on ZES-Resolute showed that ZES-Resolute was similar to everolimus eluting stents for target vessel revascularisation, although the point estimate favoured everolimus eluting stents (rate ratio 0.65, 95% credibility interval 0.38 to 1.05). In addition, there was still an 80% probability that everolimus eluting stents was associated with the lowest rates of target vessel revascularisation compared with all other stents, including the ZES-Resolute. This analysis, however, is highly exploratory and more data are needed with ZES-Resolute before any robust conclusions can be made on the relative efficacy. Of note, both in the Resolute All Comers trial (odds ratio 1.45 (95% confidence interval 0.82, 2.58) for target lesion failure with ZES-Resolute v everolimus eluting stents) and the TWENTE trial (rate ratio 1.81 (0.91 to 3.60) for target vessel failure with ZES-Resolute v everolimus eluting stents, 13.9% v 7.7%, P=0.08), the point estimates favoured everolimus eluting stents over ZES-Resolute in the subgroup with diabetes.
Finally, in the present analysis, everolimus eluting stents were the most efficacious and the safest stents. These results are consistent with the results in the subgroups of patients without diabetes. Of note, in all the analyses the credibility intervals for the comparisons of everolimus eluting stents and sirolimus eluting stents crossed unity. Probability analyses, however, showed that there was an 87%, 81%, and 62% probability that everolimus eluting stents were associated with the lowest rates of target vessel revascularisation, myocardial infarction, and any stent thrombosis, respectively, but these were low for sirolimus eluting stents (probability of 12%, 17%, and 30%, respectively).
The limitations of previous analyses have mainly been the limited sample sizes and pooling of one type of drug eluting stent and comparison with all other types. The strengths of our analyses are that we have data from more than 22,000 patient years of follow-up. In addition, we compared each type of drug eluting stent with each other, thus avoiding comparison of one type against a heterogeneous mixture of other types. In addition, our search strategy was fairly extensive with use of data from multiple sources, thereby reducing outcome reporting bias.
As in other meta-analyses, though we undertook detailed sensitivity analyses on many variables, given the heterogeneity of the study protocols, clinically relevant differences could have been missed and are best assessed in a meta-analysis of individual patient data. Given clinical heterogeneity, though we used a conservative approach using a random effects model (despite low statistical heterogeneity) and despite detailed sensitivity analyses on many variables, confounding by indication cannot be ruled out. Not all of the trials reported each of the outcomes assessed. In addition, we included the pooled SPIRIT and COMPARE trials data rather than individual trials as this pooled analyses provided more comprehensive and longer term follow-up and reported data exclusively on the diabetic cohort compared with the individual trials alone. The results of the sensitivity analyses are best described as secondary and hypothesis generating only. The differences seen within types of drug eluting stents are applicable only to the specific stents evaluated in this study. Nonetheless, this large study offers important insights into their relative safety and efficacy.
Among patients with diabetes, currently used drug eluting stents are highly efficacious at reducing the risk of target vessel revascularisation/target lesion revascularisation without compromising safety outcomes, including very late stent thrombosis, compared with bare metal stents. We found considerable differences in the relative efficacy and safety of currently used drug eluting stents, such that everolimus eluting stents were the safest and most efficacious. There were limited published data on zotarolimus eluting Resolute stent in the diabetes subgroup, and more data are need before any inference can be made on this stent.
Discussion
In patients with diabetes all drug eluting stents are highly efficacious at reducing the risk of target vessel revascularisation without increases in any adverse safety outcomes, including very late stent thrombosis, when compared with bare metal stents. There were significant differences among types of drug eluting stent for efficacy and safety, such that everolimus eluting stents were the most efficacious and safe.
Diabetes and Outcomes After Percutaneous Coronary Intervention
Coronary artery disease is a major cause of morbidity and mortality in patients with diabetes. Compared with patients without diabetes, those with diabetes have had worse outcomes with percutaneous transluminal coronary angioplasty, bare metal stents, and drug eluting stents. They have smaller calibre vessels, diffuse disease that often progresses rapidly, a greater burden of atherosclerotic disease, and exaggerated neointimal hyperplasia, all of which increase the likelihood of the need for repeat revascularisation. In addition, glycosylation of vascular collagen and elastin is thought to result in more diffuse pattern of restenosis. Though use of drug eluting stents has considerably reduced the risk of restenosis, this still remains a major limitation in patients with diabetes. Stents differ in the amount of neointimal hyperplasia (as measured by late lumen loss), with bare metal stents having the highest followed by zotarolimus eluting stents, paclitaxel eluting stents, sirolimus eluting stents/everolimus eluting stents (in order of decreasing late lumen loss), probably accounting for differences in relative efficacy and safety. In the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial of patients with stable ischaemic heart disease, a strategy of revascularisation with optimal medical treatment did not reduce the risk of death or myocardial infarction compared with optimal medical treatment alone. In BARI 2D only 30% of patients received a drug eluting stent. In our analysis, the point estimate for sirolimus eluting stents (rate ratio 0.71, 95% credibility interval 0.49 to 1.05) and everolimus eluting stents (0.52, 0.21 to 1.09) favoured these stents compared with bare metal stents for myocardial infarction. In addition, there was an 80% probability that everolimus eluting stents had the lowest rates of myocardial infarction of all stents including bare metal stents (probability of only 0.5% of having the lowest rate). We therefore do not know if the results of trials of revascularisation versus medical treatment would have changed with the use of newer generation stents.
Stent Choice in Diabetes
There have been inconsistent results of clinical outcomes among various drug eluting stents as well as when drug eluting stents are compared with bare metal stents in patients with diabetes.
Drug Eluting Stents Versus Bare Metal Stents. A pooled patient level meta-analysis of four trials comparing sirolimus eluting stents with bare metal stents suggested an increased risk of mortality with sirolimus eluting stents in the subgroup with diabetes. This analysis, however, included only 428 patients with diabetes. Our analysis with a 25-fold greater sample size failed to show any important safety concerns with any of the currently used drug eluting stents compared with bare metal stents. These observations are consistent with those of Stettler and colleagues and extend the finding to newer generation drug eluting stents.
Sirolimus Eluting Stents Versus Paclitaxel Eluting Stents. Earlier studies and analyses comparing sirolimus eluting stents and paclitaxel eluting stents in patients with diabetes had discordant conclusions, with subgroup analyses/pooled analyses from patients with diabetes enrolled in randomised controlled trials and several registry studies suggesting that a paclitaxel eluting stent (Taxol) might perform similarly to a sirolimus eluting stent (limus), with other studies showing superiority of sirolimus eluting stents. While the limitations of earlier studies were mainly the small sample size of the cohort with diabetes, dedicated randomised controlled trials in patients with diabetes have shown superiority of sirolimus eluting stents compared with paclitaxel eluting stents. In the Drug-Eluting Stent in patients with DIABETES mellitus (DES-DIABETES) trial, sirolimus eluting stents were associated with reduction in restenosis and major adverse cardiac outcomes during up to two years of follow-up. At four years, however, there was no difference in the outcomes between the two stents. The collaborative network meta-analysis by Stettler and colleagues, which included 3852 patients with diabetes, showed no difference between sirolimus eluting stents and paclitaxel eluting stents for the efficacy (hazard ratio 0.76 (95% confidence interval 0.53 to 1.05) for target lesion revascularisation) and safety outcomes. The point estimate for target lesion revascularisation, however, favoured sirolimus eluting stents. Our analysis, with close to three times the sample size of the previous analysis, showed similar trend for the outcome of target vessel revascularisation (0.81, 95% credibility interval 0.65 to 1.01) but superiority of sirolimus eluting stents over paclitaxel eluting stents (0.73, 0.55 to 0.95) for the outcome of target lesion revascularisation and are consistent with head-to-head trials of sirolimus eluting stents versus paclitaxel eluting stents, in which sirolimus eluting stents have consistently been associated with lower late lumen loss. In addition, in a randomised trial of sirolimus eluting stents versus paclitaxel eluting stents in the same patient with multiple lesions, sirolimus eluting stents fared significantly better with lower late lumen loss.
Everolimus Eluting Stents Versus Paclitaxel Eluting Stents. A pooled analysis from the SPIRIT and COMPARE trials showed an interaction between diabetes mellitus and stent type on clinical outcomes. In patients without diabetes mellitus, everolimus eluting stents resulted in two year reductions in death, myocardial infarction, stent thrombosis, and target lesion revascularisation, whereas no significant differences in safety or efficacy outcomes were found in patients with diabetes. This study had only 1869 patients with diabetes. The point estimates favoured everolimus eluting stents, though the confidence intervals were wide (odds ratio 0.87 (95% confidence interval 0.55 to 1.40) for myocardial infarction, 0.90 (0.59 to 1.37) for target lesion revascularisation, and 0.80 (0.39 to 1.67) for stent thrombosis). Our analysis, with larger sample size, showed a significant benefit of everolimus eluting stents over paclitaxel eluting stents for target vessel revascularisation and target lesion revascularisation (rate ratio 0.68 (95% credibility interval 0.44 to 0.95) and 0.60 (0.33 to 0.93), respectively). In addition, probability analyses showed that there was an 87%, 81%, and 62% probability that everolimus eluting stents had the lowest rates of target vessel revascularisation, myocardial infarction, and any stent thrombosis, respectively, but these probability rates were low for paclitaxel eluting stents (probability of 0.3%, 2.1%, 4.5%, respectively).
Zotarolimus Eluting Stents. In our analyses, zotarolimus eluting stents were associated with a higher rate of repeat revascularisation (compared with sirolimus eluting stents or everolimus eluting stents) and higher rate of myocardial infarction (compared with sirolimus eluting stents/paclitaxel eluting stents or everolimus eluting stents). The credibility interval around the estimates for zotarolimus eluting stent were wide, suggesting less precision and confidence in the estimates, and is probably because of limited published data on the use of zotarolimus eluting stents in patients with diabetes. In the diabetes subgroup analysis from the Danish Organization for Clinical Trials with Clinical Outcome (SORT OUT) III trial, zotarolimus eluting stents were associated with a fourfold increase in the risk of a major cardiac event (18.3% v 4.8%; P<0.001), an eightfold increase in myocardial infarction (4.7% v 0.6%; P=0.049), an fivefold increase in target vessel revascularisation (14.2% v 3.0%; P=0.001), and an 11-fold increase in target lesion revascularisation (12.4% v 1.2%; P=0.002), with trends for worse definite stent thrombosis (1.8% v 0.0%) compared with sirolimus eluting stents. In patients with diabetes, given their extensive atherosclerosis and smaller reference vessel diameters, an increased late loss (such as that observed with zotarolimus eluting stents) might lead to an increase in restenosis, with a lesser margin for “tolerated late loss”. In our sensitivity analysis, inclusion of the only two published randomised trials on ZES-Resolute showed that ZES-Resolute was similar to everolimus eluting stents for target vessel revascularisation, although the point estimate favoured everolimus eluting stents (rate ratio 0.65, 95% credibility interval 0.38 to 1.05). In addition, there was still an 80% probability that everolimus eluting stents was associated with the lowest rates of target vessel revascularisation compared with all other stents, including the ZES-Resolute. This analysis, however, is highly exploratory and more data are needed with ZES-Resolute before any robust conclusions can be made on the relative efficacy. Of note, both in the Resolute All Comers trial (odds ratio 1.45 (95% confidence interval 0.82, 2.58) for target lesion failure with ZES-Resolute v everolimus eluting stents) and the TWENTE trial (rate ratio 1.81 (0.91 to 3.60) for target vessel failure with ZES-Resolute v everolimus eluting stents, 13.9% v 7.7%, P=0.08), the point estimates favoured everolimus eluting stents over ZES-Resolute in the subgroup with diabetes.
Finally, in the present analysis, everolimus eluting stents were the most efficacious and the safest stents. These results are consistent with the results in the subgroups of patients without diabetes. Of note, in all the analyses the credibility intervals for the comparisons of everolimus eluting stents and sirolimus eluting stents crossed unity. Probability analyses, however, showed that there was an 87%, 81%, and 62% probability that everolimus eluting stents were associated with the lowest rates of target vessel revascularisation, myocardial infarction, and any stent thrombosis, respectively, but these were low for sirolimus eluting stents (probability of 12%, 17%, and 30%, respectively).
Limitations and Strengths
The limitations of previous analyses have mainly been the limited sample sizes and pooling of one type of drug eluting stent and comparison with all other types. The strengths of our analyses are that we have data from more than 22,000 patient years of follow-up. In addition, we compared each type of drug eluting stent with each other, thus avoiding comparison of one type against a heterogeneous mixture of other types. In addition, our search strategy was fairly extensive with use of data from multiple sources, thereby reducing outcome reporting bias.
As in other meta-analyses, though we undertook detailed sensitivity analyses on many variables, given the heterogeneity of the study protocols, clinically relevant differences could have been missed and are best assessed in a meta-analysis of individual patient data. Given clinical heterogeneity, though we used a conservative approach using a random effects model (despite low statistical heterogeneity) and despite detailed sensitivity analyses on many variables, confounding by indication cannot be ruled out. Not all of the trials reported each of the outcomes assessed. In addition, we included the pooled SPIRIT and COMPARE trials data rather than individual trials as this pooled analyses provided more comprehensive and longer term follow-up and reported data exclusively on the diabetic cohort compared with the individual trials alone. The results of the sensitivity analyses are best described as secondary and hypothesis generating only. The differences seen within types of drug eluting stents are applicable only to the specific stents evaluated in this study. Nonetheless, this large study offers important insights into their relative safety and efficacy.
Conclusions
Among patients with diabetes, currently used drug eluting stents are highly efficacious at reducing the risk of target vessel revascularisation/target lesion revascularisation without compromising safety outcomes, including very late stent thrombosis, compared with bare metal stents. We found considerable differences in the relative efficacy and safety of currently used drug eluting stents, such that everolimus eluting stents were the safest and most efficacious. There were limited published data on zotarolimus eluting Resolute stent in the diabetes subgroup, and more data are need before any inference can be made on this stent.
