Outcomes With Various Stents in Diabetic Patients
Outcomes With Various Stents in Diabetic Patients
We identified 42 randomised controlled trials that satisfied our inclusion criteria (Figure 1). For the SPIRIT and COMPARE trials, we used the pooled data in patients with diabetes that was recently published as this provided more comprehensive longer term data than the published individual trials for the diabetic subgroup. Figure 2 shows the network of available treatment comparisons.
(Enlarge Image)
Figure 1.
Selection of studies examining efficacy or safety, or both, of various drug eluting or bare metal stents in patients with diabetes mellitus
(Enlarge Image)
Figure 2.
Network of comparisons of types of stents in studies examining efficacy or safety, or safety, of various drug eluting or bare metal stents in patients with diabetes mellitus. Links between stent types represent direct comparisons (solid line) or indirect comparisons (dashed line). Numbers along links represent number of trial arms providing direct comparison between stent types
Table 1 and Table 2 describe the trial characteristics and quality analysis. The 42 trials enrolled 10,714 patients with 22,844 patient years of follow-up. Two trials were three arm trials, but the rest were two arm trials. Thirty seven trials were considered to be at low risk of bias, while five were at intermediate or high risk of bias. In 34 of the 42 trials, clopidogrel was used for at least six months in the drug eluting stents arm ( Table 2 ).
When compared with bare metal stents (reference rate ratio of 1), all drug eluting stents were associated with a 37% to 69% reduction in the rate of target vessel revascularisation (Figure 3), but the magnitude of this reduction varied with the type of stent. Sirolimus eluting stents were significantly more efficacious than zotarolimus eluting stents but similar to paclitaxel eluting stents or everolimus eluting stents. In the comparison between sirolimus eluting stents and paclitaxel eluting stents, however, the point estimate favoured sirolimus eluting stents (Figure 3). Similarly, everolimus eluting stents were more efficacious than paclitaxel eluting stents or zotarolimus eluting stent. There was an 87% probability that everolimus eluting stents have the lowest rate of target vessel revascularisation ( Table 3 ) compared with all other stent types. The median target vessel revascularisation rate with bare metal stents was 109.40 per 1000 patient years of follow-up, and the rate with the most efficacious drug eluting stent (everolimus eluting stent) was 34.55 per 1000 patient years ( Table 3 ).
(Enlarge Image)
Figure 3.
Stent type and risk of target vessel revascularisation and target lesion revascularisation with 95% credibility intervals
The results were largely similar in the sensitivity analyses that included only trials in which patients had used clopidogrel for more than six months ( Fig A1 in Appendix 2); in trials with low bias risk ( Table B in Appendix 1); that excluding acute coronary syndrome trials ( Table C in Appendix 1); and in the direct comparison meta-analysis ( Table D in Appendix 1). For the outcome of target lesion revascularisation the results were largely similar, except that the results of the comparison between bare metal stents and zotarolimus eluting stent was no longer significant (trend favouring zotarolimus eluting stent) and sirolimus eluting stents were significantly more efficacious than paclitaxel eluting stents (Figure 3 and Fig A2 in Appendix 2).
Compared with bare metal stents, there was no increase in death with any of the drug eluting stents or among any comparisons between pairs of drug eluting stents (Figure 4). The median death rate with bare metal stents was 17.51 per 1000 patient years of follow-up ( Table 3 ). The median death rate with drug eluting stents varied between 14.51 and 20.27 per 1000 patient years ( Table 3 ). There was a 57% probability that everolimus eluting stents was associated with the lowest death rate ( Table 3 ).
(Enlarge Image)
Figure 4.
Stent type and risk of myocardial infarction and death with 95% credibility intervals
For the outcome of myocardial infarction, there was no significant increase with any of the drug eluting stents compared with bare metal stents (Figure 4). Among types of drug eluting stent, sirolimus eluting stents, paclitaxel eluting stents, and everolimus eluting stents were all associated with a lower rate of myocardial infarction compared with zotarolimus eluting stents (Figure 4). The credibility interval around the increased risk with the zotarolimus eluting stent, however, was rather wide (Figure 4). The median rate of myocardial infarction with bare metal stents was 19.16 per 1000 patient years. There was an 81% probability that everolimus eluting stents had the lowest rate of myocardial infarction with a rate of 10.13 per 1000 patient years ( Table 3 ).
For the outcome of “any” stent thrombosis, there was no significant increase with any of the drug eluting stents compared with bare metal stents (Figure 5). Among types of drug eluting stent, there was no increased risk with any one type compared with another, though most comparisons did not favour zotarolimus eluting stents. There was a 62% probability that everolimus eluting stents had the lowest rate of any stent thrombosis ( Table 3 ). The results were largely similar for the outcomes of definite or probable stent thrombosis and definite stent thrombosis, with a suggestion for better outcomes with drug eluting stents other than zotarolimus eluting stents (Figure 5). For the outcome of very late stent thrombosis, there was no increased risk with any drug eluting stents compared with bare metal stents nor was there a difference between types of drug eluting stents (Figure 5). For this outcome, probability analysis failed to identify one stent type that was the best (the probability of being best was 25% for bare metal stent, 27% for sirolimus eluting stents, and 36% for everolimus eluting stents).
(Enlarge Image)
Figure 5.
Stent type and risk of any stent thrombosis, definite or probable stent thrombosis, definite stent thrombosis, and very late stent thrombosis with 95% credibility intervals
We performed a sensitivity analyses including the only two published trials of ZES-Resolute stents (TWENTE, RESOLUTE all comers trials). For these two trials, given the availability of target lesion/vessel failure endpoints in the diabetic cohort, we substituted this for the target vessel revascularisation outcome. ZES-Resolute was associated with similar rate ratio for target vessel revascularisation compared with other drug eluting stents, with significant benefit compared with bare metal stents ( Fig A8 in Appendix 2). Compared with ZES-Resolute, however, the point estimate (rate ratio 1.54, 95% credibility interval 0.95 to 2.63) favoured everolimus eluting stents. Moreover, the probability analysis showed that there was still an 80% probability that everolimus eluting stents were associated with the lowest rates of target vessel revascularisation compared with all other stents, including the ZES-Resolute. Given the limited data, this analysis should be viewed as highly exploratory.
For all of the above analyses, sensitivity analyses in trials in which patients had used clopidogrel for more than six months ( Fig A3 , Fig A4 , Fig A5 , Fig A6 , and Fig A7 in Appendix 2), trials at low risk of bias ( Table B in Appendix 1), and trials after exclusion of acute coronary syndrome trials ( Table C in Appendix 1) and the direct comparison meta-analysis ( Table D in Appendix 1) yielded largely consistent results.
The heterogeneity between trials for the various network models showed low to moderate heterogeneity for most of the analyses ( Table E in Appendix 1). In addition, evaluation of the goodness of fit for the various models showed adequate fit for the various analyses ( Table F , Table G , and Table H in Appendix 1; Fig B1 , Fig B2 , Fig B3 , Fig B4 , Fig B5 , Fig B6 , and Fig B7 in Appendix 2).
Results
Study Selection
We identified 42 randomised controlled trials that satisfied our inclusion criteria (Figure 1). For the SPIRIT and COMPARE trials, we used the pooled data in patients with diabetes that was recently published as this provided more comprehensive longer term data than the published individual trials for the diabetic subgroup. Figure 2 shows the network of available treatment comparisons.
(Enlarge Image)
Figure 1.
Selection of studies examining efficacy or safety, or both, of various drug eluting or bare metal stents in patients with diabetes mellitus
(Enlarge Image)
Figure 2.
Network of comparisons of types of stents in studies examining efficacy or safety, or safety, of various drug eluting or bare metal stents in patients with diabetes mellitus. Links between stent types represent direct comparisons (solid line) or indirect comparisons (dashed line). Numbers along links represent number of trial arms providing direct comparison between stent types
Characteristics of Included Trials
Table 1 and Table 2 describe the trial characteristics and quality analysis. The 42 trials enrolled 10,714 patients with 22,844 patient years of follow-up. Two trials were three arm trials, but the rest were two arm trials. Thirty seven trials were considered to be at low risk of bias, while five were at intermediate or high risk of bias. In 34 of the 42 trials, clopidogrel was used for at least six months in the drug eluting stents arm ( Table 2 ).
Efficacy Outcomes
When compared with bare metal stents (reference rate ratio of 1), all drug eluting stents were associated with a 37% to 69% reduction in the rate of target vessel revascularisation (Figure 3), but the magnitude of this reduction varied with the type of stent. Sirolimus eluting stents were significantly more efficacious than zotarolimus eluting stents but similar to paclitaxel eluting stents or everolimus eluting stents. In the comparison between sirolimus eluting stents and paclitaxel eluting stents, however, the point estimate favoured sirolimus eluting stents (Figure 3). Similarly, everolimus eluting stents were more efficacious than paclitaxel eluting stents or zotarolimus eluting stent. There was an 87% probability that everolimus eluting stents have the lowest rate of target vessel revascularisation ( Table 3 ) compared with all other stent types. The median target vessel revascularisation rate with bare metal stents was 109.40 per 1000 patient years of follow-up, and the rate with the most efficacious drug eluting stent (everolimus eluting stent) was 34.55 per 1000 patient years ( Table 3 ).
(Enlarge Image)
Figure 3.
Stent type and risk of target vessel revascularisation and target lesion revascularisation with 95% credibility intervals
The results were largely similar in the sensitivity analyses that included only trials in which patients had used clopidogrel for more than six months ( Fig A1 in Appendix 2); in trials with low bias risk ( Table B in Appendix 1); that excluding acute coronary syndrome trials ( Table C in Appendix 1); and in the direct comparison meta-analysis ( Table D in Appendix 1). For the outcome of target lesion revascularisation the results were largely similar, except that the results of the comparison between bare metal stents and zotarolimus eluting stent was no longer significant (trend favouring zotarolimus eluting stent) and sirolimus eluting stents were significantly more efficacious than paclitaxel eluting stents (Figure 3 and Fig A2 in Appendix 2).
Safety Outcomes
Compared with bare metal stents, there was no increase in death with any of the drug eluting stents or among any comparisons between pairs of drug eluting stents (Figure 4). The median death rate with bare metal stents was 17.51 per 1000 patient years of follow-up ( Table 3 ). The median death rate with drug eluting stents varied between 14.51 and 20.27 per 1000 patient years ( Table 3 ). There was a 57% probability that everolimus eluting stents was associated with the lowest death rate ( Table 3 ).
(Enlarge Image)
Figure 4.
Stent type and risk of myocardial infarction and death with 95% credibility intervals
For the outcome of myocardial infarction, there was no significant increase with any of the drug eluting stents compared with bare metal stents (Figure 4). Among types of drug eluting stent, sirolimus eluting stents, paclitaxel eluting stents, and everolimus eluting stents were all associated with a lower rate of myocardial infarction compared with zotarolimus eluting stents (Figure 4). The credibility interval around the increased risk with the zotarolimus eluting stent, however, was rather wide (Figure 4). The median rate of myocardial infarction with bare metal stents was 19.16 per 1000 patient years. There was an 81% probability that everolimus eluting stents had the lowest rate of myocardial infarction with a rate of 10.13 per 1000 patient years ( Table 3 ).
For the outcome of “any” stent thrombosis, there was no significant increase with any of the drug eluting stents compared with bare metal stents (Figure 5). Among types of drug eluting stent, there was no increased risk with any one type compared with another, though most comparisons did not favour zotarolimus eluting stents. There was a 62% probability that everolimus eluting stents had the lowest rate of any stent thrombosis ( Table 3 ). The results were largely similar for the outcomes of definite or probable stent thrombosis and definite stent thrombosis, with a suggestion for better outcomes with drug eluting stents other than zotarolimus eluting stents (Figure 5). For the outcome of very late stent thrombosis, there was no increased risk with any drug eluting stents compared with bare metal stents nor was there a difference between types of drug eluting stents (Figure 5). For this outcome, probability analysis failed to identify one stent type that was the best (the probability of being best was 25% for bare metal stent, 27% for sirolimus eluting stents, and 36% for everolimus eluting stents).
(Enlarge Image)
Figure 5.
Stent type and risk of any stent thrombosis, definite or probable stent thrombosis, definite stent thrombosis, and very late stent thrombosis with 95% credibility intervals
We performed a sensitivity analyses including the only two published trials of ZES-Resolute stents (TWENTE, RESOLUTE all comers trials). For these two trials, given the availability of target lesion/vessel failure endpoints in the diabetic cohort, we substituted this for the target vessel revascularisation outcome. ZES-Resolute was associated with similar rate ratio for target vessel revascularisation compared with other drug eluting stents, with significant benefit compared with bare metal stents ( Fig A8 in Appendix 2). Compared with ZES-Resolute, however, the point estimate (rate ratio 1.54, 95% credibility interval 0.95 to 2.63) favoured everolimus eluting stents. Moreover, the probability analysis showed that there was still an 80% probability that everolimus eluting stents were associated with the lowest rates of target vessel revascularisation compared with all other stents, including the ZES-Resolute. Given the limited data, this analysis should be viewed as highly exploratory.
For all of the above analyses, sensitivity analyses in trials in which patients had used clopidogrel for more than six months ( Fig A3 , Fig A4 , Fig A5 , Fig A6 , and Fig A7 in Appendix 2), trials at low risk of bias ( Table B in Appendix 1), and trials after exclusion of acute coronary syndrome trials ( Table C in Appendix 1) and the direct comparison meta-analysis ( Table D in Appendix 1) yielded largely consistent results.
The heterogeneity between trials for the various network models showed low to moderate heterogeneity for most of the analyses ( Table E in Appendix 1). In addition, evaluation of the goodness of fit for the various models showed adequate fit for the various analyses ( Table F , Table G , and Table H in Appendix 1; Fig B1 , Fig B2 , Fig B3 , Fig B4 , Fig B5 , Fig B6 , and Fig B7 in Appendix 2).