Our collaborative network meta-analysis suggests that previously reported increases in the risk of death associated with sirolimus eluting stents compared with bare metal stents in people with diabetes5
probably resulted from the restricted duration of dual antiplatelet therapy of less than six months in early trials. In trials with dual antiplatelet therapy for less than six months, the risk of death associated with sirolimus eluting stents was more than twice the risk associated with bare metal stents, which translates into a number needed to harm as low as 7 to cause one death over four years. Conversely, trials with dual antiplatelet therapy for six months or more showed no increase in risk from using sirolimus eluting stents compared with bare metal stents. Restricting the network to trials with dual antiplatelet therapy of six months or longer resulted in a clear reduction of the inconsistency and hazard ratios near 1, which were robust to all sensitivity analyses. We found similar patterns for analyses of cardiac death and stent thromboses. The restriction of the network resulted in a smaller evidence base: eight trials of 613 people with diabetes were excluded from the analysis. Despite this, statistical precision was improved owing to the accompanying decrease in the network’s inconsistency.
Compared with bare metal stents, target lesion revascularisation rates are strongly decreased by use of sirolimus and paclitaxel drug eluting stents in people with and without diabetes. Numbers needed to treat to reduce one event over four years are 6 in people with diabetes and 8 in people without diabetes. Active angiographic follow-up increases the absolute rates of target lesion revascularisation.16 17
For example, the rate of target lesion revascularisation at one year in patients who had undergone implantation of a bare metal stent in the TAXUS IV trial was 18.9% in those allocated to active follow-up and 14.3% in those allocated to regular clinical follow-up without mandatory angiography. The number needed to treat to avoid one revascularisation would therefore be somewhat lower in clinical routine. Assuming revascularisation rates of 12% in people with diabetes and 9% in people without diabetes, as found in the Cardiac Care Network of Ontario at two years,18
numbers needed to treat were estimated as 13 for people with diabetes and 18 for people without diabetes.
Our study comprises a large body of evidence from randomised controlled trials in people with and without diabetes treated with one of two drug eluting stents or bare metal stents. Investigators and manufacturers provided additional data according to uniform outcome definitions, including a standardised definition for stent thrombosis according to the Academic Research Consortium consensus.13
This increases comparability between trials and limits bias, such as the censoring of events after intervening revascularisation.
Our previous network meta-analysis1
was recently criticised for integrating evidence from direct and indirect comparisons, for not comparing like with like, and for using random effects models that give undue weight to small studies.19
Our model was based on relative treatment effects (log hazards ratio), and variations in characteristics of patients or lesions between trials are fully accounted for in the analysis by maintaining randomised comparisons within each trial.1
Network meta-analysis makes similar assumptions to standard meta-analysis of direct comparisons within trials, but requires that these assumptions hold over the entire set of trials in the network.10
The smaller the heterogeneity between trials and the smaller the inconsistency of the data, the more likely relative treatment effects originate from the same distribution and less likely small trials get undue weight in the analysis. Therefore a careful exploration of heterogeneity between trials and inconsistency of the data is mandatory. Inspecting the entire network allowed us to gain insights into potential sources of variation, which could not have been achieved by an isolated look at just one set of trials comparing only two stent types. This led us to suggest a plausible explanation for the previously reported increase in the risk of death associated with sirolimus eluting stents compared with bare metal stents in people with diabetes5
—that is, a restricted duration of dual antiplatelet therapy particularly in early trials.
Our exploration of inconsistency is observational in nature and has the same limitations as other observational studies.20
Most importantly, earlier trials had specified shorter durations of dual antiplatelet therapy than later trials. The duration of therapy was therefore bound to be negatively correlated with the duration of follow-up, and confounding could exist between the duration of therapy and the length of follow-up. Other potential confounders include changes over time in patient selection and procedural characteristics, such as an under-sizing or under-expansion of stents in early trials, or methodological quality. We addressed this by repeating tests of interaction between treatment effect and components of methodological quality or length of follow-up after the exclusion of trials with a duration of dual antiplatelet therapy of less than six months and found no evidence for an interaction in any of these analyses (data available on request).
We acknowledge that our results could be corroborated by an analysis of the actual duration of dual antiplatelet therapy in individual patients, but precise durations in individual patients are unavailable in most trials and we lacked the resources to retrospectively ascertain and validate usage data. Eight trials had specified a duration of dual antiplatelet therapy of less than six months. For five trials we are confident that the actual duration of dual antiplatelet therapy corresponded to the specified duration in at least 90% of patientsw7 w16-w19
; in three trials, however, between 10% and 50% of the patients had dual antiplatelet therapy at six months.w3 w20 w26
Results were unaffected by the reclassification of these three trials to have a duration of dual antiplatelet therapy of six months or longer, and the P value for interaction between relative risk of death and duration of dual antiplatelet therapy became even smaller. Additionally, strut thickness or type of bare metal stent used in comparison groups might affect clinical outcomes.w21
Even though our results are robust to the adjustment for these characteristics of bare metal stents,1
we cannot fully exclude the possibility that differences in bare metal stents as comparators contributed to the observed variation in mortality between trials with short and long durations of dual antiplatelet therapy. Four trials included only people with diabetesw1-w3 w29
and one trial only people without diabetes.w33
Performing network meta-analyses separately for people with and without diabetes allowed us to also incorporate these trials in our analysis. An alternative approach would have been to model differences between people with and without diabetes directly within each trial, but at the price of excluding these five trials.w1-w3 w29 w33
A final limitation of our study is that we were unable to record information on specific antidiabetic treatment or on glycaemic control in people with diabetes mellitus and to perform separate analyses for people with diabetes who did or did not use insulin. Although these aspects are related to cardiovascular outcomes,21
they were per definition randomly distributed across comparison groups within each trial and it seems unlikely that they influenced results.
We found that the duration of dual antiplatelet therapy modified the safety profile of drug eluting stents mainly in people with diabetes. The beneficial effect of prolonged therapy in people with diabetes may be mainly related to differences in lesion characteristics. People with diabetes tend to have smaller vessels and longer lesions than people without diabetes and therefore require stents of smaller size and longer length. Previous studies have identified both vessel size and lesion length as predictors of stent thrombosis,22
which may explain the predisposition of people with diabetes to this adverse event in the absence of adequate antiplatelet therapy. In necropsy studies, drug eluting stents delayed arterial healing and re-endothelialisation compared with bare metal stents.23 24
Again, this effect may be enhanced in people with diabetes, particularly in the absence of dual antiplatelet therapy. Moreover, overall longer stents in people with diabetes may result in a prolongation of the healing and re-endothelialisation process. Finally, people with diabetes may be more likely to experience aspirin resistance than people without diabetes25
and may have a particular benefit from a complementary antiplatelet therapy with clopidogrel or ticlopidine. Taken together, these mechanisms may explain why prolonged dual antiplatelet therapy may be particularly important in people with diabetes.
We recently reported a potentially reduced average risk of myocardial infarction associated with sirolimus eluting stents compared with bare metal stents but not with paclitaxel eluting stents compared with bare metal stents.1
Our analysis suggests that this effect is likely to be present in people with diabetes, but wide credibility intervals of stratified analyses preclude firm conclusions. Stone et al found that about 1.4% of patients undergoing target lesion revascularisation developed a myocardial infarction associated with the procedure.26
A stent that decreases revascularisation rates will therefore result in a reduction of procedure related myocardial infarctions but this will result in a maximum reduction of the relative risk of about 4%, whereas the actually observed average relative risk reduction was 19%.1
Other mechanisms will therefore have to be considered. The process of restenosis in itself may result in myocardial infarction in some patients,27
and a more pronounced reduction of restenosis of sirolimus eluting stents may directly contribute to decreasing the risk of myocardial infarction. Although stent thrombosis is uncommon it is associated with a high incidence of myocardial infarction,26
and the benefits of drug eluting stents for myocardial infarctions are less likely to be offset by stent thromboses in sirolumus eluting stents than in paxlitaxel eluting stents.1
The mechanisms of action of the two drugs merit some consideration. Sirolimus, a macrocyclic lactone, inhibits mammalian target of rapamycin (mTOR) thereby blocking cell division by interfering at the transition from G1 to S phase.28
People with diabetes show a breakdown in the phosphatidylinositol 3 kinase insulin signal transduction pathway, where mTOR has an important role,29
and this has been thought to limit the effectiveness of sirolimus in people with diabetes mellitus. Paclitaxel, which affects cell replication by stabilising microtubules, does not seem to be influenced by insulin resistance and was therefore hypothesised to be superior to sirolimus in people with diabetes. The present study does not support these speculations: although paclitaxel eluting stents tended to reduce the risk of target lesion revascularisation more strongly in people with diabetes than in people without diabetes, sirolimus eluting stents were superior to paclitaxel eluting stents in reducing the risk of revascularisation in people both with and without diabetes.
Rapid technological developments led to novel, second generation drug eluting stents using different antiproliferative substances, absorbable polymers used as drug carriers, and fully bioabsorbable stent systems. Although the short term results for effectiveness of these new generation devices are encouraging,30 31 32
their long term safety profile in people with and without diabetes is still ill defined. An expansion of the present network meta-analysis will be required as soon as longer term follow-up data become available for these novel stent systems.
In trials with a duration of dual antiplatelet therapy of six months or longer drug eluting stents were safe and effective in people with and without diabetes. It seems prudent to adhere to a minimal duration of dual antiplatelet therapy of six months in patients undergoing implantation of a drug eluting coronary stent. The potential benefits of a longer duration of therapy need to be balanced against potential risks, such as clinically relevant bleeding. The optimal duration can only be determined in adequately powered large scale randomised controlled trials.
What is already known on this topic
- People with diabetes are at an increased risk for coronary heart disease and have more restenoses after the implantation of coronary stents
- A meta-analysis suggested a strongly increased risk of death associated with sirolimus eluting stents compared with bare metal stents in people with diabetes
What this study adds
- Reported increases in the risk of death associated with drug eluting stents compared with bare metal stents in people with diabetes were probably due to dual antiplatelet therapy lasting less than six months in early trials
- In trials with dual antiplatelet therapy for six months or longer drug eluting stents were safe and effective in people both with and without diabetes
- In clinical practice it seems prudent to adhere to a minimal duration of dual antiplatelet therapy of six months in all patients undergoing implantation of a drug eluting coronary stent