|Adjusted indirect comparison of intracoronary drug-eluting stents: evidence from a metaanalysis of randomized bare-metal-stent-controlled trials
|Biondi-Zoccai G G, Agostoni P, Abbate A, Testa L, Burzotta F, Lotrionte M, Crea F, Biasucci L M, Vetrovec G W, Colombo A
This review compared the effectiveness of different intracoronary drug-eluting stents. The authors concluded that polymeric paclitaxel-eluting and sirolimus-eluting stents are effective, and polymeric everolimus-eluting stents seem promising, but most other drug-eluting stents are significantly inferior. Given that some review processes were unclear, study quality was not assessed and differences between the studies were not investigated, the robustness of the conclusions is unclear.
To compare the effectiveness of different intracoronary drug-eluting stents using an adjusted indirect comparative meta-analysis, based on randomised studies using a bare metal stent as the control.
BioMed Central, the Cochrane CENTRAL Register, CINAHL, meta Register of Controlled Trials and PubMed were searched up to May 2004 without any language restrictions. The proceedings of major international cardiological meetings and the bibliographies of relevant papers and review articles were also searched.
Study designs of evaluations included in the review
Randomised controlled trials (RCTs) were eligible for inclusion.
Specific interventions included in the review
Studies comparing any drug-eluting stent, except the Quanam polymeric sleeved paclitaxel analogue-eluting stent, with a bare metal stent implantation were eligible for inclusion. The included studies assessed polymeric actinomycin-d-eluting stent (polymeric AES), apolymeric paclitaxel-eluting stent (apolymeric PES), polymeric sirolimus-eluting stent (polymeric SES), polymeric everolimus-eluting stent (polymeric EES), micophenolate-eluting stent (MES), and slow and moderate release polymeric PES. Comparisons were made with a range of different bare metal stents.
Participants included in the review
Studies of patients undergoing percutaneous coronary intervention (PCI) were eligible for inclusion. The included studies were of patients with de novo coronary lesions only. The proportion of diabetic patients in the included studies ranged from 2 to 29%. The reference vessel diameter ranged from 2.20 to 3.06 mm and the lesion length from 8.9 to 20.6 mm. Further details of the participants are available from an earlier systematic review (see Other Publications of Related Interest no.1).
Outcomes assessed in the review
The rate of target lesion revascularisation (TLR), at up to 12 months, was the primary outcome of interest. TLR was defined as repeat PCI or surgical revascularisation of the originally stented lesion, owing to clinically or angiographically significant restenosis. The secondary outcome was the angiographic binary restenosis rate (BRR), defined as greater than 50% diameter stenosis of the target lesion at follow-up angiography, at up to 12 months. The length of follow-up in the included studies ranged from 5 to 12 months for the primary outcome.
How were decisions on the relevance of primary studies made?
The authors did not state how the papers were selected for the review, or how many reviewers performed the selection.
Assessment of study quality
The authors did not report that they assessed validity, but referred to a validity assessment available in an earlier systematic review (see Other Publications of Related Interest no.1). The authors did not state how the validity assessment was performed.
The authors did not state how the data were extracted for the review, or how many reviewers performed the data extraction. The event rates for TLR and BRR were extracted for the individual studies.
Methods of synthesis
How were the studies combined?
Studies of the same or similar drug-eluting stents were pooled using a random-effects model to investigate the effectiveness of drug-eluting stents compared with bare metal stents (these data are not summarised here as this was not the focus of the review). An adjusted indirect comparison using the common comparator (bare metal stents) was conducted, using a random-effects model, according to Song et al. (see Other Publications of Related Interest no.2). The indirect comparison was made between SES and all other drug-eluting stents and PES and all other drug-eluting stents.
A funnel plot and the Egger test were used to investigate publication bias.
How were differences between studies investigated?
Statistical heterogeneity was assessed using the I-squared (I2) statistic. Mild heterogeneity was defined as an I2 of 25%, moderate heterogeneity as an I2 of 50%, and severe heterogeneity as an I2 of 75%. A subgroup analysis of diabetic participants and of the use of in-segment analysis was conducted for one indirect comparison.
Results of the review
Seventeen RCTs (n=6,440) were included.
SES versus other drug-eluting stents.
There was no statistically significant difference between SES and polymeric PES for the rate of TLR, the primary outcome (OR 0.74, 95% confidence interval, CI: 0.44, 1.25, P=0.26), though there was a statistically significant difference in BRR favouring SES (OR 0.28, 95% CI: 0.15, 0.53, P<0.001). There was evidence of moderate statistical heterogeneity for this comparison. There was no statistically significant difference between SES and EES for TLR (OR 0.53, 95% CI: 0.08, 3.70, P=0.52) or BRR. The remaining three drugs were statistically significantly inferior to SES for TLR and BRR: for the outcome TLR, the OR was 0.08 (95% CI: 0.04, 0.18, P<0.001) for SES versus AES, 0.19 (95% CI: 0.06, 0.62, P=0.006) for SES versus MES, and 0.31 (95% CI: 0.18, 0.55, P<0.001) for SES versus apolymeric PES. There was evidence of moderate or severe statistical heterogeneity in all three of these comparisons.
Polymeric PES versus other drug-eluting stents.
There was no statistically significant difference between polymeric PES and EES for TLR (OR 0.71, 95% CI: 0.10, 4.89, P=0.73) or BRR. The remaining three drugs were statistically significantly inferior to polymeric PES for TLR and BRR: for the outcome TLR, the OR was 0.11 (95% CI: 0.05, 0.23, P<0.001) for polymeric PES versus AES, 0.30 (95% CI: 0.10, 0.90, P=0.03) for polymeric PES versus MES, and 0.42 (95% CI: 0.26, 0.68, P<0.001) for polymeric versus apolymeric PES. There was evidence of moderate or severe statistical heterogeneity for the comparisons with AES and MES.
The authors stated that the funnel plot did not suggest significant publication bias (plot not displayed), and that the Egger test was not statistically significant for TLR or BRR.
The meta-analysis confirmed the effectiveness of polymeric PES and SES, supported the promising role of EES, and suggested the significant inferiority of most other drug-eluting stents. However, prospective confirmation of the findings is required given the inherent limitations of indirect comparisons.
The review addressed a clear research question using defined inclusion criteria. Relevant electronic databases were searched for studies; however, details of the search strategy were not reported. Attempts were made to locate unpublished studies, thereby reducing the risk of publication bias, and language restrictions were not applied. Some relevant details of the study populations were provided. An appropriate method of indirect comparison was used and the authors appropriately highlighted the limitations of making indirect comparisons between interventions.
The review had some limitations. The quality of the included studies was not assessed and it was unclear whether appropriate methods were used to reduce error and bias in the study selection and data extraction stages. In addition, although statistical heterogeneity was assessed, it was not investigated where it was found. Adverse events were not considered. Although the authors' conclusion follows from the evidence presented, its robustness is unclear given the limitations in the review methods, lack of consideration of study quality, and the uninvestigated heterogeneity.
Implications of the review for practice and research
Practice: The authors did not state any implications for practice.
Research: The authors stated that large RCTs directly comparing different drug-eluting stents are required.
Biondi-Zoccai G G, Agostoni P, Abbate A, Testa L, Burzotta F, Lotrionte M, Crea F, Biasucci L M, Vetrovec G W, Colombo A. Adjusted indirect comparison of intracoronary drug-eluting stents: evidence from a metaanalysis of randomized bare-metal-stent-controlled trials. International Journal of Cardiology 2005; 100(1): 119-123
Other publications of related interest
1. Hill RA, Dundar Y, Bakhai A, Dickson R, Walley T. Drug-eluting stents: an early systematic review to inform policy. Eur Heart J 2004;25:902-19. 2. Song F, Altman D, Glenny AM, Deeks JJ. Validity of indirect comparison for estimating efficacy of competing interventions: empirical evidence from published meta-analysis. BMJ 2003;326:472-5.
Subject indexing assigned by NLM
Coronary Disease /therapy; Humans; Immunosuppressive Agents /administration & Odds Ratio; Paclitaxel /administration & Prosthesis Design; Randomized Controlled Trials as Topic; Sirolimus /administration & Stents; derivatives; dosage; dosage; dosage /analogs &
Date bibliographic record published
Date abstract record published
This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.