CLINICAL RESEARCH: INTERVENTIONAL CARDIOLOGY
Use of Drug-Eluting Stents in Acute Myocardial InfarctionA Systematic Review and Meta-Analysis
Somjot S. Brar, MD*,
Martin B. Leon, MD,
Gregg W. Stone, MD,
Roxana Mehran, MD,
Jeffrey W. Moses, MD,
Simerjeet K. Brar, BS and
George Dangas, MD, PhD
Center for Interventional Vascular Therapy, Columbia University Medical Center, and the Cardiovascular Research Foundation, New York, New York
Manuscript received January 27, 2009;
revised manuscript received February 25, 2009,
accepted March 2, 2009.
* Reprint requests and correspondence: Dr. Somjot S. Brar, Center for Interventional Vascular Therapy, Columbia University Medical Center, 161 Fort Washington Avenue, 5th Floor, New York, New York 10032 (Email: SBrar{at}cvri.org).
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Abstract
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Objectives: The primary aim of the analysis was to compare outcomes by stent type for death, myocardial infarction (MI), target vessel revascularization (TVR), and stent thrombosis in randomized trials of ST-segment elevation myocardial infarction (STEMI). A secondary analysis was performed among registry studies.
Background: It is not known whether there are differences in outcomes between drug-eluting stents (DES) and bare-metal stents (BMS) for STEMI.
Methods: We searched MEDLINE, EMBASE, the Cochrane Library, and Internet sources for articles comparing outcomes between DES and BMS among patients with STEMI between January 2000 and October 2008. Randomized controlled trials and registries including patients 18 years of age and older receiving a DES or BMS were included. We extracted variables related to the study design, setting, participants, and clinical end points.
Results: Thirteen randomized trials were identified (N = 7,352). Compared with BMS, DES significantly reduced TVR (relative risk [RR]: 0.44; 95% confidence interval [CI]: 0.35 to 0.55), without increasing death (RR: 0.89; 95% CI: 0.70 to 1.14), MI (RR: 0.82; 95% CI: 0.64 to 1.05), or stent thrombosis (RR: 0.97; 95% CI: 0.73 to 1.28). These observations were durable over 2 years. Among 18 registries (N = 26,521), DES significantly reduced TVR (RR: 0.54; 95% CI: 0.40 to 0.74) without an increase in MI (RR: 0.87, 95% CI: 0.62 to 1.23). Death was significantly lower in the DES group within 1 year of the index percutaneous coronary intervention, but there were no differences within 2 years (p = 0.45).
Conclusions: The use of DES appears safe and efficacious in randomized trials and registries of patients with STEMI. The DES significantly reduce TVR compared with BMS, without an increase in death, MI, or stent thrombosis within 2 years of the index procedure.
Key Words: stent • drug-eluting • myocardial infarction • meta-analysis • systematic review • meta-regression
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Abbreviations and Acronyms
| | BMS = bare-metal stent(s) | | CI = confidence interval | | DES = drug-eluting stent(s) | | MI = myocardial infarction | | NNT = number needed to treat | | PCI = percutaneous coronary intervention | | RCT = randomized controlled trial | | RD = risk difference | | RR = relative risk | | STEMI = ST-segment elevation myocardial infarction | | TIMI = Thrombolysis In Myocardial Infarction | | TVR = target vessel revascularization |
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The aim of primary percutaneous coronary intervention (PCI) is to rapidly achieve complete myocardial reperfusion. Although balloon angioplasty can restore TIMI (Thrombolysis In Myocardial Infarction) flow grade 3, stents provide added benefit by reducing the risk of reocclusion and reinfarction after PCI (1,2). Whether additional benefit can be achieved with the use of drug-eluting stents (DES) remains undetermined. The primary benefit of DES is a marked reduction in restenosis; whether this should be a consideration during primary PCI remains unknown. Patients with ST-segment elevation myocardial infarction (STEMI) were excluded from the pivotal SIRIUS (Sirolimus-Eluting Stent in de Novo Native Coronary Lesions) and TAXUS IV (Paclitaxel-Eluting Stent) trials that led to Food and Drug Administration (FDA) approval of these devices, and DES for primary PCI remains an "off-label" use (3,4). Recent reports have raised concerns about the relative safety of DES, in particular for off-label use, including STEMI (5–8).
We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) reporting outcomes of DES versus bare-metal stents (BMS) in patients with STEMI. For comparison, we also performed an analysis from available registry studies to determine outcomes in a "real-world" setting.
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Methods
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Study objectives and design.
The primary aim of the meta-analysis was to compare the outcomes of DES versus BMS in randomized trials of STEMI. The outcomes of interest were mortality, myocardial infarction (MI), target vessel revascularization (TVR), and stent thrombosis defined according to the study protocols. We also performed a secondary analysis for death, MI, TVR, and stent thrombosis for identified registry studies.
Study search strategy.
Using Medline, EMBASE, and the Cochrane Library, we performed searches for possible abstracts using various combinations of the terms "myocardial," "infarction," "acute," "elevation," "drug," "stent," and "eluting" in the abstract/title. Two reviewers (S.S.B. and S.K.B.) identified articles eligible for further review by performing a screen of abstracts and titles. If a study was deemed relevant, the manuscript was obtained and reviewed. We also searched conference proceedings for the Scientific Sessions of the American College of Cardiology, American Heart Association, Transcatheter Cardiovascular Therapeutics, and the European Society of Cardiology. Web sites, including cardiosource.com, TCTMD.com, theHeart.org, and escardio.org, were also searched for relevant materials. Review articles and prior meta-analysis of the subject were sought (9–11). The references of these were reviewed for additional possible studies.
Study identification.
We searched through the previously described data sources for possible studies from January 1, 2000, to October 30, 2008. These dates were thought to be appropriate as the first DES was not FDA approved until 2003. The search was not limited to the English-language literature. We performed text searches for studies that met the following criteria: 1) direct comparison between either FDA-approved DES (Cypher or Taxus) and a BMS in patients with STEMI; 2) reporting of outcomes before October 30, 2008; and 3) reporting of the incidence of death.
The final search identified 31 studies, 13 randomized trials, and 18 registries, which directly compared 1 of the 2 FDA-approved DES to BMS (Fig. 1).
Data extraction.
We extracted pre-specified data elements from each trial, including study design, stent type, sample characteristics, pharmacologic strategy, duration of clopidogrel therapy, sample size, outcome measures, primary end point, and other study characteristics. The number of events in each trial were extracted, when available, on the basis of the intention-to-treat approach. If TVR was not reported, we used target lesion revascularization instead. All outcomes were defined according to the protocol definition (see the Online Appendix for end point definitions). For registry studies we used adjusted treatment effects whenever possible. When a study reported follow-up at 1 and 2 years, outcomes for both time periods were abstracted. Two authors (S.S.B. and S.K.B.) independently extracted all trial data (kappa 0.95).
Statistical analysis.
From the abstracted data, we calculated the relative risk (RR) using the inverse variance method for each study outcome to allow for pooling of similar outcomes. For the randomized trials, we also report the outcomes as the absolute risk difference (RD), because this conveys both the absolute magnitude and the direction of effect. Furthermore, the number needed to treat (NNT) is easily calculated from this measure (NNT = 1/RD). In this analysis, a negative RD indicates an advantage for DES compared with BMS. In contrast, a positive RD means that BMS is favored over DES.
The average effects for the outcomes and 95% confidence intervals (CI) were obtained using a random effects model, as described by DerSimonian and Laird (12). We chose the random effects method because of its conservative summary estimate and incorporating between and within study variance. To assess heterogeneity of RRs across trials, we used the Cochrane Q statistic (a p value  0.1 was considered significant) and the I2 statistic.
Sensitivity analyses were performed to assess the effects of selected measures of study quality and clinical factors on death, MI, TVR, and stent thrombosis. The influence of each study was estimated by deleting each in turn from the analysis and noting the degree to which the effect size and significance of the treatment effect changed. This analysis was performed for each study outcome. We considered a study influential if the exclusion of it changed our conclusion or the effect estimate by at least 20%. Meta-regression was used to evaluate predictors of death, MI, and TVR by stent type.
Using regression techniques, we explored the relationship between baseline risk, defined as the TVR rate in the BMS group, and the treatment effects. The absolute risk difference was modeled as a weighted linear function of the TVR rate in the BMS group. Because of the limitations of this approach, we then applied a bivariate multilevel random effects model for the binomial outcomes (13–15). The bivariate model had distinct random effects for the DES and BMS groups. The model was constructed using Proc NLMIXED in SAS (SAS Institute, Cary, North Carolina) and yielded maximum likelihood estimates for between trial variance in each treatment group.
Funnel plots were used to assess for the presence of publication and other reporting biases by plotting the precision (inverse of the standard error) against the log risk ratio. Using the Begg and Mazumdar rank correlation (16) and Egger's linear regression (17) method, we examined the association between the study size and estimated treatment effects. The Duval and Tweedie (18) nonparametric trim and fill method was used to obtain symmetry in the funnel plot and to determine the impact of hypothetical negative or imputed studies on the pooled estimate.
The p value threshold for statistical significance was set at 0.05 for effect sizes. Analyses were conducted in STATA 10.0 (Stata Corp., College Station, Texas), Comprehensive Meta-analysis 2.0 (Biostat, Englewood, New Jersey), and SAS version 9.2 (SAS Institute, Cary, North Carolina). The study was performed in accordance with the recommendations set forth by the Quality of Reporting of Meta-Analysis (QUOROM) and the Meta-Analysis of Observational Studies in Epidemiology (MOOSE) work groups (19,20).
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Results
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Eligible studies.
Table 1
lists the study characteristics for the 13 randomized trials selected for inclusion (21–33). These trials yielded a cumulative total of 7,352 patients, 4,515 of whom were randomly assigned to DES and 2,837 to BMS. In 3 of the trials, both the sirolimus- and the paclitaxel-eluting stents were used; in 4 trials, the paclitaxel-eluting stent was used; and in 6 studies, sirolimus-eluting stents were used. The mean ages ranged from 59 to 63 years. The frequency of diabetes mellitus ranged from 10% to 21%. The left anterior descending artery was identified as the culprit vessel in 41% to 55% of the patients. All randomized patients received aspirin (at least 75 mg) indefinitely and clopidogrel loading (300 to 600 mg). The minimum duration of clopidogrel therapy ranged from 6 to 12 months for all studies except 2: the STRATEGY (Single High-Dose Bolus Tirofiban and Sirolimus-Eluting Stent vs Abciximab and Bare Metal Stent in Myocardial Infarction) trial and the MULTISTRATEGY (Multicentre Evaluation of Single High-Dose Bolus Tirofiban vs Abciximab With Sirolimus-Eluting Stent or Bare Metal Stent in Acute Myocardial Infarction Study) trial required a minimum duration of 3 months of clopidogrel therapy.
Mortality.
All 13 randomized trials reported mortality data. There were 288 events among the 7,352 patients (3.9%). The incidence in the DES group was 3.7% (167 of 4,515), and in the BMS group it was 4.3% (121 of 2,837); the corresponding pooled RR for DES versus BMS was 0.89 (95% CI: 0.70 to 1.14; p = 0.36) (Fig. 2A). The pooled RD between the groups was –0.4%, nonsignificantly in favor of DES (95% CI: –1.4% to 0.5%; p = 0.38). There was no evidence of statistical heterogeneity among these studies (p heterogeneity = 0.48).
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Figure 2 Outcomes in Randomized Trials
Size of data markers indicates the weight of the study: (A) mortality; (B) myocardial infarction; (C) target vessel revascularization (TVR); and (D) stent thrombosis. BMS = bare-metal stent(s); CI = confidence interval; DES = drug-eluting stent(s).
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There were 2 trials with a nonsignificant RD in favor of BMS, the DEDICATION-STENT (Drug Elution and Distal Protection During Percutaneous Coronary Intervention in ST Elevation Myocardial Infarction) trial and the HAAMU-STENT (Helsinki Area Acute Myocardial Infarction Treatment Re-Evaluation) trial. The former was a randomized comparison of the paclitaxel- or sirolimus-eluting stents versus BMS. Major adverse cardiac events—a composite of death, MI, and target lesion revascularization—was lower in the DES group (8.9% vs. 14.4%, p < 0.001), driven by a reduction in target lesion revascularization with DES (5.1% vs. 13.1%, p < 0.001). Cardiac mortality and overall mortality were nonsignificantly greater in the DES group, 4.2% versus 1.6% (p = 0.09) and 5.1% versus 2.6% (p = 0.14), respectively. However, this difference in death could not be attributed to stent thrombosis, which was identical in the 2 arms. The HAAMU-STENT trial randomly allocated 164 patients to either a paclitaxel-eluting stent or BMS; the trial was underpowered for assessment of clinical end points. Mortality at 1 year was 4.9% in the BMS group compared with 9.8% in the paclitaxel-eluting stent group, a difference that was not significant (p = 0.23). Consistent with a practice that is common in some European countries, 45% of the patients in the HAAMU-STENT trial were treated with a facilitated PCI approach, a treatment strategy that remains controversial.
MI.
There were 261 events among the 7,352 participants (3.6%). The incidence of MI was 3.4% (153 of 4,515) in the DES group and 3.8% (108 of 2,837) in the BMS group; the corresponding pooled RR for DES versus BMS was 0.82 (95% CI: 0.64 to 1.05; p = 0.12) (Fig. 2B). The pooled RD between the groups was –0.4% (95% CI: –1.3% to 0.3%), nonsignificantly in favor of DES (p = 0.19). There was no evidence of statistical heterogeneity between studies (p heterogeneity = 0.92). The point estimates for any given study did not reach statistical significance in favor of either DES or BMS.
TVR.
Among the 13 selected randomized trials, the incidence of TVR was lower with DES compared with BMS. In 9 of the studies, the reduction was statistically significant (Fig. 2C). There were 569 TVR events among the 7,352 participants (7.7%). The incidence of TVR was 5.3% (241 of 4,515) in the DES group and 11.5% (328 of 2,837) in the BMS group; the corresponding pooled RR was 0.44 (95% CI: 0.35 to 0.55; p < 0.001), yielding a 56% risk reduction in TVR with DES. The pooled RD between groups was –7.0%, significantly in favor of DES (95% CI: –9.2% to –4.7%; p < 0.001). The NNT with a DES to prevent 1 TVR was 14 patients (95% CI: 11 to 21).
We explored whether the baseline risk of patients in each trial was related to the magnitude of the treatment benefit with DES for TVR. Baseline risk or the control rate was defined as the TVR event rate in the BMS group. A weighted regression analysis for the TVR rate in the BMS group showed that the benefit of DES was greater in higher risk groups (p < 0.001) (Fig. 3). Because of the limitations of this approach, namely regression to the mean, we applied a bivariate random-effects mixed model for the binomial outcome. The estimated residual variance given the control rate was 0.0106, and was considerably smaller than the variance of the treatment effect, 0.1280. In summary, 92% of the variation in the treatment effects was explained by the control rate; so the variation in the treatment effect was largely explained by variation in the baseline risk.
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Figure 3 Relationship Between Baseline Risk and Risk Difference for TVR in Randomized Controlled Trials
Relationship between baseline risk (target vessel revascularization [TVR] rate in the bare-metal stent [BMS] group) and risk difference for TVR in randomized controlled trials. The plot shows the regression of baseline risk on the risk difference. A negative risk difference favors drug-eluting stents, whereas a positive risk difference favors BMS. The size of each circle relates to the weight of each trial. p < 0.001.
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Stent thrombosis.
All 13 randomized trials reported the frequency of stent thrombosis (Fig. 2D). Among 7,352 patients, there were 194 stent thrombosis events (2.6%). The incidence of stent thrombosis was 2.7% (120 of 4,515) in the DES group and 2.6% (74 of 2,837) in the BMS group in the first year; the corresponding relative risk was 0.96 (95% CI: 0.72 to 1.30; p = 0.81). The pooled RD was 0.1% (95% CI: –0.8% to 0.6%), not significantly different between groups (p = 0.79). There was no evidence of statistical heterogeneity among the trials (p heterogeneity = 0.95).
Four trials reported outcomes beyond the first year (22,24,27,32). There was no difference in the effect for stent thrombosis between the first and the second year after PCI (p = 0.99). In the second year, the RD was –0.6% (95% CI: –2.3% to 1.1%; p = 0.51); the corresponding RR was 0.78 (95% CI: 0.38 to 1.67; p = 0.52).
Sensitivity and influence analysis.
We also examined the robustness of the findings among the randomized studies to different assumptions in a sensitivity analysis for mortality, MI, TVR, and stent thrombosis (Fig. 4). The overall effect calculated by either a random or fixed effects model yielded similar overall estimates for each of the end points.
We then performed stratified analysis across a number of key study characteristics and clinical factors. Methodological quality was assessed in terms of trial size and single-center versus multicenter trial design. By trial size, the estimated treatment effect was similar for small (<20 deaths) and large ( 20 deaths) studies. The 8 single-center studies indicated greater benefit for DES than did the 5 multicenter studies, but confidence intervals widely overlapped. All 13 trials reported methods for concealment of allocation; only 1 trial was double blinded (33). While studies varied in length of follow-up, that had little effect on estimates. With up to 24 months of follow-up, there was no difference in death, MI, TVR, or stent thrombosis between DES and BMS. Lastly, the duration of clopidogrel therapy, 6 months versus >6 months, had little effect on estimates.
The influence of each study was estimated by deleting each in turn from the analysis; there was no significant change in the pooled treatment effect for death, MI, TVR, or stent thrombosis. There continued to be no evidence of statistical heterogeneity across trials. In influence analysis for TVR, the NNT to prevent 1 TVR event with DES ranged from 13 to 16 patients. Lastly, omission of the HORIZONS-AMI (Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction) trial, the largest trial in the series, did not appreciably change our findings. The RRs (95% CI) for death, MI, stent thrombosis, and TVR in the absence of this trial were 0.82 (0.63 to 1.07), 0.82 (0.59 to 1.13), 0.99 (0.69 to 1.43), and 0.40 (0.32 to 0.49), respectively.
Registry studies.
We identified 18 registry studies of STEMI where the outcomes were reported by stent type (Table 2) (34–51). There were 26,521 patients with STEMI, of whom 11,866 were treated with DES and 14,656 with BMS. Mortality data were available from all 18 registries. Data on myocardial infarction and TVR were available from 14 registries. Eleven studies reported outcomes beyond 1 year.
The pooled treatment effect for mortality yielded a significant 32% reduction in mortality with DES within 1 year of the index PCI (RR: 0.68; 95% CI: 0.54 to 0.88; p < 0.01) (Fig. 5A). However, the mortality difference within 2 years of the index PCI was no longer statistically significant but remained in favor of DES (RR: 0.89; 95% CI: 0.64 to 1.22; p = 0.45). Among the observational studies, only the GRACE (Global Registry of Acute Coronary Events) registry reported a statistically significant excess of mortality with DES. The GRACE registry is a multinational registry of >30,000 patients with acute coronary syndromes. The STEMI cohort from the GRACE registry represented a small percentage of the full registry; of 2,269 patients with STEMI, only 569 were treated with DES. In contrast to GRACE, several large registries have observed a significant reduction in mortality with DES at 1 and 2 years (35,39,45,47). Among these registries, the RR in favor of DES ranged from 0.59 to 0.68 (p 0.01). Also, most of the heterogeneity between studies could be accounted for by the GRACE registry; in its absence, heterogeneity, measured as I2, decreased from 86% to 6% (p heterogeneity = 0.39).
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Figure 5 Outcomes in Registry Studies
Size of data markers indicates the weight of the study: (A) death within 1 year and within 2 years; (B) myocardial infarction (MI) within 1 year and within 2 years; (C) target vessel revascularization (TVR) within 1 year and within 2 years; and (D) stent thrombosis within 1 year and within 2 years. RR = relative risk; other abbreviations as in Figure 2.
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The pooled RR (95% CI) for myocardial infarction within 1 and 2 years from the index PCI was not significantly different between DES and BMS groups at 0.87 (0.62 to 1.23) and 0.96 (0.81 to 1.13), respectively (Fig. 5B). There was no evidence of statistical heterogeneity among the registry studies for myocardial infarction (p heterogeneity > 0.10).
TVR was significantly reduced with DES in the registry studies (Fig. 5C). Within 1 year of the index PCI, DES was associated with a 46% reduction in TVR (RR: 0.54; 95% CI: 0.40 to 0.74; p < 0.01). By 2 years, there remained a significant reduction in TVR with DES (RR: 0.71; 95% CI: 0.61 to 0.83; p < 0.01).
Stent thrombosis within 1 year of the index PCI was lower with DES (RR: 0.52; 95% CI: 0.31 to 0.88; p = 0.01) (Fig. 5D), whereas there was no difference between stent types at 2 years (RR: 0.94; 95% CI: 0.60 to 1.45; p = 0.77).
Publication bias.
Visual inspection of the funnel plot for death did not reveal asymmetry in RCTs (Fig. 6A). In support, the Begg rank correlation test and Egger's regression test were not statistically significant (p = 0.39 and p = 0.52, respectively). However, on visual inspection, there was asymmetry in the funnel plot in the registry studies (Fig. 6B). Given the asymmetry in the funnel plot on visual inspection, we further explored any potential bias using the Duval and Tweedie trim and fill method. In this analysis, the asymmetric studies from the left-hand side of the funnel plot are trimmed to locate the unbiased effect, and then the plot is filled by reinserting the trimmed studies on the left as well as their imputed counterparts to the right of the mean effect, producing a symmetric funnel plot. The analysis incorporating 8 hypothetical or imputed studies showed the pooled estimates for death were no longer significant in the registry studies.
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Figure 6 Publication Bias
Funnel plot with pseudo 95% confidence limits for assessment of publication bias for mortality among (A) randomized controlled trials and (B) registry studies. Open circles represent original studies. Solid circles represent hypothetical or imputed studies. Open diamonds represent the pooled treatment effects from the original studies. The solid diamonds and vertical lines represent the pooled treatment effects incorporating the imputed studies.
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Discussion
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This meta-analysis of 13 randomized trials, which compared outcomes of DES and BMS in 7,352 randomized patients, suggests that DES use significantly decreases restenosis compared with BMS use in patients with STEMI. The DES use yielded a relative and absolute reduction in TVR of 56% and –7.0%, respectively (p < 0.001). Treatment of 13 patients with a DES in the STEMI setting could prevent 1 restenosis event within the studied time frame. The analysis also suggests that this benefit does not come at the expense of increased death, reinfarction, or stent thrombosis within 2 years of the index PCI.
Efficacy of DES.
The efficacy and safety of DES are largely supported by the analysis of 18 registry studies, including 26,521 patients with STEMI. Among the registries, there was also a statistically significant reduction in TVR without an increase in death, MI, or stent thrombosis. However, the magnitude of the reduction in TVR with DES was slightly less compared with that of the randomized trials; the RR in the registries and randomized trials were 0.54 and 0.44, respectively. These differences likely reflect the use of DES in a broader, more complex, and heterogeneous population with STEMI in the registry studies, more reflective of real-world experiences. These differences may also be attributed to selection bias and unknown or unmeasured confounders. The –7.0% absolute reduction in TVR with DES among the randomized trials is slightly less compared to patients undergoing PCI for indications other than STEMI. In the pivotal TAXUS-IV and SIRIUS (Study of the Sirolimus-Eluting Stent in De Novo Native Coronary Lesions) trials, the absolute reduction in TVR was –8.3% and –12.5%, respectively.
The reduction in the TVR rate with DES also appears to be related to the population baseline risk. In studies with higher baseline risk, measured as the TVR rate in the BMS groups, the magnitude of benefit was greater with DES. In a bivariate meta-analysis, as previously described, the majority of the variation in the treatment effects was explained by the baseline risk or the TVR rate in the BMS groups. These findings are consistent with those of prior reports of greater magnitude of benefit with DES in patients at higher risk for restenosis (52–55).
Safety of DES.
The benefit of DES against restenosis should be balanced against the risk of adverse events, stent thrombosis in particular. Stent thrombosis remains a serious complication, associated with increased morbidity and mortality (8,56). The use of DES in STEMI has been identified as a predictor of stent thrombosis in some observational studies (7,57). However, in the present analysis, stent thrombosis does not appear to differ between DES and BMS. The RR for stent thrombosis within 2 years of primary PCI in RCTs and registries was 0.97 and 0.94, respectively, nonsignificantly in favor of DES (p > 0.40).
For the patient with STEMI and treated emergently, it can be difficult to ascertain the likelihood of compliance with dual antiplatelet therapy, need for future surgical procedures, and prior bleeding complications. It is plausible that the clinical sequelae of noncompliance or premature discontinuation of dual antiplatelet therapy should manifest as an increase in death, MI, and stent thrombosis, in the DES group in particular (58,59). However, we did not observe an increase in any of these adverse events within 1 or 2 years with DES across the RCTs and registries. Furthermore, there was no difference in adverse events among studies requiring >6 or <6 months of clopidogrel therapy. Accordingly, the results are consistent with other reports and meta-analysis of stent thrombosis in varied acute coronary syndrome settings (60).
Interestingly, there was a statistically significant decrease in mortality with use of DES in the registry studies at 1 year that was not apparent at 2 years. While the direction of the overall effect for mortality in the randomized trials also favored DES, it was not statistically significant at any time point. Although we used adjusted effect measures from registry studies when possible, residual confounding and selection bias could explain, in part, the lower mortality associated with DES. Moreover, the heterogeneity between registries for mortality and the visual asymmetry in the funnel plot suggesting publication bias could also explain this potential benefit. In fact, after correction for the asymmetry in the funnel plot, there was no longer a statistically significant difference for death in the registries.
In the aggregate, the present data do not support the concerns that use of DES in patients with STEMI may increase the risk of death or MI, driven in part by increased stent thrombosis. Post-mortem studies, including those of patients with stent thrombosis, have shown incomplete endothelialization, persistent inflammation, and late malaposition (61). While informative, these observations remain significantly biased, given the select cohort from which they are derived. The true incidence of these pathologic changes and the frequency with which they lead to death, MI, or stent thrombosis remains unknown. In the absence of an increase in adverse clinical events with DES across multiple randomized trials and registries, the incidence of these pathologic findings is likely to be low. Furthermore, the favorable clinical outcomes in the present analysis suggest that many patients heal the stented segment and overcome those initial pathologic disadvantages.
Study limitations.
Some studies suggest that the risk of very late stent thrombosis (>2 years from the index PCI) may be slightly increased with the use of DES (62). The current study does not address this issue adequately, given that only 2 studies had follow-up beyond 24 months. Furthermore, data on clopidogrel adherence were unavailable. The random allocation of study subjects in the RCTs should have yielded, in theory, a similar incidence of clopidogrel noncompliance in both stent groups. However, among the registries, the duration of clopidogrel therapy likely differed, with the DES group more likely treated with prolonged therapy. That could have contributed, in part, to the improved 1-year mortality with DES in the registries and is consistent with a prior report on improved outcomes with prolonged clopidogrel therapy as recommended by the current guidelines (58,63). Efforts directed at the education of patients and other health care providers on the importance of compliance with dual antiplatelet therapy should help further improve outcomes (58,59). Meanwhile, percutaneous therapy continues to rapidly evolve with improvements in stent platforms and adjunctive medical therapy. With 5 years of planned follow-up, the HORIZONS-AMI trial will provide valuable insight into the long-term outcomes of the paclitaxel-eluting stent in patients with STEMI (64).
Although we observed that the reduction in TVR with DES compared with BMS was related to underlying baseline risk, an association with study level covariates does not conclusively establish a relationship at the patient level. Also, the optimal method for relating baseline risk to treatment effect remains controversial, and alternate methods have been proposed (65,66). Nevertheless, using multiple methods, our results are in support of such a relationship, and are consistent with prior reports of higher rates of restenosis in higher-risk cohorts (52,53).
Lastly, this meta-analysis was performed at the study level. Availability of individual patient data could improve the reliability of the findings and permit more flexible analyses. However, a major limitation of individual patient data analyses remains the inability to obtain patient-level data from all investigators, unpublished studies in particular. Therefore, the selective inclusion of studies in individual patient data meta-analysis can introduce publication and other biases.
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Conclusions
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In this meta-analysis of 33,873 patients with STEMI, the use of DES appears safe and efficacious compared with BMS across randomized trials and registries. The use of DES significantly decreased restenosis without an increase in the incidence of death, MI, or stent thrombosis within 2 years of the index PCI. Longer-term follow-up is necessary to determine the durability of these observations.
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Appendix
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For a table on the end points analyzed by trial, please see the online version of this article.
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Footnotes
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Dr. Somjot Brar receives research grant support from Boston Scientific. Dr. Leon is on the scientific advisory board of Abbott, Boston Scientific, and Medtronic. Dr. Stone receives research support from Boston Scientific, Abbott Vascular, and The Medicines Company. Dr. Mehran is a speaker/consultant to Cordis, Abbott, Medtronic, and Boston Scientific (all modest, <$10,000). Dr. Moses is a speaker for Cordis, Abbott, and Boston Scientific (all modest, <$10,000). Drs. Dangas is a speaker/consultant to Cordis, Abbott, Medtronic, and Boston Scientific (all modest, <$10,000).
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References
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