A Meta-Analysis of Randomized Controlled Trials of Conventional Stenting Versus Direct Stenting in Patients With Acute Myocardial Infarction

Abstract: Background. Direct stenting (DS) is commonly used during percutaneous coronary intervention for acute myocardial infarction (AMI) to prevent distal embolization; however, no guideline recommendations exist regarding DS. We sought to compare DS with conventional stenting (CS) in patients presenting with AMI in a meta-analysis of randomized controlled trials. Methods. Studies were identified from EMBASE, MEDLINE, and Cochrane databases. To be included, randomized controlled trials must have compared DS with CS in patients with AMI. Data were extracted and articles were critically appraised by two authors. A fixed effects model was used, with Peto odds ratios (ORs). The primary endpoint was death from cardiovascular causes. Results. Five trials (n = 754) met the eligibility criteria. ST-segment resolution occurred in 68.9% (146/212) in the DS group vs 60.2% (127/211) in the CS group (OR, 1.51; 95% CI, 1.00-2.27; P=.05; I²=52%). No-reflow occurred in 6.6% in the DS group compared with 6.9% in the CS group (OR, 0.78; 95% CI, 0.39-1.55; P=.48; I²=0%). DS was associated with a significant reduction in the risk of in-hospital cardiovascular death (OR, 0.21; 95% CI, 0.06-0.77; P=.02; I²=0%). No significant differences were observed in myocardial infarction (OR, 0.38; 95% CI, 0.09-1.51; P=.17; I²=7%) or target lesion revascularization (OR, 1.20; 95% CI, 0.36-3.97; P=.76; I²=0%). Conclusion. Small trials suggest a potential benefit to DS in AMI. Further large-scale randomized trials are warranted to confirm the benefit of this approach.

J INVASIVE CARDIOL 2015;27(9):405-409. Epub 2015 June 15

Key words: acute MI, percutaneous coronary intervention, risk reduction, myocardial infarction

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Percutaneous coronary artery intervention (PCI) has been shown to improve clinical outcomes in both ST-segment elevation myocardial infarction (STEMI) and non-STEMI.^1-5 An emerging concept is that avoiding balloon predilation and instead direct stenting (DS) may prevent distal embolization and limit myocardial necrosis. In an acute myocardial infarction (AMI), particularly in STEMI, there is typically a large thrombus burden in the target vessel. DS has the potential to trap thrombus behind the stent, thus preventing no-reflow and increases in infarct size.⁶ Potential disadvantages of DS include failure to cross the lesion, stent undersizing, and stent underexpansion.⁶

Currently, there are no guideline recommendations with regard to DS.^1,2 Therefore, we sought to perform a meta-analysis of randomized trials to compare the clinical outcomes of DS with conventional stenting (CS) in patients presenting with AMI.

Methods

Clinical trial selection. All randomized controlled trials comparing the two techniques in patients presenting with AMI and including data on death, MI, or target vessel revascularization (TVR) were included in the analysis. Trials that randomized patients to two or more interventions simultaneously (ie, thrombectomy with DS) such that the effect of DS could not be evaluated individually were excluded. No language or time criteria were set. We searched MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials. We searched references of included articles and also performed a cited reference search using Web of Knowledge. The search was performed in June 2014. We combined MeSH terms, EMTREE terms, and keywords including: myocardial infarction; heart infarction; acute coronary syndrome; STEMI; coronary occlusion; and stents. The search strategy is detailed in Appendix 1. The systematic review was performed in accordance with the PRISMA statement.⁷

Study outcomes. The primary outcome was cardiovascular death. Secondary outcomes included ST-segment resolution, no-reflow rates, MI, TVR, procedural time, and contrast use. The rate of crossover between the two groups was reported. Outcomes were collected if available.

Data collection and quality assessment. Two review authors blinded to the study’s hypothesis independently determined if each study met the inclusion criteria for the review, with differences resolved by consensus or a third author. The risk of bias of the included studies was assessed by two independent review authors, using the Cochrane risk-of-bias assessment tool.⁸ Each entry in the table addressed a specific feature of the study. “Low” indicated low risk of bias, “high” indicated high risk of bias, and “unclear” indicated either lack of sufficient reporting or uncertainty in potential bias. Sequence generation and allocation concealment deal with selection bias; blinding deals with performance bias. Attrition bias is addressed by incomplete outcome data and blinding. Detection bias is covered by blinding and other possible risks of bias.

Two review authors independently abstracted data from each study using data abstraction forms and were cross-checked. Discrepancies were resolved by consensus or a third author. For each study, data extraction regarding citation, method and design, participants, interventions, assessment tools, outcomes, sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting, and other sources of bias were established a priori.

Data synthesis and analysis. For dichotomous data, we collected 2 x 2 tables, confidence intervals (CIs), and P-values. Dichotomous data were summarized as odds ratios (ORs). For continuous data, we collected means of values and standard deviations. Continuous data were summarized as weighted mean difference. Overall data summaries were performed with the Peto OR. The Peto fixed-effects model is most appropriate when few events occur, group sizes contain similar numbers of patients, and it does not require corrections for zero cell counts.^9-11 Weighing the data was based on the inverse variance of effect estimates, or if unavailable then based on the number of participants in each trial. Results were considered statistically significant at a P-value of <.05. Heterogeneity of data was tested with the chi-squared test and I² test. Sensitivity analyses using random-effects model were performed. Statistical analyses were performed with Review Manager 5.1.4 (RevMan, The Nordic Cochrane Centre, The Cochrane Collaboration).

Results

Eligible studies. The initial search identified 4836 unique references, which were screened based on titles and abstracts. Initial screening led to 33 reports retrieved in full text. After obtaining the full-text articles, 5 trials were included in the meta-analysis (Figure 1).^12-16 Appendix 2.1 and 2.2 details the excluded studies.

Study characteristics. The 5 trials included 754 patients. A total of 375 patients were randomized to DS, and 379 patients were randomized to CS. Of the patients randomized, 551 (73%) presented with STEMI, and 181 (24%) presented with non-STEMI or unstable angina. Table 1 summarizes the main characteristics of included studies. Four of the 5 trials were single-center trials.

Patients with left main stenosis, tortuous or calcified lesions were excluded from the trials. All 5 trials used bare-metal stents. All protocols administered heparin during the procedure, and dual-antiplatelet therapy (aspirin and ticlopidine) after the procedure.

Risk of bias. The risk of bias, with respect to cardiovascular death, for included studies is summarized in Table 2. The risk of bias could not be assessed for some of the items due to poor reporting; thus, many items were scored as unclear bias risk.

In-hospital clinical outcomes. The primary outcome of in-hospital cardiovascular mortality occurred in 0.27% (1/375) in the DS group and 2.11% (8/379) in the CS group (OR, 0.21; 95% CI, 0.06-0.77; P=.02; I²=0), as shown in Figure 2.

In a sensitivity analysis using a random-effects model (Table 3), the result was similar but the difference was not statistically significant (OR, 0.26; 95% CI, 0.06-1.06; P=.06).

Four trials reported outcomes on in-hospital MI and TVR. The differences in MI (OR, 0.38; 95% CI, 0.09-1.51; P=.17; I²=7%) and TVR (OR, 1.20; 95% CI, 0.36-3.97; P=.76; I²=0%) were not statistically significant (Figures 3 and 4).

Long-term outcomes. Three studies reported longer clinical follow-up (2 studies at 6 months and 1 study at 1 year). All 3 were combined in a pooled analysis of outcomes at longest available follow-up. Cardiovascular death occurred in 7/240 patients (2.9%) in the DS group vs 10/242 patients (4.1%) in the CS group (OR, 0.68; 95% CI, 0.25-1.81; P=.44; I²=0%). MI occurred in 9/240 patients (3.7%) in the DS group vs 8/242 patients (3.3%) in the CS group (OR, 1.15; 95% CI, 0.44-3.05; P=.44; I²=16%). TVR occurred in 20/240 patients (8.3%) in the DS group vs 15/242 patients (6.2%) in the CS group (OR, 1.36; 95% CI, 0.68-2.70; P=.77; I²=0%).

STEMI subgroup analysis. Three trials included 473 patients presenting with STEMI. A total of 237 patients were randomized to DS, and 236 patients were randomized to CS. ST-segment resolution occurred in 146/212 (68.9%) in the DS group vs 127/211 (60.2%) in the CS group (OR, 1.51; 95% CI, 1.00-2.27; P=.05; I²=52%). No-reflow occurred in 10/212 (4.7%) in the DS group vs 15/211 (7.1%) in the CS group (OR, 0.65; 95% CI, 0.29-1.46; P=.30; I²=0%). The results of sensitivity analyses using a random-effects model are summarized in Table 3.

The primary outcome of in-hospital cardiovascular mortality occurred in 1/237 (0.42%) in the DS group vs 7/236 (3.0%) in the CS group (OR, 0.22; 95% CI, 0.05-0.89; P=.03; I²=0). In a sensitivity analysis using a random-effects model, the difference was not statistically significant (OR, 0.25; 95% CI, 0.05-1.18; P=.08).

Two trials reported outcomes on in-hospital MI and TVR. The differences in MI (OR, 1.01; 95% CI, 0.14-7.21; P=.99; I²=22%) and TVR (OR, 1.20; 95% CI, 0.36-3.97; P=.76; I²=0%) were not statistically significant.

Only 1 study reported longer clinical follow-up. Therefore, data were insufficient for long-term outcomes in the STEMI subgroup.

Procedural time, contrast volume, and crossover rate. Four studies reported data on procedural times. DS was associated with a reduction in procedural time of 4.11 minutes (95% CI, 2.61-5.60; P<.001); however, moderate heterogeneity was observed, with an I² of 52%. A sensitivity analysis using a random-effects model resulted in a similar finding (4.71 minutes; 95% CI, 2.19-7.23; P<.001). Three studies reported data on contrast use. DS was associated with a reduction in contrast volume use of 14.49 mL (95% CI, 4.43-24.54; P=.01; I²=0%). Using a random-effects model, the result was similar with a 14.49 mL reduction in contrast volume (95% CI, 4.43-24.54; P=.01). The crossover rate from DS to CS ranged from 0%-11.8%, with a mean of 8.8% (Table 1).

Discussion

In this meta-analysis of small, randomized trials, there appeared to be improvement in in-hospital cardiovascular mortality with DS compared with CS in patients with AMI. However, the low event rates and the large effect size suggest that a large-scale randomized trial is needed to test if routine DS improves clinical outcomes.

Proponents of predilatation argue that it provides better vessel sizing and allows one to avoid placing a stent in a non-dilatable lesion. Proponents of DS argue that it prevents distal embolization and no-reflow. The meta-analysis showed a nominally significant improvement in ST resolution, but with no reduction in the incidence of no-reflow.

Observational analyses have shown improvements in clinical outcomes with DS in MI.^17,18 However, the risk of confounding due to selection bias should make us interpret this observational data with caution. The reduction in short-term mortality observed in this meta-analysis is larger than would be expected based on the effect on the surrogate outcome of ST resolution.

The TAPAS trial randomized patients to both manual aspiration thrombectomy and DS vs predilatation with no thrombectomy.¹⁹ However, this trial was not included in the meta-analysis due to the inability to separate the effect of thrombectomy from DS. We cannot rule out that some of the benefit observed in the TAPAS trial was due to the interaction between manual aspiration thrombectomy and DS. The mortality benefit observed in the trial has been attributed entirely to thrombectomy.

Study limitations. It is important to note that 4 of the 5 trials excluded patients with completely occluded, tortuous, or calcified lesions. Patients with calcified lesions should likely not undergo DS due to the risk of placing a stent in a non-dilatable lesion. A limitation of this meta-analysis is that ticlopidine has been largely replaced by clopidogrel and newer antiplatelet drugs. However, a meta-analysis of randomized controlled trials showed similar clinical outcomes between ticlopidine and clopidogrel.²⁰ Another limitation of this meta-analysis is the small size of the individual randomized trials and lack of multicenter trials. It has been observed that single-center trials may overestimate the treatment effect when compared with larger, multicenter, randomized trials.²¹ The available trials were of variable quality.

Conclusion

DS during PCI for AMI may improve ST resolution and improve clinical outcomes. Future large-scale randomized trials are needed to confirm the benefit of DS in AMI.

Acknowledgments. The authors would like to thank Mrs Jo-Anne Petropoulos for advice on developing the search strategy.

References

1.    Antman E, Hand M, Armstrong P, et al. 2007 Focused update of the ACC/AHA 2004 guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association task force on practice guidelines: developed in collaboration with the Canadian Cardiovascular Society and endorsed by the American Academy of Family Physicians. Circulation. 2008;117:296-329.

2.    Van de Werf F, Bax J, Betriu A, et al. Management of acute myocardial infarction in patients presenting with persistent ST-segment elevation: the task force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology. Eur Heart J. 2008;29:2909-2945.

3.    Anderson J, Adams C, Antman E, et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non–ST elevation myocardial infarction. J Am Coll Cardiol. 2007;50:e1-e157.

4.    Wright R, Anderson J, Adams C, et al. 2011 ACCF/AHA focused update of the guidelines for the management of patients with unstable angina/non-ST elevation myocardial infarction. J Am Coll Cardiol. 2011;57:1920-1959.

5.    Hamm CW, Bassand JP, Agewall S, et al. ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: the task force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J. 2011;32:2999-3054.

6.    Barbato E, Marco J, Wijns W. Direct stenting. Eur Heart J. 2003;24:394-403.

7.    Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. Br Med J. 2009;339:b2700.

8.    Higgins JPT, Green S (eds). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration. 2011. Available from www.cochrane-handbook.org

9.    Yusuf S, Peto R, Lewis J, Collins R, Sleight P. Beta blockade during and after myocardial infarction: an overview of the randomized trials. Prog Cardiovasc Dis. 1985;27:335-371.

10.    Sweeting MJ, Sutton AJ, Lambert PC. What to add to nothing? Use and avoidance of continuity corrections in meta-analysis of sparse data. Stat Med. 2004;23:1351-1375.

11.    Bradburn MJ, Deeks JJ, Berlin JA, et al. Much ado about nothing: a comparison of the performance of meta-analytical methods with rare events. Stat Med. 2007;26:53-77.

12.    Loubeyre C, Morice MC, Lefèvre T, Piéchaud JF, Louvard Y, Dumas P. A randomized comparison of direct stenting with conventional stent implantation in selected patients with acute myocardial infarction. J Am Coll Cardiol. 2002;39:15-21.

13.    Sabatier R, Hamon M, Zhao QM, et al. Could direct stenting reduce no-reflow in acute coronary syndromes? A randomized pilot study. Am Heart J. 2002;143:1027-1032.

14.    Ballarino MA, Moreyra E, Damonte A, et al. Multicenter randomized comparison of direct vs conventional stenting: the DIRECTO trial. Catheter Cardiovasc Interv. 2003;58:434-440.

15.    Ozdemir R, Sezgin AT, Barutcu I, Topal E, Gullu H, Acikgoz N. Comparison of direct stenting versus conventional stent implantation on blood flow in patients with ST-segment elevation myocardial infarction. Angiology. 2006;57:453-458.

16.    Gasior M, Gierlotka M, Lekston A, et al. Comparison of outcomes of direct stenting versus stenting after balloon predilation in patients with acute myocardial infarction (DIRAMI). Am J Cardiol. 2007;100:798-805.

17.    Ly HQ, Kirtane AJ, Buros J, et al. Angiographic and clinical outcomes associated with direct versus conventional stenting among patients treated with fibrinolytic therapy for ST-elevation acute myocardial infarction. Am J Cardiol. 2005;95:383-386.

18.    Antoniucci D, Valenti R, Migliorini A, et al. Direct infarct artery stenting without predilation and no-reflow in patients with acute myocardial infarction. Am Heart J. 2001;142:684-690.

19.    Vlaar PJ, Svilaas T, van der Horst IC, et al. Cardiac death and reinfarction after 1 year in the Thrombus Aspiration during Percutaneous coronary intervention in Acute myocardial infarction Study (TAPAS): a 1-year follow-up study. Lancet. 2008;371:1915-1920.

20.    Bhatt DL, Bertrand ME, Berger PB, et al. Meta-analysis and registry comparisons of ticlopidine with clopidogrel after stending. J Am Coll Cardiol. 2002;39:9-14.

21.    Dechartres A, Boutron I, Trinquart L, Charles P, Ravaud P. Single-centre trials show larger treatment effects than multicentre trials: evidence from a meta-epidemiologic study. Ann Intern Med. 2011;155:39-51.

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From the ¹Department of Medicine, McMaster University, Hamilton, Ontario, Canada; and ²the Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Jolly reports a grant from Medtronic. The remaining authors report no conflicts of interest regarding the content herein.

Manuscript submitted January 19, 2015 and accepted January 21, 2015.

Address for correspondence: Dr Sanjit S. Jolly, Rm. C3-118 DBCSVRI Building, Hamilton General, Hospital, 237 Barton St. East, Hamilton, On, Canada, L8L 2X2, Email: sanjit.jolly@phri.ca