2.1

Randomised studies of SES in STEMI

One of the earliest studies to address the issue of safety and efficacy of DES in STEMI patients was the Single High Dose Bolus Tirofiban and Sirolimus Eluting Stent vs Abciximab and Bare Metal Stent in Myocardial Infarction (STRATEGY) trial . STRATEGY randomised 175 patients presenting with STEMI or presumed new left bundle branch block (LBBB) to either a single, high-dose tirofiban bolus plus SES ( n =87) or a standard dose abciximab plus BMS ( n =88). At 8 months, the tirofiban/SES group had a significantly lower cumulative incidence of death, reinfarction, and TVR compared to the abciximab/BMS group, predominantly driven by a reduction in the rates of TVR (18% vs. 32%; P =.04). Binary restenosis was also significantly lower in the tirofiban/SES group (9% vs. 36%; P =.002). At 2 years, the tirofiban/SES group continued to maintain its superiority with regard to the cumulative end points (24.2% vs. 38.6%; P =.04) and the need for TVR (9.8% vs. 25.5%; P =.01) with no differences in the rates of ST . However, although the tirofiban/SES group continued to have a significantly lower rate of TVR (10.3% vs. 26.1%; P =.007) at 5 years with no significant difference in the rates of ST, there was no longer any difference in the cumulative incidence of death, MI, and TVR (29.9% vs. 43.2%; P =.07) . Although small in terms of sample size, STRATEGY suggested that, in patients with STEMI, SES might be both safe and efficacious.

The safety and efficacy of SES in patients presenting with STEMI were further evaluated by the Trial to Assess the Use of the Cypher Stent in Acute Myocardial Infarction Treated with Balloon Angioplasty (TYPHOON) investigators . In this study, Spaulding et al. randomised 712 patients with STEMI to receive either SES or BMS. After 8 months, follow-up angiography was performed in 174 patients from selected centres. After 1 year, the primary end point of target vessel failure, defined as target vessel-related death, recurrent MI, or TVR, was significantly lower in the SES group than in the BMS group (7.3% vs. 14.3%; P =.004), driven predominantly by a reduction in the rates of TVR (5.6% vs. 13.4%; P <.001) .

The benefits of SES in STEMI were further confirmed in two other randomised studies. The Randomised Trial of Sirolimus-eluting Stent versus Bare-metal Stent in Acute Myocardial Infarction (SESAMI) trial randomised 320 patients with acute STEMI to either SES or BMS . At 1 year, the SES group had a statistically lower rate of restenosis (9.3% vs. 21.3%; P =.03), target lesion revascularisation (TLR) (4.3% vs. 11.2%; P =.02), TVR (5% vs. 13.1%; P =.01), major adverse cardiac events (6.8% vs. 16.8%; P =.005), and target vessel failure (8.7% vs. 18.7%; P =.007). There was no difference in the rates of ST (1.2% vs. 0.6%; P >.05). In the Multicenter Evaluation of Single High Dose Bolus Tirofiban vs Abciximab with Sirolimus Eluting Stent or Bare Metal Stent in Acute Myocardial infarction study (MULTISTRATEGY) study, 745 patients with STEMI or new onset LBBB were randomised in a 2×2 fashion to receive high-dose bolus tirofiban or abciximab infusion and SES or BMS . After 8 months, the composite of death from any cause, reinfarction, and TVR was statistically lower in the SES group than in the BMS group (7.8% vs. 4.5%; P =.004) . As in previous trials, this was driven by a reduction in the rate of TVR. This trial did not report on the rates of ST in the two groups.

2.2

Randomised studies of PES in STEMI

The Paclitaxel Eluting Stents versus Bare Metal Stents in Myocardial Infarction with ST-segment Elevation (PASSION) trial was one of the earliest studies into the role of PES in patients with STEMI . Laarman et al. randomised 619 patients presenting with STEMI to receive either a PES or a BMS. The primary end point was a composite of cardiac death, reinfarction requiring hospitalisation, and ischemia-driven TLR at 1 year. However, the study failed to show a statistical difference between the two groups in any of these end points. Lack of angiographic follow-up, improvements in the design of the PES, and a lack of power in the study have been proposed as some of the potential reasons as to why PASSION did not show any benefits with PES.

The Single-Center Randomized Evaluation of Paclitaxel-eluting versus Conventional Stents in Acute Myocardial Infarction (SELECTION) trial also studied the role of PES in STEMI . In this relatively small, single-centre trial, Chechi et al. randomised 80 consecutive patients with STEMI to receive either PES or BMS. The primary end point was defined as the percentage of neointimal proliferation within the stent as assessed by intravascular ultrasound at angiography after 7 months. The secondary end points were the rates of binary restenosis and the composite of death, MI, and TLR. SELECTION demonstrated a significant benefit with PES in reducing neointimal proliferation at 7 months (4.6% vs. 20%; P <.001), which was not surprising given the effects of drug elution on neointimal proliferation and the composite end points (7.5% vs. 2.5%; P =.001).

The safety and efficacy of PES in the setting of STEMI were further confirmed in the Harmonizing Outcomes with Revascularization and Stents in AMI (HORIZONS-AMI) trial in which 3006 patients presenting with STEMI were randomised to receive either PES ( n =2257) or BMS ( n =749) . At 12 months, the PES group had a statistically lower rate of ischemia-driven TLR (4.5% vs. 7.5%; P =.002) and TVR (5.8% vs. 8.7%; P =.006). PES was also associated with a significantly lower rate of binary restenosis at 13 months (10% vs. 29.9%; P <.001). The 12-month rates of death and ST were similar in the two groups. Therefore, as in many SES trials, the results of this trial confirmed that the major advantage of DES in the setting of acute STEMI appears to be a reduction in the rates of revascularisation.

2.3

Randomised studies of PES and SES in STEMI

One of the earliest randomised trials to compare DES against BMS in the context of acute STEMI was the Drug Eluting versus Bare Metal Stents in Patients with ST-segment Elevation Myocardial Infarction (DEDICATION) trial . Kelbaek et al. randomised 626 patients with STEMI presenting within 12 h of symptom onset to either DES or BMS with or without a distal protection device. Of the stents implanted in the DES group, 47% were SES, 40% were PES, and 13% were the zotarolimus-eluting stent. Distal protection devices were successfully used in 40% of each group. At 8 months’ follow-up, the DES group had a statistically lower late luminal loss as assessed by angiography (0.06 vs. 0.47; P <.001) and by the composite end point of cardiac death, recurrent MI, and TLR (8.6% vs. 14.4%; P =.03). There was no difference in the rates of cardiac death (4.2% vs. 1.6%; P =.09) or ST (2% vs. 2.6%; P =.72). However, as accepted by the investigators, DEDICATION was not blinded to the patients or to the investigators and only 83% of the study population underwent repeat angiography. Furthermore, there was no direct comparison between the three DES used in the study.

The benefits of DES in STEMI were further evaluated in the Long-term Outcome of Drug-eluting Stents Compared with Bare Metal Stents in ST-segment Elevation Myocardial Infarction: Results of the Paclitaxel or Sirolimus Eluting Stent versus Bare Metal Stent in Primary Angioplasty (PASEO) trial . PASEO randomised 270 consecutive patients with STEMI to PES ( n =90), SES ( n =90), or a BMS ( n =90). At 1 year, the primary end point of TLR was statistically lower in both PES [4.4%; hazard ratio (HR)=0.29; 95% CI=0.095–0.89; P =.02] and SES (3.3%; HR=0.21; 95% CI=0.06–0.75; P =.02). This was maintained at longer-term follow-up (1233±215 days) (BMS: 21.1%; PES: 6.7%; P =.008; SES: 5.6%; P =.002) . The groups did not differ in the secondary outcome of death and reinfarction either at 1 year or at longer-term follow-up. Again, there were no direct comparisons between PES and SES. The authors concluded that both SES and PES were safe and more effective than BMS in patients undergoing primary PCI for STEMI.

2.4

Registry studies of PES and SES

The rate of death and recurrent MI attributed to DES was examined in the Massachusetts Registry . This study examined 7217 patients who had undergone stenting at 21 centres: 3379 for STEMI and 3838 for NSTEMI. Of these patients, 4016 were treated with DES (71% SES, 27% PES, and 2% a combination of SES and PES) and 3201 were treated with BMS. After propensity score matching, the DES group had a lower 2-year mortality than the BMS group (10.7% vs. 12.8%; P =.02). This difference persisted in the matched cohort of patients with either a STEMI (8.5% vs. 11.6%; P =.008) or a NSTEMI (12.8% vs. 15.6%; P =.04). The DES group also had a statistically lower rate of TVR, which was evident for both types of MIs (9.6% vs. 14.5%; P <.001). However, there was no difference in the two groups in the rates of reinfarction at 2 years (8.8% vs. 10.2%; P =.09), except in patients with NSTEMI (10.3% vs. 13.3%; P =.02). This registry therefore suggested that in patients with MI, DES were associated with reduced rates of mortality and TVR at 2 years of follow-up in an unselected population.

The results of the Massachusetts Registry were not supported by the Global Registry of Acute Coronary Events (GRACE) multinational registry of 5093 STEMI patients who had received either a DES (26%) or a BMS (74%) . The risk factor profile of the patients was markedly different with diabetes, hypertension, increased body mass index, and hyperlipidemia being more common in the DES group, but the average GRACE risk score was higher in patients receiving BMS, indicating that these patients were at a greater risk of death. Two-year follow-up was available in 55% of the BMS group and in 60% of the DES group. In propensity- and risk-adjusted survival analyses, there was no significant difference in mortality between the two groups up to 6 months ( P =.21) and 1 year. However, the DES group had a statistically higher rate of 6-month to 2-year mortality (HR=4.9; 95% CI=1.42–16.9; P =.01) as well as 1–2 years’ mortality (HR=7.06; 95% CI=1.36–36.6; P =.02). Although observational and non-randomised, this study has raised an important issue regarding DES in the setting of acute STEMI. First, the randomised studies reported so far have not been sufficiently powered for detecting differences in mortality and, as a whole, the follow-up period has not been sufficiently long enough.

Further insight into the use of DES in STEMI has been provided by a number of other large (patient population >1000) registries. Data from New York State’s Percutaneous Coronary Intervention Reporting System (PCIRS) regarding the outcome of 1926 patients (1154 receiving DES and 772 receiving BMS) demonstrated that, at 2 years, the DES group had a statistically lower rate of mortality compared to the BMS group (5% vs. 8.6%; P =.007) and subsequent coronary artery bypass graft surgery (3% vs. 6.4%; P =.004) . There was no difference in the two groups in terms of the rates of TVR (HR=0.74; 95% CI=0.35–1.58). By contrast, although the Western Denmark Heart Registry of 3756 patients reported a lower 2-year mortality with DES (7.8% vs. 11.4%; P <.004), the 2-year incidence of TLR was significantly lower in the DES group (7.2% vs. 8.7%; P =.01) . This registry also reported a higher rate of very late (≥12 months) ST with DES (0.4% vs. 0.06%; P =.03). More conflicting data were provided by the Strategic Transcatheter Evaluation of New Therapies (STENT) group, who reported on the outcome of 2324 patients with STEMI of <24 h of duration (1407 receiving DES and 565 receiving BMS) . In this population, there was no significant difference in the rates of death or MI at 9 months or 2 years, but the DES group had a lower rate of TVR over the same period (4% vs. 7.5% and 8% vs. 11.3%, respectively; P <.05). Interestingly, although the DES group had a lower rate of ST at 9 months (1% vs. 2.7%; P =.04), this difference no longer existed at 2 years. The results of this registry were supported by Vlaar et al. who reported on the composite end point of all-cause mortality, TVR, and non-fatal MI in 1129 patients (552 receiving DES and 577 receiving BMS) undergoing primary or rescue PCI for STEMI. In their population, the use of DES was not associated with a significant difference in the composite end points, but the rate of TVR was statistically lower in the DES group (4.7% vs. 11.1%; P <.001).

Given the conflicting data of both randomised and registry studies, a number of meta-analyses have been undertaken to assess the efficacy and safety of DES in patients with acute MI. In a meta-analysis of eight randomised trials comparing SES and/or PES against BMS in patients with acute STEMI and involving 2786 patients, Kastrati et al. demonstrated that, compared to BMS, DES were associated with a HR of 0.38 for reintervention (95% CI=0.29–0.50; P =<.001). The advantage for DES was evident from the first month of the index procedure and continued to increase thereafter. However, this meta-analysis found no difference between BMS and DES with regard to the outcomes of death (HR=0.76; 95% CI=0.53–1.1; P =.14), recurrent MI (HR=0.72; 95% CI=0.48–1.08; P =.11), or ST (HR=0.8; 95% CI=0.46–1.39; P =.43). Stettler et al. conducted a meta-analysis of 38 trials, involving 18,023 patients with a follow-up of up to 4 years and again demonstrated no mortality benefit with DES, but a lower rate of TLR, an effect that was more pronounced with SES than with PES (HR=0.70; 95% CI=0.56–0.84; P =.002). Furthermore, this meta-analysis demonstrated that PES were associated with a greater risk of late (>30 days) ST (HR=2.11; 95% CI=1.19–4.23; P =.02 for BMS; HR=1.85; 95% CI=1.02–3.85; P =.04 for SES). Yet more conflicting data have been provided in the meta-analysis by Piscione et al. demonstrating that the use of DES was associated with a reduction in TVR (5.1% vs. 11.2%; P <.0001) and recurrent MI (3% vs. 3.7%; P =.02) with no differences in the rates of either cardiac death or ST. It therefore appears that the only certainty in the use of DES in acute STEMI is the reduction in the rates of TVR.