Comparison of Zotarolimus-Eluting Stents and Sirolimus-Eluting Stents in Patients With Coronary Artery Disease - SORT OUT III

Jun 27, 2014
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Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
Cordis and Medtronic
Date Updated:
06/27/2014
Original Posted Date:
06/27/2014
References

Description:

Zotarolimus-eluting stents (ZES) are newer drug-eluting stents that have recently become available. The SORT OUT III study sought to compare the relative safety and efficacy of ZES with sirolimus-eluting stents (SES).

Hypothesis:

ZES would be similar in efficacy and safety to SES.

Study Design

  • Parallel

Patients Screened: 9,221
Patients Enrolled: 2,333
Mean Follow Up: 18 months, 3 years, 5 years
Mean Patient Age: 64.3 years
Female: 26%
Mean Ejection Fraction: 51%

Patient Populations:

  • Patients undergoing PCI for any indication
  • Age ≥18 years
  • Chronic stable coronary artery disease or acute coronary syndrome
  • At least one target lesion needing treatment with drug-eluting stent

Exclusions:

  • Life expectancy <1 year 
  • Allergy to aspirin, clopidogrel, sirolimus, ticlopidine, zotarolimus
  • Participants in another randomized controlled trial

Primary Endpoints:

Safety:
  • All-cause mortality
  • Cardiac mortality
  • MI
  • Definite stent thrombosis

Efficacy:
  • Clinically driven target lesion revascularization
  • Clinically significant re-stenosis (ISR)

Drug/Procedures Used:

Percutaneous coronary intervention (PCI) with ZES or SES in a 1:1 fashion

Concomitant Medications:

Dual antiplatelet therapy for 12 months; lipid-lowering therapy (70%), glycoprotein IIb/IIIa inhibitors (17%)

Principal Findings:

A total of 2,333 patients were randomized, 1,162 to ZES and 1,170 to SES. Baseline characteristics were fairly similar between the two groups. About 15% of the patients had diabetes. About one-half of the patients (52%) underwent PCI for stable angina, 38% for unstable coronary syndromes, and 7% for ST-elevation myocardial infarction (STEMI). Most patients (70%) had one-vessel disease. The mean number of stents per patient was 1.7, with a mean stent length of 18.0 mm.

The incidence of the composite MACE endpoint at 9 months was significantly higher with ZES compared with SES (6% vs. 3%, hazard ratio [HR] 2.15, 95% confidence interval [CI] 1.43-3.23, p = 0.0002). There was no difference between ZES and SES in the incidence of all-cause mortality at 9 months (2% vs. 2%, HR 1.40, 95% CI 0.76-2.56, p = 0.28). MI was significantly higher in the ZES arm compared with the SES arm (2% vs. <1%, HR 4.55, 95% CI 1.54-13.4, p = 0.006). Similarly, definite stent thrombosis was significantly higher in the ZES arm compared with the SES arm (1% vs. <1%, p = 0.05). The need for target lesion revascularization (TLR) was also significantly higher with ZES compared with SES (4% vs. 1%, HR 4.25, 95% CI 2.26-7.97, p < 0.0001), with a significantly higher rate of in-stent restenosis (3% vs. 1%, HR 6.28, 95% CI 2.65-14.9, p < 0.0001).

At 18 months, there was still an increase in the incidence of the composite endpoint in the ZES arm compared with SES (10% vs. 5%, p < 0.0001), as well as mortality (4% vs. 3%, p = 0.035), MI (2% vs. 1%, p = 0.03), TLR (6% vs. 2%, p < 0.0001), and in-stent restenosis (5% vs. 1%, p < 0.0001). The incidence of definite stent thrombosis was similar between the two arms (1% vs. 1%, p = 0.13).

Three-year outcomes: The primary MACE endpoint was still higher in the ZES arm at 3 years (12.9% vs. 10.1%, p = 0.022), primarily due to an increased need for TLR (6.8% vs. 3.9%, p = 0.0016). Other outcomes including mortality (7.3% vs. 5.9%, p = 0.17) and definite stent thrombosis (1.1% vs. 1.4%, p = 0.61) were similar. However, on landmark analysis at 1 year, MACE (5.3% vs. 6.4%, p = 0.32) and TLR (1.4% vs. 2.5%, p = 0.078) rates were similar between the ZES and SES arms. Definite stent thrombosis rates were, in fact, lower in the ZES arm (0% vs. 1.1%, p = 0.0005).

Five-year outcomes: The primary MACE endpoint was no longer different between the ZES and SES arms at 5 years (17.0% vs. 15.6%, p = 0.40), with similar rates of TLR (7.6% vs. 6.0%, p = 0.15), mortality (13.2% vs. 11.8%, p = 0.37), and definite stent thrombosis (1.2% vs. 2.1%, p = 0.08). On landmark analysis at 1 year, MACE events were similar between the two arms (9.9% vs. 12.3%, p = 0.07), with lower rates of TLR (2.4% vs. 4.8%, p = 0.003) and stent thrombosis (0.1% vs. 1.8%, p = 0.003) in the ZES arm compared with SES.

Interpretation:

The results of the SORT OUT III trial indicate that the ZES (Endeavor Sprint) are associated with a higher incidence of MI, TLR, clinically significant restenosis, as well as definite stent thrombosis at 9 months, compared with SES. In addition, patients receiving ZES had a significantly higher mortality, as compared with patients receiving SES at 18 months. However, after following up on these patients for 5 years, overall MACE, mortality, and stent thrombosis rates were similar. Further, on landmark analysis after the first year, TLR and stent thrombosis at 5 years were actually lower with ZES compared with SES. Both groups were on dual antiplatelet therapy for at least 12 months. In this trial, the investigators tried to include as diverse a population as possible, with no major exclusions, thus mirroring “real-world” practice as best as possible.

These results are interesting, and suggest that Endeavor ZES may have inferior performance compared with SES for the first year, but thereafter, rates of adverse events are very low. Specifically, the very late stent thrombosis rate for ZES (beyond 1 year) was 0.1%, whereas for SES, it was 1.8% between years 1 and 5 (the latter being consistent with prior studies: approximately 0.5%/year). These results also highlight the need for long-term follow-up of stent trials, especially DES. It should be noted that the Endeavor ZES stent platform studied in this trial is different from that studied in the recent RESOLUTE ZES stent trials.

One limitation of this trial is that although they prospectively followed patients, outcomes data were obtained from national registries, rather than direct patient contact. Thus, although it is unlikely that there would be a differential bias with respect to outcomes, there could be an under-reporting or a lag in reporting of certain outcomes. In events with a low incidence rate, such as stent thrombosis, this might be an important consideration.

References:

Maeng M, Tilsted HH, Jensen LO, et al. Differential Clinical Outcomes After 1 Year Versus 5 Years in a Randomised Comparison of Zotarolimus-Eluting and Sirolimus-Eluting Coronary Stents (The SORT OUT III Study): A Multicentre, Open-Label, Randomised Superiority Trial. Lancet 2014;383:2047-56.

Editorial: Stefanini GG, Windecker S. Stent Performance: Never Too Late to Sort It Out. Lancet 2014;383:2024-6.

Maeng M, Tilsted HH, Jensen LO, et al. 3-year clinical outcomes in the randomized SORT OUT III superiority trial comparing zotarolimus-eluting and sirolimus-eluting coronary stents. JACC Cardiovasc Interv 2012;5:812-18.

Rasmussen K, Maeng M, Kaltoft A, et al. Efficacy and safety of zotarolimus-eluting and sirolimus-eluting coronary stents in routine clinical care (SORT OUT III): a randomised controlled superiority trial. Lancet 2010;375:1090-9.

Presented by Dr. Michael Maeng at the ACC.10/i2 Summit, Atlanta, GA, March 2010.

Presented by Dr. Jens Flensted Lassen at the Transcatheter Cardiovascular Therapeutics meeting (TCT 2008), Washington, DC, October 2008.

Keywords: Coronary Artery Disease, Myocardial Infarction, Acute Coronary Syndrome, Follow-Up Studies, Angina, Stable, Drug-Eluting Stents, Sirolimus, Percutaneous Coronary Intervention, Stents, Registries, omega-Chloroacetophenone, Thrombosis, Research Personnel, Confidence Intervals, Diabetes Mellitus


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