Target Lesion Revascularization After Bare-Metal or Drug-Eluting Stents: Clinical Presentation and Outcomes

   While the clinical presentation of target lesion revascularization (TLR) following bare-metal stent (BMS) placement was previously perceived to be “benign,” several studies have now shown that BMS restenosis may present as acute coronary syndrome (ACS) in a significant proportion of patients.^1–3 An important related issue has been whether TLR following drug-eluting stent (DES) placement has a more benign or malignant course than BMS. Of course, several randomized, controlled trials (RCTs) have shown that DES re- duce the incidence of TLR, but the question remained: When TLR does occur, does it differ in clinical presentation based on the stent type?⁴ Also, reports of late stent thrombosis following placement of first-generation DES (Cypher and Taxus) were of concern.⁵    In this issue of the Journal, Hayes et al tackle the important question about clinical presentation of patients undergoing TLR following BMS or DES placement.⁶ In addition, they report clinical outcomes (non-fatal myocardial infarction [MI] or death) over a 3- year follow-up period, and outcomes following TLR over the next 1 year. TLR was defined as the need for repeat target lesion percutaneous coronary intervention (PCI) and included patients who presented with MI and stent thrombosis. The BMS cohort (n = 1,147) was comprised of patients who underwent PCI in the pre-DES era. Inclusion of such historical controls decreased the possibility of selection bias in stent choice. In the DES group (n = 1,246), sirolimus-eluting (Cypher) and paclitaxel-eluting (Taxus) stents were used at the time of the index PCI as well as TLR.    In this study, TLR was noted to be significantly higher with BMS vs. DES (9.2% vs. 4.5%, p 7,8 Clinical presentation at the time of TLR was not always benign, irrespective of the stent type. Acute coronary syndrome was the predominant clinical presentation, and one-third of patients in each group presented with MI (25% in BMS vs. 34% in DES group, p = 0.217). Unstable angina was found to be the most common presentation at the time of TLR in both the BMS and DES groups (52% vs. 45%, respectively, p = 0.350). Stable angina was noted in only a small proportion of patients (BMS 23% vs. DES 21%, p = 0.836).    Consistent with prior studies, stent thrombosis was present in a significantly higher proportion of DES patients compared with BMS at the time of TLR (20% vs. 8%, p = 0.024). However, overall rates of stent thrombosis for DES versus BMS groups at 3 years were similar (1.8% DES vs. 1.7% BMS, p = 0.837).⁹ The authors noted that a similar proportion of patients (50%) in both BMS and DES groups were taking dual antiplatelet therapy at the time of TLR.    There was a higher prevalence of TLR in patients who under- went vein-graft PCI at the time of index procedure, although they were equally distributed in both groups. It is important to note that brachytherapy was used as the primary revascularization method in patients who had BMS TLR (43%).    One-fourth of patients in the BMS group received stents at the time of TLR in comparison to 71% in the DES group. The mean time to TLR was longer with DES than BMS (320 days vs. 140 days, p 7,8,10,11    Similar to this study, prior reports on clinical presentation of BMS TLR have shown a high prevalence of ACS.^12–14 Chen et al analyzed patients who underwent PCI from a single institution during a 4-year period and found that 9.5% of cases of BMS restenosis presented as acute MI (7.3% as non ST-segment elevation MI [NSTEMI] and 2.2% as ST-segment elevation MI [STEMI]), 26.4% presented with unstable angina requiring hospitalization, and 64.1% as exertional angina. Similarly, Nayak et al analyzed 2,462 consecutive patients who underwent PCI at a single institution during 1 1⁄2-year period and found that clinical in-stent restenosis frequently presented as MI (10.4%), and such patients were more likely to have a diffuse angiographic pattern of restenosis.¹⁵ Steinberg et al studied 2,539 patients with BMS restenosis referred for repeat revascularization. They found that 46.6% of patients had unstable angina, and 6.7% had MI at the time of presentation.¹⁶ Interestingly, they reported that the presence of ACS at the time of TLR did not predict a negative outcome in terms of MI or death at 6-month follow up after TLR.    Although multiple RCTs have consistently shown that DES are superior to BMS in reducing restenosis, there is no convincing evidence that DES reduce mortality or risk of future MI. Stone et al reported similar rates of death and MI in DES (sirolimus-eluting and paclitaxel-eluting coronary stents) and BMS patients in a double blinded randomized controlled trial after 4 years of follow up, although they found a significant reduction in the incidence of target vessel revascularization (TVR) and TLR.5 Similarly, Chacko et al showed a sustained reduction in TLR for sirolimus-eluting stent in comparison to BMS in 5-year follow-up data of a randomized clinical trial on patients with de novo coronary lesions.10 However, there was no difference in TVR remote from the target lesion, death, MI, or non-target vessel revascularization throughout the 5- year follow up. Similar to Hayes et al, Malenka et al studied out- comes of non-emergent coronary stenting between patients who had BMS in the pre-DES era and patients who had DES and found that relative to the BMS era, patients treated in the DES era had a lower 2-year risk for repeat revascularization (17.1% vs. 20.0%, p 11    Interestingly, in a recent report of registry data by Mauri et al analyzing 11,556 patients who had DES, and 6,237 patients who had BMS in a regional contemporary U.S. practice, DES treatment was associated with lower rates of mortality after 2 years (risk-adjusted mortality rates were 9.8% for DES vs.12.0% for BMS, p = 0.0002). Similarly, lower rates for MI (8.3% vs. 10.3%, p = 0.0005) and TVR (11.0% vs. 16.8%, p 7    The initial experience from RCTs of newer generation DES has shown a further reduction in the rates of TLR. In the SPIRIT III trial,¹⁷ a prospective RCT involving 1,002 patients at 65 institutions comparing everolimus-eluting (Xience) and paclitaxel-eluting (Taxus) stents in patients with de novo native coronary artery disease, there was a significant 32% reduction in target-vessel failure (10.7% vs. 15.4%; HR 0.68; CI 0.48–0.98; p = 0.04) and a 45% reduction in major adverse cardiac events (cardiac death, MI or TLR; 7.3% vs. 12.8%; HR 0.55; 95% CI 0.36–0.83; p = 0.004) at 2-year follow up.    Stone et al recently published 1-year results of the SPIRIT IV trial,¹⁸ a prospective RCT comparing the use of everolimus-eluting and paclitaxel-eluting stents.¹⁸ The trial enrolled a total of 3,687 patients at 66 sites across the U.S. The use of the everolimus-eluting stents led to a 39% relative risk reduction (4.2% vs. 6.8%; HR 0.61; 95% CI 0.46–0.82; p = .0008) in the primary endpoint of target vessel failure at 1 year defined as cardiac death, target vessel MI or ischemia-driven TLR. There was a 46% relative risk reduction (2.5% vs. 4.6%; HR 0.55, 95% CI 0.38–0.78; p = 0.0008) in ischemia-driven TLR with everolimus-eluting stents, and no difference in the safety endpoint of cardiac death or target vessel MI (2.2% vs. 3.2%; HR 0.69; CI 0.46–1.04; p = 0.09). The everolimus-eluting stent group also had a 73% relative risk reduction of definite and probable stent thrombosis (0.29% vs. 1.06%; HR 0.27; CI 0.11–0.67; p = 0.003).    Similarly, in the ENDEAVOR IV trial, 1,548 patients were randomly enrolled to receive either a zotarolimus-eluting (Endeavor) or paclitaxel-eluting stents (Taxus). Three-year results have shown no significant difference in TLR between the stent groups, although there was a significant reduction in death and MI in the zotarolimus stent group. While stent thrombosis rates within the first year were not different, they were found to be significantly lower in the Endeavor group after the first year in this study (0.1% vs. 1.0 %, p = 0.006).^19,20    In conclusion, this study by Hayes et al published in the current edition of the journal, provides important contemporary data on clinical presentation and outcomes of TLR in a “real-world” cohort of patients who received BMS in the pre-DES era and DES. Patients undergoing BMS placement have significantly higher rates of TLR compared with DES. Clinical presentation at the time of TLR is not “benign” regardless of the stent type with nearly one- third of patients presenting with acute MI. In addition, patients undergoing TLR after stent placement constitute a high-risk subgroup of population that have worse outcomes in terms of non- fatal MI or death over the subsequent year.    Although initial studies of newer-generation DES have shown promise in further decreasing in the rates of restenosis and stent thrombosis compared with first-generation DES, the findings noted in this study are relevant to current practice, as BMS still offer a distinct advantage over DES in patients in whom bleeding risk is considered too high or in whom a prolonged course of dual antiplatelet treatment is undesirable or contraindicated.

_________________________________________________ From the Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, Massachusetts. The authors report no conflicts of interest regarding the content herein. Address for correspondence: Nipun Arora, MD, Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, PBB-1, Boston, MA 02115. E-mail: narora@partners.org

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