EXPEDITED REVIEW: EDITORIAL COMMENT
Drug-Eluting Stenting for Unprotected Left Main Coronary Artery Disease
Are We Ready to Replace Bypass Surgery?*
Donald S. Baim, MD, FACC*,
Laura Mauri, MD, MS and
Donald C. Cutlip, MD, FACC
Harvard Clinical Research Institute (HCRI), Boston, Massachusetts.
* Reprint requests and correspondence: Dr. Donald S. Baim, Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts 02115. (Email: dbaim{at}partners.org).
It has been five years since our last editorial in the Journal regarding the role of stenting in the treatment of unprotected left main coronary artery disease. In the intervening time, the landscape of coronary stenting has changed dramatically. In particular, the advent of drug-eluting stents (DES) in mid-2003 has pushed the rate of clinical restenosis below 5% for most lesion types (1,2). The effect of such low restenosis rates has reduced the one-year repeat revascularization rate for multivessel disease to approach that of bypass surgery (7.4% vs. 3.7%) (3), and some estimates may reduce the need for coronary artery bypass surgery by up to 46% (4). Nevertheless, many of the questions that were raised five years ago regarding the role of stenting versus surgery for an unprotected left main coronary artery are still in play.
Despite 25 years of progressive improvements in procedural safety and long-term lesion outcomes for percutaneous coronary intervention (PCI) (including a decade of bare-metal stents [BMS] and three years of DES), the unprotected left main has remained mostly the province of cardiac surgery. Clinical trials conducted in the late 1970s in patients with significant narrowing of the left main trunk demonstrated that bypass surgery reduces the substantial three-year mortality seen with medical therapy (i.e., from 31% to 9%) (5). While there have been progressive improvements in left main PCI over the last 20 years, no prospective randomized trial has been performed comparing left main PCI to surgery. Accordingly, interventional cardiologists have generally respected this lesion as one of the last bastions of surgical dominance, given concerns about high acute procedural risk or poor long-term durability (i.e., restenosis, which in this anatomic location may present as either recurrent angina or sudden death).
Still, progressive interventional forays into this area have been made, first in patients with left main lesions "protected" by a patent bypass graft to the left anterior descending or circumflex, and then in patients with unprotected left main lesions whose other underlying conditions made them poor candidates for surgery. These experiences showed that the earlier concerns about acute safety of left main PCI were largely unfounded; despite fears that even temporary left main occlusion during balloon inflation would lead to hemodynamic collapse, even the early balloon angioplasty experience showed that patients with good baseline left ventricular function can tolerate left main angioplasty without hemodynamic support. The fear of lethal dissection and abrupt closure of the left main has similarly been allayed by the dominance of stenting, first as a bail-out and then as a preemptive treatment. In contrast, concerns about the durability of the initial result have yielded more gradually. Durability for unprotected left main balloon angioplasty was poor, with 30% one-year mortality (6). Coronary stenting improved both acute results and restenosis rates compared with balloon angioplasty, as demonstrated by several groups in the late 1990s (7–12). Repeat revascularization rates, however, remained 25% to 30% (about two-thirds repeat PCI and one-third coronary artery bypass grafting [CABG]), with substantial one-year mortality (up to 30% in some series).
What became clear, however, was that the observed in-hospital and one-year mortality depended strongly on patient selection, being as high as 78% in patients with poor left ventricular function and acute ischemic syndromes, and as low as 3.4% in patients without such high-risk markers (who made up 32% of the Unprotected Left Main Trunk Intervention Multicenter Assessment [ULTIMA] registry) (11). Similarly, it became clear that the restenosis risk for bare-metal stenting was influenced significantly by lesion location, lowest when the left main lesion was confined to the ostium or mid-shaft, higher if it involved the distal bifurcation (restenosis rate 23% overall), and higher still if multiple stent approaches to the distal bifurcation (T, V, Culotte, or crush) were used. Enthusiasm about left main stenting thus continued to be tempered by the high restenosis risk, and the recognition that unrecognized and, therefore, untreated restenosis of the left main may present as sudden cardiac death (7).
With the availability of DES and the dramatic reduction in restenosis rates they provide, the results of left main stenting have improved further. Several recent registry reports (13–15) have demonstrated excellent acute procedural results (although mostly restricted to patients with good left ventricular function). Restenosis has been rare for ostial and mid-shaft lesions, but it has been significantly higher (8% to 17%) for distal left main lesions, especially with the two-stent techniques (Table 1). Indeed, the Park et al. (14), Chieffo et al. (15), and Valgimigli et al. (13) registries demonstrated that restenosis after left main drug-eluting stenting was essentially confined to distal bifurcation lesions. The ostium of the left circumflex is a particular issue, accounting for about one-half of the restenosis cases in these series. In our own experience, there have also been several cases of stent fracture in the circumflex simultaneous kissing stent at the bend leaving the left main, resulting in severe focal restenosis at this location.
The same pattern seen in other bifurcation lesions is also evident in the left main bifurcation—placement of a single stent across the circumflex (with balloon angioplasty rescue if required) seems to offer results at least as satisfactory as any of the current two-stent techniques (16). But the currently available left main DES series clearly shows lower target vessel revascularization rates than the BMS data from the same operators. In addition, most repeat revascularizations require only repeat PCI, with a 6- to 12-month mortality rate (2% to 4% excluding patients in cardiogenic shock) that remains acceptably low. This begs the question of whether these improved short- and intermediate-term outcomes now make drug-eluting stenting a viable alternative to bypass surgery in patients with left main stenosis.
This issue of the Journal contains two non-randomized studies of drug-eluting stenting of the left main coronary artery that help to place this question in sharper focus. Lee et al. (17) compared 50 consecutive patients undergoing PCI for unprotected left main coronary stenoses to a consecutive series of 123 patients undergoing CABG during the same time period. Most lesions (60%) were located at the distal left main bifurcation and were treated with one of several two-stent techniques (crush, kissing, or T stenting). The rate of acute procedural success was 98% for PCI, and 30-day mortality was low (2% for PCI vs. 5% for CABG, p = NS) despite a somewhat higher clinical risk profile. With six-month follow-up, the PCI cohort continued to have a non-significantly better survival compared with the surgical cohort (96% vs. 87% at six months), with higher composite freedom from death, myocardial infarction, urgent target vessel revascularization, and adverse cerebrovascular events (83% vs. 75% at one year). However, systematic surveillance for myocardial infarction by routine lab evaluation was not performed post-procedure, angiographic follow-up was incomplete (only 42% after PCI), and clinical follow-up (reported overall mean six months) was nearly one month shorter for the PCI than the CABG cohort, raising concerns about whether these end points were completely ascertained. Moreover, the freedom from repeat revascularization remained higher for the surgical cohort compared to the PCI cohort (95% vs. 87% at one year), although all repeat procedures were performed percutaneously. These data are echoed by the Milan experience, with lower 1-year mortality (2.8% vs. 6.4%) but higher target lesion revascularization (15.8% vs. 3.6%), for drug-eluting stenting versus CABG of unprotected left main stenosis (18).
Price et al. (19) present additional data in this issue about the angiographic follow-up of DES-treated left main lesions. This 50-patient registry consists predominantly of distal bifurcation lesions (94%), treated using the kissing stent technique. Technical success was uniform, and no in-hospital deaths occurred despite a more complex patient mix. There were two acute stent thromboses (both with kissing stents) and five deaths at one year (although only one appears to have been cardiac). The concern, however, lies in the follow-up angiography, which was performed at three and nine months (94% and 90% compliance among eligible patients). It showed angiographic restenosis in 23% in the left main to left anterior descending coronary artery (LAD) location, and 35% in the circumflex location, for an overall angiographic restenosis rate of 42% in any vessel (left main, ostial LAD, or ostial left circumflex artery). The combined rate of death, myocardial infarction, repeat revascularization, and stent thrombosis was 10% in-hospital and 44% at a median follow-up of nine months. This reflected mostly the 19 patients (38%) who underwent target lesion revascularization (18 of whom had been treated with bifurcation stenting), of which only 7 (14%) were ischemia-driven. Again, all of the repeat revascularization was achieved via repeat PCI.
With this latest round of data, it is fair to ask "Have we finally reached the point where patients with left main disease can be offered elective DES treatment as an alternative to coronary artery bypass surgery?" There is no doubt that we have made further progress, that the 6- to 12-month mortality rates of 2% to 4% are now similar to in-hospital mortality rates reported for surgery for left main disease (20,21), and that DES-treated lesions in the ostial or mid-left main have a very low (<5%) rate of angiographic or clinical restenosis with DES. In the ostial to mid-vessel location, however, one limitation remains the lack of current DES that can be expanded above 4.5 mm. A more important limitation is that the majority of left main lesions treated are located in the distal left main bifurcation, for which we still do not have an ideal stenting approach. If the circumflex is small or not relatively diseased, a single stent approach (left main into LAD, with balloon rescue of the circumflex if needed) has much to recommend it, but most cases have a circumflex that is both large and diseased. None of the current two-stent DES strategies (with a 2% stent thrombosis rate and a 20% to 44% angiographic restenosis rate) have been able to meet the durability standard we have come to expect for DES coronary revascularization. The current level of restenosis thus makes it necessary to perform routine surveillance angiography, perhaps at both three and nine months as per the Price et al. report (19), to detect restenosis and perform repeat PCI if restenosis is present. Without that safety net, one would expect an up-tick in late mortality events resulting from unrecognized restenosis in this critical location.
Fortunately, novel stents are now being developed to provide better mechanical solutions for bifurcation lesions, and will rapidly be converted from bare-metal to drug-eluting status. Within the next two years, one would expect a wave of registry data regarding the use of these newer bifurcation stents in distal left main bifurcation lesions. If these data are more encouraging, the time will have come to initiate direct randomized trials of drug-eluting stenting versus bypass surgery for even low-risk surgical candidates. Even for the ostial and mid-left main, where greater successes have been achieved with drug-eluting stenting, one might well require longer-term (three- to five-year) data before applying such a strategy to all-comers. Because the merit of surgery for left main lesions is based mostly on mortality reduction, a surgically equivalent mortality reduction should be demonstrated by PCI. This may be difficult (despite coronary artery bypass surgery’s higher initial mortality) because over the longer term it protects against events related to entire zones of proximal vulnerability, thereby reducing the incidence or lethality of subsequent myocardial infarctions (22). While there are clearly challenges of a randomized trial comparing surgery to PCI, such a trial could demonstrate non-inferiority of left main stenting in approximately 300 to 500 subjects.
Until such a trial is completed, however, broad elective use of drug-eluting stenting in low-risk surgical candidates, particularly the majority of that group who have distal bifurcation lesions that would warrant a two-stent approach, is probably premature. Certainly that option can continue to be offered to patients with anatomically suitable left main disease who present a higher surgical risk, as long as they accept the need for prolonged dual antiplatelet therapy and surveillance follow-up angiography. With these precautions, the main downside will likely remain limited to a need for angiographic surveillance and angiographically triggered repeat percutaneous interventions (plus some late bypass surgery), without a surplus of late deaths and myocardial infarctions.
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Footnotes
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* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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References
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