In the current issue of this journal, Valgimigli and colleagues report a pooled analysis of 340 patients receiving drug eluting stents (DES) for unprotected left main coronary artery (LMCA) stenosis1. This seminal study is important for three reasons. It not only constitutes the largest series of such patients reported in the literature, but by describing the combined experience of leading experts, using only DES, it represents ‘state of the art’ practice in interventional cardiology. Nevertheless, of several qualifications which apply to the superficially encouraging results, the most important is the very limited duration of follow-up (a duration of six to twelve months, but enthusiastically described by the authors as ‘mid-term’). The main danger, however, is the very real risk that patients will yet again pay the price for professionals to re-learn why, after promising early results, previous attempts at stenting in LMCA stenosis succumbed not only to high re-intervention rates but, more importantly,
to excess mortality.
Background to CABG and stenting in LMCA stenosis
Both randomised trials and large observational studies, from over two decades ago, consistently demonstrated a marked survival advantage for CABG versus medical treatment in LMCA stenosis2,3. Since then, there have been significant advances in both medical therapy (applicable to both medical and surgical groups) and surgical techniques (particularly the widespread use of the internal mammary artery graft). Nevertheless, the size of the survival benefit of revascularisation in LMCA stenosis (up to at least six years3) has ensured that CABG has remained the “gold standard” treatment in eligible patients with LMCA stenosis.
However, with the introduction of percutaneous coronary intervention (PCI), LMCA stenosis was soon considered a potentially suitable target because of its proximity in the coronary circulation and its relatively large diameter. This approach, however, ignored three key factors which strongly predicated against long-term success of PCI for this lesion. Rather than the more suitable ostial or shaft lesions, over 90% of LMCA stenosis are bifurcation lesions4,5, around half
of which have significant calcification5 and both of these factors predict poorer technical outcomes with PCI6. Furthermore, around 90% of patients have simultaneous multi-vessel coronary disease4,5 when CABG produces far better survival than PCI7-10.
Initial attempts at PCI with balloon angioplasty in LMCA stenosis were prone to vessel dissection, but the ability of bare metal stents (BMS) to prevent this complication encouraged renewed efforts. Despite early satisfactory results, continuing high rates of mortality and the need for further revascularisation led to abandonment of stenting except in patients who were not surgical candidates11,12. Indeed, on the basis of these results both the ESC13 and ACC14 guidelines state that PCI is largely contra-indicated in patients with LMCA stenosis except in those who are ineligible for CABG.
Current practice of PCI in LMCA stenosis
One recent survey reported that up to 30% of patients in Europe and 20% of patients in the USA now undergo PCI with stents for LMCA stenosis4. Yet interpretation of the appropriateness and results of such practice is virtually impossible. As in the current pooled study1, it is rarely reported what proportion of these patients are ineligible for CABG (this is important because patients who are at high risk for CABG are inevitably also at high risk for PCI), and what proportion have distal/bifurcation lesions and simultaneous multi-vessel coronary artery disease. This is compounded by very short term follow-up, frequently less than a year, despite – and as acknowledged in the current report1 – the continuing limitations of stents, both BMS and DES, well beyond a year.
Results with surgery
In the United Kingdom in 2003 the mortality for over five thousand patients undergoing CABG for LMCA stenosis was 3%15. However, as this figure included all patients including one third who were high risk (because of the urgency of the operation, advanced age and/or or poor left ventricular function) this mortality rate could be improved by simply excluding higher risk patients.
Another consideration is that LMCA stenosis may lend itself particularly well to the use of bilateral internal mammary artery (IMA) grafts. The angiographic patency of both IMA placed to the left sided coronary vessels is over 95% at one week and at seven years after CABG16. And this superior angiographic patency may translate into a significant survival benefit. In a meta-analysis of over 15,000 CABG patients receiving single or bilateral IMA grafts and matched for age, gender, diabetes and left ventricular function we reported
a significant survival benefit in patients with bilateral IMA grafts, with a HR of 0.82 for death (or a NNT of 13-16 patients)16. And such a surgical approach appears safe and feasible. Indeed in a current randomised trial of bilateral versus single IMA grafts (ART Trial), sponsored by the Medical Research Council and British Heart Foundation of the United Kingdom, in over 2000 patients operated in 22 centres in 5 countries the overall 30 day mortality is 1.2%17.
Why PCI is unlikely to ever equal the results of CABG for LMCA stenosis
There are three reasons why it is unlikely that PCI, even with DES, will ever match the success of CABG over the longer term for patients with LMCA stenosis.
(i) The proven survival benefit of CABG over the long term is because of its ability to protect whole zones of proximal myocardium as the graft is placed to the mid coronary vessel rather than the more proximal location of stents (which leaves the vessel susceptible to restenosis or distal de novo lesions)7-10.
(ii) PCI frequently results in incomplete revascularisation and this adversely affects survival proportional to the incompleteness of revascularisation18.
(iii) Three large meta-analyses have shown no clinical advantage in terms of survival or reduction in myocardial infarction with DES vs BMS because although DES reduce angiographic rates of restenosis compared to BMS, they are (unlike CABG) ineffective against de novo lesions19-21.
The importance of follow-up
What is the true rate of re-stenosis of DES in LMCA stenosis? The evidence in the literature is conflicting because few studies have complete angiographic follow-up. Indeed, in the current pooled study only 69% of patients underwent repeat angiography at six to twelve months (and it is noteworthy that are we are not told the rate of restenosis in these patients)1. In a recent study by Price and colleagues who reported complete angiographic follow-up of fifty patients (94% with distal LMCA stenosis) receiving DES, restenosis increased from 34% at three months to 44% at nine months22. Most importantly, as restenosis was frequently asymptomatic, Price and colleagues cautioned that serial angiographic follow up was necessary. Their recommendation was supported in an accompanying editorial by Baim et al who wrote that “without that safety net, one would expect an up-tick in late mortality events resulting from unrecognised restenosis in this critical location.”23 These recommendations argue strongly against the more complacent view advocated in the current pooled analysis1. And probably angiographic follow-up should continue beyond a year, in view of the increasing recognition of late stent failure and thrombosis24 in such a vital position.
Summary and conclusion
LMCA stenosis carries major adverse prognostic implications. CABG provides well established survival benefits over the long term because of its ability to protect whole zones of proximal myocardium, and should remain the preferred option in eligible patients and particularly in those with bifurcation LMCA stenosis and associated multi-vessel coronary disease. PCI has an important role in those who are ineligible for or refuse CABG, but mandates careful follow-up. Although the intensity, invasiveness and duration of follow-up is not yet agreed, the fact that restenosis is frequently asymptomatic should sound a very important cautionary note.
