Author + information
- aIcahn School of Medicine at Mount Sinai, New York, New York
- bCardiothoracic Department, Division of Cardiology, University Hospital of Pisa, Pisa, Italy
- ↵∗Reprint requests and correspondence:
Dr. Roxana Mehran, Mount Sinai Hospital, One Gustave L. Levy Place, Box 1030, New York, New York 10029.
The SYNTAX (Synergy Between PCI With Taxus and Cardiac Surgery) trial is the largest randomized study to date comparing complete myocardial revascularization with percutaneous coronary intervention (PCI) or coronary artery bypass graft surgery (CABG) among patients with 3-vessel or left main coronary artery disease. The 1-year results of the SYNTAX trial found that CABG was associated with a significantly lower rate of repeat revascularization, albeit with an excess risk of stroke compared with PCI. The recently published 5-year results of the SYNTAX trial represent a win for CABG over PCI in terms of repeat revascularization and myocardial infarction (MI), but demonstrate similar results in terms of other clinical outcomes including stroke and all-cause mortality (Figure 1) (1). In this issue of JACC: Cardiovascular Interventions, Parasca et al. (2) present a subanalysis of the SYNTAX 5-year results analyzing predictors and impact of repeat revascularization on long-term outcomes after initial PCI or CABG. Although revascularization is a common and often dominant component of composite endpoints in contemporary trials, correlates and risks thereafter are not well known and the authors are to be commended for studying this important topic.
Indeed, Parasca et al. (2) found that repeat revascularization was not uncommon, occurring in 25.9% and 13.7% of patients after PCI and CABG, respectively. In addition, most revascularizations occurred at a target vessel, with nontarget vessel revascularization occurring in fewer than 10% of patients. Perhaps most relevant, the authors found that repeat revascularization was associated with a higher risk of subsequent major adverse cardiac events after initial PCI but not CABG. Although certainly intriguing, these findings must be considered within certain limitations of such a post hoc analysis. First, excess risk after repeat revascularization was confined to MI; whereas, rates of stroke and death did not differ between groups. Second, as with any subgroup analysis, the possibility of a false positive and spurious result cannot be excluded. Third, the authors did not present a formal test of interaction which would strengthen the claim that repeat revascularization is a modifier of risk after initial PCI but not CABG.
These limitations notwithstanding, the generalizability of these findings must also take into account the stent platforms, adjunctive pharmacotherapy, and practice patterns prevalent in the SYNTAX trial. For example, contemporary PCI with current-generation drug-eluting stents (DES) bears little resemblance to the PCI of the SYNTAX trial, with respect to both indication and technique. Per protocol, patients randomized to PCI in the SYNTAX trial received complete myocardial revascularization consisting of the treatment of every lesion angiographically assessed as >50% stenosed. This might lead to an excessive length of stented coronary arteries, an important consideration because there is a graded association between stent length and risk for subsequent thrombosis or restenosis. Moreover, current clinical guidelines on myocardial revascularization and appropriate use criteria for PCI define significant stenosis at 70%, not 50%. Therefore, some of the procedures in the SYNTAX trial may not have met the appropriate use criteria (AUC) updated in 2012. With the publication of the AUC guidelines, the use of PCI has diminished in U.S. hospitals with a subsequent reduction in the rate of PCI-related complications. In addition, following the results of the FAME (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation) trial, the use of fractional flow reserve (FFR) to guide PCI in angiographically intermediate stenoses has further limited stent implantation only to lesions proved to cause myocardial ischemia (3). At 1 year, an FFR-guided PCI strategy significantly reduced the rate of the composite endpoint of death, MI, or repeat revascularization in this complex coronary artery disease (CAD) population. One might reasonably speculate whether the results of the SYNTAX trial would have been different if the current AUC for PCI had been in effect at the time of enrollment? The SYNTAX trial enrolled patients between 2005 and 2009, before the current AUC and FFR guidance were in place and before the latest stent platforms were available. In fact, all patients in the SYNTAX trial were treated with first-generation paclitaxel-eluting stents. This particular DES is now obsolete because it has been replaced by second- and third-generation DES, which relatively reduce in-stent restenosis, repeat revascularization, and MI, even in complex procedures.
With respect to adjunctive pharmacotherapy, emerging data show a clear reduction in risks for MI after PCI with prolonged durations of antiplatelet therapy in certain patient subsets. Because use of paclitaxel-eluting stents per se is an independent predictor of ischemic events and included within the dual antiplatelet therapy (DAPT) score, probably most of the SYNTAX trial patients, with only 1 additional ischemic risk factor, would qualify for DAPT beyond 1 year (4). It has also been reported that the benefits of prolonged DAPT increase proportionally with the number of diseased vessels, with the highest benefit in patients with 3-vessel disease (5). Nevertheless, only 73% of PCI-treated patients in the SYNTAX trial were still receiving DAPT at 1 year after PCI. Hence, it is not unreasonable to assume that the adverse effects of repeat revascularization observed in the SYNTAX trial among PCI-treated patients may have been mitigated with use of either newer-generation stents or prolonged DAPT durations.
With the speed of medical innovation and development, it is easy, perhaps even inevitable, to label a trial “outdated” by the time of its 5-year follow-up. Nowadays, it would be rare to perform PCI with the same indications and technique as in the SYNTAX trial. The real question is: what if the PCI in the SYNTAX were more representative of current practice? What if, for instance, we only stented lesions angiographically >70%, with positive FFR, in symptomatic patients using everolimus-eluting stents (EES), would the results be different? Would PCI be at least equivalent to CABG? The BEST (Bypass Surgery Versus Everolimus-Eluting Stent Implantation for Multivessel Coronary Artery Disease) trial, a randomized, multicenter study sought to answer such a question (6). Patients with >70% stenosis in at least 2 coronary territories were randomly assigned to PCI with EES or CABG. The trial ended early due to slow enrollment and was underpowered to detect differences. Although at 2 years the rate of the primary composite endpoint (death, MI, target vessel revascularization) was similar between the 2 groups, at the 4-year follow-up there was an excess of repeat revascularization and MI in the PCI arm. The similarity with the SYNTAX trial, despite a more contemporary approach to treatment, is worrisome. More comforting results come from a recent observational study showing significantly lower rates of stroke in PCI-treated patients with EES and similar 1-year mortality compared with CABG (7). Although repeat revascularization was still more frequent among PCI patients, the risk of spontaneous MI was higher only in the subset of PCI who received incomplete revascularization. In aggregate, these findings betray the current expectations for the use of PCI in complex CAD, although an improvement seems to be possible with the use of newer-generation DES and novel antiplatelet therapies (Figure 1).
Most recently, the limitations of the SYNTAX trial have been addressed by the EXCEL (Evaluation of the Xience Everolimus-Eluting Stent Versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization) trial, an international randomized study that tested the use of EES versus CABG in patients with unprotected left main coronary artery disease and a SYNTAX score <32 (8). The EXCEL trial will be the first randomized trial in patients with significant left main artery disease powered to provide information on the use of contemporary PCI techniques in moderately complex CAD patients (7). While we eagerly await the EXCEL trial 3-year follow-up results, it is clear that secondary prevention is still suboptimal. Repeat revascularization and recurrence of MI are important issues after revascularization with any technique, especially PCI. The bottom line is that we must do all we can to treat patients appropriately and pay special attention to risk factors and optimal medical management, even after complete revascularization.
↵∗ Editorials published in JACC: Cardiovascular Interventions reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Interventions or the American College of Cardiology.
Dr. Mehran has research grant support from Eli Lilly/Daiichi-Sankyo, Bristol-Myers Squibb, AstraZeneca, The Medicines Company, Abbott Laboratories, Watermark Research Partners, Novartis Pharmaceuticals, Medtronic, AUM Cardiovascular, Beth Israel Deaconess Medical Center, OrbusNeich, Bayer, CSL Behring, and Abbott Laboratories; has received institutional grant support from The Medicines Company, Bristol-Myers Squibb/Sanofi, AstraZeneca, Watermark Research Partners, Novartis Pharmaceuticals, Medtronic, AUM Cardiovascular, Beth Israel Deaconess Medical Center, Eli Lilly and Company/Daiichi-Sankyo, OrbusNeich, Bayer, and CSL Behring; has served as a consultant to and received consulting fees from Janssen Pharmaceuticals, The Medicines Company, Boston Scientific, Merck & Company, Cardiovascular Systems, Sanofi, Shanghai BraccoSine Pharmaceutical, AstraZeneca, Osprey Medical, Watermark Research Partners, and Medscape; has served on the executive committee for Janssen Pharmaceuticals and Osprey Medical; has served on the Data Safety Monitoring Board for Watermark Research Partners; owns equity in Claret Medical and Elixir Medical Group; and has served on the advisory board of Abbott Laboratories. Dr. Faggioni has reported that she has no relationships relevant to the contents of this paper to disclose.
- American College of Cardiology Foundation
- Mohr F.W.,
- Morice M.C.,
- Kappetein A.P.,
- et al.
- Parasca C.A.,
- Head S.J.,
- Milojevic M.,
- et al.
- Giustino G.,
- Chieffo A.,
- Palmerini T.,
- et al.
- Kappetein A.P.,
- Serruys P.W.,
- Sabik J.F.,
- et al.