By Jeffrey Zimmet, MD, PhD
Associate Professor of Medicine, University of California, San Francisco; Director, Cardiac Catheterization Laboratory, San Francisco VA Medical Center
Dr. Zimmet reports no financial relationships relevant to this field of study.
SYNOPSIS: Patients with non-ST elevation myocardial infarction and multi-vessel disease were randomized to percutaneous coronary intervention (PCI) of all significant lesions during the index procedure, or to staged PCI. Those undergoing single-stage PCI had lower rates of major adverse cardiovascular and cerebrovascular events at 1 year, driven by lower rates of target-lesion revascularization.
SOURCE: Sardella G, et al. Single-staged compared with multi-staged PCI in multivessel NSTEMI patients: The SMILE Trial. J Am Coll Cardiol 2016;67:264-272.
In patients presenting with non-ST elevation myocardial infarction (NSTEMI) and multi-vessel disease for whom a percutaneous coronary intervention (PCI) is a treatment strategy, multiple questions remain about the extent and timing of treatment. This is a common scenario. Some reports have estimated that as many as 50% of NSTEMI patients present with multi-vessel disease. Although full revascularization is clearly the standard when patients undergo coronary artery bypass surgery, the landscape is more murky for PCI-treated patients. When pursuing a complete revascularization approach, how should one accomplish it? Should one approach only the “culprit” lesion during the index procedure? Should one undertake treatment of the non-culprit vessels during the same session?
The SMILE trial, performed at two centers in Italy, addresses the latter question. SMILE was an unblinded investigation of 548 consecutive NSTEMI patients, randomized in a 1:1 fashion to single- or multi-stage PCI. Those assigned to multi-stage revascularization had PCI of only the culprit lesion at the initial procedure and subsequently underwent a second procedure between 3 and 7 days later during the index hospitalization. Researchers used transradial access in > 80% of cases, although that number dropped to approximately 65% during the second procedure in the multi-stage group. Researchers employed fractional flow reserve (FFR) in approximately 25% of patients. The baseline characteristics of each group were similar, as were the use of drug-eluting stents, completeness of revascularization, and medical regimens at time of hospital discharge.
At 1 year, the rate of major adverse cardiovascular and cerebrovascular events (MACCE) was significantly lower in the single-stage group (13.63% vs 23.19%; hazard ratio [HR], 0.549; 95% confidence interval [CI], 0.363-0.828; P = 0.004). This difference was driven primarily by a higher rate of target vessel revascularization (TVR) in the multi-stage group (n = 40 [15.20%] vs n = 22 [8.33%]; 95% CI, 0.310-0.878; P = 0.01). Cardiac and overall death, myocardial infarction (MI), stroke, and hospitalization for unstable angina were not different between groups. The Bleeding Academic Research Consortium (BARC) type 1 bleeding (minor bleeding that is “not actionable” and does not generally cause the patient to seek treatment) was higher in the multi-stage group, although the more clinically-meaningful BARC types 2, 3, 4, and 5 were not significantly different between groups.
The authors concluded that in patients with NSTEMI and multi-vessel disease, single-stage PCI during the initial procedure is superior to multiple procedures in terms of MACCE and minor bleeding at 1 year.
One of the most surprising things about SMILE is that the study was designed with the assumption that multi-stage revascularization would be superior to single. As the study reached the opposite conclusion, we are left asking what happened and whether we should believe the results.
The first thing we should realize is that this study does nothing to address what is likely the more interesting question regarding multi-vessel disease: the issue of whether complete revascularization itself is superior to more-selective revascularization. SMILE used complete revascularization as the default approach and only examined the timing of PCI.
SMILE tells us that BARC type 1 bleeding was significantly less common in patients undergoing a single procedure compared with those who received two. This is a plausible and understandable difference — patients in the multi-stage group were exposed to arterial access and to procedural anticoagulation twice, as opposed to once, and a higher rate of transfemoral access was used in the staged procedures.
This is where easy explanations end. The paper stated that single-stage revascularization is superior to multi-stage in terms of 1-year MACCE, “mainly due to an unexplained higher incidence of TVR.” A closer look at TVR shows the curves don’t separate until about 6 months from randomization. For two groups who achieved similar levels of complete revascularization and left the hospital on similar medications, it is difficult to fathom how this difference could be explained. The authors related this to a higher rate of stress testing at 6 months in the multi-stage group, but again failed to explain why this should make sense. The accompanying editorial, by Drs. Henriques and Claessen, noted that the TVR rate in the multi-stage group (15.4% at 12 months) was considerably higher than what is generally observed in contemporary trials (“when interpreting SMILE, one may find a reason to frown,” according to the editorial). This TVR rate was even higher than in the SYNTAX trial, which enrolled patients with significantly higher burden of disease and used now-obsolete first-generation drug-eluting stents.
How, then, might this study change practice? Although the superiority of single-stage revascularization may not be a fully believable result, it is important to note that these patients clearly did not have a detriment in terms of important outcomes including death, MI, and contrast-induced nephropathy. The original hypothesis, after all, was that longer procedure times, higher contrast volumes, and higher likelihood of periprocedural MI and other complications would doom single-stage PCI to a second-place finish. In the end, we are left with the opportunity to tailor therapy to our patients and their particular circumstances. SMILE assures us that we are not harming patients by undertaking single-stage procedures for patients without major comorbidities and with modest lesion complexity. Patients with chronic kidney disease and those with higher degrees of technical difficulty, among other issues, will still benefit from a staged approach.