Rethinking stent implantation for stable coronary artery disease

William WIJNS,
Mandeep S. SIDHU,1,2,3MD, PhD
Cardiovascular Centre
OLVZ, Aalst

Rethinking stent implantation for stable coronary artery disease

by W. Wijns, Belgium

The practice of percutaneous revascularization for treatment of coronary artery disease (CAD) has significantly evolved over time as a consequence of numerous technical and pharmacological advances in the field. These advances have resulted in improved outcomes and the ability to treat sicker patients with more complex coronary morphology. Marked changes over recent decades in patient characteristics, procedural pharmacotherapy, and secondary prevention have transformed the immediate and longer-term outcomes achievable with percutaneous revascularization, especially in patients presenting with acute coronary syndromes. However, in patients with stable CAD, both the indications for and benefit (and hence appropriateness) of stented angioplasty applied as a default therapy based on angiographic anatomical guidance have been challenged. With the advent of pressure-derived fractional flow reserve, an invasive vessel-specific measurement of the extent to which epicardial stenosis reduces normal vessel conductance, it has become clear that many seemingly severe stenoses on angiography actually fail to be of hemodynamic significance. Moreover, the combined use of anatomical and functional guidance for stent targeting in revascularization has been shown to produce results that are symptomatically equivalent and prognostically superior to those involving targeting driven only by angiographic anatomical guidance. This article reviews recent evidence derived from ischemia-guided stent implantation trials demonstrating the benefits of appropriately targeted stent implantation on symptoms, prognosis, and health economics.

Medicographia. 2014;36:55-62 (see French abstract on page 62)

This article will review the strengths and limitations of stented angioplasty for treatment of patients with stable coronary artery disease (CAD). Analysis of practice patterns and trial data has shown that in at least 50% of cases, stents implanted under angiographic guidance are directed at inappropriate targets. This is due to a combination of factors, but it relates primarily to the inaccuracy of the angiogram in identifying whether coronary stenoses are flow limiting and responsible for stress-induced ischemia. The key message of this article will be that dual targeting combining anatomical and functional guidance for revascularization provides results that are symptomatically equivalent and prognostically superior to those of single targeting driven only by angiographic guidance. Rethinking stent implantation in light of this paradigm shift will likely impact on the merits of adding revascularization to optimal medical care, and may fill the gap between stented angioplasty and bypass surgery in higher-risk subsets of patients with stable CAD.

Coronary stent implantation: an established
therapeutic modality and the dominant mode
of myocardial revascularization

Major technical and procedural advances have transformed coronary balloon dilatation as initially performed by Grùntzig1 into a safe, reliable, efficacious, predictable, and durable therapy involving implantation of drug-eluting coronary stents.2 At the same time, procedures have remained minimally invasive and patient friendly. Patients presenting with acute myocardial infarction or other unstable coronary syndromes are best treated with early percutaneous intervention. Patients with complex lesions who were traditionally referred for bypass surgery have progressively more often been treated with stents, including those with complex bifurcation stenosis, chronic coronary occlusion, left main stenosis, or multiple diseased vessels. Currently, the main limitation of stented angioplasty no longer relates to technical feasibility, but rather its ability to address extensive and diffuse CAD such as is seen in patients with diabetes, with worse outcomes reported in this context than with surgery.3,4 There seems to be a limit to the number of stent implants, ie, the epicardial vessel length that is covered by metal, beyond which outcomes start to degrade. With the emergence of fully bioresorbable scaffolds,5 this last frontier may be crossed in the near future (scaffolds are fully biodegradable drug-eluting stents that disappear within a few years after implantation). Today, however, the anatomical extent and severity of CAD is the frontier, and the borders are defined by the upper tertile of the SYNTAX score (SYNergy between percutaneous coronary intervention with TAXus and cardiac surgery).3,6 This score qualifies the anatomical extent of the disease using coronary angiography, and identifies patients with extensive disease who should be recommended for bypass surgery rather than implantation of multiple permanent stents.7

Percutaneous revascularization has greatly benefited from advances in adjunctive medical therapies. Antithrombotic and antiplatelet drugs have reduced periprocedural and in-hospital stent thrombosis rates to 1%-3%. Late stent thrombosis rates have decreased with use of the newer-generation drug- eluting stents to the extent that long-term dual antiplatelet therapy (beyond 6 months) may no longer be required.8,9 As a result, antiplatelet drug prescriptions and secondary prevention regimes are now driven by the disease indications, rather than the device.

In this context, percutaneous revascularization using stented angioplasty has become the first-choice mode of therapy in many clinical and anatomical situations. Because of all of the aforementioned, it comes as no surprise that stents represent the dominant mode of revascularization, constantly exceeding the annual number of bypass procedures performed since the late 1990s.

Evidence and evolving practice patterns

The evidence base for stent implantation in patients with stable CAD is derived from randomized clinical trials, large propensity- matched observational registries, and their meta-analyses.7 Only 2 studies have shown a mortality benefit, both of which included patients with recent myocardial infarction.10,11 In one of these studies by Jeremias et al, after excluding patients with myocardial infarction from their meta-analysis, the authors still reported evidence for reduced mortality (hazard ratio, 0.82; confidence interval, 0.68-0.99).11 Data consistently show an improvement in symptoms with use of stent implantation, but for the most part, no reduction in hard outcome events: no benefit of percutaneous revascularization over medical treatment with respect to mortality, nonfatal periprocedural myocardial infarction, or the need for repeat revascularization.7

Because of the significant advances in both revascularization and medical therapies over the last 2 decades, many of the reported clinical trials have limited relevance in today’s clinical practice. The randomized trial COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive druG Evaluation), which was discussed earlier in this issue (see preceding article), did demonstrate that major adverse cardiac outcome events after 4.6 years of best contemporary medical therapy were not improved by performance of angioplasty as the initial strategy.12 It was concluded from COURAGE that percutaneous revascularization should be restricted to patients who remain symptomatic after medical therapy, a conclusion that can hardly be drawn from the study design, as only patients with known coronary anatomy were eventually considered for randomization in the study. As is usually the case in randomized clinical trials, only a small proportion of eligible patients were included in the trial, which thus limits the possibility of extrapolation of the results to all patients seen in routine clinical practice, especially those whose coronary anatomy is not known.

Nevertheless, the impact of COURAGE on interventional practice has been very significant, with fewer stented angioplasty procedures being performed in stable CAD patients than previously. Procedures in catheterization laboratories now involve an increasing proportion of patients with acute CAD in whom the benefits of revascularization by stent implantation have been proven.7 Of note, identification of the offending stenosis in such patients is mostly unambiguous. Moreover, the remaining indications for stent implantation in stable CAD patients are now carefully scrutinized and sometimes declared inappropriate,13 especially when they are primarily—let alone exclusively—based on technical feasibility.

Indications for revascularization in patients with
stable CAD

The guidelines on myocardial revascularization that were issued in 2010 by both the European Society of Cardiology and the European Association for Cardiothoracic Surgery7 were the first to propose a stepwise decision process whereby the appropriateness of revascularization is addressed first, followed only secondly by the technical discussion about the relative merits of bypass versus stent implantation. Revascularization can be justified on symptomatic grounds, with persistent limiting symptoms of angina or angina equivalent despite optimal medical care. Prognostic indications, which are most often present in conjunction with symptoms, but can even be present in asymptomatic patients, are justified in anatomical subsets associated with proven large territories of stress-inducible ischemia. Significant left main or proximal left anterior descending stenosis, especially in the presence of multivessel disease, represents an anatomical situation that involves large areas of myocardium at risk, and thus has the potential to show an improved outcome after revascularization.

These recommendations underscore the prognostic importance of ischemic burden and demonstrable ischemia (death, myocardial infarction, acute coronary syndromes). While there is no prognostic benefit of revascularization in symptomatic patients with little evidence of ischemia, patients with 10% or more of the myocardium at jeopardy will enjoy a lower risk of death or infarction after revascularization, as shown from large functional imaging studies.14 A small nuclear substudy of COURAGE has confirmed these findings in the era of contemporary medical treatment, showing lower event rates with reduced mass of ischemic myocardium under treatment, be it revascularization or medical therapy only.15 The evidence for a lack of benefit in the absence of demonstrable ischemia is perhaps even stronger and has been augmented over the last decade by studies incorporating ischemia detection into the decision-making process regarding whether to revascularize or to defer (see Table I).14,16-24

Anatomy-guided versus ischemia-guided

With the extension of the indications for percutaneous revascularization, decisions regarding whether to revascularize or not have increasingly been made solely on the basis of angiography findings; namely, the presence of seemingly “significant” coronary narrowing. Indeed, in many patients who reach the catheterization laboratory, a functional evaluation has not been undertaken. This can be for one, or several, of the following reasons25:(i) with more complex anatomy, noninvasive functional testing often only identifies the most severe abnormalities; (ii) in the presence of multivessel disease, the ability of all imaging techniques to qualify the significance of individual stenoses on a “per vessel” basis remains far from perfect26; (iii) in patients with prior myocardial infarction, diagnosis of ischemia in other territories is difficult; and (iv) ad hoc revascularization (meaning that stented angioplasty is performed immediately after diagnostic angiography) is convenient, but increases the likelihood that stent implantation will be performed in the absence of functional testing.

Table I
Table I. Studies assessing the benefit of percutaneous revascularization
in the presence or absence of ischemia.

Abbreviations: ACIP, Asymptomatic Cardiac Ischemia Pilot; BARI 2D, Bypass
Angioplasty Revascularization Investigation 2 Diabetes; COURAGE, Clinical
Outcomes Utilizing Revascularization and Aggressive druG Evaluation; DEFER,
not an acronym; FAME, Fractional flow reserve versus Angiography for Multivessel

These (and other) limitations of noninvasive functional testing are real and explain why precatheterization examinations often fall short of providing the interventional cardiologist with clear directions as to where to act. This situation is unfortunate, but explains why invasive doctors often have had no choice but to react to images, applying the so-called oculostenotic reflex. This is indeed unfortunate, because angiography is notoriously known to not provide a reliable estimate of stenosis severity.27,28 Whether or not ischemia will be inducible downstream of a coronary stenosis depends on stenosis severity and geometry, as well as several other factors. Among these factors, the most important are the mass and viability of downstream myocardium, and above all, the effectiveness of collateral circulation, which can hardly be assessed by angiography.29

Figure 1
Figure 1. Understanding (in)appropriate use of percutaneous
coronary intervention.
Each data point refers to a coronary stenosis that was evaluated both with
quantitative coronary angiography (an objective method to calculate the stenosis
severity from the angiogram) and fractional flow reserve (FFR). The horizontal axis
shows the percentage diameter stenosis, with a 50% stenosis as the threshold
for significance. The vertical axis shows the corresponding FFR value,
with the abnormality threshold at 0.80.
The individual data clusters in 4 quadrants. Quadrants I and III correspond to
consistent evaluation between anatomy and physiology. Less than 50% diameter
stenosis with preserved FFR (quadrant I): PCI inappropriate. More than 50%
diameter stenosis with abnormal FFR (quadrant III): PCI appropriate. However,
many seemingly severe stenoses by angiography do not alter FFR (quadrant II):
PCI questionable. Other seemingly nonobstructive stenoses do nevertheless
alter FFR (quadrant IV): PCI deferral is inappropriate.

Abbreviations: FFR, fractional flow reserve; PCI, percutaneous coronary intervention.
After reference 28: Wijns et al. J Nucl Cardiol. 2007;14(3)366-370. © 2007,
American Society of Nuclear Cardiology.

With the validation and clinical application of pressure-derived fractional flow reserve (FFR) measurement, it became obvious that many seemingly severe stenoses on angiography actually fail to be of hemodynamic significance (Figure 1).28 FFR is an invasive, vessel-specific measurement of the extent to which epicardial stenosis reduces normal vessel conductance. The measurement is based on the simultaneous registration of proximal and distal intracoronary pressures during maximal hyperemia. Thus, FFR identifies the likelihood that epicardial vessel conductance is sufficiently reduced that it will cause downstream myocardial ischemia during increased demand. As a corollary, mechanical treatment by percutaneous coronary intervention or coronary artery bypass grafting (CABG) becomes increasingly likely to augment maximal flow, and hence eliminate symptoms and improve prognosis, when applied to stenoses with more severely reduced FFR.30

Prospective studies have indeed shown that angiographic guidance in the absence of functional testing, be it noninvasive or FFR-based, results in about 30% overtreatment and 20% under treatment, which equates to inadequate stent placement in as many as 50% of patients.16,23 The clinical implications of this are massive. Studies have shown that stented angioplasty could be safely deferred whenever stenoses were not limiting maximal flow capacity.16,17 When using stents to dilate stenoses in patients with preserved FFR, patients showed no symptom improvement over medically-treated patients.16,17,23,24 Actually, stent implantation in the absence of ischemia should not be of any benefit and could even be harmful.23 Although infrequent, as with any invasive procedure, there remains the potential for complications with stent implantation. Table II shows the results of FAME (Fractional flow reserve versus Angiography for Multivessel Evaluation) 1, in which revascularization strategies based on angiography alone are compared with those using angiography and fractional flow reserve.23,24 The implications for health technology assessment are equally striking (Figure 2).31 Revascularization based solely on anatomical results is an unnecessary consumption of resources. By contrast, combined angiographic and functional guidance provides better outcomes at lower costs, a rather unique feature in contemporary medicine.31

From a clinical trial perspective, randomized allocation to percutaneous stent implantation in patients with coronary lesions that do not cause ischemia will confound and dilute trial results regarding any beneficial effects of revascularization. Understandably, the benefit of the procedure will be restricted to patients with extensive ischemia. Indeed, if up to half of stents are inadequately targeted in angiography-driven trials, sample size calculations will be skewed, side effects will be magnified, and net outcome trial results will be flawed.

Table II
Table II. Results of the FAME 1 study comparing revascularization
strategies based on angiography alone versus angiography plus
fractional flow reserve (1:1 randomization).

Abbreviations: CABG, coronary artery bypass grafting; DES, drug-eluting stent;
FAME, Fractional flow reserve versus Angiography for Multivessel Evaluation; FFR,
fractional flow reserve; No., number; PCI, percutaneous coronary intervention.
Based on data from references 23 and 24.

Figure 2
Figure 2. The incremental cost-effectiveness ratio
balances costs and outcomes.
Most often, improving outcomes requires additional cost. Western
societies are currently willing to spend US $50 000 per qualityadjusted
life-year gained. A disruptive technology or treatment
is associated with improved outcomes while at the same time
saving resources. With fractional flow reserve guidance for
revascularization, the vast majority of data points (each dot
corresponding to a percutaneous coronary intervention procedure)
fall into the “happy” zone where better outcomes are
achieved at no extra cost.

Abbreviations: FFR, fractional flow reserve; ICER, incremental
cost-effectiveness ratio; QALY, quality-adjusted life-year.
After reference 31: Fearon et al. Circulation. 2010;122(24):
2545-2550. © 2010, American Heart Association.

Rethinking stent implantation for stable CAD

Targeting revascularization procedures to stenoses proven to cause ischemia results in a totally new paradigm that challenges previously accepted standards. With this knowledge at hand, the FAME 2 trial was designed to show the superiority of stented angioplasty over optimal medical therapy in patients with ischemia documented by FFR who were then randomized 1:1 to medical treatment only or medical treatment plus stent implantation.20 The final report of the study is awaited, but initial outcome data were presented after study enrolment was stopped prematurely due to an excess of urgent hospitalization events requiring unplanned revascularization in the group assigned to optimal medical care only.20 Because enrolment was halted prematurely, it is unlikely that the trial hypothesis will be met when the primary outcome data at 24 months become available (the planned release is during the first quarter of 2014). However, unplanned hospitalization events requiring urgent revascularization—as opposed to comfort interventions—were associated with an increased rate of death or myocardial infarction between 8 and 215 days (Figure 3, page 60).20 These data indicate that a default strategy of medical therapy alone is inappropriately denying 11.1% of patients revascularization, while also exposing them to significant risk (strongly positive interaction). In addition, 8.6% of patients randomized to optimal medical care remained symptomatic and required elective revascularization on average as soon as 6 months after inclusion. Whether the remaining 80.3% of the subset of ischemic patients randomized to optimal medical care who were appropriately spared from upfront revascularization (either for prognostic or symptomatic indications) can be identified a priori has yet to be evaluated.

The ongoing trial ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches)32 is attempting to resolve the remaining uncertainty and address some of the limitations of FAME 2. The primary end point in ISCHEMIA will be death or nonfatal myocardial infarction, and the trial will be powered accordingly. Unlike the FAME trials, the functional evaluation will evaluate noninvasive testing and imaging techniques. Based on the recent experience with FAME 2, it may turn out to be a challenge to successfully complete this randomized trial.33 Specifically, 2 major challenges will have to be managed. First, if investigators are reluctant to include and randomize patients with a large ischemic burden or severe coronary disease, only lower-risk patient subsets will be included and event rates will be low, and this trial will neither be conclusive nor generalizable to practice. Conversely, if high-risk patients are indeed included and randomized, an excess of unplanned revascularization procedures will occur in the medical treatment arm and safety considerations may emerge, potentially challenging the continued inclusion of such patients. For both FAME and ISCHEMIA, data safety monitoring committees play a critical role in monitoring trial execution and progress.

Future impact of new stenting paradigms:
disruption of existing practices and outcomes

Implementation of combined functional-anatomical guidance for coronary stenting and myocardial revascularization will be disruptive of current practice in several respects. The results of FAME 1 showed an inherent weakness in revascularization guidance based primarily on the coronary angiogram. Anatomy is misleading, and treatment decisions based on this type of guidance can be flawed: too many stents are deployed and are inappropriately targeted to stenoses that do not need stenting, and many stenoses are inappropriately denied treatment, because although they are flow-limiting in reality, they appear mild in anatomical terms. It is no surprise if revascularization fails to show superior outcomes when more than half of the interventions are doomed to have no other effect than cosmetic at best, or unnecessary complications in the worst case scenario. FAME 1 thus demonstrates that more stents does not mean more care.23,24

Figure 3
Figure 3. Landmark analysis of the primary end point and its components in the FAME 2 trial.

The relative risk of the primary end point of death, myocardial infarction, or urgent revascularization and of components of the primary end point are shown, according to the time from randomization (solid boxes at 7 days or less versus open boxes at 8 days or more). Percutaneous coronary intervention plus the best available medical therapy was shown to be consistently more beneficial after the landmark point of 7 days after randomization than before this point; there were significant interactions between time and treatment with respect to the primary end point.
Abbreviations: CI, confidence interval; FAME, Fractional flow reserve versus Angiography for Multivessel Evaluation; No., number; PCI, percutaneous coronary intervention.
After reference 20: De Bruyne et al. N Engl J Med. 2012;367:991-1001. © 2012, Massachusetts Medical Society.

The results of FAME 2 illustrated the limitations of applying in clinical practice the results of previously reported trials that concluded inadequately that revascularization has no prognostic value.20 Between a strategy that uses too many stents upfront and a strategy of default initial medical therapy with no initial use of stents at all, optimal care likely resides in the middle, whereby stents are used where needed in the presence of proven ischemia. Such a strategy requires combined functional-anatomical guidance, and has been demonstrated to be disruptive of current practice through provision of superior outcomes while saving resources.31

The implications are far reaching. By replacing the previous gold standard based on anatomy with a combined functional anatomical strategy, the definitions of disease and disease subsets are changing. The extent and severity of coronary disease is being reclassified; from triple-vessel to double-vessel or single- vessel disease, from double-vessel to single-vessel disease, or sometimes to disease that is called “nonsignificant” and thus amenable to optimal medical care only. Risk stratification based on anatomy (the SYNTAX score) changes accordingly when the “functional” SYNTAX score is applied.34 Likewise, demands on the completeness of revascularization procedures are being modified, and are now defined by functional significance and not just anatomical criteria.35 Applying the new standard to bypass surgery might impact on procedural technique, graft selection, and patency, and potentially outcomes after CABG.36,37 Lastly, the relative indications of bypass surgery versus interventional therapies are being challenged.

Figure 4
Figure 4. Kaplan-Meier cumulative event
curves for repeat revascularization during
5 years of follow-up in the SYNTAX trial.

Final results of the SYNTAX trial comparing
patients with multiple vessel disease randomized
1:1 to either stented angioplasty or to bypass
surgery. The primary noninferiority end point of
the trial was not met. The secondary end point of
repeat revascularization due to stent or bypass
failure, respectively, shows an accrued advantage
of surgery over the years. We hypothesize that
stent failure stems largely from inappropriate stent
implantation as a result of sole angiographic
Abbreviations: CABG, coronary artery bypass
grafting; SYNTAX, SYNergy between percutaneous
coronary intervention with TAXus and
cardiac surgery; TAXUS, paclitaxel-eluting stent.
After reference 3: Mohr et al. Lancet. 2013;381
(9867):629-638. © 2013, Elsevier.

It is tempting to speculate that the results of trials such as SYNTAX, which compared multiple-vessel stenting with bypass surgery, would have been different had stenting indications not been based solely on anatomy (Figure 4).3 The trial failed to meet its primary noninferiority end point, with the significant difference at 5 years in favor of bypass surgery being primarily driven by stent failure, mostly causing an excess in the need for repeat revascularization.3 The average number of implanted stents was 4.6±2.3 per patient, the average stent length was 86.1 mm, and 48% of patients received 5 stents or more. Side effects increase with stent length, and on the basis of what was known then, it is unavoidable that a sizable proportion of stents were targeted at non–flow-limiting stenoses. As discussed earlier, outcome results are confounded— mostly degraded—by the side effects or complications that result from inappropriately targeted stent implants. Appropriate stenting might therefore no longer be inferior to surgery, but this remains purely speculative, and the burden of proof rests on our shoulders.

In summary, more stents are not equivalent to more care, but rather the opposite. Dual targeting based on anatomy and function is superior to single targeting based solely on angiographic guidance. More is often less, and less is sometimes more.

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Keywords: angiography; coronary artery disease; fractional flow reserve; ischemia; myocardial infarction; percutaneous intervention; stenting