Letter from the Editor
Invasive Imaging Tools for Optimizing Coronary Stent Deploymentdelete
March 2008
By significantly reducing restenosis rates, drug-eluting stents (DES) have allowed interventional cardiologists to approach longer and more complex lesions, as well as multi-vessel disease patients. This dramatic reduction in restenosis has led to the adoption of DES as the dominant percutaneous coronary intervention (PCI) strategy in catheterization laboratories in the United States during the past 5 years. However, in the last 18 months, reports of late stent thrombosis have raised concerns about the long-term safety of DES. Some studies have suggested that late (>30 days to 1 year) and very late (>1 year) stent thrombosis rates may be higher with DES compared with bare-metal stents (BMS).1-3 Autopsy studies have indicated that the mechanism of late stent thrombosis may involve lack of complete endothelialization of DES struts and placement of DES edges in the necrotic core segment of atherosclerotic plaque. 4 Furthermore, in contrast to BMS, DES have been associated with a paradoxical vasoconstriction response to acetylcholine at the proximal and distal stent edge, indicating dysfunctional endothelium immediately upstream and downstream from the stent. 5-7 This delayed and/or diminished endothelialization has necessitated long-term dual anti-platelet therapy. Thus, the overall benefit of DES over BMS relates to the balance between reduction in restenosis, the cost differential (accounting for increased upfront cost and fewer repeat revascularizations), the increased bleeding risks associated with long-term dual anti-platelet therapy, and the possible increased risk of late stent thrombosis.
Such complex revascularization decisions are often made by the treating cardiologist in the cath lab and require careful consideration of the clinical picture, angiographic analysis and increasingly, use of invasive imaging tools such as fractional flow reserve (FFR) and intravascular ultrasound (IVUS). The interventionalist has to address three important questions that help guide revascularization: 1) does the lesion(s) need revascularization?; 2) if PCI is to be performed, should DES or BMS be used?; and 3) are the stents optimally deployed for best short- and long-term outcomes?
1. Does the lesion need revascularization?
While revascularization improves survival in a subgroup of patients those with ST-elevation myocardial infarction, cardiogenic shock, severe left main and triple-vessel disease with depressed ventricular function the majority of PCIs are performed for relief of anginal symptoms or treatment of inducible ischemia. Therefore, in the setting of stable syndromes, if there is doubt about the hemodynamic significance of lesions, it is incumbent on the interventionalist to ascertain this before proceeding with PCI. The best way to avoid short- and long-term stent complications is not to deploy stents unless indicated!
Even an experienced interventional cardiologist can not accurately assess the hemodynamic significance of moderate (40-70%) lesions by visual angiographic analysis. 8 Furthermore, a homogeneously diseased vessel may appear angiographically normal because no segment is worse than its adjacent reference segment. These limitations of angiography are compounded in overlapped, tortuous, eccentric, calcified lesions, as well as ostial and bifurcation lesions. Additionally, significant inter- and intra-observer variability exists in the angiographic interpretation of lesion severity. 9-11 Given these limitations of angiography, physiologic techniques and IVUS have emerged as important adjunctive tools. Several physiologic measures of stenosis severity have been developed: FFR, coronary flow reserve (CFR), and hyperemic stenosis resistance (HSR).
FFR was developed as a pressure index of epicardial stenosis severity and is defined as the ratio of the maximal blood flow achievable in an epicardial coronary artery with a stenosis relative to the maximal flow in the same vessel without the stenosis. 12-16 A lesion with an FFR 16 FFR is relatively independent of loading conditions or myocardial contractility and FFR ≤ 0.78 has been shown to accurately reflect hemodynamic lesion severity even in patients with recent infarction or with elevated left ventricular mass index. 17,18
Coronary flow reserve is defined as the ratio of hyperemic blood velocity to the resting blood velocity. The CFR value ≤ 2.0 predicts inducible myocardial ischemia on stress testing with good predictive accuracy (89% to 96%).8,16,19-22 However, CFR reflects both the epicardial and the microvascular resistance, therefore, conditions such as diabetes, myocardial infarction, ventricular hypertrophy, and advanced age can impair microvascular function and reduce CFR independent of the epicardial stenosis severity. To overcome this limitation, the concept of relative CFR (rCFR) was introduced. The rCFR is obtained by dividing the CFR of the culprit vessel by the CFR of an adjacent normal vessel. A rCFR 23,24 It is defined as the ratio of the translesional pressure gradient and velocity at maximal hyperemia, requiring simultaneous measurements of intracoronary pressure and velocity. 23,24 An HSR > 0.8mmHg/cm/sec has been shown to be predictive of reversible ischemia on stress testing and may be particularly helpful for assessing hemodynamic severity of a stenosis in patients with microvascular disease. However, there are no prospective studies evaluating the deferral of PCI based on HSR and further research is needed before HSR can be widely adopted.
Several studies have demonstrated that PCI with BMS can be safely deferred for FFR > 0.75 and CFR values greater than 2.0. 16 The largest of these studies, the randomized Deferral of PTCA Versus Performance of PTCA (DEFER) trial, demonstrated that deferred PCI based on an FFR >0.75 confers no adverse prognosis compared to routine PCI using BMS. 25 In fact, at five years, there was a non-significant trend toward lower rates of cardiac death and myocardial infarction in the defer group compared to the perform group (3.3 vs. 7.9%, p = 0.21). 26
In addition to accurately determining the hemodynamic severity of focal lesions, FFR may be particularly useful in guiding revascularization in more complex subsets of patients such as serial stenoses, diffuse disease, ostial and bifurcation disease, and multi-vessel disease. For serial lesions or diffuse disease, a pressure pullback during intravenous (IV) adenosine infusion can be useful. 16,27 Pressure loss due to focal stenosis can be differentiated by an abrupt increase in pressure during a pullback. This technique may help avoid unnecessary revascularization using longer or overlapping DES, which are known to increase the risk of both restenosis and thrombosis. 2 Ostial lesions are notoriously difficult to accurately gauge angiographically and can easily be interrogated with FFR. The angiographic assessment of the ostia of side branches of bifurcation lesions after PCI is difficult. 28-30 In addition, off-label use of DES in bifurcation lesions is associated with increased rates of restenosis and stent thrombosis. 2 Despite severe angiographic appearance in the ostium of jailed bifurcations, more than 70% to 80% of these bifurcation lesions are not hemodynamically significant by FFR. 31 Thus, jailed side-branch lesions are often not functionally significant and PCI of the side branch can often be deferred. This single stent technique with provisional stenting of the side branch only if hemodynamically significant can improve short- and long-term outcomes of bifurcation PCI. Finally, a retrospective study of multi-vessel disease indicated that an FFR-guided strategy resulted in deployment of fewer stents, lower cost and improved outcomes compared to an angiographic-guided approach. 32 This approach is currently being prospectively investigated in a randomized trial. 33
IVUS can also be used in the assessment of moderate coronary lesions. In one study of 51 epicardial lesions evaluated by both IVUS and FFR, a minimal lumen cross-sectional area (MLA) of 60% area stenosis predicted a hemodynamically significant lesion compared to FFR.34 In another study of 53 lesions, a MLA of 3.5 mm in diameter.36 A cohort of 233 patients who underwent single-vessel PCI with DES in arteries >3.5 mm had similar outcomes as 233 propensity-matched patients who received BMS. At one-year follow up, major adverse cardiac events (MACE) occurred in 8.5% of the patients with DES and 7.7% of the patients with BMS (p = 0.80). Thus, patients with large vessels (>3.5 mm) represent a population with a low risk for MACE using BMS. These findings are in line with subgroup analysis of the TAXUS-IV trial, where the benefit of DES over BMS for restenosis was limited to vessels 36,37
Another approach might be the use of baseline FFR in determining which lesions would have favorable outcomes with BMS. It is known from a multi-center registry of 750 patients that FFR > 0.90 after BMS deployment is associated with a low (20%) MACE. A recent analysis of that registry indicated that baseline FFR and stent diameter could predict optimal post stent FFR and outcomes, suggesting that both baseline FFR and expected stent diameter could be used to guide the choice of BMS versus DES. 39
3. How can stent deployment be optimized?
Invasive imaging tools may be very helpful in optimizing stent deployment by reducing stent thrombosis, BMS restenosis, and possibly identifying lesions that are high risk for peri-procedural distal embolization.
With either BMS or DES, the most important procedure-related risks for stent thrombosis are smaller final lumen dimensions due to stent under-expansion and/or malapposition, increased stent length, persistent slow coronary flow, multiple stents, positive remodeling, dissections, geographic miss, and late stent malapposition due to thrombus resolution. 2,40-43 Post-PCI IVUS can often detect malapposition, under-expansion, residual stenosis, dissections, and geographic miss. Early studies with IVUS showed that 40-70% of angiographically well-deployed stents have under-expanded regions when examined by IVUS. 44-46 These findings led to the deployment of stents at higher inflation pressure to increase stent expansion and apposition. 47 However, even in the era of stent deployment at high pressure, IVUS-guided trials suggest that incomplete strut apposition occurs in 4% to 22% of PCIs. 48
Achieving adequate stent expansion with large post stent minimal luminal areas also reduce the risk of restenosis with BMS. While the results of randomized studies of IVUS-guided versus angiographic-guided BMS deployment are mixed, they favor IVUS guidance. In the Can Routine Ultrasound Influence Stent Expansion (CRUISE) study, IVUS guidance led to less target vessel revascularization (8.5% versus 15.2%, p 49 Similarly, the Thrombocyte activity evaluation and effects of Ultrasound guidance in Long Intracoronary stent Placement (TULIP) study investigated IVUS-guided stenting in long, diffuse coronary lesions50 and found lower restenosis rates with IVUS guidance (23% versus 46%, p = 0.008). However, the REStenosis after Intravascular ultrasound STenting (RESIST) trial showed only a trend toward reduction in restenosis in the IVUS-guided group51 and the OPTimization with ICUS to reduce stent restenosis (OPTICUS) trial showed no difference between in the IVUS-guided and angiographic guided groups. 52 The differences in procedural endpoints in these randomized trials and the use of various adjunctive treatment strategies make these trials difficult to compare. However, taken together, these results demonstrate that IVUS guidance of stent deployment leads to larger final vessel sizes, reduced stent under-expansion, and probably reduced restenosis rates with BMS. Accepted IVUS criteria for optimal BMS deployment include: (a) minimal stent cross-sectional area (CSA) > 7 mm2, (b) minimal stent CSA > 80% of average proximal and distal reference segments, and (c) complete stent apposition to vessel wall. 53,54 A minimal stent CSA > 9 mm2 is associated with the lowest restenosis rates. 45,55 While there are no published randomized studies of IVUS-guided DES deployment, IVUS guidance may be important to assure optimal stent expansion and strut apposition with DES. 56
In addition to achieving larger final vessel sizes, IVUS guidance may be important in the detection of atherosclerosis plaque composition during PCI. Recent studies suggest that increased necrotic core plaque content detected by radiofrequency backscatter IVUS analysis (virtual histology) is an independent predictor of distal embolization during PCI in patients presenting with both STEMI and anginal syndromes. 57,58 As distal protection devices may reduce peri-procedural embolization, it may be important to identify necrotic core content before stent deployment. 59 While these data are very intriguing, this strategy of using plaque characterization to guide PCI strategy is currently unproven and warrants further study.
Finally, FFR can also provide information regarding successful stent deployment. In a study with BMS, a post stent FFR > 0.94 had a concordance rate of 91% with IVUS for detecting optimally deployed stents. 60 However, this finding was not confirmed in a larger study. 61 At present, IVUS is more commonly used than FFR to assess for optimal stent deployment.
Conclusions
Fractional flow reserve and IVUS are important adjuncts to angiography and help guide PCI. These tools may help avoid unnecessary revascularizations, guide stent selection, decrease costs and optimize outcomes.
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