Abstract
Symptomatic coronary artery disease may be commonly due to significant atherosclerotic disease involving coronary vessels of relatively small caliber (i.e., with reference vessel diameter <2.75 mm). Whenever medical therapy fails and in other selected cases, revascularization by means of percutaneous coronary intervention (PCI) or bypass surgery is indicated even for small vessel coronary disease. However, despite the numerous developments and improvements in devices and techniques, PCI of small coronary vessels is still fraught with a significant risk of midterm restenosis after both balloon-only PCI and bare-metal stent implantation. Drug-eluting stents, especially those associated with very low angiographic late lumen loss (<0.20 mm), appear to significantly improve angiographic and clinical outcomes after PCI of small coronary vessels. The present article provides a concise and updated review on percutaneous coronary revascularization in patients with symptomatic small vessel coronary artery disease.
1
Introduction
Coronary artery disease remains a major cause of morbidity and mortality worldwide despite the major improvements in primary and secondary prevention strategies. Whereas aggressive medical therapy is safe and effective as an initial management approach in patients with stable coronary artery disease , percutaneous coronary intervention (PCI) or surgical revascularization is clearly indicated in most patients with acute coronary artery disease or those stable subjects failing medical therapy .
Atherosclerotic coronary involvement extends often to distal and small-caliber coronaries, such that as much as 20–30% of patients undergoing PCI may have significant disease in coronary segments whose diameter is relatively small (e.g., <2.75 mm) . In this setting, balloon-only PCI or bare-metal stents (BMS) have proved only partially effective, as early and midterm failures could occur in up to 50% of patients . The recent development of drug-eluting stents (DES) has, however, drastically changed the percutaneous management of small vessel coronary disease, thanks to their potent antirestenotic effect and remarkable early and midterm safety . The aim of this article is to provide a concise and updated review on current and future approaches for percutaneous coronary revascularization in patients with symptomatic small vessel coronary artery disease. This review is based on a systematic PubMed search strategy, whose details are available in the Appendix .
2
Definition and prevalence
Several definitions of small vessel coronary disease have been proposed in the past. However, most recent studies on the topic have identified an angiographic reference vessel diameter equal or lower than 2.75 mm as the most appropriate cutoff . Thus, as a rule of thumb, it can be stated that any coronary vessel amenable to percutaneous treatment with a 2.75 mm or smaller device should be considered as small. In addition, thanks to the market approval and subsequent availability of DES with a 2.25-mm diameter, some authors have suggested the term very small vessel coronary artery disease for those coronary segments that are amenable to percutaneous treatment with a 2.25-mm device.
Despite varying definitions in the literature, there is universal agreement that small vessel coronary artery disease is highly prevalent (up to 20–30% of patients with symptomatic coronary artery disease) and that patients with diabetes mellitus or chronic renal failure are at even higher risk of developing this specific type of coronary artery disease . The prognostic implications of small coronary artery disease are also great, as a small reference vessel diameter in the coronary segment undergoing percutaneous PCI is significantly and directly associated with an increased risk of adverse clinical events, including restenosis and thrombosis , in comparison to larger reference vessel diameters.
A common conceptual framework is useful before a detailed description of available approaches for the percutaneous revascularization of small vessel coronary artery disease. Indeed, the goal of PCI is to improve the minimum lumen diameter in a given target coronary segment, which has a specific reference vessel diameter (roughly defined as the average of the diameters of apparently normal segments localized proximally and distally to the target segment). Thus, the minimum lumen diameter increases significantly after the procedure, yet decreases at follow-up, mainly because of recoil and hyperplasia phenomena. Late lumen loss is precisely the difference between the postprocedural minimum lumen diameter and the follow-up minimum lumen diameter, and ranges between 0.05 and 0.10 (for the most effective DES) and 1.0 and 1.5 mm (for balloon-only PCI) ( Fig. 1 ) . Whereas a low late loss is generally beneficial, it appears even more important in small coronary vessels (i.e., vessels with reference vessel diameter ≤2.75 mm) ( Fig. 2 ). The statistical distribution of late loss is non-Gaussian and bimodal, and this makes speculations based only on late loss largely exploratory . Nonetheless, predicted binary restenosis rates can be built upon average differences in late loss, even if they should be viewed with caution ( Fig. 3 ).
It should be thus stressed that not all small vessel coronary lesions are born equal. Indeed, an extensively diseased proximal left anterior descending lesion with negative remodeling might appear having a reference vessel diameter similar to that of a distal secondary branch of a posterolateral artery; yet, the clinical relevance and management strategy differ significantly. For instance, if there is a large amount of myocardium at risk, efforts should be maximized to provide the most appropriately sized and effective treatment [e.g., a DES associated with low late loss, with lesion preparation with appropriate pre-dilation, and stent size chosen based on intravascular imaging such as intravascular ultrasound (IVUS)]. Conversely, a small diameter coronary lesion providing flow to a small portion of myocardium is often not worth major therapeutic efforts and should be often better served with conservative medical therapy only.
2
Definition and prevalence
Several definitions of small vessel coronary disease have been proposed in the past. However, most recent studies on the topic have identified an angiographic reference vessel diameter equal or lower than 2.75 mm as the most appropriate cutoff . Thus, as a rule of thumb, it can be stated that any coronary vessel amenable to percutaneous treatment with a 2.75 mm or smaller device should be considered as small. In addition, thanks to the market approval and subsequent availability of DES with a 2.25-mm diameter, some authors have suggested the term very small vessel coronary artery disease for those coronary segments that are amenable to percutaneous treatment with a 2.25-mm device.
Despite varying definitions in the literature, there is universal agreement that small vessel coronary artery disease is highly prevalent (up to 20–30% of patients with symptomatic coronary artery disease) and that patients with diabetes mellitus or chronic renal failure are at even higher risk of developing this specific type of coronary artery disease . The prognostic implications of small coronary artery disease are also great, as a small reference vessel diameter in the coronary segment undergoing percutaneous PCI is significantly and directly associated with an increased risk of adverse clinical events, including restenosis and thrombosis , in comparison to larger reference vessel diameters.
A common conceptual framework is useful before a detailed description of available approaches for the percutaneous revascularization of small vessel coronary artery disease. Indeed, the goal of PCI is to improve the minimum lumen diameter in a given target coronary segment, which has a specific reference vessel diameter (roughly defined as the average of the diameters of apparently normal segments localized proximally and distally to the target segment). Thus, the minimum lumen diameter increases significantly after the procedure, yet decreases at follow-up, mainly because of recoil and hyperplasia phenomena. Late lumen loss is precisely the difference between the postprocedural minimum lumen diameter and the follow-up minimum lumen diameter, and ranges between 0.05 and 0.10 (for the most effective DES) and 1.0 and 1.5 mm (for balloon-only PCI) ( Fig. 1 ) . Whereas a low late loss is generally beneficial, it appears even more important in small coronary vessels (i.e., vessels with reference vessel diameter ≤2.75 mm) ( Fig. 2 ). The statistical distribution of late loss is non-Gaussian and bimodal, and this makes speculations based only on late loss largely exploratory . Nonetheless, predicted binary restenosis rates can be built upon average differences in late loss, even if they should be viewed with caution ( Fig. 3 ).
It should be thus stressed that not all small vessel coronary lesions are born equal. Indeed, an extensively diseased proximal left anterior descending lesion with negative remodeling might appear having a reference vessel diameter similar to that of a distal secondary branch of a posterolateral artery; yet, the clinical relevance and management strategy differ significantly. For instance, if there is a large amount of myocardium at risk, efforts should be maximized to provide the most appropriately sized and effective treatment [e.g., a DES associated with low late loss, with lesion preparation with appropriate pre-dilation, and stent size chosen based on intravascular imaging such as intravascular ultrasound (IVUS)]. Conversely, a small diameter coronary lesion providing flow to a small portion of myocardium is often not worth major therapeutic efforts and should be often better served with conservative medical therapy only.
3
Role of medical therapy and bypass surgery
Before discussing in greater detail current PCI strategies for small coronary artery disease, it is worth emphasizing that a trial of aggressive medical therapy (i.e., antiplatelet agents, beta-blockers, angiotensin-converting enzyme inhibitors, and/or statins) is recommended in all patients with stable coronary artery disease without high-risk features (e.g., unprotected left main disease), as PCI in this setting may only provide a symptomatic benefit . Conversely, bypass surgery is still traditionally considered the first-line revascularization means for diabetics with multivessel disease or subjects with unprotected left main stenosis or multivessel disease and concomitant significant left ventricular systolic dysfunction . Recommendations for both medical therapy in low-risk stable patients and surgical therapy for high-risk subjects hold true even in the presence of small vessel coronary artery disease. However, in the latter case, there should be an individualized appraisal of the risk–benefit balance of surgical vs. percutaneous revascularization, as bypass surgery is more likely to achieve anatomically or functionally complete coronary revascularization but at the expense of an increase in periprocedural complications . Moreover, coronary artery bypass surgery in patients with small vessel disease is also associated with an increase in late adverse clinical events since small vessels provide poor distal runoff for the aortocoronary grafts, a phenomenon which often results in graft occlusion or malfunctioning.
Beyond standard medical therapy for the primary and secondary prevention of coronary artery disease, there has been recently a diffuse interest on systemic drug therapy for the prevention of restenosis after PCI in both large and small coronary arteries. Whereas promising data have been occasionally reported for oral rapamycin , steroids , and cilostazol , further clinical data are needed before routinely recommending such treatments.
4
Role of balloon-only angioplasty
Balloon-only PCI has been the main percutaneous revascularization approach in patients with small vessel coronary artery disease for almost 2 decades. Since its introduction, balloon-only PCI proved in fact relatively safe and effective , at least in comparison to other more aggressive technical approaches such as directional atherectomy, rotational atherectomy, or laser-based interventions . Despite such favorable comparisons, binary restenosis rates following balloon-only PCI of small coronary vessels can reach 50–60%, thus determining angiographic and clinical recurrence of small coronary disease in many patients ( Fig. 3 ) . Nonetheless, a favorable midterm outlook can be predicted whenever balloon-only PCI achieves a satisfactory postprocedural angiographic result (e.g., diameter stenosis <20%). Indeed, in such cases, balloon-only PCI of small coronary vessels appears noninferior even in comparison to BMS .
5
Role of nonstent devices
Despite the disappointing results of nonballoon and nonstent devices (such as directional, laser, or rotational atherectomy) in coronary artery disease in general and in small vessel disease in particular , several investigators have attempted using other coronary devices, albeit with inconclusive results. To date, only very selective usage of cutting balloon, Fx MiniRail, or Angioscore can be envisaged in either large or small vessel coronary artery disease .
6
Role of BMS
The introduction of bare-metal, balloon-expandable stents led to major improvements in acute success of PCI and also reduced significantly the risk of midterm restenosis, at least in medium- and large-sized coronary arteries . Several energies were soon focused in the BMS era on the identification of predictors of restenosis . Hausleiter et al. reported from a cohort of 3156 patients treated with BMS in small coronary arteries that early adverse clinical outcomes were mainly predicted by acute coronary syndrome at admission and left ventricular ejection fraction, whereas binary restenosis at midterm follow-up could vary between 30% and 55% and was directly dependent on lesion length and total stent length. Another major factor implicated in the risk of restenosis was strut thickness and density, as stents with lower strut thickness yielded less abundant neointimal hyperplasia . More poignantly, Kasaoka et al. performed extensive angiographic and IVUS analyses to identify risk factors for restenosis after BMS implantation, disclosing that total stent length, smaller reference lumen diameter and smaller final minimum lumen diameter were strong predictors of in-stent restenosis. In lesions with IVUS guidance, IVUS stent lumen cross-sectional area was actually an even better independent predictor than angiographic measurements.
Thus, it was soon appreciated that small vessel coronary artery disease was a more challenging subset for testing the performance of coronary stents. Several randomized trials comparing BMS and balloon-only PCI in small coronary vessels were then conducted, with largely inconclusive results. In 2005, Agostoni et al. finally conducted an extensive meta-analysis including 13 studies and 4383 patients, showing that BMS may have an overall beneficial impact on binary restenosis (27.8% vs. 35.8% for balloon-only PCI, P =.003) and target lesion revascularization (TLR) (14.9% vs. 18.7%, P =.02). However, this benefit was heterogeneous ( P =.001), and further exploratory analyses demonstrated that it was largely limited to studies in which optimal balloon-only PCI (i.e., aimed at postprocedural diameter stenosis <20%) was not systematically sought.
Most recent data on BMS have confirmed this comprehensive meta-analysis , even in the setting of acute ST-segment-elevation acute myocardial infarction treated with primary PCI .
7
Role of drug-eluting stents
The introduction of effective DES into clinical practice has revolutionized PCI by providing a device that effectively prevents restenosis in low-risk lesions and reduces significantly its risk in more complex lesions, thus providing clinically relevant benefits in terms of TLR and major adverse cardiac events . Whereas few studies have been focused specifically on small coronary disease in the DES era, several post hoc observations are also available, clarifying the exact role of DES in this setting. Specifically, the Canadian Study of the Sirolimus-Eluting Stent in the Treatment of Patients With Long. De Novo Lesions in Small Native Coronary Arteries (C-SIRIUS) trial showed that sirolimus-eluting stents (Cypher, Cordis, Miami, FL, USA) reduced in such relatively small vessel coronary lesions binary restenosis from 52% with BMS to only 2% with sirolimus-eluting stents ( P <.001), with obvious ensuing clinical benefits . The only randomized trial specifically focused to date on the comparison of DES vs. BMS in truly small vessel coronary artery disease (reference vessel diameter ≤2.75 mm as inclusion criteria but actually 2.17±0.26 mm in the BMS group and 2.22±0.29 mm in the DES group), the Sirolimus-Eluting Stent and a Standard Stent in the Prevention of Restenosis in Small Coronary Arteries Trial (SES-SMART) study, further validated these observations. Specifically, among the 257 patients enrolled, BMS were associated at midterm angiographic follow-up with a binary in-segment restenosis rate of 53% vs. 10% after sirolimus-eluting stent implantation ( P <.001) . Similar results were provided by sub-analyses of other trials or registries on sirolimus-eluting stents, clearly establishing that these devices are associated with very low late loss (ranging between 0.05 and 0.20 mm) and, thus, can be a very effective tool in small vessel coronary artery disease .
Paclitaxel-eluting stents (Taxus, Boston Scientific, Natick, MA, USA) remain among the most effective first-generation DES, as clearly demonstrated by the pivotal dedicated trials . However, these devices are associated with a late loss averaging 0.30 mm, which could potentially impact unfavorably on outcomes in very small coronary arteries. Indeed, whereas paclitaxel-eluting stents clearly outperform BMS in small vessels , direct comparison to other DES associated with lower late loss (e.g., sirolimus-eluting stents and everolimus-eluting stents) suggests that superior outcomes in small coronary arteries can be obtained with the latter devices rather than with the former. These conclusions are largely based on head-to-head randomized comparisons , also confirmed in observational registries, including those focusing on stents as small as 2.25 mm in diameter .
Other stents have been recently approved in Europe and/or in the US, including zotarolimus-eluting stents [Endeavor and Endeavor Resolute (both from Medtronic, Minneapolis, MN, USA) which differ in polymer covering (phosphorylcholine and BioLinx, respectively)] and everolimus-eluting stents [Xience V (Abbott Vascular, Abbott Park, IL, USA), and Promus (Boston Scientific] ]. Interestingly, Endeavor is, to date, among the DES with the highest associated late loss (ranging between 0.50 and 0.70 mm) and, thus, it may appear less appealing in patients with small vessel coronary artery disease. This conclusion is based on the fact that, in small vessels, even a mild increase in late loss may lead to increase in binary restenosis ( Fig. 3 ) and also on direct comparisons between Endeavor and sirolimus-eluting stents .
Conversely, everolimus-eluting stents are associated with very low late lumen loss (lower than 0.20 mm), making them attractive alternatives to sirolimus-eluting stents, which have conversely well-known limitations in stent/balloon platform flexibility and deliverability. Indeed, there is already clear randomized clinical proof that everolimus-eluting stents are superior to BMS and to paclitaxel-eluting stents in general and, thus, may have an even more favorable risk-benefit profile in small vessel coronary artery disease ( Fig. 4 ) . Specifically, there is already evidence from the 1002-patient SPIRIT III randomized trial that everolimus-eluting stents reduce, in comparison to paclitaxel-eluting stents, late lumen loss (0.16±0.41 vs. 0.30±0.53 mm, P =.002) and binary angiographic restenosis in (2% vs. 6%, P =.06), as well as major adverse cardiac events (6% vs. 10%, P =.02) .
