Abstract: Objectives. To report adverse event rates after rotational atherectomy (RA) with contemporary drug-eluting stent (DES) implantation and compare RA to cutting balloon (CB) angioplasty and balloon-only angioplasty (BA) in the all-comers ADAPT-DES trial. Background. Percutaneous coronary intervention (PCI) of calcified lesions is increasingly common and is associated with a high risk of adverse events. RA can ablate calcified plaque and facilitate stent delivery; however, in conjunction with first-generation DES, RA was not superior to BA alone in regard to adverse events. Methods. ADAPT-DES enrolled 8582 patients who underwent successful PCI with DES, of whom 2644 had calcified target lesions and were included in this study. Among these patients, 1610 had exclusively second-generation DESs implanted. We present Kaplan-Meier rates for the primary endpoint of target-vessel failure (TVF; defined as death, myocardial infarction, or target-vessel revascularization) as well as its components, for patients who had RA, CB, or BA. Results. Among the 2644 patients, RA and CB were used in 150 patients (5.7%) and 53 patients (2.0%), respectively. TVF occurred in 20.8% of the RA patients, 24.1% of the CB patients, and 17.9% of the BA patients over the 2-year study period (P=.41) and was primarily driven by target-vessel revascularization (13.8%, 11.4%, and 10.2%, respectively). RA patients with acute coronary syndromes had nominally higher 2-year TVF rates than RA patients with stable coronary artery disease. Conclusion. TVF is common after contemporary DES-PCI of calcified lesions, independent of the technique used to prepare the vessel for stent implantation. Better treatment strategies are needed.
J INVASIVE CARDIOL 2017;29(11):378-386. Epub 2017 June 15.
Key words: major adverse cardiac events, PCI, rotational atherectomy, second-generation drug-eluting stent
Percutaneous coronary intervention (PCI) of calcified lesions is common and is associated with an increased risk of death, myocardial infarction, stent thrombosis, and the need for revascularization.1-6 Rotational atherectomy (RA) can ablate calcified plaques, facilitate stent delivery and expansion, and allow for increased procedural success.7,8 Despite similar clinical endpoints, an increase in procedural success rate, and a decrease in major complications such as stent loss, the ROTAXUS (Atherectomy Prior to Taxus Stent Treatment for Complex Native Coronary Artery Disease) trial failed to demonstrate the superiority of RA compared with standard balloon dilation in regard to the primary endpoint of 9-month late loss. In fact, RA was associated with a small but significant increase in late loss (0.31 mm for balloon only vs 0.44 mm for RA; P=.04).9,10 Limitations of the ROTAXUS trial include the use of first-generation drug-eluting stents (DESs) and the small number of patients. Currently, there is a paucity of data available on the use of RA before the implantation of contemporary DESs. Also, there is a lack of contemporary data comparing the use of other devices, such as cutting balloon (CB), with RA in the treatment of severely calcified lesions. Therefore, we present the 2-year rates of adverse ischemic events after RA, CB angioplasty, and balloon-only angioplasty for the preparation of calcified lesions before DES implantation. Finally, we compared our results to findings of other important studies.11-13
Study population. ADAPT-DES was a prospective, multicenter, observational study specifically designed to determine the association between platelet reactivity on clopidogrel and stent thrombosis after successful DES implantation. The design and primary results of ADAPT-DES have been previously reported.14 Briefly, a total of 8582 “all comers” were prospectively enrolled at 11 sites in the United States and Germany. All patients who were successfully treated with ≥1 DES and who were adequately loaded with aspirin and clopidogrel were eligible for enrollment, regardless of clinical presentation or procedural complexity. The only major exclusion criteria were any intraprocedural or periprocedural major complication or if bypass surgery was planned after PCI. Platelet reactivity on aspirin and clopidogrel was assessed using the VerifyNow aspirin, P2Y12, and IIb/IIIa assays (Accumetrics) after an adequate loading period to ensure full antiplatelet effect. After PCI, patients were treated with aspirin indefinitely, and clopidogrel was recommended for at least 1 year. All other treatments were as per standard of care. Clinical follow-up was scheduled at 30 days, 1 year, and 2 years. An independent clinical events committee blinded to VerifyNow results adjudicated ischemic events using original source documents. The institutional review board at each participating center approved the study, and all eligible patients signed written informed consent prior to enrollment.
All patients included in the ADAPT-DES registry who had moderate or severe coronary calcification as reported in the case report form by the operator and who received only second-generation DESs were included in this study. We compared three groups: (1) patients in whom RA was used for lesion preparation; (2) patients in whom no RA was used but a CB was used; and (3) patients who had balloon-only angioplasty (Figure 1).
Study objectives and definitions. The primary objective of this study was to describe the rate of target-vessel failure (TVF, defined as any death, myocardial infarction, or target-vessel revascularization [TVR]) for a contemporary cohort of patients who underwent RA, CB angioplasty, or balloon-only angioplasty before DES implantation for severely calcified lesions. The secondary objective of the study was to describe and compare separately the major adverse cardiac events (MACE, defined as any cardiac death, myocardial infarction, or stent thrombosis), death, myocardial infarction, stent thrombosis, and TVR for patients who underwent RA, CB angioplasty, or balloon-only angioplasty. We also present the adverse event rates for the subgroup of patients who had exclusively second-generation DESs implanted.
We defined stent thrombosis as any target lesion with definite or probable stent thrombosis according to the Academic Research Consortium definition.15 Myocardial infarction was defined according to the Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) criteria.14,16
Statistical analysis. Descriptive statistics are presented as mean ± standard deviation and were compared with the Student’s t-test; categorical variables are reported as percentages and were tested with the Chi-squared test. We fitted Kaplan-Meier curves and compared groups by the log-rank test. We estimated hazard ratios (HRs) associated with RA use using the Cox model17 and adjusted HRs using propensity scores. The consistency of the effect of RA vs balloon-only angioplasty across DES generation was assessed by including an indicator variable for the exclusive use of second-generation DESs in the model. The propensity score was constructed from a logistic regression model indicating whether the patient had RA. The multivariable logistic regression models included predictors entered as continuous variables (age and lesion length) and as binary variables indicating the presence of a characteristic or disease (diabetes, male sex, previous coronary artery bypass graft [CABG] surgery, acute coronary syndromes [ACS] or stable coronary artery disease [CAD] for clinical presentation, smoking, renal insufficiency [creatinine clearance <60 mL/min], multivessel CAD, history of congestive heart failure, history of peripheral arterial disease, and treatment at a hospital in the United States). All tests were 2-sided, and P-values <.05 were considered statistically significant. All statistical analyses were performed in SAS version 9.4 (SAS Institute), and all statistical definitions and models were specified in advance.
Clinical and procedural characteristics. From the entire cohort of 8582 patients, a total of 2644 (30.8%) underwent PCI of at least 1 calcified lesion. Among these, 2441 (92.3%) underwent balloon-only angioplasty, 150 (5.7%) underwent RA, and 53 (2.0%) underwent CB angioplasty before stent implantation. When restricted to the 1610 patients receiving exclusively second-generation DESs, 1476 patients (91.7%), 100 patients (6.2%), and 34 patients (2.1%) underwent balloon-only angioplasty, RA, and CB angioplasty before stent implantation, respectively (Figure 1).
Baseline and procedural characteristics are presented in Tables 1 and 2. Compared to patients who had balloon-only angioplasty, patients undergoing RA or CB angioplasty were more likely to have had previous CABG or PCI and had lower hemoglobin level and lower creatinine clearance. Compared with the two other groups, patients undergoing RA were older, were less likely to be treated by radial approach, and had longer lesions, with more stents implanted. Compared to patients who had balloon-only angioplasty, patients undergoing RA or CB angioplasty were more likely to receive dual-antiplatelet therapy at 1 and 2 years post PCI, whereas the use of other drugs was similar in the three groups (Table 3).
One and two-year clinical outcomes. Kaplan-Meier failure rates for the composite endpoint of TVF and other adverse ischemic events are presented and compared in Figure 2 and Table 4. At 2 years, RA and CB angioplasty showed numerically higher TVF rates compared with balloon-only angioplasty (20.8% for RA vs 24.1% for CB angioplasty vs 17.9% for balloon-only angioplasty; P=.41) (Figure 2A). MACE and TVR rates were similar in the three groups (Figures 2B and 2C). Event rates were similar when the study population was restricted to patients who were treated exclusively with second-generation DESs (Supplemental Figure 1; see end of article), and there was no statistical interaction between the use of RA vs balloon-only angioplasty and DES generation (Pinteraction=.38).
Among patients who had RA, the adverse outcome rates were numerically higher for patients who presented with ACS than patients who presented with stable CAD (Figure 3), a finding that was also consistent when the study population was restricted to patients who received exclusively second-generation DESs (Supplemental Figure 2; see end of article).
The propensity-score adjusted HR for TVF associated with RA use was 1.04 (95% confidence interval [CI], 0.70-1.53; P=.86). The propensity-adjusted HR for MACE associated with RA use was 0.72 (95% CI, 0.39 -1.34; P=.72).
To the best of our knowledge, this analysis of patients who underwent PCI of calcified lesions is the most contemporary report on outcomes after RA, CB angioplasty, or balloon angioplasty for lesion preparation followed by contemporary DES implantation. The main results of our study are as follows: (1) the presence of calcification at the targeted lesion is frequent, with one-third of the patients undergoing PCI having detectable calcification at the PCI site as assessed by clinician operators; (2) adjunctive devices to better prepare calcified lesions before stent implantation were rarely used; (3) even with the use of second-generation DES implantation, TVF occurs in an important proportion of these patients, with approximately 1 in 5 patients experiencing adverse events within 2 years; and (4) patients with ACS may have a higher risk for adverse events after RA than patients with stable CAD.
Calcified lesions were frequent in the ADAPT-DES registry, with 31% of patients identified by operators as having calcification at the PCI site. This finding is similar to previous large studies published among all-comer patients showing ~30% of patients undergoing PCI having moderate or severe calcification at the target-lesion site as assessed by an independent angiographic core laboratory.1,18 In the current study, RA was used in 5.7% of the cases in which calcified lesions were identified, which mirrored data from the large pooled analysis of the ACUITY and HORIZONS-AMI trials, which found severe calcium present in 5.9% of target lesions.1 CB angioplasty was used in only 2% of the cases in which calcium was present. While CB angioplasty has proven useful for other types of resistant lesions, such as restenosis,19 its role in heavily calcified lesions remains to be better defined. Whether the use of CB angioplasty or RA in patients with less severe (ie, moderate) calcified lesions would be beneficial remains to be explored. The ongoing PREPARE-CALC (Comparison of Strategies to PREPARE Severely CALCified Coronary Lesions Trial; NCT02502851) will provide meaningful insight in regard to this question.
The current report shows that patients with calcified lesions who underwent second-generation DES-PCI using contemporary techniques are still at a considerable risk of adverse ischemic events. This is consistent with previous reports and is partly explained by a high overall coronary risk profile of these patients.1-6 Another contributing factor to the increased risk associated with calcified lesions is the difficulty in achieving optimal procedural results. Coronary calcification complicates stent delivery and may damage the drug polymer and/or stent platform.20 Incomplete stent expansion or stent deformation/fracture may result in an increased risk of subsequent ischemic events. A well-prepared lesion facilitates stent delivery and increases the likelihood of procedural success and favorable longer-term outcomes.21
Coronary atherectomy devices were developed to better prepare calcified lesions for stent implantation. That being said, ischemic event rates remained high at 2 years, with 34.3% of patients in the ROTAXUS trial experiencing ischemic adverse events and 16.7% having TVR.9,10 In our study, event rates were lower, with adverse events occurring in 22.1% of the patients and TVR occurring in 15.2% when RA was used. These differences may be explained by several factors: (1) difference in risk profile of the study population; (2) difference in DES platforms used (first-generation DES vs second-generation DES); (3) difference in lesion calcification severity; and (4) inclusion in the current study of only successful PCIs.
In contrast to ROTAXUS, which included only patients with stable CAD, approximately one-half of the patients who underwent RA for calcified lesions in ADAPT-DES presented with ACS. In the ADAPT-DES study, event rates were higher for patients with ACS than for patients with stable CAD, a finding that is consistent with a previous study demonstrating that patients presenting with ACS (either ST-segment elevation myocardial infarction or non-ST segment elevation myocardial infarction) have a poor prognosis when moderately to severely calcified lesions are present.1 Similar to the ROTAXUS trial, the ORBIT II (Evaluate the Safety and Efficacy of OAS in Treating Severely Calcified Coronary Lesions) single-arm prospective registry, which demonstrated lower adverse event rates compared with ROTAXUS, included only patients with stable CAD who had a considerably lower coronary risk profile than the ADAPT-DES cohort despite having a high proportion (>90%) of patients with an angiographically confirmed presence of severe calcification.12 Table 5 summarizes the major findings from these important studies.
The high TVR rates at 2 years among the subpopulation that had successful PCI with second-generation DESs underscore the need for better strategies to optimize the treatment of calcified lesions. Calcified lesions are increasingly common targets of contemporary PCI, as complex lesions are more frequently being attempted.22 While the purist interpretation of the ROTAXUS trial deems it a “negative” study based on the statistically significant increase in 9-month late loss (by 0.13 mm, from 0.31 mm to 0.44 mm; P=.04) with no difference in 9-month risk of death, TVR, or stent thrombosis9,10 compared with lesion preparation with balloon-only angioplasty, the down side of not using appropriate lesion preparation with atherectomy could arguably be seen as detrimental. Balloon-only angioplasty was associated with initial strategy failure (defined as the need to cross over to atherectomy) in >15% of the patients among the entire study population (moderate to severe calcification) and up to 30% when restricted to patients with severe coronary calcification. Therefore, one needs to weigh the increased risk of late loss with the increased likelihood of procedural and strategy success rates. Resources and cost-effectiveness of each strategy also need to be considered when choosing the best first-line strategy. Whether a novel atherectomy device leads to better outcomes still remains to be established, since the lack of much-needed head-to-head comparison studies between different devices makes any conclusion speculative.11,12 To this end, a mechanistic and intracoronary imaging study would also be useful to better understand the different mechanisms of action for different strategies.13 The ongoing PREPARE-CALC and ECLIPSE (Evaluation of Treatment Strategies for Severe CaLcifIc Coronary Arteries: Orbital Atherectomy vs. Conventional Angioplasty Prior to Implantation of Drug Eluting StEnts) trials will hopefully clarify some of these important questions.
Study limitations. First, this is a post hoc analysis from the ADAPT-DES study, and as such, it should be considered hypothesis-generating rather than definitive. Second, the relatively low numbers of patients increases the risk of committing a type II statistical error; however, this is one of the largest contemporary cohorts of patients treated with RA and contemporary DES, particularly second-generation DESs, due to calcified lesions. Third, ADAPT-DES enrolled patients who had undergone successful PCI. The inclusion of patients with an unsuccessful procedure would have most likely increased adverse events rates, potentially more importantly in the balloon-only angioplasty group. On the other hand, ADAPT-DES is largely an all-comer prospective study with considerably more liberal inclusion and exclusion criteria than other prospective studies of patients with calcified lesions who undergo PCI. Finally, a proportion of RA use might have occurred after failure of the balloon-only angioplasty strategy; therefore, patients within the balloon-only angioplasty group most likely represent patients with less complex coronary calcification successfully treated with balloon-only angioplasty before DES implantation. This possibility once again supports the need for a well-designed head-to-head randomized trial if such biases are to be avoided.
Adverse ischemic events are common after contemporary PCI of calcified lesions regardless of whether RA is used. Improvements in these techniques are necessary to improve outcomes in this patient cohort.
Supplemental Figures 1 and 2
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From the 1Cardiovascular Research Foundation, New York, New York; 2NewYork-Presbyterian Hospital/Columbia University Medical Center, New York, New York; 3Helios Amper-Klinikum, Dachau, Germany; 4Shaare Zedek Medical Center, Jerusalem, Israel; 5LeBauer-Brodie Center for Cardiovascular Research and Education/Cone Health, Greensboro, North Carolina; 6Minneapolis Heart Institute Foundation at Abbott Northwestern Hospital, Minneapolis, Minnesota; 7Cedars-Sinai Heart Institute, Los Angeles, California; 8Icahn School of Medicine at Mount Sinai, New York, New York; 9Hôpital du Sacré-Coeur de Montréal, Montréal, Québec, Canada; and 10Gagnon Cardiovascular Institute, Morristown Medical Center, Morristown, New Jersey.
Disclosures: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Maehara reports grant support from Boston Scientific, St. Jude Medical; consultant fees from Boston Scientific, OCT Medical Imaging; speaker fees from St. Jude Medical. Dr Witzenbichler reports consultant fees from Volcano. Dr Weisz reports advisory board fees from AngioSlide, AstraZeneca, Corindus, Filterlex, M.I. Medical Incentive, Medtronic, Medivizor, TriSol, and Vectorious. Dr Stuckey reports advisory board fees from Boston Scientific; speaker honoraria from Boston Scientific, Eli Lilly/Daiichi-Sankyo. Dr Henry reports scientific advisory board fees from Abbott Vascular, Boston Scientific, and The Medicines Company; steering committee for TRANSLATE (sponsored by Eli Lilly and Daiichi Sankyo). Dr Mehran reports institutional research grant support from Eli Lilly/Daiichi-Sankyo, Inc, Bristol-Myers Squibb, AstraZeneca, The Medicines Company, OrbusNeich, Bayer, CSL Behring, Abbott Laboratories, Watermark Research Partners, Novartis Pharmaceuticals, Medtronic, AUM Cardiovascular, Inc, Beth Israel Deaconess Medical Center; executive committee for Janssen Pharmaceuticals, Osprey Medical, Inc; data safety monitoring board for Watermark Research Partners; consulting fees from Medscape, The Medicines Company, Boston Scientific, Merck & Company, Cardiovascular Systems, Inc (CSI), Sanofi USA, Shanghai BraccoSine Pharmaceutical Corp, AstraZeneca; equity in Claret Medical, Inc, Elixir Medical Corporation. Dr Kirtane reports institutional research grants to Columbia University from Boston Scientific, Medtronic, Abbott Vascular, Abiomed, St. Jude Medical, Vascular Dynamics, and Eli Lilly. Dr Généreux reports speaker’s fees from Abbott Vascular and Edwards Lifesciences; consulting fees from CSI, PiCardia, Soundbite Medical Solutions; institutional research grants from Boston Scientific, Tryton Medical.
Manuscript submitted February 1, 2017 and accepted February 17, 2017.
Address for correspondence: Philippe Généreux, MD, Cardiovascular Research Foundation, 1700 Broadway, 8th Floor, New York, NY 10017. Email: firstname.lastname@example.org