Revascularization Strategies for Calcified Lesions in Patients Presenting With Acute Coronary Syndromes (From the Acute Catheterization and Urgent Intervention Triage StrategY [ACUITY] Trial)

Abstract: Background. Revascularization of calcified coronary lesions has been shown to be associated with suboptimal outcomes. The optimal revascularization strategy for calcified lesions in patients presenting with non-ST segment elevation acute coronary syndromes (NSTEACS) has yet to be defined. Methods. Outcomes in patients presenting with NSTEACS and moderately or severely calcified target lesions in native coronary vessels, as assessed by an independent angiographic core lab, were examined according to revascularization strategy (percutaneous coronary intervention [PCI] vs coronary artery bypass graft [CABG] surgery) from the large-scale, prospective ACUITY trial. Propensity-adjusted multivariable analysis was used to identify the independent predictors of events at 30 days. Results. Of 1315 NSTEACS patients with moderately and severely calcified lesions in whom revascularization was performed, a total of 334 (25%) and 981 (75%) underwent CABG and PCI, respectively. CABG patients had more severe baseline comorbidities and coronary artery disease. By propensity-adjusted multivariable analysis, the CABG group had higher 30-day rates of reinfarction, composite death or reinfarction, major bleeding, and thrombocytopenia. Conclusions. In this large-scale study of patients presenting for NSTEACS, 30-day adverse events were more frequent after revascularization of calcified coronary lesions with CABG rather than PCI. Further studies are warranted to evaluate means of improving early safety outcomes in this high-risk patient group with complex coronary disease.

J INVASIVE CARDIOL 2016;28(1):10-16

Key words: coronary artery bypass graft surgery, percutaneous coronary intervention, acute coronary syndromes, revascularization, coronary artery calcification

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Coronary calcification is common in patients presenting with acute coronary syndromes (ACS), with rates as high as 45%.^1-4 Revascularization of calcified lesions in ACS patients has been suggested to be associated with high rates of adverse events, whether with percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) surgery.^2-16 However, this space remains understudied, and the optimum revascularization strategy in patients with calcified lesions remains unclear. Therefore, we sought to compare outcomes by revascularization strategy (PCI vs CABG) for patients presenting for non-ST segment elevation acute coronary syndromes (NSTEACS) with calcified lesions in the large-scale Acute Catheterization and Urgent Intervention (ACUITY) trial.¹⁷

Methods

Study protocol. The design and primary results of the ACUITY trial have been previously described in detail.^17,18 Briefly, ACUITY was a multicenter, prospective, randomized trial of 13,819 moderate-risk to high-risk patients presenting with NSTEACS who underwent treatment with an early invasive strategy. Patients ≥18 years with symptoms of unstable angina for at least 10 minutes up to 24 hours were eligible to be enrolled if 1 or more of the following criteria were met: (1) new ST-segment depression or transient elevation of at least 1 mm; (2) troponin I or T or creatinine kinase-MB elevation; (3) known coronary artery disease (CAD); or (4) positive for all four Thrombolysis in Myocardial Infarction (TIMI) unstable angina risk criteria.¹⁹ Exclusion criteria included acute ST-segment elevation myocardial infarction or shock; bleeding diathesis or major bleed within 2 weeks prior to presentation; thrombocytopenia; creatinine clearance <30 mL/min; recent administration of warfarin, abciximab, fibrinolytics, bivalirudin, two or more doses of low-molecular-weight heparin, or fondaparinux; and allergy to study drugs or iodinated contrast that could not be controlled with premedication.

Patients were randomly assigned to heparin (unfractionated or low-molecular-weight) plus a glycoprotein IIb/IIIa inhibitor, bivalirudin plus a glycoprotein IIb/IIIa inhibitor, or bivalirudin monotherapy prior to coronary angiography, which was performed within 72 hours of randomization. Triage between revascularization strategy (PCI or CABG) and medical therapy was per local investigator discretion. Similarly, stent choice (bare-metal vs drug-eluting) was left to individual operators. Dual-antiplatelet therapy with aspirin and clopidogrel was recommended for at least 1 year. All major adverse events were adjudicated by an independent clinical events committee blinded to treatment assignment. The study was approved by the institutional review board or ethics committee at each participating center, and all patients signed a written informed consent.

Objectives, patient population, and angiographic analysis. The primary objective of this study was to assess short-term and long-term outcomes by revascularization strategy (PCI vs CABG) for patients presenting for NSTEACS with moderate-to-severe coronary lesion calcification. As determined by an independent angiographic core laboratory blinded to randomization assignment and clinical outcomes (Cardiovascular Research Foundation, New York, New York), moderate calcification was defined as radiopaque densities noted only during the cardiac cycle and typically involving only one side of the vascular wall, while severe calcification was defined as radiopaque densities noted without cardiac motion prior to contrast injection and generally involving both sides of the arterial wall. Intercore and intracore lab variability testing was performed, and kappa values were found to be 0.83 and 0.89, respectively. Patients were considered to have moderate or severe coronary calcification if at least one treated targeted lesion was identified as such.

Endpoint definitions and statistical analysis. The definitions for major adverse cardiovascular event (MACE) and net adverse clinical event (NACE) have been previously reported. Thirty-day and 1-year MACE rates and its individual components, including death, myocardial infarction (MI), and ischemia-driven target-vessel revascularization (TVR) were determined. Additionally, 30-day rates of NACE, defined as any MACE or non-CABG major bleeding, were determined. As per the ACUITY trial design, non-CABG major bleeding was defined as intracranial or intraocular bleeding, access-site hemorrhage requiring intervention, hematoma ≥5 cm in diameter, reduction in hemoglobin levels ≥4 g/dL without an overt bleeding source or ≥3 g/dL with an overt source, reoperation for bleeding, or any blood product transfusion. Additionally, we defined total major bleeding as any major bleed attributable to PCI or CABG within the first 30 days of revascularization.

Continuous data are presented as mean ± standard deviation and were compared using the Student’s t-test. Binary variables are presented as percentages and were compared between groups with the chi-square test. Thirty-day and 1-year event rates were estimated using Kaplan-Meier methodology and compared using the log-rank test. A propensity score was constructed for revascularization strategy (PCI vs CABG) accounting for variables based on both clinical importance and statistical significance. The variables included in the propensity model included age, sex, diabetes, hyperlipidemia, current smoking status, previous PCI, renal insufficiency (creatinine clearance <60 mL/min), baseline platelet count, baseline cardiac biomarker elevation, ST-segment deviation ≥1 mm, left main disease, number of lesions per patient, preprocedural thienopyridine administration, randomized to bivalirudin monotherapy. Propensity-adjusted multivariable Cox regression was performed to assess the association between revascularization strategy and 30-day outcomes, including all-cause death, reinfarction, all-cause death or reinfarction, total major bleeding, thrombocytopenia, MACE, and NACE, as well as 1-year outcomes, including all-cause death, reinfarction, all-cause death or reinfarction, and MACE. P-values <.05 were considered to be statistically significant. Statistical analyses were performed using SAS version 9.2 (SAS Institute, Inc).

Results

After excluding patients triaged to medical therapy and those with a history of CABG, we proceeded with our analysis with the remaining 1315 patients who presented for NSTEACS with moderate-to-severe coronary calcification in the ACUITY trial. Of these patients, 981 were triaged to PCI and 334 to CABG.

Baseline clinical characteristics are shown in Table 1. Patients who received PCI were more likely to be smokers and have previous PCI. Patients in the CABG group were more likely to be male, to have lower baseline creatinine clearance, and to have higher rates of baseline cardiac biomarker positivity and ST-segment deviation ≥1 mm.

Angiographic characteristics, procedure strategy, and medications are presented in Table 2. Patients who underwent CABG were more likely to have multivessel disease, more diseased vessels per patient, more lesions per patient, and worse lesions with TIMI 0/1 flow. Although the PCI group was more likely to receive preprocedural thienopyridines, there were no differences in antithrombotic regimen at randomization by revascularization strategy.

Unadjusted rates of adverse events at 30 days and 1 year, stratified by revascularization strategy, are presented in Figure 1. Comparisons after propensity-adjusted multivariable analysis for clinical and procedural variables at 30 days and 1 year are presented in Table 3. At 30 days, rates of reinfarction (16.5% vs 9.1%; P=.02), all-cause death or reinfarction (17.7% vs 9.7%; P=.02), total major bleeding (54.2% vs 9.3%; P<.001), and thrombocytopenia (59.6% vs 9.1%; P<.001) were significantly greater in the CABG group; both PCI and CABG had no differences in rates of MACE (18.0% vs 12.7%; P=.27) and NACE (21.0% vs 18.2%; P=.85). At 1 year, there was no significant difference in all-cause death (5.5% vs 4.4%; P=.77), reinfarction (17.4% vs 12.0%; P=.15), all-cause death or reinfarction (21.6% vs 14.5%; P=.08), and MACE (23.4% vs 23.1%; P=.78) between CABG and PCI groups. 

Discussion

To the best of our knowledge, this study, drawn from a cohort of 1315 patients enrolled in the large-scale ACUITY trial is the first to evaluate outcomes by revascularization strategy for NSTEACS patients with moderate-to-severe calcified coronary lesions. The principal findings of this study are as follows: (1) 30-day unadjusted rates of reinfarction, death or reinfarction, MACE, total major bleeding, and thrombocytopenia were higher in the CABG group; (2) 1-year unadjusted rates of reinfarction and death or reinfarction were higher in the CABG group; (3) CABG was associated with greater rates of reinfarction, death or reinfarction, total major bleeding, and thrombocytopenia at 30 days after propensity adjustment; and (4) despite being numerically higher in the CABG group, there were no statistically significant differences in adverse event rates by revascularization strategy at 1 year after propensity adjustment.

The prevalence of moderate-to-severe coronary lesion calcification in patients who underwent revascularization for NSTEACS in the ACUITY trial was approximately 30%, and nearly 75% of these patients received PCI rather than CABG. According to the 2011 American College of Cardiology/American Heart Association guidelines, the selection of PCI or CABG as the means of revascularization in a patient with ACS should generally be used on the same considerations as those without ACS (class I, level B).²⁰ However, as there have been a limited number of studies comparing revascularization strategies in calcified lesions, the optimal approach to revascularization strategy for similar extent of CAD in such patients is yet to be defined.

Interestingly, 30-day rates of reinfarction were high in both the PCI and CABG groups, and these rates were higher among CABG patients, even after propensity adjustment. As ACUITY enrolled higher-risk patients, these rates understandably contradict those observed in patients who received PCI and CABG in the all-comer, large-scale, randomized controlled SYNTAX trial.²¹ Several reasons can explain the higher reinfarction rates after revascularization in ACS patients with moderate-to-severely calcified lesions. First, the presence, extent, and severity of coronary calcification strongly correlate with atherosclerotic burden and predict future coronary events.^22,23 Second, calcification in atherosclerotic lesions has been suggested to contribute to plaque instability.²⁴ Finally, some reports even found an association between thrombin generation and severity of coronary calcification, making these patients hypercoagulable.^25,26

The risk of coronary events is known to increase further with PCI in this high-risk patient population due to manipulation of calcified coronary lesion. Non-compliant calcified lesions often require varying techniques (cutting balloon, Angiosculpt, rotational or orbital atherectomy) and higher-pressure balloon dilation, increasing the risk of dissection, perforation, thrombi formation, and reinfarction.²⁴ Calcified lesions are associated with particulate embolization during PCI, increasing the risk of periprocedural myonecrosis. Stent underexpansion, asymmetric expansion, and malapposition are also more common in calcified lesions and are known to be associated with stent thrombosis and reinfarction.^6,27 Although the advent of drug-eluting stent (DES) implantation was able to reduce rates of restenosis, late and very late stent thrombosis remain a challenge.²⁸

Severe coronary calcification poses also the risk of incomplete revascularization during PCI, leaving untreated lesions to pose the risk of future coronary events.^29-31 The use of plaque modifying devices, such as rotational atherectomy, has been shown to improve stent delivery and procedural success;³² however, these devices may increase the risk for recurrent ischemic events (reinfarction, restenosis) due to microparticle embolization, thermal injury, increased platelet activity, and vessel perforation.²⁴ It remains to be seen whether novel devices such as orbital atherectomy catheters^33,34 can provide a safer alternative to reduce the risk of recurrent ischemic events after PCI in calcified lesions in the ACS population.

In terms of adjunctive medical treatment, dual-antiplatelet therapy is recommended in ACS patients after PCI for secondary prevention.²⁰ However, calcification may reduce the efficacy of antiplatelet agents and may increase the risk of thrombotic events due to high platelet reactivity.³⁵ More importantly, these patients frequently share bleeding risk factors (renal insufficiency, old age, small weight, peripheral vascular disease), increasing the risk for future adverse events.¹⁵ Novel therapies are needed to help prevent adverse events in patients with such lesions.

Outcomes in patients presenting with ACS after revascularization with CABG in calcified lesions have not been well studied. In the present study, the CABG group experienced higher reinfarction rates compared with the PCI group at 30 days. This tends to contradict the expectation that CABG can be equally effective in both calcified and non-calcified lesions, as CABG allows restoration of coronary perfusion through alternate conduits that bypass the diseased segments. However, we have previously demonstrated that 30-day and 1-year reinfarction rates after CABG were higher in patients with severely calcified lesions compared with those who had non-calcified lesions.³ Coronary calcium may pose a technical challenge during cardiac surgery, increasing the likelihood for suboptimal anastomosis, leading to incomplete revascularization and future coronary events.³⁶ Patients with coronary calcification are also more likely to have aortic calcification, increasing the risk of perioperative neurological events.^37,38

The higher rates of reinfarction after CABG compared with PCI in our study are likely due to a number of factors. With regard to unadjusted rates of adverse events, patients who were triaged to CABG (compared with PCI) generally had more risk factors and greater coronary disease burden, increasing their vulnerability for coronary events after revascularization. However, even after propensity-adjusted multivariable analysis, accounting for a number of baseline clinical characteristics and procedural variables, patients with CABG still experienced higher adverse event rates. Although the possibility exists for unmeasured confounders, this may speak to the fact that CABG is inherently a more invasive and higher-risk procedure, with increased adverse event rates in sicker patients (ie, patients with diffuse coronary and arterial calcification). Additionally, it has been suggested that lesion progression and calcification are more likely to develop proximal to patent coronary grafts after CABG compared with native vessels,³⁹ thus likely increasing the risk for adverse events. Moreover, the release of systemic inflammatory mediators is likely greater after CABG compared with PCI, which may contribute to the risk for progression of atherosclerosis and future coronary events.⁴⁰

The high rates of thrombocytopenia and bleeding events, especially in the CABG group, can be explained by several factors. ACS patients usually are at high risk for bleeding from low platelet count, platelet dysfunction, and hypocoagulable condition due to routine use of antithrombotic agents with an early invasive angiography for risk stratification and revascularization.⁴¹ The presence of calcification has previously been suggested to increase bleeding risk.¹⁵ Although this may be due to a number of mechanisms, two likely ones include impaired vessel hemostasis and shared risk factors, such as chronic kidney disease, that predispose to bleeding events.¹⁵ Furthermore, calcification at coronary lesions may increase the likelihood for technical difficulties during PCI, leading to iatrogenic bleeding events. The invasive nature of CABG and more frequent occurrence of low platelet count, platelet dysfunction, and alteration in coagulation mechanisms during CABG all likely contribute to the increased bleeding observed in these patients.^42-44 The high rates of thrombocytopenia and bleeding transfusions in CABG patients also likely contributed to the risk for reinfarction, as has been previously suggested.^45,46

Study limitations. Our study has limitations that should be acknowledged. As an observational post hoc analysis, our findings do not prove causality but may identify correlations. Despite propensity adjustment, the potential remains for unmeasured confounders. The results of the study do not necessarily apply to patients presenting with ST-segment elevation myocardial infarction or stable ischemic disease, as this study focused on patients presenting with NSTEACS. Finally, as patients were included based on angiographic core laboratory assessment of moderate-to-severe target-lesion calcification, interobserver variability may have influenced these findings.⁴⁷

Conclusion

In this large-scale study of NSTEACS patients, 30-day adverse events were more frequent after revascularization of calcified coronary lesions with CABG vs PCI. Further studies are warranted to evaluate means of improving early safety outcomes in this high-risk patient group with complex coronary disease.

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________________________________________________

From the ¹Cardiovascular Research Foundation, New York, New York; ²University of Illinois at Chicago, Chicago, Illinois; ³NewYork-Presbyterian Hospital/Columbia University Medical Center, New York, New York; ⁴Hôpital du Sacré-Coeur de Montréal, Université de Montréal, Montréal, Canada; ⁵Shaare Zedek Medical Center, Jerusalem, Israel; and ⁶Icahn School of Medicine at Mount Sinai, New York, New York.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Tarigopula is a postdoctoral research fellow under a National Institute of Health T-32 grant. Dr Genereaux reports institutional research support, consultant and speaker fees from Cardiovascular Systems, Inc; grant from Boston Scientific. Dr Madhavan was supported by a grant from the Doris Duke Charitable Foundation to Columbia University to fund a clinical research fellowship. Dr Mehran reports grants from Sanofi-Aventis, The Medicines Company, Abbott Vascular, Boston Scientific, Bristol-Myers Squibb, and Astra-Zeneca; consultant/advisory board for Eli Lilly and Daiichi Sankyo. Dr Stone reports a grant to his institution for CECs and core laboratory work; consultant fees to The Medicines Company, Eli Lilly-Daiichi Sankyo, Boston Scientific, Osprey, Cardiovascular Systems, Inc, InspireMD, InfraReDx, Velomedix, Vascular Dynamics, Miracor, TherOx, Reva, and Matrizyme; equity/options in Caliber, Biostar family of funds, MedFocus family of funds, Guided Delivery Systems, Micardia, Vascular Nanotransfer Technologies, Cagent, and Qool Therapeutics. The remaining authors report no conflicts of interest regarding the content herein.

Manuscript submitted April 14, 2015, provisional acceptance given May 26, 2015, final version accepted June 23, 2015.

Address for correspondence: Gregg W. Stone, MD, Columbia University Medical Center, Cardiovascular Research Foundation, 111 E. 59th St., 11th Floor, New York, NY 10022. Email: gs2184@columbia.edu