Impact of Impaired Renal Function in Patients With Severely Calcified Coronary Lesions Treated With Orbital Atherectomy

Abstract: Objectives. We evaluated the clinical outcomes of patients with chronic kidney disease (CKD) who underwent orbital atherectomy for severe coronary artery calcification (CAC) prior to stent implantation. Background. Percutaneous coronary intervention (PCI) of lesions with severe CAC is associated with increased rates of adverse clinical events. Patients with CKD are at increased risk for atherosclerotic cardiovascular disease, including vascular calcification, and have worse outcomes after PCI. Methods. Of the 456 consecutive real-world patients in our retrospective multicenter registry with severe CAC who underwent orbital atherectomy, 88 patients (19.3%) had CKD (creatinine ≥1.5 mg/dL). The primary endpoint was the 30-day rate of major adverse cardiac and cerebrovascular event (MACCE), defined as death, myocardial infarction (MI), target-vessel revascularization (TVR), and stroke. Results. The CKD group had a higher prevalence of diabetes mellitus and hypertension as well as a lower mean left ventricular ejection fraction. The primary endpoint was similar in the CKD and non-CKD groups (3.4% vs 1.9%; P=.40), as were 30-day rates of death (2.2% vs 1.1%; P=.30), MI (1.1% vs 0.5%; P=.40), TVR (0% vs 0%; P>.99), and stroke (0% vs 0.3%; P>.99). Angiographic complications and stent thrombosis rates were low and did not differ between the two groups. Conclusion. Despite higher-risk baseline characteristics, patients with CKD had no significant differences in MACCE. Orbital atherectomy represents a reasonable treatment strategy for the treatment of severe CAC in patients with CKD. A prospective randomized trial with long-term follow-up is needed to identify the optimal treatment for these patients. 

J INVASIVE CARDIOL 2017;29(6):203-206. Epub 2017 Jan 15.

Key words: atherectomy, calcification, percutaneous coronary intervention, coronary artery disease, kidney disease

Coronary artery calcification (CAC) is observed in approximately 38% of people during angiography and 73% with intravascular ultrasound (IVUS).¹ Severe CAC increases the complexity of percutaneous coronary intervention (PCI) due to difficulty advancing balloons and stents to the lesion, potential damage to the polymer and stent during advancement, and inability to fully expand the stent, leading to increased rates of adverse cardiac events including death, myocardial infarction (MI), and target-vessel revascularization (TVR).^2,3 Clinical outcomes are worse after PCI in patients with severe CAC. Patients with severe CAC are commonly excluded from clinical trials given the high adverse event rates after PCI. 

The Centers for Disease Control and Prevention reported that in 2014 more than 10% of adults in the United States – more than 20 million people – have chronic kidney disease (CKD).⁴ Patients with CKD are at increased risk for atherosclerotic cardiovascular disease, including MI and stroke.⁵ Vascular calcification is commonly observed in patients with CKD. Patients with CKD who undergo PCI have worse clinical outcomes including higher rates of death, MI, TVR, and stroke.^6-9 

Modification of calcified plaque can facilitate stent delivery and optimal stent expansion.² Coronary atherectomy modifies plaque by changing the compliance of heavily calcified lesions, leading to increased procedural success. The ORBIT II trial demonstrated the safety and efficacy of orbital atherectomy (Cardiovascular Systems, Inc) in 443 patients for the treatment of severely calcified coronary lesions.¹⁰ The outcomes from a multicenter real-world registry of patients with severely calcified lesions corroborated the safety and efficacy of orbital atherectomy.¹¹ However, outcome data are limited on the outcomes of patients with CKD who undergo orbital atherectomy. This retrospective subanalysis of our multicenter registry compares the outcomes of patients with severe CAC treated with orbital atherectomy grouped by the presence or absence of CKD.

Methods

Study population. This retrospective analysis comprised 456 consecutive patients with severe CAC who underwent orbital atherectomy between October 2013 and December 2015 at three centers (UCLA Medical Center, Los Angeles, California; St. Francis Hospital, Roslyn, New York; and Northwell Health, Manhasset, New York). Patients were divided into two groups based upon a history of CKD (creatinine ≥1.5 mg/dL) (88/456; 19.3%) or no CKD (creatinine <1.5 mg/dL) (368/456; 80.7%). Severe coronary calcification was defined by the presence of radioopacities on fluoroscopy involving the vessel wall. The institutional review board at each site approved the review of the data. 

Device description. The description of the orbital atherectomy device (Cardiovascular Systems, Inc [CSI]) has been previously described.¹⁰ After the 0.014˝ ViperWire (CSI) traverses the lesion, the device is advanced over the guidewire while the ViperSlide (CSI) lubricant infuses through the drive shaft in order to reduce friction. The 1.25 mm eccentrically mounted crown is coated with 30-micron diamonds; the crown rotates and laterally expands utilizing centrifugal force, resulting in lesion preparation by ablating calcified plaque. 

Procedure and antiplatelet therapy. Standard techniques were used to perform PCI. Operator discretion was used regarding the use of a transvenous pacemaker and a hemodynamic support device. The device was always initially activated at low speed (80,000 rpm). High-speed (120,000 rpm) atherectomy was performed at the discretion of the operator and was only performed if the reference vessel diameter was at least 3 mm. The duration of each pass was limited to ≤20 seconds. The decision to predilate the lesion, the choice of stent type, and use of intravascular imaging (intravascular ultrasound or optical coherence tomography) were left to the discretion of the operator. Antiplatelet regimen and duration were also left to the discretion of the operator. Dual-antiplatelet therapy was continued for at least 1 month if bare-metal stents were used and 12 months if drug-eluting stents were used. 

Endpoints. The primary endpoint was 30-day major adverse cardiac and cerebrovascular event (MACCE), as defined as all-cause mortality, MI, TVR, and stroke. Myocardial infarction was defined as recurrent symptoms with new ST-segment elevation or reelevation of cardiac markers >2x the upper limit of normal. Target-vessel revascularization was defined as a repeat revascularization of the target lesion because of restenosis within the stent or in the 5 mm distal or proximal segments. The Academic Research Consortium definition of stent thrombosis was used.¹² A dedicated PCI database was established to record demographic, angiographic, and procedural data, and clinical outcomes were collected from medical records.

Statistical analysis. Continuous variables are expressed as mean and standard error of the mean and compared using Student’s t-test. Categorical variables are expressed as percentages and compared using Chi² test. A P-value <.05 was considered statistically significant. Statistical analysis was performed with GraphPad Prism 6 (GraphPad Software, Inc).

Results

Baseline characteristics. In the CKD group, 17 out of 88 patients (19.3%) were on dialysis. Patients with CKD had a higher prevalence of diabetes mellitus (65.9% vs 36.4%; P<.001), hypertension (95.5% vs 8.5%; P<.01), previous history of coronary artery bypass grafting (25.0% vs 14.9%; P=.03), and presentation with MI (22.7% vs 8.4%; P<.01), as well as lower mean left ventricular ejection fraction (48.2 ± 9.5% vs 52.8 ± 10.7%; P<.001) (Table 1). Baseline angiographic and procedural characteristics were well matched except that the total volume of contrast used was higher in the CKD group (159.0 ± 8.9 mL vs 149.9 ± 4.9 mL; P<.01) (Table 2).

Procedural results. Angiographic complications were also low and similar in patients with and without CKD: perforation (1.1% vs 0.5%; P=.50), dissection (0% vs 0.5%; P>.99), and no reflow (1.1% vs 0.5%; P=.50) (Table 3).

Thirty-day clinical outcomes. The primary endpoint of 30-day MACCE was similar in patients with CKD and without CKD (3.4% vs 1.9%; P=.40) (Table 4). Similarly, there were no differences in 30-day rates of death (2.2% vs 1.1%; P=.30), MI (1.1% vs 0.5%; P=.40), TVR (0% vs 0%; P>.99), and stroke (0% vs 0.3%; P>.99). Stent thrombosis (0% vs 1.1%; P=.20) and emergent coronary artery bypass grafting (0% vs 0.8%; P>.99) were also low in both groups.

Discussion

In this subset analysis of the largest registry of patients with severely calcified lesions who underwent orbital atherectomy, there were no significant differences in adverse clinical events in patients with and without CKD despite higher-risk profile in CKD patients. 

Premature death from all causes including cardiovascular death is higher in patients with CKD vs those without CKD.⁴ Cardiovascular disease is the most common cause of death in CKD patients. The 2-year mortality rate is over 70% in patients with CKD who present with acute coronary syndromes.¹³ The 1-year MACE rates increase with decreasing renal function in patients with acute coronary syndromes who underwent PCI.¹⁴ Increased mortality observed in CKD patients can be partially explained by accelerated atherosclerosis, chronic inflammatory state, endothelial dysfunction, and altered cytokine levels.^15-18 These patients commonly also have long, diffuse, and severely calcified lesions, making PCI more technically challenging due to difficulty expanding the stent, thus increasing the risk of ischemic events including death, MI, stent thrombosis, and restenosis.¹⁹ Hyperphosphatemia, uremia, hyperglycemia, and other metabolic disturbances are thought to initiate the process of transforming vascular smooth muscle cells to a chondrocyte or osteoblast-like cell, leading to vascular calcification.⁴ Vascular calcification is also modulated by deficiencies in circulating or locally produced inhibitors of calcification. 

The only other evaluation of CKD patients who underwent orbital atherectomy was the subanalysis from the ORBIT II trial, which demonstrated that patients with CKD had a higher rate of 30-day MI (CK-MB >3x upper limit of normal) vs patients with no CKD (12.0% vs 2.8%; P=.01).²⁰ However, the MI rates were similar if MI was diagnosed according to the Society for Cardiovascular Angiography and Intervention criteria for clinically meaningful periprocedural MI (CK-MB >10x upper limit of normal) (2.4% vs 0.9%; P=.69). Of note, the ORBIT II trial excluded patients with serum creatinine >2.5 mg/dL and those who were not on dialysis, while our registry included these patients. 

Study limitations. Our registry was a retrospective non-randomized study. Comparison with a control group who underwent PCI without orbital atherectomy was not performed. The impact of CKD on in-stent restenosis and the need for repeat revascularization is unknown because the length of follow-up was short. Quantitative coronary analysis was not performed by a core lab. Periprocedural MI was likely underdiagnosed because cardiac biomarkers were not routinely obtained after PCI if the patient was asymptomatic. However, the patients who had MI were clinically significant.

Conclusion

Despite a higher-risk profile, there were no significant differences in clinical outcomes in patients with CKD at 30 days. Lesion preparation with orbital atherectomy is a safe and effective option for patients with severely calcified coronary lesions despite renal impairment. The results of subsequent studies with longer-term follow-up will help clarify the role of orbital atherectomy in this high-risk subset of patients. 

References

1.     Mintz GS, Popma JJ, Pichard AD, et al. Patterns of calcification in coronary artery disease. A statistical analysis of intravascular ultrasound and coronary angiography in 1155 lesions. Circulation. 1995;91:1959-1965.

2.     Lee MS, Shah N. The impact and pathophysiologic consequences of coronary artery calcium deposition in percutaneous coronary interventions. J Invasive Cardiol. 2016;28:160-167.

3.     Lee MS, Yang T, Lasala J, Cox D. Impact of coronary artery calcification in percutaneous coronary intervention with paclitaxel-eluting stents: two-year clinical outcomes of paclitaxel-eluting stents in patients from the ARRIVE program. Catheter Cardiovasc Interv. 2016;88:891-897. Epub 2016 Jan 12.

4.     https://www.cdc.gov/diabetes/pubs/pdf/kidney_factsheet.pdf

5.     Moe SM, Chen NX. Mechanisms of vascular calcification in chronic kidney disease. J Am Soc Nephrol. 2008;19:213-216. 

6.     Patel AD, Ibrahim M, Swaminathan RV, et al. Five-year mortality outcomes in patients with chronic kidney disease undergoing percutaneous coronary intervention. Catheter Cardiovasc Interv. 2016 Aug 13 (Epub ahead of print).

7.     Wang HT, Chen YL, Wu CJ. Impact of chronic kidney disease on clinical outcomes in patients with non-ST elevation myocardial infarction receiving percutaneous coronary intervention - a five-year observational study. Int J Cardiol. 2016;220:166-172.

8.     Saltzman AJ, Stone GW, Claessen BE, et al. Long-term impact of chronic kidney disease in patients with ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention: the HORIZONS-AMI (Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction) trial. JACC Cardiovasc Interv. 2011;4:1011-1019.

9.     Parikh PB, Jeremias A, Naidu SS, et al. Impact of severity of renal dysfunction on determinants of in-hospital mortality among patients undergoing percutaneous coronary intervention. Catheter Cardiovasc Interv. 2012;80:352-357.

10.     Chambers JW, Feldman RL, Himmelstein SI, et al. Pivotal trial to evaluate the safety and efficacy of the orbital atherectomy system in treating de novo, severely calcified coronary lesions (ORBIT II). JACC Cardiovasc Interv. 2014;7:510-518.

11.     Lee MS, Shlofmitz E, Kaplan B, Alexandru D, Meraj P, Shlofmitz R. Real-world multicenter registry of patients with severe coronary artery calcification undergoing orbital atherectomy. J Interv Cardiol. 2016;29:357-362.

12.     Cutlip DE, Windecker S, Mehran R, et al; Academic Research Consortium. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation. 2007;115:2344-2351.

13.     Keeley EC, Kadakia R, Soman S, et al. Analysis of long-term survival after revascularization in patients with chronic kidney disease presenting with acute coronary syndromes. Am J Cardiol. 2003;92:509-514.

14.     Bonello L, De Labriolle A, Roy P, et al. Impact of optimal medical therapy and revascularization on outcome of patients with chronic kidney disease and on dialysis who presented with acute coronary syndrome. Am J Cardiol. 2008;102:535-540.

15.     Thambyrajah J, Landray MJ, McGlynn FJ, Jones HJ, Wheeler DC, Townend JN. Abnormalities of endothelial function in patients with predialysis renal failure. Heart. 2000;83:205-209.

16.     Sechi LA, Zingaro L, Catena C, Perin A, De Marchi S, Bartoli E. Liproprotein(a) and apoprotein(a) isoforms and proteinuria in patients with moderate renal failure. Kidney Int. 1999;56:1049-1057.

17.     Kronenberg F, Kuen E, Ritz E, et al. Lipoprotein(a) serum concentrations and apolipoprotein(a) phenotypes in mild and moderate renal failure. J Am Soc Nephrol. 2000;11:105-115.

18.     Stenvinkel P, Heimburger O, Paultre F, et al. Strong association between malnutrition, inflammation and atherosclerosis in chronic renal failure. Kidney Int. 1999;55:1899-1911.

19.     Goodman WG, Goldin J, Kuizon BD, et al. Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis. N Engl J Med. 2000;342:1478-1483.

20.     Lee MS, Lee AC, Shlofmitz RA, et al. ORBIT II sub-analysis: impact of impaired renal function following treatment of severely calcified coronary lesions with the orbital atherectomy system. Catheter Cardiovasc Interv. 2016 Aug 27 (Epub ahead of print).

From the ¹UCLA Medical Center, Los Angeles, California; ²Northwell Health, Manhassat, New York; ³St. Francis Hospital-The Heart Center, Roslyn, New York. 

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Lee, Dr Evan Shlofmitz, and Dr Richard Shlofmitz report speaker’s honoraria from Cardiovascular Systems, Inc. Dr Lluri has no conflicts of interest to report regarding the content herein.

Manuscript submitted September 21, 2016, manuscript accepted September 28, 2016.

Address for correspondence: Michael S. Lee, MD, Associate Professor of Medicine, 100 Medical Plaza Suite 630, Los Angeles, CA 90095. Email: mslee@mednet.ucla.edu