Subanalysis of the CONFIRM Registries: Acute Procedural Outcomes in Claudicant and Critical Limb Ischemia Patients With Varying Levels of Calcification Treated for Peripheral Arterial Disease With Orbital Atherectomy

Abstract: Purpose. Patients with peripheral arterial disease (PAD) can be classified into groups based upon the severity of the disease using the Rutherford classification system. This analysis compares the procedural outcomes of PAD patients treated with orbital atherectomy stratified by Rutherford class (1-3 = intermittent claudication; 4-6 = critical limb ischemia [CLI]), and acute angiographic outcomes of these patients stratified by degree of lesion calcification. Methods. The CONFIRM registry series was analyzed and included 1697 patients with intermittent claudication (Rutherford class 1-3) and 1320 patients with CLI (Rutherford class 4-6) treated with orbital atherectomy. The composite rate of dissection, perforation, slow-flow, vessel closure, spasm, embolism, and thrombus formation was compared between claudicants and CLI patients with varying degrees of lesion calcification. Results. Patients with CLI were older and had a higher prevalence of diabetes, coronary artery disease, and renal disease (P<.001). Claudicants with moderately/severely calcified lesions had a lower rate of dissection (both non-flow limiting and flow-limiting) than claudicants with mildly/minimally calcified lesions. CLI patients with mildly/minimally calcified lesions had higher rates of embolism and thrombus than CLI patients with moderately/severely calcified lesions. Conclusions. Plaque modification with orbital atherectomy resulted in similar low procedural complication rates in the CLI group compared with the claudicant group. These results suggest that orbital atherectomy is safe and effective for treating calcified lesions in high-risk patients with varying severity of PAD symptoms.

J INVASIVE CARDIOL 2015;27(11):516-520

Key words: atherectomy, peripheral arterial disease, claudication, critical limb ischemia, calcification

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Peripheral arterial disease (PAD) is the chronic obstruction of the arteries supplying the lower extremities and affects an estimated 10-12 million people in the United States.¹ Patients can be stratified into groups according to the Rutherford classification system. Incidence of PAD is on the rise¹ and encompasses a myriad of symptoms that differ in their severity. Nearly one-half of adults suffering from PAD are symptomatic; of those, approximately 40% experience intermittent claudication, or pain due to poor oxygenation from an acute peripheral blockage (Rutherford classification 1-3, Fontaine II). As the acute peripheral blockage progresses toward full blockage, the degree of ischemia increases and the symptoms typically worsen, resulting in critical limb ischemia (CLI). Approximately 10% of symptomatic PAD patients suffer from CLI (Rutherford classification 4-6, Fontaine III/IV).² Patients with intermittent claudication are at an increased risk for myocardial infarction, stroke, and cardiac death, and patients suffering from CLI have a risk profile three times higher.³ CLI is responsible for 80% of amputations worldwide and the incidence of CLI is projected to increase due to higher rates of diabetes and renal insufficiency, as well as an aging population.⁴ 

Revascularization strategies for PAD patients are complicated by localized calcium deposits that increase the risk of adverse events during balloon angioplasty.⁵ The Orbital Atherectomy System (OAS; Cardiovascular Systems, Inc) is a minimally invasive system developed for the treatment of PAD with calcified plaque burden;⁶ however, data on the outcomes of patients with varying degrees of PAD who undergo OA are limited. We sought to compare outcomes between patients with varying degrees of peripheral arterial calcification who had intermittent claudication or CLI undergoing OA in a large, prospective registry of PAD patients. 

Methods

Study design. The CONFIRM registry series is a multicenter, prospective, non-randomized, consecutive registry series that included PAD patients on an “all-comer” basis without exclusion from October 2009 through June 2011.⁷ Data collected included: demographics; ankle-brachial index (ABI); Rutherford classification; lesion characteristics, including lesion length, plaque morphology, and extent of stenosis pre- and post treatment; procedural data; device usage parameters; adjunctive therapy; and acute procedural outcomes. Plaque morphology was reported by the principal interventionist with no core lab adjudication using the following criteria: severe calcium (>75%), moderate calcium (50%-75%), mild calcium (25%-50%), minimal calcium (<25%), fibrotic, or soft plaque. Plaque reduction was determined angiographically by the principal interventionist with no core lab adjudication. Procedural complications were reported by the principal interventionalist with no core lab adjudication. Slow-flow was defined as sluggish posttreatment flow as compared with pretreatment flow. Abrupt closure/no reflow was defined as closure of the vessel, typically related to vessel recoil, intimal flap formation, or embolization. Spasm was defined as constriction of the vessel as seen on cine. Thrombus was defined as a blood clot and macroembolization was reported if there was flow-limiting debris. 

Over 200 United States institutions participated in the combined CONFIRM registry series and enrolled 3135 patients with 4766 lesions. The combined CONFIRM registries are the largest and most unique resource of its type to date. The three combined registries included 3017 patients representing 4561 lesions with known Rutherford classification; these patients were divided into two groups: those with claudication (Rutherford class 1-3; 1697 patients, 2470 lesions) and those with CLI (Rutherford class 4-6; 1320 patients, 2091 lesions). Patients with unknown Rutherford classification were excluded from this subanalysis. 

Device description. All patients were treated with the OAS. Three device iterations were evaluated over the registry series: CONFIRM I registry evaluated the Diamondback360°; CONFIRM II evaluated the Predator360°; and CONFIRM III evaluated three devices (Diamondback360°, Predator360°, and Stealth360°). The OAS has been previously well described.^7-10 The current subanalysis pooled the results from the three CONFIRM registries, and did not differentiate between device iteration. Crown sizes ranged from 1.25-2.25 mm, allowing the treatment of vessels throughout the lower extremities, from above-the-knee to the foot. Distal embolization protection is not required for use with the OAS; thus, no data on distal embolization protection were collected in the CONFIRM registries. Use of vasodilators during the procedure was at the discretion of the treating physician.

Statistical methods. The procedural outcomes of PAD patients treated with OA stratified by Rutherford class and acute angiographic outcomes of these patients stratified by degree of lesion calcification (moderately/severely calcified lesions versus mildly/minimally calcified, fibrotic, or soft-plaque lesions) were compared. Data regarding patient characteristics are reported as frequency counts and percentages. Percentages were computed using available data only, with missing values excluded from analyses. Means and standard deviations are reported for quantitative measurements, whereas minimum and maximum values are reported to indicate data ranges. Relationships between various patient or lesion characteristics and patient outcomes were analyzed by cross-tab analysis. Embolism and thrombus data were not collected in CONFIRM I; dissection, perforation, slow-flow, closure, and spasm were collected for all lesions studied (n = 4561), while embolism and thrombus data were collected in only 3519 lesions. Rarely observed data categories were combined (eg, pretreatment stenosis percentages of <70% were collapsed into a single category of stenosis ≤70%) as necessary to allow sufficient counts in cells for valid Chi-square analysis. Chi-squared P-values are reported. P-values <.05 were considered statistically significant. Statistical analyses were performed using SAS version 9.3 (SAS Institute, Inc).

Results

Patient and lesion characteristics. Demographics for patients with non-missing Rutherford classification and plaque morphology are included in Table 1. Of the 3017 patients analyzed, 56% were claudicants (n = 1697) and 44% had CLI (n = 1320). Compared with claudicants, patients with CLI were older (P<.001) and had higher prevalence of diabetes (P<.001), coronary artery disease (P<.001), and renal disease (P<.001). Patients with CLI were also more likely to have never smoked (P<.001). 

Compared with claudicants, patients with CLI had longer lesions (78.4 ± 78.4 mm vs 67.5 ± 66.1 mm; P<.001) and a higher proportion of severe calcium (P<.001) (Table 2). Claudicants had a higher proportion of moderate (P<.001) and mild (P<.001) calcium (Table 2). In the claudicant population, treated lesions were more often located above-the-knee (P<.001) compared with CLI patients, who had a higher percentage of lesions below-the-knee (P<.001) and in the popliteal region (Table 3). Compared with claudicants, patients with CLI presented with higher preprocedural percent stenosis (89 ± 12% vs 87 ± 12%; P<.001) and higher post-OA percent stenosis (36 ± 20% vs 35 ± 18%; P<.001). Final residual stenosis rates were not different between the two groups (10 ± 11% vs 10 ± 11%). Other procedural metrics, including OAS run time, maximum inflation pressure, and total inflation time, were not different between claudicants and CLI patients (Table 3). The number of adjunctive therapies was statistically similar between groups; however, in claudicants there was a trend toward higher stent usage (stent only or with balloon) compared with CLI patients (9% vs 7%; P=.06). 

Procedural complications. Procedural complications for claudicants and CLI patients were further analyzed by plaque morphology. Morphologies categorized as severe/moderate calcium were compared vs those with mild/minimal calcium, fibrotic, or soft-plaque morphology (Table 4, Supplemental Table 1). Complications included dissection, perforation, slow-flow, closure, spasm, embolism, and thrombus. 

Analysis of all patients enrolled in the CONFIRM series revealed 1697 patients with claudication (Rutherford 1-3) with documented lesion morphology. Angiographic complication rates for claudicants grouped by plaque morphology are listed in Table 4. Eighty-two percent of claudicants treated with the OAS had moderately/severely calcified lesions. There was no significant difference in the rate of perforation (0.6% vs 0%), slow-flow (2.9% vs 2.6%), closure (1.4% vs 2.3%), spasm (3.8% vs 6.3%), embolism (1.7% vs 2.6%), or thrombus (1.1% vs 1.3%) in claudicants with moderately/severely calcified lesions vs without moderately/severely calcified lesions, respectively. Claudicants with moderate/severe calcium had fewer total dissections than those with mildly/minimally calcified lesions (10.9% vs 16.2%; P=.01), however flow-limiting and non-flow limiting dissection rates were similar between plaque morphologies.

Of all the patients in the CONFIRM series, a total of 1320 had CLI (Rutherford class 4-6) with documented lesion morphology. Eighty-seven percent of CLI patients presented with moderately/severely calcified lesions. There was no significant difference in the rate of dissection of any kind (9.1% vs 12.2%), perforation (0.9% vs 0.6%), slow-flow (5.7% vs 4.7%), closure (1.6% vs 1.2%), or spasm (6.4% vs 9.3%) in CLI patients with moderately/severely calcified lesions vs those without moderately/severely calcified lesions, respectively (Supplemental Table 1). Patients with CLI with moderate/severe calcium had a lower rate of embolization (1.7% vs 5.2%; P=.01) and lower rate of thrombus formation (0.9% vs 4.4%; P=.01) compared with patients who had mildly/minimally calcified lesions.

In order to investigate whether adverse outcomes were attributed to disease severity (Rutherford class) instead of inherent differences between patient populations, a logistic regression analysis was performed. Age, diabetes, gender, plaque morphology, renal disease, Rutherford class, and vessel location were all examined as contributing variables to composite adverse events. This logistic regression identified advanced age (odds ratio [OR], 0.879; P=.01), plaque morphology of mild calcium, minimal calcium, soft plaque, or fibrotic plaque (OR, 1.448; P=.01), Rutherford class 4-6 (OR, 0.813; P=.04), and vessel location below-the-knee (OR, 0.560; P<.001) to be significant predictors of composite adverse events.

Discussion

The trends observed in PAD patients were recapitulated in the current subanalysis of the CONFIRM registries: patients suffering from CLI presented with significantly higher rates of diabetes, coronary artery disease, and renal disease. History of hypertension and hyperlipidemia were prevalent in both claudicants and CLI patients, and were not significantly different between groups. 

Although there are many causes leading to intermittent claudication and CLI, atherosclerosis and calcified plaque accumulation is the predominant cause of PAD and remains a key obstacle in treatment strategies.¹¹ Modification of calcified plaque may improve the clinical outcomes in this patient population, which has led to the advent of a number of novel technologies. The CONFIRM registry enrolled PAD patients with varying levels of calcified plaque burden who were treated with the OAS. Over 80% of the patients in the CONFIRM series had moderately/severely calcified lesions. 

The CONFIRM registry is the largest study to date evaluating acute procedural outcomes after OAS treatment; as such, it provides a useful source of data. In the CONFIRM series, the stent-utilization rate in both CLI and claudicants was low (7% vs 9%, respectively) and would likely translate to a procedural cost-savings. This is consistent with a published economic analysis demonstrating that the index procedure costs and cost-effectiveness to 1 year were comparable for OAS plus balloon angioplasty vs balloon angioplasty alone.¹² This potential cost-savings might be useful to physicians when making treatment decisions.

Eighty-two percent of patients with intermittent claudication (Rutherford class 1-3) were deemed to have moderately/severely calcified lesions, and this number increased to almost 87% of CLI patients. Interestingly, there were higher rates of total dissection (including flow-limiting and non-flow limiting) in claudicants with mildly/minimally calcified, fibrotic, or soft-plaque lesions when compared with their moderately/severely calcified lesion counterparts; however, individual rates of flow-limiting and non-flow limiting dissections did not differ between groups. In CLI patients, those with mildly/minimally calcified, fibrotic, or soft-plaque lesions had higher rates of embolism and thrombus compared with the severely calcified lesion group. Additionally, increased rates of angiographic complications in the mildly/minimally calcified, fibrotic, or soft-plaque lesion groups vs the moderately/severely calcified lesion groups may suggest that the mechanism of action of the OAS results in optimal outcomes in severely calcified lesions. 

CLI patients included in this CONFIRM subanalysis typically had poorer baseline characteristics compared with claudicants, including higher rates of diabetes, coronary artery disease, and renal disease. In addition, CLI patients had higher levels of pre-OAS and post-OAS percent stenosis compared with claudicants, which was expected. Treatment location varied with symptom severity, as more patients with intermittent claudication had lesions treated above-the-knee and more patients with CLI had lesions treated below-the-knee or in the popliteal region. Regardless of symptom severity or lesion location, patients with both intermittent claudication and CLI had nearly identical rates of final residual stenosis (10 ± 11% in both). These rates were favorable compared with the final residual stenosis rates reported for patients following rotational aspiration atherectomy (36 ± 24%)¹³ and directional atherectomy (12 ± 18%).¹⁴ This subanalysis demonstrates the effectiveness of the device in patients with varying degrees of PAD.

Study limitations. There are several limitations of this study. First, this is a non-randomized, single-arm registry of all patients undergoing treatment of PAD with the use of the OAS. As such, observational bias may be present. Similarly, all data were physician reported; thus, there was no core lab adjudication of the angiographic data, and the grading system to determine calcification was subjective, allowing for operational bias regarding plaque morphology. Second, these data are without long-term follow-up, which may be more clinically and economically relevant. Third, patients with claudication and CLI were included in this analysis and significant differences may exist between these two patient groups. Similarly, there were significant differences in baseline characteristics as well as lesion characteristics and treatment location, and the majority of patients had moderately/severely calcified plaque, all of which may complicate our findings. 

Conclusion

This subanalysis of the CONFIRM registries based on Rutherford classification revealed that there were similar treatment outcomes that may be attributable to the modification of calcific plaque with OA in patients with intermittent claudication and those with CLI. Patients with CLI were older and typically presented with more comorbidities than claudicants. Compared with patients with moderately/severely calcified lesions, claudicants with mildly/minimally calcified, fibrotic, or soft-plaque lesions had a higher rate of total dissection (including flow-limiting and non-flow limiting). CLI patients with mildly/minimally calcified, fibrotic, or soft-plaque lesions had higher rates of embolism and thrombus compared with their moderately/severely calcified counterparts. Treatment location varied significantly between groups; however, both claudicants and CLI patients had favorable rates of final residual stenosis. These results suggest that OA is safe and effective in high-risk patients with varying severity of PAD symptoms.

References

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7.     Das T, Mustapha J, Indes J, et al. Technique optimization of orbital atherectomy in calcified peripheral lesions of the lower extremities: the CONFIRM series, a prospective multicenter registry. Catheter Cardiovasc Interv. 2014;83:115-122. 

8.     Safian RD, Niazi K, Runyon JP, et al. Orbital atherectomy for infrapopliteal disease: device concept and outcome data for the OASIS trial. Catheter Cardiovasc Interv. 2009;73:406-412. 

9.     Shammas NW, Lam R, Mustapha J, et al. Comparison of orbital atherectomy plus balloon angioplasty vs balloon angioplasty alone in patients with critical limb ischemia: results of the CALCIUM 360 randomized pilot trial. J Endovasc Ther. 2012;19:480-488. 

10.     Staniloae CS, Korabathina R. Orbital atherectomy: device evolution and clinical data. J Invasive Cardiol. 2014;26:215-219.

11.     Rocha-Singh KJ, Zeller T, Jaff MR. Peripheral arterial calcification: prevalence, mechanism, detection, and clinical implications. Catheter Cardiovasc Interv. 2014;83:E212-E220.

12.    Weinstock B, Dattilo R, Diage T. Cost-effectiveness analysis of orbital atherectomy plus balloon angioplasty vs balloon angioplasty alone in subjects with calcified femoropopliteal lesions. Clin Outcomes Res. 2014;6:133-139. 

13     Zeller T, Krankenberg H, Rastan A, et al. Percutaneous rotational and aspiration atherectomy in infrainguinal peripheral arterial occlusive disease: a multicenter pilot study. J Endovasc Ther. 2007;14:357-364. 

14.     Zeller T, Sixt S, Schwarzwälder U, et al. Two-year results after directional atherectomy of infrapopliteal arteries with the Silverhawk device. J Endovasc Ther. 2007;14:232-240.

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From ¹Rex Healthcare, Garner, North Carolina; ²Cardiology and Interventional Vascular Associates, Dallas, Texas; ³UCLA Medical Center, Los Angeles, California; ⁴Mount Sinai Medical Center, Miami Beach, Florida; and ⁵Metro Health Hospital, Wyoming, Michigan.  

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Adams, Dr Das, Dr Lee, Dr Beasley, and Dr Mustapha report consulting fees from Cardiovascular Systems, Inc.

Manuscript submitted May 18, 2015, provisional acceptance given June 1, 2015, final version accepted July 31, 2015.

Address for correspondence: George Adams, MD, MHS, Rex Healthcare, 4414 Lake Boone Trail, Suite 402, Raleigh, NC 27607. Email: George.Adams@rexhealth.com