Clinical Outcomes of Patients With Critical Limb Ischemia who Undergo Routine Coronary Angiography and Subsequent Percutaneous Coronary Intervention

Abstract: Background. Critical limb ischemia (CLI) is associated with a high risk of cardiovascular ischemic events. We assessed the strategy of routine coronary angiography and subsequent coronary revascularization, if clinically indicated, in patients with CLI who underwent percutaneous transluminal angioplasty (PTA). Methods. Of a total 286 consecutive CLI patients treated by PTA, 252 patients who underwent coronary angiography before or after PTA were enrolled. Coronary artery disease (CAD) was defined as angiographic stenosis ≥50% and significant CAD as ≥70% stenosis. Results. Of the 252 patients with CLI who underwent coronary angiography, a total of 167 patients (66.3%) had CAD and 85 patients (33.7%) did not have CAD. Patients in the CAD group were older, had a higher prevalence of diabetes and cerebrovascular disease, and had a lower mean ejection fraction. In the CAD group, of the 145 patients with significant CAD, percutaneous coronary intervention (PCI) was performed in 114 patients (78.6%). At 1 year, the CAD and non-CAD groups had no statistically significant differences in mortality (7.1% vs 4.7%; P=.45), myocardial infarction (1.1% vs 0%; P=.31), and PCI (4.7% vs 1.1%; P=.31). These outcomes were similar after the adjustment of baseline confounders. At 1 year, the CAD and non-CAD groups had similar rates of repeat PTA (16.7% vs 17.6%; P=.86), target lesion revascularization (13.7% vs 14.1%; P=.94), and amputation (19.1% vs 16.4%; P=.60). Conclusion. A strategy of routine coronary angiography and coronary revascularization may be a reasonable treatment option for these patients who have high risk for severe CAD. A randomized trial is needed to determine if this is the preferred strategy for CLI patients.

J INVASIVE CARDIOL 2015;27(4):213-217

Key words: critical limb ischemia, coronary artery disease

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Atherosclerosis is a systemic illness that can manifest in multiple vascular territories. The main cause of death in patients with peripheral arterial disease (PAD) is coronary artery disease (CAD).¹ Critical limb ischemia (CLI) represents an exceptionally aggressive form of extensive systemic atherosclerosis and is the most common cause of non-traumatic limb loss and amputation.² Percutaneous transluminal angioplasty (PTA) is a viable treatment strategy for limb salvage in patients with CLI. Patients with CLI have a high prevalence of diabetes mellitus as well as a history of smoking, and carry a high risk of cardiovascular events including death. Given the high prevalence of CAD and limited life expectancy due to the high risk of subsequent death from cardiovascular causes, the ideal diagnostic and treatment strategies for CAD in patients with CLI are unknown. In this prospective registry of patients with CLI undergoing PTA, in addition to optimal medical therapy, we evaluated the strategy of routine angiography and subsequent coronary revascularization based upon clinical judgment.

Methods

Study population. Of the 286 consecutive patients with CLI who underwent PTA, a total of 252 patients (88.1%) underwent routine coronary angiography before or after PTA between November 2004 to October 2012 at Korea University Guro Hospital in Seoul, Korea and were prospectively evaluated. The CAD group (n = 167 patients) included patients with significant CAD (n = 145 patients) and prior coronary revascularization without significant CAD (n = 22 patients). The non-CAD group had 85 patients. Approval of the Institutional Review Board was obtained for this study.

Study endpoints and definitions. The primary endpoint was 1-year major adverse cardiac event (MACE) occurrence, defined as all-cause death, myocardial infarction, and percutaneous coronary intervention. Coronary artery disease was defined as angiographic stenosis ≥50% of one or more coronary vessels. Significant CAD was defined as ≥70% stenosis of one or more coronary vessels or ≥50% stenosis of the unprotected left main coronary artery (ULMCA). All-cause death was defined as death from any cause. Cardiac death was defined as death from myocardial infarction or cardiac arrhythmia. Death was considered cardiac if the cause was unknown. Myocardial infarction was defined as the development of pathologic Q-waves (≥30 msec in duration and ≥0.1 mV in depth) in two or more contiguous precordial leads or two or more adjacent limb leads, or an elevation of creatine kinase MB isoenzyme levels (or total creatine kinase if measurements of creatine kinase MB were not available) to at least two times the upper limit of the normal range. Target lesion revascularization was defined as a repeat revascularization to treat a luminal restenosis that was treated during the index PTA. Target extremity revascularization was defined as repeat revascularization to treat a luminal stenosis in the extremity that was treated during the index PTA. Critical limb ischemia was defined as ischemic pain at rest, ulcer, or gangrene in one or both legs attributed to objectively proven arterial occlusive disease. Echocardiography was performed to determine the ejection fraction. 

Percutaneous transluminal angioplasty. Percutaneous transluminal angioplasty was performed with standard techniques. The goal was to achieve straight-line flow from the abdominal aorta to the distal extremity. Balloon angioplasty was performed for severe stenosis in lower extremities. For infrapopliteal arteries, 0.014˝ guidewires were used to traverse the lesions and balloon sizes ranged from 1.5-4.0 mm after the successful wiring under the 5 Fr Heartrail guiding catheter support (Terumo Corporation). Prolonged balloon inflations (120 seconds) were performed. Stenting was performed on a provisional basis when balloon angioplasty results were suboptimal. For chronic total occlusion (CTO), either true lumen angioplasty by dedicated CTO wires or subintimal angioplasty with provisional stenting was performed for longer CTO lesions. For femoropopliteal CTO lesions, reentry by CTO wires or reentry device (Outback catheter, Cordis Corporation) was used if the subintimal wiring failed to reenter the distal true lumen. On the other hand, retrograde approach from the distal superficial femoral artery, popliteal artery, and pedal arteries was performed in selective cases.

Percutaneous coronary intervention and medications. The decision to perform PCI was based upon clinical judgment. Percutaneous coronary intervention was performed via the transfemoral or transradial approach according to standard procedures. If the severity of the coronary lesion was intermediate, assessment of fractional flow reserve was obtained. For the antiplatelet regimen, aspirin 100 mg and clopidogrel 300-600 mg were administered before the procedure and continued for at least 1 month for bare-metal stents and 1 year for drug-eluting stents. The choice of stent type was at operator discretion, but most patients received drug-eluting stents, even in the acute coronary syndrome setting.

Statistical analysis. For continuous variables, differences between two groups were evaluated by unpaired t-test or Mann-Whitney rank test. For discrete variables, differences were expressed as counts and percentages and analyzed with χ² or Fisher’s exact test between groups, as appropriate. To adjust for potential confounders, propensity score analysis was performed using the logistic regression model, testing the propensity to show with CAD rather than without CAD. We tested all available variables that could be of potential relevance: male, age, hypertension, diabetes, dyslipidemia, stroke (hemorrhagic and ischemic), chronic kidney disease, current smoking, current alcoholism, lesion location (distal aorta, iliac, femoral, popliteal, tibial, and peroneal arteries), and the presence of a wound. The logistic model by which the propensity score was estimated showed good predictive value (C statistic = 0.680). Multivariate logistic regression analysis including baseline confounding factors was used for assessing the independent impact factors. A two-tailed P-value of <.05 was considered to be statistically significant. Data were expressed as mean ± standard deviation. Analyses were performed using SPSS 20.0 (SPSS, Inc).

Results

Baseline characteristics. Of the 252 patients who had coronary angiography, 71.0% had CAD and 57.5% had significant CAD (Table 1). Ten patients (5.9%) had prior surgical revascularization and 41 patients (24.5%) had prior PCI. There were no differences in the baseline clinical presentation between the 2 groups except the CAD group had a lower percentage of patients with Buerger’s disease (Table 2). Patients in the CAD group were older, had a higher prevalence of diabetes mellitus (including insulin-dependent diabetes) and cerebrovascular disease, and had a lower mean ejection fraction (Table 3).

Procedural and angiographic data are presented in Table 4. The CAD group had a higher requirement for bilateral PTA. In the CAD group, there was a higher percentage of patients who underwent PCI for ULMCA stenosis (12.6%), multivessel CAD (52.0%), and left anterior descending artery disease (55.0%). All revascularization procedures were performed percutaneously.

Clinical outcomes. In the CAD group, of the 145 patients with significant CAD, PCI was performed in 114 patients (78.6%) (Table 5). At 1 year, the CAD and non-CAD groups had no statistically significant differences in MACE rate (11.9% vs 5.8%; P=.13), all-cause death (7.1% vs 4.7%; P=.45), cardiac death (2.9% vs 1.1%; P=.37), non-cardiac death (4.1% vs 3.5%; P=.80), myocardial infarction (1.1% vs 0%; P=.31), and PCI (4.7% vs 1.1%; P=.31). At 1 year, the CAD and non-CAD groups had similar rates of repeat PTA (16.7% vs 17.6%; P=.86), target lesion revascularization (13.7% vs 14.1%; P=.94), and amputation (19.1% vs 16.4%; P=.60).  These outcomes were similar after the adjustment of baseline confounders.

Discussion

The high prevalence of CAD in patients with CLI highlights the importance of diagnosis of CAD and treatment for these patients to possibly minimize the risk of cardiac events. A strategy of routine coronary angiography to diagnose significant CAD and coronary revascularization based upon clinical judgment was associated with low cardiac morbidity and mortality, despite the fact that the CAD group had more comorbidities. 

Evaluation for myocardial ischemia is essential given the high prevalence of CAD in patients with CLI.³ There is no consensus regarding the screening modality to assess for myocardial ischemia. Patients with CLI may not report cardiac symptoms like angina because of their limited mobility, which restricts full exercise capacity. Furthermore, nearly three-quarters of our patients had diabetes mellitus; angina may be under-reported given development of autonomic neuropathy in these patients. CLI has been identified as a CAD risk equivalent.^4,5 In our study, of the 252 patients who underwent routine coronary angiography after presentation with CLI, two-thirds of patients had CAD, with significant CAD observed in 57.5%. Nearly one-quarter of our patients had chronic kidney disease and are at increased risk of contrast-induced nephropathy, especially if given the additive contrast load from the PTA. The development of contrast-induced nephropathy is associated with increased mortality. A similar strategy of routine coronary angiography was used to risk stratify patients prior to vascular surgery.⁶ The lack of severe CAD can be predicted with a positive predictive value of 96% for patients who have no history of (1) diabetes, (2) angina, (3) myocardial infarction, or (4) congestive heart failure.

Our study potentially has high relevance given that the mortality rate in patients with CLI is 25% at 1 year and over 60% at 5 years and is mostly due to myocardial infarction and stroke.^1,7-10 The mortality from cardiovascular disease was 15-fold higher in patients with severe large-vessel CLI.⁴ Given that cardiovascular disease is the most common cause of death in patients with CLI, the question remains whether an aggressive strategy of preemptive coronary angiography and coronary revascularization, when warranted, should be performed in these patients to reduce the risk of future cardiac events. Although no clinical trial has demonstrated a survival benefit of elective revascularization in patients with stable CAD, our patients did have a high prevalence of ULMCA disease and diabetics with multivessel CAD, subgroups that have demonstrated that surgical revascularization provides a survival benefit. 

When compared to the non-CAD group, the CAD group had similar mortality rates, despite older age, higher prevalence of diabetes mellitus (including insulin-dependent diabetes) and cerebrovascular disease, and a lower mean ejection fraction. An explanation for the lack of difference in clinical outcomes between the 2 groups may be explained by the strategy of routine angiography to diagnose significant CAD and subsequent coronary revascularization based upon clinical judgment, even in asymptomatic patients.

Given that cardiovascular disease is the most common cause of death in patients with CLI, our study raises the question of whether or not these patients should undergo coronary angiography and revascularization. Risk stratification with non-invasive stress testing was not performed to assess the burden of ischemia and aid in the decision to perform coronary angiography and subsequent revascularization if needed. Given the high pretest probability of CAD in these high-risk patients with CLI, non-invasive assessment for myocardial ischemia may be a suboptimal diagnostic strategy. Approximately 4% of patients who undergo angiography have ULMCA disease.¹¹ In our study, 12.6% of patients in the CAD group underwent revascularization for ULMCA disease. Non-invasive coronary assessment for ULMCA as well as multivessel CAD may be limited because of the possibility of balanced ischemia, leading to under-diagnosis of CAD. No reversible perfusion defect was observed on single-photon emission computed tomography imaging in approximately 19% of patients with ULMCA disease.¹² There is a paucity of data with respect to the use of stress echocardiography and the diagnosis of ULMCA disease.¹³

The CAD group included 12.6% of patients who underwent PCI for ULMCA disease; revascularization in patients with ULMCA disease is recommended due to a significantly higher mortality rate in those treated medically (50% mortality rate at 3 years).^14-16 While surgical revascularization has traditionally been the preferred mode of revascularization for ULMCA, data support that PCI is often a viable option, and recent guidelines now suggest that PCI be considered in appropriate patients, including those with ostial or trunk left main disease and those with low Syntax scores (ie, <23).^17,18 In our study, the vast majority had diabetes mellitus (77.2%), and 52% of patients in the CAD group underwent PCI for multivessel CAD. At a follow-up of 10 years in the MASS (Medicine, Angioplasty, or Surgery Study)-II trial, the mortality rate in diabetic patients was the highest in those who did not undergo revascularization compared with PCI and surgical revascularization (37.5%, 31.3%, and 27.5%, respectively).¹⁹ In the FREEDOM (Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease) trial, surgical revascularization was superior to PCI in terms of death and myocardial infarction, although the risk of stroke was higher in diabetic patients and multivessel CAD.²⁰ In our study, all coronary revascularization was performed percutaneously. The results of the FREEDOM trial were not available during our study. Surgical revascularization in diabetic patients could have reduced the mortality rates even further. Furthermore, the Coronary Artery Surgery Study reported a survival benefit with surgical revascularization compared with the group receiving medical therapy among patients with severe PAD.²¹ 

The role of coronary revascularization in patients with PAD requiring vascular revascularization has been previously evaluated. The CARP (Coronary Artery Revascularization Prophylaxis) trial reported that elective coronary revascularization among patients with stable CAD prior to elective vascular surgery did not improve survival.²² However, all of our patients had CLI, as compared with the revascularization group in the CARP trial, where one-quarter of the patients had CLI. Therefore, our patients represent a higher-risk group.

Study limitations. This was a non-randomized, single-center study with a relatively small number of patients. Non-invasive assessment of myocardial ischemia was not performed to diagnose the presence of CAD. There was no control cohort of patients with CAD who did not undergo routine coronary angiography to determine the potential benefit of coronary angiography and subsequent coronary revascularization. The decision to perform PCI was based upon clinical judgment rather than ischemic burden diagnosed with non-invasive imaging or the presence of clinical symptoms. While the short-term results were favorable, longer-term follow-up is needed to assess the safety and efficacy of the strategy of routine coronary angiography. Follow-up coronary angiography was not performed on all patients unless clinically indicated. In patients who had severe CAD on coronary angiography, a comparison of PCI versus medical therapy was not performed. However, based upon historical data of patients with CLI, our patients compared favorably with respect to survival.  Ankle-brachial index and toe-brachial index were not obtained on all patients. 

Conclusion

Patients with CLI have a high prevalence of CAD. The ideal strategy of evaluation for CAD in these high-risk patients is unknown. Although it may be considered aggressive, routine angiography may be a reasonable strategy for the detection of severe CAD given its high prevalence in patients with CLI. In addition to optimal medical therapy, coronary revascularization for severe CAD performed based upon clinical judgment provided an acceptable mortality rate for these high-risk patients. A large randomized trial is needed to determine whether a strategy of routine angiography followed by revascularization provides a clinical benefit over a conservative strategy.

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From the ¹Division of Cardiology, UCLA Medical Center, Los Angeles, California; ²Cardiovascular Center, Korea University Guro Hospital, Seoul, Korea; and ³the Department of Plastic Surgery, Korea University Guro Hospital, Seoul, Korea.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.

Manuscript submitted July 2, 2014, provisional acceptance given August 25, 2014, final version accepted October 6, 2014.

Address for correspondence: Seung-Woon Rha, MD, PhD, FACC, FAHA, FESC, FSCAI, FAPSIC, Cardiovascular Center, Korea University Guro Hospital, 80, Guro-dong, Guro-gu, Seoul, 152-703, Korea. Email: swrha617@yahoo.co.kr