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Temporal Trends and Outcomes of Patients With Chronic Limb-Threatening Ischemia With and Without History of Coronary Artery Disease: Insights From the US National Inpatient Sample Database
Abstract
Background. The burden and prognostic significance of coronary artery disease (CAD) in adults with peripheral artery disease and chronic limb-threatening ischemia (CLTI) is unknown. Methods. Temporal trends in prevalence of significant CAD (history of myocardial infarction or coronary revascularizations) in hospitalizations for CLTI were determined using the 2000 to 2018 National Inpatient Sample (NIS) database. A multivariable regression analysis of outcomes was performed based on presence or absence of CAD. Results. Among 13 575 099 hospitalizations for CLTI (41% female, 69% white, mean age 69 years), 23% had concomitant CAD, of which 11% underwent lower extremity arterial revascularization (43.6% endovascular and 56.4% surgical). The prevalence of concomitant CAD with CLTI increased from 15.3% in 2000 to 23.1% in 2018. Furthermore, the frequency of endovascular revascularization in adults with CAD and CLTI increased from 15.1% to 48.3%, while there was a decreasing trend of surgical revascularization, from 84.9% to 51.7%. After multivariate adjustments, CLTI with CAD was associated with increased risk of in-hospital mortality (OR, 1.40; 95% CI, 1.32-1.47; P < .0001) and bleeding requiring transfusion (OR, 1.10; 95% CI, 1.06-1.12; P < .0001) compared with patients with CLTI without CAD. As compared with surgical revascularization, endovascular revascularization was associated with lower risk of in-hospital mortality in both patients with CLTI with CAD (OR, 0.69; 95% CI, 0.63-0.76; P < .001) and CLTI without CAD (OR, 0.71; 95% CI, 0.67-0.76; P < .001). Conclusions. Prevalence of CAD has increased in adults presenting with CLTI and is associated with poor outcomes, warranting the need for effective interventions and secondary prevention in this high-risk population.
Introduction
Chronic limb-threatening ischemia (CLTI) is the most severe presentation of peripheral artery disease (PAD), with manifestations ranging from rest pain in the affected limb to ischemic gangrene.1 It has been associated with 1-year mortality rates as high as 50%2 and has a higher prevalence amongst PAD patients who did not undergo revascularization.3 The prevalence of CLTI in the US adult population aged 40 years or older is estimated to be 1.3%,4 which is increasing at a rapid rate along with the increase in cardiovascular risk factors.5,6 Within the larger PAD population, coronary artery disease (CAD) is a well-described comorbidity shown to increase the risk of adverse cardiovascular outcomes, lower limb amputation, and mortality.7,8 More specifically, in PAD patients undergoing lower extremity revascularization, complications associated with CAD are known to be the leading causes of postoperative morbidity and mortality.9 While several studies have evaluated the revascularization trends and their outcomes in patients with CLTI stratified by the presence or absence of comorbidities such as diabetes and chronic kidney disease,10,11 few contemporary studies have assessed the impact and association of concomitant CAD on long-term clinical outcomes in patients with CLTI. Therefore, we aimed to assess trends in the burden of CAD and outcomes in patients presenting with CLTI in the US. Furthermore, we compared the trends and outcomes of endovascular vs surgical revascularization in patients with CLTI with and without CAD.
Methods
Data source and population. The National Inpatient Sample (NIS) is a part of the Healthcare Cost and Utilization Project (HCUP) family of databases; it is the largest all-payer database of inpatient hospital stays in the US. It includes data on over 7 million hospital stays each year at over 1000 hospitals, and represents a 20% stratified random sample of all hospital discharges nationwide. The data is weighted using inverse probability within the complex sampling design; weighted, the NIS contains more than 35 million annual discharges, representing more than 95% of the national population.12
The study flow is depicted in Figure 1. Hospitalizations with a primary diagnosis of CLTI by International Classification of Diseases-9th Edition (ICD-9) or International Classification of Diseases-10th Edition (ICD-10) diagnostic codes were identified in the NIS database from 2000 to 2018. Hospitalizations were then classified based on secondary diagnostic codes for significant CAD. Patients with a history of myocardial infarction (MI) and those who underwent prior coronary revascularization such as a percutaneous coronary intervention (PCI) or a coronary artery bypass graft surgery (CABG) were classified as having a history of significant CAD. Clinical characteristics and revascularization modalities (endovascular vs surgical) in patients with CLTI with CAD vs CLTI without CAD were also identified using ICD-9 and ICD-10 coding.13 Endovascular revascularization included catheter-directed thrombolysis (ICD-9-CM procedure codes 99.10 plus 88.42, 88.47, or 88.48) and peripheral angioplasty/stenting (ICD-9-CM procedure codes 39.50, 39.90, or 00.55). Surgical revascularization was defined using ICD-9-CM procedure codes 38.06, 38.08, 38.16, 38.18, 38.46, 38.48, 39.25, 39.29, 39.49, 39.56, or 39.57. ICD-9 codes were subsequently mapped to ICD-10 codes to include data from 2015 to 2018. Since the data used in this study was de-identified, it does not qualify as human participant research and therefore did not require institutional review board approval.
Outcomes. In the primary analysis, temporal trends and in-hospital outcomes were evaluated in patients with CLTI with and without CAD. Secondary analyses were also performed in those who underwent endovascular vs surgical revascularization stratified by CAD status. The primary outcome of interest was in-hospital mortality, and secondary outcomes included acute stroke, acute kidney injury, respiratory complications, major amputation, minor amputation, postoperative infection, major bleeding requiring transfusion, and length of hospital stay. The rate of complications was calculated based on the total number of hospitalizations. The length of stay and costs associated with endovascular and surgical revascularization were also assessed in the cohort.
Statistical analysis. Baseline patient characteristics and outcomes were compared using the chi-square test for categorical variables, and the differences between nonparametric continuous variables were tested using the Wilcoxon rank sum test. Temporal trends in the prevalence of CAD, frequency of revascularization procedures, and prevalence of complications in patients with CLTI were evaluated using Poisson regression analysis with %SURVEYGENMOD as defined by Silva.14 Multivariable logistic regression was used to examine the impact of CAD as well as the impact of endovascular vs surgical revascularizations on outcomes of interest in adults with CLTI requiring intervention. Analyses were limited to those requiring intervention to eliminate the possibility of CLTI rule-out hospitalizations. Multivariate analyses were adjusted for age; sex; race; obesity; and history of coagulopathy, hypertension, thyroid disease, chronic kidney disease, chronic liver disease, anemia, diabetes, heart failure, valvular disease, transient ischemic attack /stroke, and tobacco use. All analysis was conducted using the SAS 9.4 (SAS Institute Inc). Sampling weights and the complex NIS survey design were accounted for in all analyses; cluster variables included hospital identification and year.
Results
Baseline characteristics. There were 13 575 099 hospitalizations identified between 2000 and 2018 with a primary diagnosis of CLTI (294 932 unweighted observations). Of these, 41% were female, 69% were White patients, and the mean age was 69 years. Among patients with CLTI, 3 073 332 (23%) patients had a history of significant CAD and 1 437 420 (11%) underwent revascularization. Surgical revascularization was observed to be more frequently performed (56.4%) than endovascular revascularization (43.6%). Baseline characteristics of patients with CLTI with and without CAD is shown in Table 1. In brief, patients with CLTI with CAD were more likely to have hypertension, hypothyroidism, chronic kidney disease, end-stage renal disease requiring hemodialysis, chronic lung disease, anemia, heart failure, valvular heart disease, and history of stroke.
Temporal trends in hospitalizations and outcomes. From 2000 to 2018, the proportion of CLTI hospitalizations involving patients with a history of CAD increased from 15.3% in 2000 to 23.1% in 2018 (P < .0001) (Figure 2). Among patients with CLTI with CAD treated with lower extremity arterial revascularization, the frequency of endovascular approach increased from 15.1% in 2000 to 48.3% in 2018 (P < .0001), while surgical revascularizations declined from 84.9% in 2000 to 51.7% in 2018 (P < .0001) (Figure 3). We observed a similar trend in patients with CLTI without CAD, showing an increasing frequency of endovascular revascularization from 15.6% in 2000 to 49% in 2018 (P < .0001) and a downward trend in the frequency of surgical revascularization from 84.4% in 2000 to 50.9% in 2018 (P < .0001).
Clinical outcomes. After multivariable adjustment, CLTI with CAD was associated with increased risk of in-hospital mortality (OR 1.40; 95% CI, 1.32-1.47; P < .0001) as compared with patients with CLTI without CAD (Figure 4). CLTI with CAD was also associated with a lower risk of major amputation (OR 0.74; 95% CI, 0.73-0.76; P < .0001), minor amputation (OR 0.77; 95% CI, 0.75-0.79; P < .0001), acute kidney injury (OR 0.95; 95% CI, 0.92-0.98; P = .0003), or infection (OR 0.76; 95% CI, 0.75-0.78; P < .0001) than CLTI without CAD, as shown in Table 2.
Among patients with CLTI and CAD, endovascular revascularization was associated with lower risk of in-hospital mortality (OR, 0.69; 95% CI, 0.63- 0.76; P < .001) and an increased risk of minor amputation (OR, 1.13; 95% CI, 1.07-1.19), AKI (OR, 1.23; 95% CI, 1.16-1.29), and infection (OR, 2.03; 95% CI, 1.95-2.12) as compared with surgical revascularization (Figure 5). Similarly, among patients with CLTI without CAD, a lower risk of in-hospital mortality (OR, 0.71; 95% CI, 0.67-0.76) and a higher risk of minor amputation (OR, 1.06; 95% CI, 1.02-1.09; P < .001), AKI (OR, 1.21; 95% CI, 1.24-1.59; P < .001) and infection (OR, 1.81; 95% CI, 1.76-1.86; P < .001) was observed in those who underwent endovascular revascularization compared with surgical revascularization (Table 3).
Discussion
In this observational analysis of a nationally representative sample of patients with CLTI in the US, the main study findings were as follows: 1) Prevalence of CAD among patients hospitalized for CLTI increased over time; 2) Presence of CAD was associated with increased risk of in-hospital mortality; 3) Among patients with CLTI and CAD, the frequency of endovascular approach increased while surgical revascularization declined over time; 4) In those treated with revascularizations, endovascular revascularization was associated with lower risk of in-hospital mortality and higher rates of minor amputation, infection, and acute kidney injury as compared with surgical revascularization, regardless of CAD status.
We observed an increasing trend in hospitalization of CAD and CLTI throughout our study period. While it is generally assumed that patients with severe PAD have concomitant severe CAD, the prevalence of significant CAD in patients with severe PAD varies widely from 28% to 94% in published reports.15,16 Previous studies have reported that approximately 30% of patients undergoing peripheral vascular revascularization have concomitant CAD;9 our study corroborates these findings, as we found that 1 in 4 patients presenting with CLTI requiring revascularization in the US had concomitant CAD. The increase in prevalence of CAD in CLTI hospitalizations in our study is likely multifactorial. First, documented history of CAD may be indicative of increased rates of prior healthcare contact, as these individuals may be more likely to seek healthcare. Most plausibly, major efforts taken by several organizations to educate health care providers regarding identification and early referral of patients with CLTI could contribute to increased hospitalization of these patients.17
We also observed an increased in-hospital mortality risk in patients with concomitant CAD and CLTI. Consistent with our results, Chen et al reported that CAD and CLTI were associated with a 52% and 64% increase in major adverse cardiovascular and cerebrovascular events (MACCE) and mortality, respectively.18 Moreover, patients with polyvascular disease showed higher rates of mortality and MACCE at 2-year follow-up.8Interestingly, concomitant PAD and MI was found to have the highest cardiovascular risk compared with patients with PAD or MI alone. Although the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial observed that macrovascular disease did not increase the risk of PAD or amputation in diabetics,19 a recent Danish study reported that the presence of CAD more than doubles the risk of lower limb revascularization and lower limb amputation.7 The increased mortality rate among these patients might be a result of a systemic inflammation from extensive atherosclerosis, greater risk of procedural complications, acute bleeding complications, or a consequence of high burden of comorbidities.20,21
According to the past European Society of Cardiology (ESC) guidelines, PAD is classified as an independent coronary heart disease risk equivalent, suggesting that PAD, and especially CLTI, confers long-term risk to patients equivalent to having an established heart disease.22,23 Consistent with these guidelines, the Reduction of Atherothrombosis for Continued Health (REACH) registry reported a slightly higher 3-year cardiovascular event rate in patients with symptomatic PAD as compared with patients with CAD.24 Moreover, a higher risk of cardiovascular morbidity and mortality was previously reported in patients with PAD compared with patients with CAD only, indicating the presence of severe advanced disease in multiple vascular beds in patients with PAD.25-28It is conceivable that the impact of CAD could be magnified in patients hospitalized with CLTI, demanding optimal treatment strategies and increased attention in this population.
Although a retrospective study observed a higher rate of guideline-directed medical therapy (GDMT) use in this cohort, the association between CAD and adverse long-term clinical outcomes was amplified in the CLTI patient population.18 In patients at early stages of PAD, higher rate of GDMT was protective against MACCE and mortality despite the presence of concomitant CAD. Early implementation of optimal GDMT along with effective interventions and risk factor modifications in patients with concomitant CAD and PAD may prove crucial in preventing progression to CLTI. Interestingly, preoperative coronary angiography along with prophylactic coronary revascularization prior to an elective PAD surgery has shown to improve survival.29,30 Other studies, however, reported no changes in the outcomes due to preoperative coronary revascularization in these patients.31,32Despite the findings in our study demonstrating the increased risk associated with CLTI and concomitant CAD, there still exists a knowledge gap along with a lack of awareness of both PAD and CLTI and their associated risks.33,34
Importantly, to date, there have not been any recommendations for screening for PAD in patients with underlying CAD and vice versa. Saleh et al proposed that PAD was prevalent in 14.7% of patients with CAD, which was significantly higher than that in patients with normal coronaries.35 Another study suggested a positive correlation of severe PAD with CAD in 72% of patients.36 This high prevalence of PAD with CAD along with the high positive predictive value of ankle-brachial index (ABI) suggest that a patient with PAD should be screened for CAD with high suspicion and pretest probability. It is conceivable that ABI could probably add to the pretest probability of CAD but cannot be a surrogate for any of the original testing modalities for CAD. Consequently, the American Heart Association/American College of Cardiology (AHA/ACC) has recently highlighted the lack of public awareness of cardiovascular risks associated with PAD.37 Effective screening could further promote early implementation of optimal GDMT, along with timely interventions and risk factor modifications in patients with concomitant CAD and PAD, which might prove crucial in improving prognosis in this high-risk population.
Our study also demonstrated an increase in endovascular revascularization and decrease in surgical revascularization in adults with CLTI over time, consistent with prior reports.38-40 In the BEST CLTI (Best Endovascular Versus Best Surgical Therapy in Patients with CLTI) trial, among patients with CLTI, those with an adequate great saphenous vein had superior outcomes in reducing major adverse limb events or death with surgical revascularization compared with endovascular revascularization. However, no difference was observed in those requiring an alternative bypass conduit when a great saphenous conduit was not available.41 On the contrary, we observed a significant decrease in the risk of in-hospital mortality in patients who underwent endovascular revascularization compared with surgical revascularization, regardless of CAD status. A lower rate of bleeding associated with endovascular revascularization could be attributed as one of the contributing factors to improved prognosis in these patients. Additionally, endovascular management of PAD/CLTI patients was observed to have higher minor amputation rates. This could be due to multiple causes. Firstly, endovascular intervention could be a staged intervention to promote healing while minor amputation was already planned. Additionally, the acuity of patients could contribute to this association. Patients with higher risk factors who are not good candidates for surgery are managed through endovascular intervention. It is conceivable that endovascular management in this high-risk population has a poor prognosis and subsequently warrants additional management of CLTI.
Limitations. Our study has certain limitations. Firstly, the NIS is susceptible to documentation and coding errors as an administrative database. Nevertheless, the NIS has been validated thoroughly and annual data quality assessments are performed to maintain internal validity of the NIS database.40 Secondly, the NIS provides only in-hospital data; it remains possible that the long-term outcomes associated with the treatment strategies would differ from those observed in the hospitalized patients in our study cohort. Thirdly, many useful data such as imaging data, prescription for GDMT, laboratory results, length of stay, cost of treatment at nursing facilities to which patients were discharged, and procedural details (eg, details on bypass grafts or endovascular devices) are not available in the NIS. Future studies might take such factors into account to provide greater insight into this population. Lastly, we were unable to determine whether the revascularization procedure performed in these patients was planned or performed as a part of a strategy for future surgery. Moreover, it is plausible that endovascular revascularization could be a planned procedure performed prior to minor amputations to augment wound healing. Despite these findings, our study addresses important knowledge gaps regarding patients with CLTI and CAD.
Conclusions
In conclusion, we observed an increase in hospitalization of patients with CAD and CLTI over time. Among patients with CLTI, CAD was associated with worse prognosis, warranting immediate attention and optimization of secondary prevention strategies in this cohort. Compared with surgery, endovascular revascularization was associated with lower in-hospital mortality as well as lower bleeding events, irrespective of the CAD status.
Affiliations and Disclosures
From the 1Department of Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA; 2Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA; 3Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; 4Division of Cardiology, University of North Carolina School of Medicine, Chapel Hill, NC, USA; 5Wellstar Cardiovascular Medicine, Marietta, GA, USA; 6Section of Interventional Cardiology & Vascular Medicine, Division of Cardiology, NorthShore University Health system, Evanston, IL, USA; 7Division of Medicine II, Division of Cardiology, Medical University of Vienna, Vienna, Austria; 8Heart and Vascular Institute, University of Illinois at Urbana-Champaign, IL, USA; 9Division of Cardiology, Advocate Christ Medical Center, Chicago, IL, USA; 10Division of Interventional Radiology, NorthShore University Health System, Evanston, IL, USA; 11Department of Vascular Surgery, Loyola University Medical Center, Maywood, IL, USA; 12Department of Vascular Surgery, NorthShore University Health System, Evanston, IL, USA
Disclosures: Dr Zelniker reports research grants from the Austrian Science Funds and the German Research Foundation; honoraria for serving on advisory boards from Boehringer Ingelheim; personal fees from Alkem Lab. Ltd, AstraZeneca, Bayer AG, Boehringer Ingelheim, and Sun Pharmaceutical Industries; and educational grants from Eli Lilly and Company. Dr Qamar has received research support from the NorthShore Auxiliary Research Scholar fund, NorthShore CardioDiabetes Pilot Grant, Novo Nordisk, Idorsia Pharmaceuticals, and Novartis and serves as a consult to Penumbra Inc. The remaining authors have no disclosures to report.
Funding: No funding was provided for this work.
Address for correspondence: Arman Qamar, MD MPH FACC, Section of Interventional Cardiology & Vascular Medicine, Center for Precision Cardiology, NorthShore University Health System, Evanston, IL, USA. Email: aqamar@alumni.harvard.edu.
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