Author + information
- Received March 28, 2017
- Revision received June 10, 2017
- Accepted June 15, 2017
- Published online December 4, 2017.
- Grant W. Reed, MD, MSc,
- Laura Young, MD,
- Imad Bagh, MD,
- Michael Maier, DPM and
- Mehdi H. Shishehbor, DO, MPH, PhD∗ ()
- Heart and Vascular Institute, Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio
- ↵∗Address for correspondence:
Dr. Mehdi H. Shishehbor, Department of Cardiovascular Medicine, Cleveland Clinic, 9500 Euclid Avenue, J3-5, Cleveland, Ohio 44195.
Objectives This study sought to determine the relationship between change in ankle-brachial index (ABI) and toe-brachial index (TBI) and outcomes following revascularization of critical limb ischemia (CLI).
Background An increase in ABI of 0.15 after revascularization for peripheral artery disease with claudication is considered significant. However, the utility of using change in ABI or TBI to predict outcomes in patients with CLI is unproven.
Methods This was an observational study of 218 patients with Rutherford class V or VI CLI that underwent endovascular therapy. Receiver-operating characteristic curve analysis determined cutpoints in post-procedure ABI and TBI, as well as change in these values for endpoints of wound healing, major adverse limb events (MALE), and repeat revascularization.
Results After multivariable Cox proportional hazards analysis adjusting for age, diabetes, glomerular filtration rate, smoking, Rutherford class, and baseline ABI or TBI, neither static post-procedure ABI nor post-procedure TBI were associated with wound healing (hazard ratio [HR]: 1.21; 95% confidence interval [CI]: 0.77 to 1.89; p = 0.40; HR: 1.49; 95% CI: 0.98 to 2.27; p = 0.065, respectively). However, change in ABI ≥0.23 was independently associated with wound healing (HR: 1.87; 95% CI: 1.12 to 3.15; p = 0.018) and less repeat revascularization (HR: 0.40; 95% CI: 0.19 to 0.84; p = 0.015), but not MALE. Increase in TBI ≥0.21 was independently associated with wound healing (HR: 1.63; 95% CI: 1.02 to 2.59; p = 0.039), and reduced MALE (HR: 0.27; 95% CI: 0.09 to 0.77; p = 0.014), but not repeat revascularization.
Conclusions A change in ABI and TBI from pre-procedural values provides prognostic value in determining which patients may have wound healing and reduced MALE.
Critical limb ischemia (CLI) is the most severe manifestation of peripheral artery disease (PAD), characterized by rest pain or tissue loss that leads to major amputation or mortality in up to 50% of patients within 1 year of presentation (1–5). The economic impact of CLI is tremendous, estimated to approach $4.5 billion USD annually. With this realization, timely diagnosis and treatment of CLI is important in reducing morbidity, mortality, and managing health care costs (6).
A major challenge in the management of patients with CLI is accurate hemodynamic assessment (7,8). Noninvasive hemodynamic assessment of lower extremity perfusion with ankle-brachial index (ABI) or toe-brachial index (TBI) testing is often used for the diagnosis of CLI. However, ABI has many limitations, and the appropriate cutpoints for changes in ABI and TBI from pre- to post-revascularization in predicting wound healing, amputation-free survival, or major adverse limb events (MALE) have not been established (7,8).
To address this, we sought to examine the utility and appropriate cutpoints for changes in ABI and TBI to predict wound healing, MALE, and repeat revascularization in patients with CLI following endovascular therapy.
Of the 306 unique patients with CLI treated with endovascular therapy in the department of Cardiovascular Medicine from November 1, 2011, to May 1, 2016, 218 had at least 1 documented lower extremity wound (Rutherford class V to VI) as defined by American Heart Association/American College of Cardiology guidelines (2,5). Only unique patients were included; if patients had endovascular therapy on both legs or repeat procedures, only the first leg was included in the analysis. Patients with claudication or rest pain (Rutherford class I to IV) were excluded. The study was approved by the institutional review board before data collection.
Patient characteristics, medication use, procedural characteristics, laboratory values, and data from noninvasive hemodynamic ABI and TBI testing were collected via the electronic medical record. Clinical outcome data were obtained via the electronic medical record or contacting patients via telephone (as is usual clinical practice in our institution). The severity of tissue loss was classified by Rutherford classification (V or VI), and the presence, dimensions, and characteristics of all wounds on the extremity undergoing endovascular therapy were documented before intervention and assessed during interval follow-up. Each patient had a follow-up visit or nursing phone call within 30 days of the index procedure. Wound characteristics and the date of wound healing were determined by a nurse, podiatrist, or physician and documented in the electronic medical record.
The study primary outcome was wound healing during follow-up. All patients were followed longitudinally in the institutional Cardiovascular Lower Extremity Wound Clinic, which comprises a multidisciplinary team of nurses, podiatrists, and physicians that assess wound healing at regularly scheduled intervals. The criteria for a healed wound was complete wound healing of the index wound(s) as documented by the wound healing team. In patients with more than 1 wound, patients were classified as “healed” if the wound in the distribution of the angiosome intervened on completely healed. Secondary endpoints included need for subsequent lower extremity endovascular therapy including percutaneous transluminal angioplasty (PTA) or stenting, or MALE defined as a composite of the first instance of major amputation (above-the-knee or below-the-knee amputation, excluding transmetatarsal or digital), surgical bypass, or surgical endarterectomy to the index limb. Procedural success was defined as successful intervention to the target artery with at least 1 vessel angiographic runoff to the foot at the end of the procedure. In patients where more than 1 below-the-knee vessel was affected, priority was given to restoring flow to the artery supplying the territory of the wound (i.e. a “direct” or angiosome reperfusion approach was used in most cases) (9–11). The decision to perform repeat intervention was made based on a multidisciplinary evaluation by podiatry, interventional cardiology, and infectious disease. Factors that were considered were inadequate wound healing, pain, or worsening hemodynamics in the presence of persistent wounds. Wound healing was only assessed at visits in person; the secondary endpoints including subsequent PTA, MALE, surgical bypass, or surgical endarterectomy were assessed via telephone in a small minority of patients (<5% of cases). All patients were evaluated in the Cardiovascular Lower Extremity Wound Clinic after intervention at least once.
The optimal post-procedure ABI and change in ABI cutpoints for discrimination of the primary endpoint of wound healing were determined via receiver-operating characteristic (ROC) curve analysis. Cox proportional hazards analysis was then used to assess whether the change in ABI cutpoint was associated with wound healing. If statistically significant, this same cutpoint was used to assess whether change in ABI was associated with the secondary endpoints of MALE or subsequent PTA. These same analyses were then repeated using post-procedure TBI and change in TBI. Patients with noncompressible pre- or post-procedure ABI, or missing post-procedure ABI were excluded from change in ABI analyses. Similarly, patients with missing post-procedure TBI were not able to be included in change in TBI analyses.
Continuous variables are presented as mean ± SD if normally distributed, median (interquartile range [IQR]) if non-normally distributed, and categorical variables as total number (percent) of patients. Student’s t test was used to compare normally distributed continuous data, the Wilcoxon rank-sum test was used for nonparametric variables, and frequency distribution utilizing chi-square or Fisher exact tests were used to compare categorical variables across groups. The optimal cutpoint values for dichotomous analysis of post-procedure ABI, change in ABI, post-procedure TBI, and change in TBI were determined using ROC analysis, as described previously. The ability of this optimal cutpoint of change in ABI and TBI to serve as predictors of outcomes was assessed via Cox proportional hazards analysis. Kaplan-Meier analysis was then used to compare the cumulative probabilities of each outcome across groups. Characteristics were tested for independent associations with outcomes via multivariable adjustment in the Cox models, utilizing as many variables as possible but avoiding overfitting in a 15:1 event-to-variable ratio, in a parsimonious fashion prioritizing variables known to be clinically significant based on prior studies. The final model was chosen in a backward selection method minimizing Akaike information criterion. Each term in the Cox model satisfied the proportionality assumption, as did the overall model. Statistical significance for all comparisons was determined as p < 0.05, using 2-tailed p values wherever appropriate. All data analysis was performed with R version 3.1.0 (R Foundation for Statistical Computing, Vienna, Austria).
Study population and procedural characteristics
Table 1 describes patient and wound characteristics of the study population. As typical of patients with CLI, there was a high prevalence of comorbidities, including hypertension, hyperlipidemia, diabetes mellitus, and history of cigarette smoking. There was a high proportion of patients (27.5%) with multiple (>1) wounds. Approximately 30% of patients had Rutherford class VI wounds, among which almost all had gangrene or osteomyelitis. Table 2 provides procedural characteristics. A total of 85.4% of patients had infrapopliteal intervention, and approximately half of patients had isolated PTA without stenting or atherectomy. There was a high degree of procedural success (91.3%).
ABI and outcomes
ABI was noncompressible in 57 (26.1%) patients, and post-procedure ABI was not available in 23 (10.6%) patients. Among those with compressible ABI, average pre-procedure ABI was 0.63, whereas post-procedure ABI was significantly higher at 0.84 (p < 0.0001) (Figure 1). On average, ABI increased 0.21 (95% confidence interval [CI]: 0.15 to 0.28) after procedure. The median post-procedure ABI was 0.91, with a 75th percentile of 1.06. The median change in ABI was 0.23, with a 75th percentile of 0.40.
During a median follow-up of 257 (IQR: 78 to 633) days, wound healing occurred in 112 (51.4%) patients, MALE in 42 (19.3%) patients, and repeat PTA in 61 (28.0%) patients. By ROC analysis, the optimal post-procedure ABI to discern patients who had wound healing during follow-up was 0.91 (area under the curve [AUC]: 0.54). However, there was no association with wound healing using this cutpoint (hazard ratio [HR]: 1.21; 95% CI: 0.77 to 1.89; p = 0.40). In contrast to using a single post-procedure value only, the change in ABI from pre-procedure was a good discriminator of wound healing, with an optimal change in ABI of 0.23 (AUC: 0.63). Using this cutpoint, there was a significant association with increased wound healing (HR: 1.73; 95% CI: 1.10 to 2.73; p = 0.018). After multivariable adjustment for the presence of diabetes, age, glomerular filtration rate, history of smoking, and Rutherford class, and pre-procedure ABI, change in ABI ≥0.23 remained an independent predictor of wound healing (HR: 1.87; 95% CI: 1.12 to 3.15; p = 0.018). A change in ABI ≥0.23 was also associated with less need for subsequent PTA after multivariable adjustment for these same variables (HR: 0.40; 95% CI: 0.19 to 0.84; p = 0.015). There was no association observed between change in ABI and MALE.
On Kaplan-Meier analysis the probability of wound healing was significantly greater in patients with an ABI increase ≥0.23 following endovascular revascularization (log-rank p = 0.017) (Figure 2). There was no difference in the cumulative probability of MALE (p = 0.75) or subsequent PTA based on this cutpoint (p = 0.11).
TBI and outcomes
Post-procedure TBI was not available in 58 (26.6%) patients. The average pre-procedure TBI was 0.19, whereas post-procedure TBI was significantly higher at 0.30 (p = 0.0001) (Figure 3). On average, TBI increased 0.11 (95% CI: 0.05 to 0.19) after procedure. The median post-procedure TBI was 0.28, with a 75th percentile of 0.48. The median change in TBI was 0.04, with a 75th percentile of 0.23.
The optimal post-procedure TBI to discern wound healing was 0.30 (AUC: 0.56). Similar to post-procedure ABI, there was no association with wound healing using this cutpoint (HR: 1.49; 95% CI: 0.98 to 2.27; p = 0.065). The optimal change in TBI cutpoint of was 0.21 (AUC: 0.56), which was significantly associated with increased wound healing during follow-up (HR: 1.57; 95% CI: 1.01 to 2.43; p = 0.044), as well as less risk of MALE (HR: 0.27; 95% CI: 0.10 to 0.78; p = 0.015). There was no significant association between an increase in TBI ≥0.21 and need for subsequent PTA. After multivariable adjustment for presence of diabetes, age, glomerular filtration rate, history of smoking, and Rutherford class, and baseline TBI, an increase in TBI ≥0.21 remained independently associated with improved wound healing (HR: 1.63; 95% CI: 1.02 to 2.59; p = 0.039) and less MALE (HR: 0.27; 95% CI: 0.09 to 0.14; p = 0.014), but not less need for subsequent PTA.
On Kaplan-Meier analysis the probability of wound healing was significantly greater in patients with a TBI increase ≥0.21 (log-rank p = 0.042) (Figure 4A). In addition, there was substantially less need for MALE in patients with an increased TBI ≥0.21 (log-rank p = 0.0094) (Figure 4B).
Hemodynamic assessment of lower extremity perfusion in patients with CLI remains a challenge; although TBI has been shown to have better accuracy for the diagnosis of CLI than for ABI (4,7–9,12,13), the value of ABI and TBI in post-intervention surveillance and prognostication is less clear. This is the first study to demonstrate the use of serial pre- and post-procedural ABI and TBI testing for the prediction of wound healing and MALE following endovascular therapy for CLI. We demonstrate that an increase in ABI ≥0.23 after endovascular therapy is independently associated with improved wound healing and less need for repeat PTA during long-term follow-up. Further, an increase in TBI ≥0.21 was independently associated with improved wound healing as well as less MALE. These findings prove the value of post-procedure ABI and TBI testing, and support measurement of these parameters after endovascular therapy for CLI.
Our results suggest that post-procedure ABI or TBI values are not associated with outcomes after endovascular therapy when considered in static. Rather, we show that the post-procedure change in ABI or TBI from pre-procedure values may be useful for prognostication of wound healing and hard limb outcomes after revascularization for CLI. Although change in ABI and change in TBI were relatively weak discriminators of outcomes given their low AUC values on ROC analysis, using the threshold values obtained from ROC analysis nonetheless allowed us to uncover significant relationships with clinical outcomes. Furthermore, many factors impact wound healing, not just perfusion; therefore, the low AUC may represent the complex nature of wound healing in patients with CLI. Ours are the first data to prove that a change in ABI and TBI may be useful to prognosticate which patients with CLI may have better wound healing, and lower MALE, following intervention.
Although ABI and TBI remain important tools to assess hemodynamics in patients with CLI, they have many limitations. Prior studies have shown that approximately 30% of patients with CLI and isolated below-knee disease have normal or noncompressible ABI (7,8), findings supported by the current study. Assessment using ABI alone in these patients will not be useful. TBI has been shown to be more accurate for the diagnosis of CLI in these patients, but it is not widely measured, and in patients with distal toe ulcer it is not feasible (7,8). Despite this, we have shown that assessment of ABI and TBI pre- and post-procedure can provide guidance to the CLI team regarding the likelihood of wound healing and MALE during follow-up.
Our cutpoints are unique and go beyond those previously recommended by the current guidelines (12). The cutpoint of a change in ABI of 0.15 previously recommended was only validated in patients with claudication, and its prognostic value in patients with wounds and CLI is unknown. In the current study, a change in ABI of 0.15 was not the best predictor of wound healing. Rather, a change in ABI ≥0.23 was clinically significant, indicating that a larger change is needed in patients with CLI and wounds. Thus, our findings do not support using the ABI 0.15 cutpoint for patients with CLI to assess wound healing. Currently, there are no established cutpoints for change in TBI; however, our results suggest that a post-revascularization increase in TBI ≥0.21 is associated with improved wound healing and less MALE in patients with CLI.
Understanding post-procedural microvascular perfusion using TBI may have many potential advantages. Although not yet studied, it is plausible that post-procedure TBI may provide guidance regarding which patients may benefit from more aggressive post-procedural adjunctive therapy such as an arterial flow pump or hyperbaric oxygen therapy. Furthermore, new tools are being developed to assess perfusion continuously, even during revascularization procedures, which may one day advance perfusion assessment beyond pre- and post-procedure ABI and TBI (14).
Improving patient outcomes with serial hemodynamic assessment pre- and post-revascularization may also have economic ramifications in the era of bundled payments and the Affordable Care Act. By identifying patients at high risk for poor wound healing and MALE, physicians can target outpatient resources to these patients in an effort to minimize adverse outcomes. Such efforts may prevent readmissions, reduce recurrent procedures, and save health care costs (15,16). These benefits of perfusion testing will need to be tested and confirmed by others. It is possible that post-procedure hemodynamic guidance in the care of CLI patients with wounds may be an important step toward minimizing the heterogeneous care that these patients often receive, and may allow for personalized treatment for these patients (9,10).
There are certain limitations of the current study. Although our sample size was relatively large for a study of patients with CLI and wounds, not all patients had post-procedure ABI or TBI due to a significant number of patients with missing or noncompressible pulse volume recordings or inability to obtain TBI because of prior transmetatarsal amputation or the presence of wounds on the first and/or second toes. This may have limited our ability to determine if a relationship between static post-procedure ABI and TBI and outcomes exists. Likewise, our modest sample size did not allow for a separate comparison of ABI and TBI cutpoints in patients with Rutherford class V and VI CLI. In addition, we did not collect detailed angiographic data, and thus an analysis of pedal arch patency and the effect on ABI, TBI, or wound healing was not performed in this study. We did not collect data on how many patients were on cilostazol, hyperbaric oxygen therapy, or arterial flow pump therapy. However, in our practice very few patients (i.e., <5%) are provided hyperbaric oxygen or arterial flow pump therapy, and thus these are unlikely to have confounded our results. Further, although the vast majority of patients followed up as scheduled in our institutional (or an affiliated) wound care centers, it is possible that some events may not have been captured. However, we were able to detect significant relationships among change in ABI, change in TBI, wound healing, and specific limb endpoints, suggestive that this likely had a limited effect on our study results.
A change in ABI or TBI from pre-procedural values provides prognostic value in determining which patients may have improved wound healing and lower MALE following endovascular therapy for CLI. Specifically, an increase in ABI ≥0.23 is associated with increased wound healing and less need for subsequent PTA, and an increase in TBI ≥0.21 is associated with better wound healing and less MALE. Our results provide support to noninvasive hemodynamic assessment of lower extremity perfusion after endovascular therapy. These data may help guide physicians and organizations in offering personalized post-procedure care to patients with CLI, tailored by their objective hemodynamic data.
WHAT IS KNOWN? The utility of using change in ABI or TBI to predict wound healing and MALE following endovascular treatment of CLI is unproven.
WHAT IS NEW? An increase in ABI ≥0.23 was independently associated with wound healing and less repeat revascularization, and an increase in TBI ≥0.21 was independently associated with wound healing and reduced MALE.
WHAT IS NEXT? Future studies are needed to develop personalized treatment strategies based on perfusion to guide patient care in patients with CLI.
Dr. Shishehbor has served as a consultant and educator for Medtronic, Boston Scientific, Abbott Vascular, and Spectranetics. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- ankle-brachial index
- area under the curve
- confidence interval
- critical limb ischemia
- hazard ratio
- major adverse limb events
- peripheral artery disease
- percutaneous transluminal angioplasty
- toe-brachial index
- Received March 28, 2017.
- Revision received June 10, 2017.
- Accepted June 15, 2017.
- 2017 American College of Cardiology Foundation
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