Lack of Association Between Limb Hemodynamics and Response to Infrapopliteal Endovascular Therapy in Patients With Critical Limb Ischemia

Abstract: Background. Non-invasive limb hemodynamics may aid in diagnosis of critical limb ischemia (CLI), although the relationship with disease severity and response to endovascular therapy is unclear. Methods and Results. This prospective, single-center study enrolled 100 CLI patients (Rutherford class 4-6) who underwent infrapopliteal endovascular revascularization (175 lesions) in the Peripheral RegIstry of Endovascular Clinical OutcoMEs (PRIME) registry. Hemodynamic measures included ankle-brachial index (ABI), toe-brachial index (TBI), and toe pressure (TP). Procedure success following revascularization was defined as stenosis ≤30%. Hemodynamic success was defined as an increase >0.15 in ABI or TBI relative to baseline. Freedom from amputation was defined as no major or minor amputation during follow-up. Clinical success was defined as a decrease of at least one Rutherford class during follow-up. Treatment success was defined as procedure success, freedom from amputation, and clinical improvement. Median baseline hemodynamic values were 0.90 for ABI, 0.39 for TBI, and 54 mm Hg for TP. Twenty-nine patients (29%) did not meet the common hemodynamic diagnostic criterion for eligibility in CLI trials (ABI ≤0.5, TBI ≤0.5, or TP <50 mm Hg). Main outcomes included 96% procedure success, 95% freedom from amputation, 64% clinical success, and 62% treatment success. There was no relationship between baseline (or with the pretreatment to posttreatment change) limb hemodynamic values and the response to infrapopliteal endovascular therapy. Conclusion. Non-invasive hemodynamic studies may have limited clinical usefulness in patients with CLI. The usefulness of these parameters to confirm eligibility and to assess response to therapy in interventional CLI clinical trials should be re-evaluated. 

J INVASIVE CARDIOL 2017;29(5):175-180.

Key words: critical limb ischemia, endovascular, hemodynamic, infrapopliteal

Symptomatic peripheral artery disease affects 15%-20% of older adults and is associated with a 4-fold increase in all-cause mortality risk and an 8-fold increase in cardiovascular mortality risk.¹ Peripheral artery disease may insidiously progress to critical limb ischemia (CLI), defined as the presence of rest pain requiring analgesia and/or ischemic tissue loss.² Prognosis following CLI diagnosis is grave, with 1-year mortality and major amputation rates ranging from 20%-50%.^3-5 These statistics underscore the importance of early diagnosis and intervention to improve tissue perfusion, relieve pain, and promote wound healing.^6-10 

The diagnosis of CLI is routinely based on clinical symptoms and confirmed by measurements of non-invasive limb hemodynamics such as ankle-brachial index (ABI), toe-brachial index (TBI), and/or toe pressure (TP).¹¹ Limb hemodynamic measures are often used to confirm eligibility in CLI clinical trials where ABI ≤0.5, TBI ≤0.5, and/or TP <50 mm Hg are required for enrollment.^6,11-16 These measures are also used to quantify response to therapy in CLI clinical trials where ABI or TBI increases >0.15 are taken as evidence of hemodynamic success.^17,18 However, recent studies have shown that many CLI patients do not meet these diagnostic hemodynamic criteria.^6,11,19 Furthermore, the association between changes in these hemodynamic parameters and clinical outcomes following endovascular therapy is unclear. The purpose of this study was to assess the relationship of limb hemodynamics with response to infrapopliteal endovascular revascularization in patients with CLI. 

Methods

Patients. This is a prospective, single-center study of consecutive CLI patients who underwent infrapopliteal endovascular revascularization in the Peripheral RegIstry of Endovascular Clinical OutcoMEs (PRIME) registry. Institutional review board approval and patient consent were obtained prior to any procedures or data collection. Eligible patients were adults ≥18 years with symptomatic CLI (Rutherford class 4-6) and angiographically confirmed infrapopliteal disease that required endovascular revascularization. Patients underwent clinical examination and noninvasive limb hemodynamic measurements, including ABI, TBI, and TP prior to revascularization and within 3 months post intervention on the affected limb. 

Procedures. Hemodynamic measures were obtained after subjects rested supine for 5 minutes. Systolic pressures were measured in both arms (brachial artery) and at the dorsalis pedis and posterior tibial arteries using a MultiLab Series 2-CP (Unetixs Vascular) or Dopplex D900 Doppler waveform analyzer (Huntleigh). ABI was calculated as the ratio between the higher of the ankle pressures and the higher brachial pressure. Systolic TP was evaluated at the hallux using a MultiLab Series 2-CP (Unetixs Vascular) or Vista Doppler waveform analyzer (Wallach Surgical Devices) by photoplethysmography. TBI was calculated as the ratio between toe pressure and the higher brachial pressure.    

Endovascular revascularization was attempted on all study subjects. Intervention included angiographic evaluation of arterial stenosis of the infrainguinal and infrapopliteal arteries by physician estimate, prior to infrapopliteal intervention of the target lesions. Revascularization method was determined by the treating physician and included one or a combination of the following: atherectomy, percutaneous transluminal angioplasty, drug-coated balloon angioplasty, and/or bare-metal or drug-eluting stent placement.  Angiography was performed to assess procedure success post revascularization. 

Outcomes and definitions. Procedure success following revascularization was defined as stenosis ≤30% determined by physician visual estimate. Hemodynamic success was defined as an increase >0.15 in ABI or TBI relative to baseline following endovascular therapy. Freedom from amputation was defined as no major (above the ankle) or minor (below the ankle) amputation during follow-up. Clinical success was defined as a decrease of at least one Rutherford class during follow-up. Treatment success was a composite endpoint that comprised procedure success, freedom from amputation, and clinical improvement. 

Data analysis. Continuous data were reported as mean and standard deviation or median and interquartile range, depending on normality assumptions. Categorical data were reported as frequencies and percentages. Group comparisons were performed with independent samples t-test for normally distributed continuous data, Mann-Whitney U-test for non-normally distributed continuous data, or Fisher’s exact test for categorical data. Longitudinal changes in clinical outcomes were assessed with paired t-tests or Wilcoxon signed-rank test, based on normality. Univariate logistic regression assessed the relationship of baseline characteristics on treatment success. Variables that loaded into the univariate model at P<.10 were evaluated in a multivariable model using backward elimination (likelihood ratio method). A P-value <.05 was considered statistically significant. Data were analyzed using Predictive Analytics Software version 22 (SPSS, Inc). 

Results

A total of 100 patients clinically diagnosed with CLI (Rutherford class 4-6) underwent infrapopliteal endovascular revascularization between January 2013 and January 2016. Mean age was 75 years and 67% were male. The most common comorbidities were dyslipidemia (92%), hypertension (89%), and diabetes mellitus (68%). Over 50% of patients presented with at least chronic kidney disease stage 3 (glomerular filtration rate <60 mL/min). Median baseline hemodynamic values were 0.90 for ABI, 0.39 for TBI, and 54 mm Hg for TP (Table 1). There was no significant association between baseline ABI and TBI values (Figure 1). Twenty-nine patients (29%) did not meet the common hemodynamic diagnostic criterion for eligibility in CLI trials (ABI ≤0.5, TBI ≤0.5, or TP <50 mm Hg).

Revascularization was performed in 175 infrapopliteal lesions. Treated segments included the popliteal artery (P3 segment) (25%), anterior tibial artery (24%), tibioperoneal trunk (15%), peroneal artery (15%), posterior tibial artery (13%), dorsalis pedis (3%), lateral plantar artery (2%), medial plantar artery (1%), lateral calcaneal artery (1%), and pedal loop (1%). Main outcomes included 96% procedure success, 95% freedom from amputation, 64% clinical success, and 62% treatment success. 

When comparing patients based on hemodynamic diagnostic eligibility, there were no observable differences in baseline characteristics or in response to infrapopliteal endovascular therapy (Table 2). Baseline ABI (Figure 2A) and TBI (Figure 2B) were not different in patients with treatment success or treatment failure. In the univariate logistic regression model, lower Rutherford class, absence of diabetes, higher glomerular filtration rate, and higher hemoglobin were associated with treatment success and subsequently included in the multivariate model. Notably, neither ABI (P=.20), TP (P=.23), nor TBI (P=.31) predicted treatment success after endovascular therapy. In the multivariate logistic regression model, only lower Rutherford class (odds ratio, 19.8; 95% confidence interval [CI], 5.5-71.6; P<.001) was associated with treatment success (Table 3). 

Despite the high procedure success rate following endovascular therapy, only minimal (albeit statistically significant) increases in limb hemodynamics were observed. Hemodynamic success was 56%, ABI increased from 0.93 ± 0.35 to 1.06 ± 0.26 (P<.001), TBI increased from 0.42 ± 0.25 to 0.49 ± 0.25 (P=.04), and TP increased from 61 ± 38 mm Hg to 71 ± 37 mm Hg (P=.04). When comparing patients with hemodynamic success vs hemodynamic failure, there were no statistical differences in procedure success, freedom from amputation, clinical success, or treatment success (Figure 3).

Discussion

Data regarding the effectiveness of endovascular modalities for the treatment of infrapopliteal disease in patients with CLI are beginning to emerge with variable outcomes. The results of this study demonstrated a lack of association of non-invasive limb hemodynamic measures with baseline patient characteristics, disease severity, and response to infrapopliteal endovascular therapy among patients with CLI. Therefore, the clinical usefulness of these measures in patients with CLI is questionable. 

The accuracy of non-invasive hemodynamic testing to identify patients with CLI with compromised infragenicular run-off has been studied by several authors. Bunte and colleagues⁶ showed that 29% of patients with CLI and abnormal infrapopliteal run-off had normal or mildly abnormal ABIs (defined as ABI >0.7 and <1.4), and that low TBI was not associated with abnormal infrapopliteal run-off. However, TBI values were somewhat higher with improved pedal perfusion, questioning the utility of these indices to assess limb hemodynamics in CLI patients with abnormal infrapopliteal anatomy. Shishehbor et al¹⁹ reported only 16% of CLI patients had abnormal ankle pressures and that abnormal TP had better specificity in CLI diagnosis. Still, 40% of patients in this study had normal TP values and neither ABI nor TP were associated with disease severity. Vallabhaneni et al²⁰ reported that CLI patients with TP ≤10 mm Hg had higher amputation rates relative to those with TP of 31-50 mm Hg (60% vs 18%, respectively; P<.001); however, patients did not have exclusive infrapopliteal disease, as in our current study. Our results suggest only a weak association between limb hemodynamics and response to infrapopliteal endovascular therapy; instead, Rutherford class was the sole predictor of treatment success in multivariate analysis.    

Commonly utilized non-invasive limb hemodynamic assessments can be misleading and unreliable in CLI, as they frequently failed to identify patients with severe disease and limb-threatening angiographic anatomies in the current study. No differences were observed in outcomes after endovascular therapy among patients with CLI regardless of baseline ABI, TBI, or TP, many of which would have been otherwise considered “normal” and possibly resulted in denial of therapy that could have otherwise proven beneficial. Ongoing studies designed to identify patients with CLI who would benefit from specific methods of endovascular therapy have used ABI, TBI, and TP values of ≤0.5, ≤0.5, and/or <50 mm Hg, respectively, as inclusion criteria (and hence as surrogate diagnostic criteria for CLI). Results from the current study suggest that the use of limb hemodynamic measures as inclusion/exclusion criteria in studies of infrapopliteal therapies is questionable, since many appropriate patients are excluded using these thresholds. Furthermore, this study questions the necessity of performing non-invasive studies as surveillance tools after infrapopliteal revascularization procedures in patients with CLI given the lack of association between hemodynamic success and clinical outcomes. Clinicians should maintain a high index of suspicion and a low threshold to proceed with repeat revascularization when dictated by clinical judgment regardless of the information provided by the aforementioned tests. Emerging modalities such as evaluation by skin perfusion pressure, transcutaneous oxygen pressure, fluorescent angiography through the use of indocyanine green dye, subcutaneous implantation of oxygen microsensors, or use of two-dimensional perfusion imaging software are promising, and given further study, may prove useful in diagnosis and prognosis of patients with complex peripheral arterial disease and CLI.^21-25

Study limitations. There were several limitations of this study that may impact interpretability. First, patient outcomes were reported through 3 months post treatment. Therefore, the relationship of limb hemodynamics with longer-term clinical outcomes after endovascular therapy in patients with infrapopliteal disease cannot be evaluated in this study. Second, physicians involved in patient follow-up were not blinded to the intervention and the results of the preprocedural non-invasive limb hemodynamics. Finally, the study represents a single-center experience, where patients were not randomized and were treated by experienced operators specifically trained in CLI therapy. 

Conclusion

Non-invasive hemodynamic studies may have limited clinical usefulness in patients with CLI. The use of these measures to confirm eligibility and to assess response to therapy in interventional CLI clinical trials should be re-evaluated. 

References

1.    Brevetti G, Schiano V, Verdoliva S, et al. Peripheral arterial disease and cardiovascular risk in Italy. Results of the Peripheral Arteriopathy and Cardiovascular Events (PACE) study. J Cardiovasc Med (Hagerstown). 2006;7:608-613.

2.    Second European Consensus Document on chronic critical leg ischemia. Eur J Vasc Surg. 1992;6:1-32.

3.    Bosiers M, Scheinert D, Peeters P, et al. Randomized comparison of everolimus-eluting versus bare-metal stents in patients with critical limb ischemia and infrapopliteal arterial occlusive disease. J Vasc Surg. 2012;55:390-398.

4.    Balzer JO, Zeller T, Rastan A, et al. Percutaneous interventions below the knee in patients with critical limb ischemia using drug eluting stents. J Cardiovasc Surg (Torino). 2010;51:183-191.

5.    Siablis D, Karnabatidis D, Katsanos K, Diamantopoulos A, Christeas N, Kagadis GC. Infrapopliteal application of paclitaxel-eluting stents for critical limb ischemia: midterm angiographic and clinical results. J Vasc Interv Radiol. 2007;18:1351-1361.

6.    Bunte MC, Jacob J, Nudelman B, Shishehbor MH. Validation of the relationship between ankle-brachial and toe-brachial indices and infragenicular arterial patency in critical limb ischemia. Vasc Med. 2015;20:23-29.

7.    Dormandy J, Heeck L, Vig S. The natural history of claudication: risk to life and limb. Semin Vasc Surg. 1999;12:123-137.

8.    Muluk SC, Muluk VS, Kelley ME, et al. Outcome events in patients with claudication: a 15-year study in 2777 patients. J Vasc Surg. 2001;33:251-257; discussion 257-258.

9.    Dormandy JA, Charbonnel B, Eckland DJ, et al; PROactive Study Investigators. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet. 2005;366:1279-1289.

10.    Nehler MR, Peyton BD. Is revascularization and limb salvage always the treatment for critical limb ischemia? J Cardiovasc Surg (Torino). 2004;45:177-184.

11.    Gray BH, Diaz-Sandoval LJ, Dieter RS, Jaff MR, White CJ. Peripheral Vascular Disease Committee for the Society for Cardiovascular A and Interventions. SCAI expert consensus statement for infrapopliteal arterial intervention appropriate use. Catheter Cardiovasc Interv. 2014;84:539-545.

12.    Medicine JH. Pivotal study. 2016;2016.

13.    ClinicalTrials.gov. NCT02234778: Evaluation of the Tissue Genesis Icellator Cell Isolation System to treat critical limb ischemia (CLI-DI). Accessed 2016.

14.    Anderson JL, Halperin JL, Albert NM, et al. Management of patients with peripheral artery disease (compilation of 2005 and 2011 ACCF/AHA guideline recommendations): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2013;127:1425-1443.

15.    de Graaff JC, Ubbink DT, Legemate DA, Tijssen JG, Jacobs MJ. Evaluation of toe pressure and transcutaneous oxygen measurements in management of chronic critical leg ischemia: a diagnostic randomized clinical trial. J Vasc Surg. 2003;38:528-534.

16.    Norgren L, Hiatt WR, Dormandy JA, et al. Inter-society consensus for the management of peripheral arterial disease (TASC II). J Vasc Surg. 2007;45:S5-S67.

17.    Conte MS, Geraghty PJ, Bradbury AW, et al. Suggested objective performance goals and clinical trial design for evaluating catheter-based treatment of critical limb ischemia. J Vasc Surg. 2009;50:1462-73.e1-e3.

18.    Eskelinen E, Alback A, Roth WD, et al. Infra-inguinal percutaneous transluminal angioplasty for limb salvage: a retrospective analysis in a single center. Acta Radiol. 2005;46:155-162.

19.    Shishehbor MH, Hammad TA, Zeller T, Baumgartner I, Scheinert D, Rocha-Singh KJ. An analysis of IN.PACT DEEP randomized trial on the limitations of the societal guidelines – recommended hemodynamic parameters to diagnose critical limb ischemia. J Vasc Surg. 2016;63:1311-1317.

20.    Vallabhaneni R, Kalbaugh CA, Kouri A, Farber MA, Marston WA. Current accepted hemodynamic criteria for critical limb ischemia do not accurately stratify patients at high risk for limb loss. J Vasc Surg. 2016;63:105-112.

21.    Brownrigg JR, Hinchliffe RJ, Apelqvist J, et al; International Working Group on the Diabetic Foot. Performance of prognostic markers in the prediction of wound healing or amputation among patients with foot ulcers in diabetes: a systematic review. Diabetes Metab Res Rev. 2016;32:128-135.

22.    Connolly PH, Meltzer AJ, Spector JA, Schneider DB. Indocyanine green angiography aids in prediction of limb salvage in vascular trauma. Ann Vasc Surg. 2015;29:1453.e1-e4.

23.    Iida O, Nakamura M, Yamauchi Y, et al; OLIVE Investigators. Endovascular treatment for infrainguinal vessels in patients with critical limb ischemia: OLIVE registry, a prospective, multicenter study in Japan with 12-month follow-up. Circ Cardiovasc Interv. 2013;6:68-76.

24.    Montero-Baker MF, Au-Yeung KY, Wisniewski NA, et al. The first-in-man “Si Se Puede” study for the use of micro-oxygen sensors (MOXYs) to determine dynamic relative oxygen indices in the feet of patients with limb-threatening ischemia during endovascular therapy. J Vasc Surg. 2015;61:1501-1509.e1.

25.    Murray T, Rodt T, Lee MJ. Two-dimensional perfusion angiography of the foot: technical considerations and initial analysis. J Endovasc Ther. 2016;23:58-64.

From ¹Metro Health Hospital, Wyoming, Michigan; ²Rex Healthcare and University of North Carolina Health Systems, Raleigh, North Carolina; ³Newton Wellesley Hospital, Boston, Massachusetts; ⁴Mount Sinai Medical Center, Miami, Florida; and ⁵Miller Scientific Consulting, Inc, Asheville, North Carolina.

Funding. L. Miller was compensated by Metro Health Hospital for statistical analysis and interpretation. The remaining authors received no compensation for their contributions to this work. 

Disclosure. The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report unrestricted research grants to Metro Health Hospital to support the PRIME registry from Bard Peripheral Vascular, Terumo Interventional Systems, Cardiovascular Systems, Inc, Access Closure, Medtronic, Boston Scientific, and Spectranetics. Dr Mustapha reports personal fees from Bard Peripheral Vascular, Terumo Interventional Systems, Cardiovascular Systems, Inc, Medtronic, Boston Scientific, and Spectranetics. Dr Diaz-Sandoval reports personal fees from Bard Peripheral Vascular, Terumo Corporation, and Cardiovascular Systems, Inc. Dr Adams reports personal fees from Bard Peripheral Vascular, Terumo Interventional Systems, Cardiovascular Systems, Inc, Medtronic, Boston Scientific, and Spectranetics. Dr Jaff reports non-financial support (non-compensated advisor) from Medtronic, Boston Scientific, Abbott Vascular, and Cordis; personal fees from Cardinal Health, Volcano, and VIVA Physicians, a 501c3 not-for-profit education and research organization (board member); equity investment in PQ Bypass. Dr Beasley reports personal fees from Bard Peripheral Vascular, Cook, Abbott Vascular, Cardinal Health, Cardiovascular Systems, Inc, Medtronic, Boston Scientific, and Spectranetics. Dr Miller reports personal fees from Metro Health Hospital, Spectranetics, and Medtronic. Dr Saab reports personal fees from Bard Peripheral Vascular, Terumo Interventional Systems, Cardiovascular Systems, Inc, Medtronic, Boston Scientific, and Spectranetics. Theresa McGoff, Sara Finton, and Dr Ansari report no conflicts of interest regarding the content herein.

Manuscript submitted January 4, 2017, final acceptance given January 11, 2017.

Address for correspondence: Jihad A. Mustapha, MD, Metro Health Hospital, 5900 Byron Center SW, PO Box 9490, Wyoming, MI 49519. Email: jihad.mustapha@metrogr.org