Abstract: Objective. Peripheral arterial disease (PAD) is associated with poor outcomes. We assessed the clinical outcomes of diabetic versus non-diabetic patients with PAD who underwent peripheral transluminal angioplasty (PTA). Methods. The outcomes of 239 consecutive patients with symptomatic PAD who underwent PTA were analyzed. Restenosis and clinical outcomes were assessed at a follow-up of 2 years. Results. Diabetic patients had a higher percentage of wound as the initial diagnosis for PTA (72.7% vs 14.2%; P<.001), chronic kidney disease (26.7% vs 6.3%; P<.01), need for dialysis (19.3% vs 3.1%; P<.01), and coronary artery disease (67.6% vs 50.7%; P=.02). Infrapopliteal PTA was more commonly performed in the diabetic group (70.4% vs 25.3%; P<.001). Diabetic patients had lower rates of angiographic follow-up at 8 months (38.6% vs 60.3%; P<.01). Diabetic patients had higher binary restenosis (54.4% vs 31.5%; P=.02) and had a trend toward a higher incidence of total occlusion (34.0% vs 19.5%; P=.08). At 2-year follow-up, the amputation rate was higher in the diabetic group (24.4% vs 1.5%; P<.001) despite PTA. Conclusion. Diabetic patients more frequently presented with critical limb ischemia compared with non-diabetic patients and had higher rates of restenosis and amputation at 2 years following standard PTA. Improved therapies are needed for this high-risk group of patients.
J INVASIVE CARDIOL 2015;27(3):167-171
Key words: amputation, critical limb ischemia, peripheral transluminal angioplasty, PTA
The prevalence of diabetes mellitus (DM) has more than tripled, from 5.6 million patients in 1980 to 20.9 million in 2011 in the United States (US).1 Diabetes mellitus is a strong risk factor for not only coronary artery disease but peripheral arterial disease (PAD). Patients with PAD are at higher risk of subsequent cardiovascular events including death, myocardial infarction, and stroke.2-7 Of the 12 million patients in the US with PAD, approximately 20%-30% of the patients have DM.8 Diabetes mellitus increases the incidence of gangrene of the lower extremities 100-fold.9 Diabetes mellitus is one of the most common causes of non-traumatic lower-limb amputations in the US.10 Diabetic patients with PAD often have a large burden of calcific and fibrocalcific disease, particularly in the distal vasculature.11 Severe calcification renders peripheral transluminal angioplasty (PTA) more technically complex and increases the risk of short-term complications.12 We prospectively evaluated the outcomes of diabetic and non-diabetic patients who underwent PTA for symptomatic PAD.
Study population. A total of 239 patients (176 diabetic and 63 non-diabetic) with symptomatic PAD who underwent PTA of the iliac, femoral, popliteal, and infrapopliteal arteries from September 2004 to October 2011 at Korea University Guro Hospital, Seoul, Korea were prospectively evaluated. Baseline clinical and procedural characteristics as well as clinical outcome data were prospectively collected. The institutional review board approved the study protocol.
Study endpoints and definitions. The primary endpoint was the rate of binary restenosis at 8-month follow-up, as determined by computed tomographic angiography or digital subtraction angiography. The secondary endpoints were repeat PTA, target lesion revascularization, target extremity revascularization (TER), and amputation at 2-year follow-up. Binary restenosis was defined as ≥50% angiographic stenosis in the treated segment after intervention. A graft is considered to have primary patency if it has had uninterrupted patency with either no procedure performed on it or a procedure (endovascular or surgical revascularization) to treat the disease in the adjacent native vessel. Primary assisted patency expresses cases in which a revision of the PTA is applied to prevent impending occlusion or progression of stenosis. Secondary patency was defined as patency of the initially treated vessel following a repeat PTA to restore patency after stenosis. 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 a repeat revascularization to treat any luminal restenosis in target extremity that was treated during the index PTA. Diabetes mellitus was defined as fasting glucose levels ≥126 mg/dL or the use of glucose-lowering medication. 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.
Percutaneous transluminal angioplasty. Standard techniques were used for PTA. For below-the-knee lesions, a 5 Fr Heartrail guiding catheter (Terumo) was used and 0.014˝ guidewire was used to traverse the lesions. Once intraluminal wiring failed, subintimal angioplasty or retrograde approach was performed. After the guidewire crossing, prolonged balloon inflations (120 seconds) with balloon sizes ranging from 1.5-3.5 mm were used. Provisional stenting was performed using self-expanding nitinol stents (Xpert, Abbott Vascular, or Maris deep; Medtronic-Invatec) if balloon angioplasty results were suboptimal.
For the superficial femoral artery (SFA) and iliac artery, true lumen angioplasty was attempted for chronic total occlusion (CTO) by dedicated 0.018˝ CTO wires. If unsuccessful, subintimal angioplasty using 0.035˝ soft Terumo wire (1.5 J curve) under the 5 Fr angiocatheter support was performed for longer CTO lesions with provisional spot stenting using self-expanding nitinol stents while wiring of the true lumen was performed for shorter CTO lesions. Reentry by CTO wires or reentry device (Outback catheter, Cordis) was used if the subintimal wiring failed to reenter the distal true lumen for femoropopliteal CTO lesions. Retrograde approach from the distal SFA, popliteal, or infrapopliteal arteries was performed in selected cases.
Statistical analysis. Differences between the two groups were evaluated by unpaired t-test or Mann-Whitney rank test for continuous variables. Differences were expressed as counts and percentages and analyzed with χ2 or Fisher’s exact test between groups as appropriate for discrete variables. A two-tailed P-value of <.05 was considered to be statistically significant. Data were expressed as mean ± standard deviation. Statistical analyses were performed using SPSS 20.0 (SPSS, Inc).
Baseline characteristics. When compared with non-diabetic patients, diabetic patients had a higher percentage of wound as the initial diagnosis for PTA (72.7% vs 14.2%; P<.001), chronic kidney disease (26.7% vs 6.3%; P<.01) as well as need for dialysis (19.3% vs 3.1%; P<.01), and coronary artery disease (67.6% vs 50.7%; P=.02), but a lower percentage of patients with a history of smoking (Table 1).
Angiographic follow-up. Diabetic patients had less angiographic follow-up at 8 months (38.6% vs 60.3%; P<.01) (Table 3). Diabetic patients had higher rates of binary restenosis compared to non-diabetic patients (54.4% vs 31.5%; P=.02) and had a trend toward a higher incidence of total occlusion of the limb (34.0% vs 19.5%; P=.08). Diabetic patients had a lower primary patency of the limb (47.8% vs 73.9%; P=.04) and primary assisted patency of the limb (55.3% vs 76.0%; P=.02).
Clinical follow-up. At 2-year follow-up, diabetic and non-diabetic patients had no significant differences in the rates of repeat PTA (21.0% vs 22.2%; P=.84) (Table 4). However, the amputation rate was higher in the diabetic group (24.4% vs 1.5%; P<.001).
The results of our study demonstrate that diabetic patients more frequently presented with wounds compared with non-diabetic patients and had higher rates of binary restenosis and amputation following standard PTA.
Diabetic patients more commonly present with critical limb ischemia (CLI), as they are at risk for tissue necrosis, chronic wounds, and foot ulcers that can subsequently deteriorate into severe infection or gangrene. Foot ulcers precede around 85% of amputations in diabetic patients.13 Arteriosclerosis and peripheral neuropathy are theorized to be the most important driving forces in the development of foot ulcers. Diabetic peripheral neuropathy can lead to the loss of protective sensation, in addition to the degeneration of sympathetic innervation of arteriovenous vessel shunts. Arteriosclerotic changes also progress at an accelerated rate in the greater arteries, further contributing to ischemic conditions.
Chen et al reported that infrapopliteal disease was significantly associated with diabetics and CLI.14 Studies of diabetics undergoing PTA for CLI show that the most important goal is to obtain a direct line of blood flow to the foot in order to salvage limbs and heal ischemic ulcers.15,16
The prevalence of DM continues to increase in our population and will likely increase the prevalence of both PAD and CLI. Approximately 12 million people in the US are affected by PAD.17 Chronic excessive sugar levels in DM greatly increase the chances of developing PAD, as patients demonstrate endothelial and vascular abnormalities that result in damaged vessel walls, hypercoagulability, and atherogenesis.17 Intermittent claudication is the most common symptom of PAD, and extreme progression of these symptoms can lead to gangrene and limb-threatening manifestations, collectively called CLI. While only 9% of non-diabetic patients with CLI progress to necrosis and gangrene, around 40% of diabetic patients will develop this manifestation.13 Hyperglycemia causes a decrease in tissue tolerance to ischemia, which may be partially responsible for the development of diabetic ulcers and eventually peripheral necrosis in the limbs.13
Study limitations. This was a small, single-center, non-randomized study. There was significant difference in baseline characteristics, which complicates our findings. This study was not designed for comparison with a control group or against other available treatment modalities. The presented data are also without long-term follow-up. Both CLI and chronic arterial occlusive disease patients were included in this analysis. There is a risk of observational bias since there was no blinding in the treatment groups.
Diabetic patients more frequently presented with CLI compared with non-diabetic patients and had higher rates of restenosis and amputation. Future studies including rigorous trials will be needed to assess which treatment options are best for diabetic patients who undergo PTA. This will be vital in treating the growing number of diabetic patients who are at a greater risk of developing occlusive arteries and CLI.
- Centers for Disease Control. Number (in millions) of civilian, noninstitutionalized persons with diagnosed diabetes, United States, 1980–2011. http://www.cdc.gov/diabetes/statistics/prev/national/figpersons.htm. Accessed on February 4, 2014.
- Weitz JI, Byrne J, Clagett GP, et al. Diagnosis and treatment of chronic arterial insufficiency of the lower extremities: a critical review. Circulation. 1996;94(11):3026-3049.
- Belch JJ, Topol EJ, Agnelli G, et al. Critical issues in peripheral arterial disease detection and management: a call to action. Arch Intern Med. 2003;163(8):884-892.
- Fowkes FG, Rudan D, Rudan I, et al. Comparison of global estimates of prevalence and risk factors for peripheral artery disease in 2000 and 2010: a systematic review and analysis. Lancet. 2013;382(9901):1329-1340. Epub 2013 Aug 1.
- Hirsch AT, Duval S. The global pandemic of peripheral artery disease. Lancet. 2013;382(9901):1312-1314. Epub 2013 Aug 1.
- Gornik HL. Peripheral arterial disease enters the biomarker era: does risk stratification tell us something that we don’t already know? Eur Heart J. 2008;29(2):150-152. Epub 2007 Dec 21.
- Malyar N, Fürstenberg T, Wellmann J, et al. Recent trends in morbidity and in-hospital outcomes of in-patients with peripheral arterial disease: a nationwide population based analysis. Eur Heart J. 2013;34(34):2706-2714. Epub 2013 Jul 17.
- Marso SP, Hiatt WR. Peripheral arterial disease in patients with diabetes. J Am Coll Cardiol. 2006;47(5):921-929. Epub 2006 Feb 9.
- Schoen FJ. Blood vessels. In: Kumar V, Abbas AK, Fausto N, eds. Robbins and Cotran Pathologic Basis of Disease. 7th ed. Philadelphia, PA: Elsevier Saunders; 2005:315-326.
- American Diabetes Association. Facts about type 2. http://www.diabetes.org. Accessed August 1, 2013.
- Bishop PD, Feiten LE, Ouriel K, et al. Arterial calcification increases in distal arteries in patients with peripheral arterial disease. Ann Vasc Surg. 2008;22(6):799-805. Epub 2008 Jul 21.
- Korabathina R, Mody KP, Yu J, et al. Orbital atherectomy for symptomatic lower extremity disease. Catheter Cardiovasc Interv. 2010;76(3):326-332.
- Lévigne D, Tobalem M, Modarressi A, Pittet-Cuénod B. Hyperglycemia increases susceptibility to ischemic necrosis. BioMed Research International. 2013;2013:490964. Epub 2012 Dec 23.
- Chen Q, Smith CR, Bailey KR, Wennberg PW, Kullo IJ. Disease location is associated with survival in patients with peripheral arterial disease. J Am Heart Assoc. 2013;2(5):e000304.
- Ward TJ, Lookstein RA. Drug-eluting stents for infrapopliteal arterial disease in the setting of critical limb ischemia. Expert Rev Cardiovasc Ther. 2011;9(10):1339-1346.
- Acin F, Varela C, Maturana I, Haro J, Bleda S, Rodriguez-Padilla J. Results of infrapopliteal endovascular procedures performed in diabetic patients with critical limb ischemia and tissue loss from the perspective of an angiosome-oriented revascularization strategy. Int J Vasc Med. 2014;2014:270539. Epub 2014 Jan 6.
- Diabetes Journals. Peripheral arterial disease in people with diabetes. http://care.diabetesjournals.org/content/26/12/3333.full. Accessed May 18, 2014.
From the 1Department of Cardiology, UCLA Medical Center, Los Angeles, California; 2Cardiovascular Center, Korea University Guro Hospital, Seoul, Korea; and 3Department 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 September 18, 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: email@example.com