Claudication and Rest Pain

Brand RN, Abbott RD and Kannel WB: Diabetic intermittent claudication and risk of cardiovascular events. The Framingham Study. Diabetes 38:504, 1989. The risk of developing claudication in both sexes is increased 2-3 fold by diabetes. The presence of claudication signifies widespread vascular disease in the diabetic: in women the incidence of coronary disease, stroke and CHF is increased 3-4 fold compared to women with either diabetes or claudication alone; likewise in men stroke is increased 2-fold and CHF 3-fold.

Coffman JD and Mannick JA: Failure of vasodilater drugs in arteriosclerosis obliterans. Ann Intern Med 76:35, 1972.

Dormandy J, Heeck L, Vig S: The natural history of claudication: risk to life and limb. Semin Vasc Surg 12:123-37, 1999. Although a patient with intermittent claudication (IC) will fear progression to severe disease and amputation, this is a relatively rare outcome of claudication, with only 1% to 3% of claudicants ever requiring major amputation over a 5-year period. Indeed, in one study, 50% of claudicants became symptom free during 5 years' follow-up. All the new evidence over the last 40 years has not altered the impression that only about one fourth of patients with IC will ever significantly deteriorate, and that deterioration is most frequent during the first year after diagnosis (6 to 9%) compared with 2% to 3% per annum thereafter. Smoking is the most important risk factor for the progression of local disease in the legs, with an amputation rate 11 times greater in smokers than nonsmokers. Diabetes, male gender, and hypertension are also important risk factors for progression. Because cerebrovascular disease (CVD), coronary artery disease (CAD), and peripheral arterial occlusive disease (PAOD) coexist, PAOD and IC should be regarded as a marker for increased risk from fatal and nonfatal cardiovascular event, and 2% to 4% of claudicants have a nonfatal cardiovascular event every year. The risk is higher in the first year after developing IC than in a long-standing stable claudicant, and the average claudicant is more likely to have a nonfatal myocardial infarction (MI) or stroke in the next year that of ever requiring a major amputation for his leg ischemia. The mortality in claudicants is 30% at 5 years, 50% at 10 years, and 70% at 15 years, without any clear decrease in these figures over the last 30 to 40 years. The mortality of claudicants is approximately two and a half times that of an age-matched general population.

Ernst E: Pentoxiflline for intermittent claudication, A critical review. Angiology 45:339-345, 1994. The author points out that not all studies find the drug clinically effective but concludes that the collective published data does show it prolongs walking distance in patients with intermittent claudication. Again, he points out that the clinical importance of the symptomatic improvement depends on the individual situation of the patient as the improvement may not be large. The pharmacological effects of the drug are briefly reviewed. Hemorheologic effects include for the erythrocyte an increase in deformability and a lowering of aggregation (disputed by some), for the white cell an increase in deformability, and for plasma viscosity and fibrinogen a decrease (again disputed by some). Other described actions have included an inhibition of platelet aggregation, a reduction of blood coagulability, an enhancement of fibrinolytic activity, a change in interleukine activity, a reduction in tumor necrosis factor and a lowering of oxygen free radicals production by white cells. The author points out that many of these actions might benefit the patient with intermittent claudication while, on the other hand, a claimed vasodilator action might produce "steal" phenomena with adverse consequences. Comments: The multiple actions of the drug are intriguing. Unfortunately, it takes several weeks before benefit is to be expected and then the benefit is generally small, perhaps a 20% increase in walking distance ( a patient capable of taking 20 steps can now take 24 steps). We have not prescribed the drug in our boot patients. If they have come to us on the drug and believe it is helping, we continue it.

Feinglass J, McCarthy WJ, Slavensky R, Manheim LM, Martin GJ: Effect of lower extremity blood pressure on physical functioning in patients who have intermittent claudication. J Vasc Surg 24:503-11, 1996; discussion 511-2. PURPOSE: Claudication patients' perceptions of walking impairment often influence recommendations for peripheral bypass and angioplasty. The actual relationship between lower extremity blood flow and physical functioning, however, has rarely been explicitly studied. METHODS: Patients were enrolled at a visit to one of 16 vascular surgery offices and clinics that participated in a prospective outcomes study. A total of 555 patients (445 men and 110 women) with an abnormal ankle-brachial index (ABI), none of whom had had previous leg revascularization or symptoms of rest pain, skin ulcers, or gangrene, completed the SF36 Health Survey and the Peripheral Arterial Disease Walking Impairment Questionnaire (WIQ). Stepwise multiple regression analysis was used to test the statistical significance and strength of association between patients' ABI level and SF36 physical functioning (PF) and WIQ community walking distance scores, controlled for sociodemographic characteristics and the presence and severity of comorbid conditions. RESULTS: Univariate correlations with ABI were modest but significant (PF score, r = 0.12, p = 0.004; WIQ distance score, r = 0.18, p < 0.001). ABI was a very significant predictor of both PF (b = 18.8; p = 0.001) and WIQ scores (b = 0.33; p < 0.0001) in the multiple regression analysis. Other positive predictors of PF scores were high-school graduation and male sex. Negative predictors of PF scores were heart, lung, and cerebrovascular disease; knee arthritis and chronic back pain; and enrollment at a Veterans Administration clinic rather than a private community or academic office. CONCLUSION: Cross-sectional findings indicate that a 0.3 improvement in ABI is associated with an average improvement of 5.6% in PF or 10.3% in WIQ distance score. However, proper selection of individual candidates for interventional therapy, that is, those patients who have lower ABIs, lower initial functioning, and fewer disabling comorbidities would be predicted to produce a much greater functional benefit. Surgeons should make a rigorous functional evaluation when recommending interventional management of claudication.Comments: The ankle/brachial index (ABI) was used in this study to evaulate blood flow. They averaged the pressure in the anterior tibial and posterior tibial at the ankle and divided the average by the highest brachial pressure. An ABI<= 0.94 was defined as abnormal. In the discussion of the paper, Dr. Strandness pointed out the ABI does not tell one the level of occlusive disease and Dr. Porter pointed out a change in the ABI in response to exercise might be more informative. The ABI, of course, may be grossly elevated in patients with medial calcinosis and advanced occlusive disease. What does one do if a patient has an ABI of 0.5 associated with normal flow down one vessel and none down the other. We have advised such patients that they already had a normal bypass in place and would not likely profit from another.

Feinglass J, McCarthy WJ, Slavensky R, Manheim LM, Martin GJ: Functional status and walking ability after lower extremity bypass grafting or angioplasty for intermittent claudication: results from a prospective outcomes study. J Vasc Surg 31(1 Pt 1):93-103, 2000. OBJECTIVE: The purpose of this study was the prospective comparison of functional outcomes after lower extremity bypass grafting surgery, angioplasty, or medical management of intermittent claudication. METHODS: The study was designed as a prospective cohort study to compare functional outcomes for patients with interventional management to medical management, including a matched (younger, with more disability) subgroup, followed for a mean of 19 months. Sixteen Chicago-area vascular surgery clinics participated in the study. The subjects were consecutively enrolled patients with an abnormal ankle-brachial blood pressure index (ABI), without signs of rest pain, ulcer, or gangrene, and without prior lower extremity revascularization procedures. The main outcome measures were changes in physical functioning, community walking distance, bodily pain, leg symptoms, and ABI. RESULTS: Of the 526 study patients, 20% underwent revascularization procedures (60 surgical bypass grafting and 44 angioplasty only). The mean ABI improved significantly for the patients who underwent bypass grafting surgery (0.20; P <.001) and modestly for the patients who underwent angioplasty (0.09; P <. 05). Patients undergoing bypass grafting and angioplasty maintained highly significant (P <.001) improvements in mean physical functioning, (17%, 14%), bodily pain (18%, 13%), and walking distance (28%, 27%) scores and reported greater leg symptom improvement. The results were far superior for the patients with greater improvement in ABI. The conditions of the 277 unmatched patients who underwent medical management declined on all outcome measures, and the conditions of the 145 matched patients who underwent medical management improved 5% (P <.001) on walking distance score. Eighteen percent of the study patients failed to complete the full study follow-up period. CONCLUSION: Most of the functional improvement achieved by patients who underwent interventional management appears to be related to improved patency rather than to selection bias or placebo effects. The functional gains were approximately half those often reported for patients for hip arthroplasty and similar to patients who undergo elective coronary angioplasty.Comments: See comments on their use of the ABI on their 1996 paper. In the discussions at the end of this paper, various criticisms are made showing the limitations of most studies like this one. Dr. Porter doubts the accuracy of patient questionnaires. He points out the treatments were not randomized and that patients agreeing to surgery in some fashions may have differed from those not desiring surgery. Again, Dr. Porter pointed out that the improvement in ABI gained by bypass was small (0.2) and that by angioplasty even smaller (0.1).

Gardner AW, Womack CJ, Sieminski DJ, Montgomery PS, Killewich LA and Fonong T: Relationship between free-living daily physical activity and ambulatory measures in older claudicants. Angiology 49: 327-338, 1998. Authors' abstract: The purpose of this study was to determine the relationship between free-living daily physical activity and ambulatory measurements in peripheral arterial occlusive disease (PAOD) patients with intermittent claudication. Thirty-four older, nonsmoking PAOD patients with intermittent claudication (age=69.0 ( 6.0 years, ankle/brachial index [ABI] =0.63(0.18) were recruited from the Vascular Clinic at the Baltimore Veterans Affairs Medical Center and from radio and newspaper advertisements. Energy expenditures of physical activity (EEPA) was determined by using doubly labeled water and indirect calorimetry techniques. Patients were also characterized on claudication distances and peak oxygen uptake during a graded treadmill test, 6-minute walking distance, weight, body mass index, and percent body fat. The claudication patients were sedentary, as EEPA was 362(266 kcal/day. EEPA was related to the 6-minute walk distance (369(68 meters; r=0.629, P<0.001), to the number of steps taken during 6 minutes (605(99 steps; r=0.485, P=0.008), to the treadmill distance to maximal claudication (313(131 meters; r=0.470; P=0.10), and to the time to relief of pain (6:21(3:57 min:sec; r=-0.417, P=0.017). None of the other ambulatory and body composition measurements were correlated with EEPA. In conclusion, a reduction in free-living daily physical activity was associated with a decrease in ambulatory ability and with more severe intermittent claudication in older PAOD patients. >Comments: The authors note the value of the 6-minute walk test. It had the highest correlation with EEPA, "supporting the notion that the ability to sustain exercise at a submaximal intensity was associated with higher levels of free-living daily physical activity". Others have shown that the 6-minute walk test is related to the symptoms, mortality and morbidity of patients with congestive heart failure and chronic lung disease. It is likely that claudication patients are limited both by their claudication and frequently by other disease which together decrease or limit their activity levels. Severe claudication and other diseases, of course, limit the ability of the claudication patient to perform prescribed walking exercises. Boot therapy may be especially advantageous for the extremely limited patient. We have had many patients arrive in their wheelchairs and recover their ability to walk variable distances... a few 100 paces in some and up to a few miles in others.

Guldager B, Jelnes R, Jargensen SJ et al.: EDTA treatment of intermittent claudication -a double-blind, placebo-controlled study. J Intern Med 231: 261-7, 1992. This study was performed in seven departments of vascular surgery in Denmark. Fifty-six women and 103 men over 40 years of age and with stable intermittent claudication of 12 or more months in duration were studied. They had an initial pain-free walking distance of 50 to 200 meters on a treadmill at 3.6 km/hr with an inclination of 10 degrees. Their arm/ankle blood pressure index in the worse leg was less than 0.8. Patients with recent changes in medication, serious illnesses or contraindications to EDTA were excluded. The therapy was administered to 80 patients in a fashion similar to that practiced by those recommending the treatment: 20 intravenous infusions of Na2EDTA, 3 g, and NaCL, 8.4 g, diluted in 1 liter of distilled water given over 3 to 4 hours a day in a course over 5 to 9 weeks. Seventy-nine patients were likewise treated with placebo solution. The patients were given vitamins, trace elements, mineral supplements and advice on diet, smoking cessation and exercise. Mean pain-free walking distances increased 74 (25) to 97(47) meters for the EDTA group compared to 82 (36) to 119 (93) meters for the placebo group. There was no significant objective or subjective differences between the groups. It was concluded that chelation was no more effective than placebo in treating intermittent claudication. Comments of Dr. Dillon: This article is included as our patients commonly ask about chelation and if we might combine it with boot therapy. I actually have done quite a bit of chelation therapy, but in a different setting. In the early 1970's we had just gained access to a new assay for parathyroid hormone and were evaluating it in the differential diagnosis of hypercalcemic states and , in particular, of hyperparathyroid states (benign single adenomas, multiple adenomas and carcinoma). Among our studies on these patients in the Clinical Research Ward of the Philadelphia General Hospital, I infused EDTA and measured serum calcium both by a fluorescent technique (measuring the free calcium and that bound to protein) and by atomic absorption (measuring total serum calcium or that free in the serum and that bound to the EDTA and protein). In addition, we measured changes in serum and urine phosphorus, changes in serum parathyroid hormone and changes in urine cyclic-AMP and hydroxyproline. With the infusion of EDTA, the serum calcium dropped abruptly with the fluorescent technique and rose abruptly with the atomic absorption technique. Parathyroid hormone rapidly rose and the increase in urinary phosphorus and cyclic-AMP reflected the action of the parathyroid hormone on the kidney while rises in urinary hydroxyproline pointed to a simultaneous bone effect. Let me explain for lay people what happened. The parathyroid glands tightly regulate the serum level of calcium. Tetany may result if it is too low. Elevations may have dire consequences also (pancreatitis, kidney stones etc). When the serum calcium level is acutely lowered, parathyroid hormone is secreted into the blood where it reacts with specific parathyroid hormone receptors on the bone and kidney. Tissues with no receptors do not react. Specifically, calcified arteriosclerotic plaques in the arteries, being essentially dead tissue with no receptors, do not react. The stimulated bone rapidly restores the serum calcium level. The calcium in the arteriosclerotic plaque is not a primary player in the arteriosclerotic process. Rather, excessive cholesterol deposits that devitalize the cells in the arterial wall are the primary players. One might make an analogy with tuberculosis in which the TB bacterium softens and devitalizes a portion of the lung. The denatured protein in the lesion can precipitate calcium effectively entombing the TB bacteria in the lesion. Here calcification of the lesion is clearly beneficial and protects the patient from the TB bacterium. In the case of the arteriosclerotic process, the arterial wall is softened and weakened by the cholesterol deposit; an aneurysm or a blowout in the vessel wall could potentially develop. Calcification of the cholesterol plaque actually is a remarkably successful patch over the diseased portion of the vessel wall. It need not block flow but commonly does when it is heaped up like bark protruding from a tree. Now where does chelation fit in here? It obviously does not in theory and the article of Guldager et al suggests it does not in clinical practice.

Hobbs SD, Bradbury AW: LETTERS TO THE EDITOR: The EXercise versus Angioplasty in Claudication Trial (EXACT): Reasons for recruitment failure and the implications for research into and treatment of intermittent claudication. J Vasc Surg 44:432-433, 2006. The options for subjects with infrainguinal peripheral arterial disease (PAD) who remain unacceptably symptomatic despite best medical therapy are specific pharmacotherapy, balloon angioplasty, supervised exercise therapy, or surgery. Unfortunately, there is little or no evidence base regarding the absolute or relative clinical and cost-effectiveness of these adjuvant treatments. (1-3) The EXercise versus Angioplasty in Claudication Trial (EXACT) was a UK Health Technology Assessment (HTA) Programme multicenter, randomized-controlled trial designed to compare the adjuvant benefits over best medical therapy of supervised exercise and balloon angioplasty in patients with mild-to-moderate intermittent claudication due to infrainguinal disease. After persistent difficulties in recruitment at all four centers, the trial was closed early in late 2004 at a point where only 10% of the required patients had been entered. This report outlines the details of the recruitment problems in one center and discusses their implication for future trials. Reasons for nonrecruitment at the initial screening assessment are detailed in the Fig. Thus of 372 screened patients at the close of the trial in September 2004, only 23 (6%) had been randomized. Fig. Consort diagram to illustrate pathway of patients during their assessment for eligibility for randomization into the EXACT trial. PAD, Peripheral arterial disease; SE, supervised exercise; BA, balloon angioplasty; MWD, maximal walking distance; BMT, best medical therapy. 432 The following specific issues are worthy of discussion: 1. Almost one quarter of the patients referred to the vascular surgical service by their general practitioner had no evidence of PAD, which casts doubt on whether a positive initial diagnosis of PAD can be made in primary care. 2. Many patients presented with bilateral symptoms of (near) equal severity. Such patients are more suitable for systemic therapy such as exercise or pharmacotherapy and not for a lesion-focused therapy such as balloon angioplasty or surgery. 3. Many patients had clear ideas about what treatment they did and did not want. In particular, several patients did not want to accept the small but nevertheless real risks of balloon angioplasty, and for others, the requirement to commit to a hospital-based supervised exercise program was a major disincentive. 4. Many patients who gave a clear history of exercise-limiting intermittent claudication were unable for a variety of reasons to reproduce their symptoms and estimated maximal walking distance on a standard treadmill test. 5. Many clinically eligible patients did not have a pattern of disease that is suitable for balloon angioplasty. It would have been possible to increase the numbers of patients in the trial by accepting more TASC category D lesions. However, the investigators and participating radiologists believed this would almost certainly have led to a much higher rate of balloon angioplasty failure and complications. 6. Last but not least, many of the relatively few eligible patients simply did not want to enter the trial after 3-6 months on best medical treatment. This is perhaps not surprising, given that intermittent claudication tends to affect an elderly population, who are often socioeconomically disadvantaged and have other comorbidity. Unfortunately, the premature closure of EXACT means that for the foreseeable future, clinicians will continue to have little or no evidence regarding the adjuvant treatment of infrainguinal intermittent claudication. The question is whether a randomized-controlled trial to compare supervised exercise and balloon angioplasty in this condition is feasible and, if so, affordable.

Illnait J, Castaño G et al: Effects of policosanol (10 mg/d) versus aspirin (100 mg/d) in patients with intermittent claudication: a 10-week, randomized, comparative study. Angiology 59:269-77, 2008. Antiplatelet therapy, including aspirin, is recommended to lower the vascular risk in patients with intermittent claudication. Policosanol has increased walking distances in these patients, probably because of its antiplatelet effects, but the effect of shorter treatment has not been studied. This double-blind study compared the effects of policosanol 10 mg/d and aspirin 100 mg/d for 10 weeks on walking distances in claudicants. Thirty-nine patients were randomized to policosanol or aspirin. Walking distances on a treadmill were assessed before and after treatment. Policosanol significantly increased the initial and absolute claudication distances, while aspirin changed neither variable. Policosanol, not aspirin, significantly lowered serum low-density lipoprotein-cholesterol and total cholesterol while raising high-density lipoprotein-cholesterol. In conclusion, treatments of policosanol, not aspirin, for 10 weeks significantly increased walking distances, but modestly, in contrast with previous results. Therefore, the duration of treatments at the doses tested was too short for meaningful effects on the treadmill test.

Jonason T and Ringqvist I: Factors of prognostic importance for subsequent rest pain in patients with intermittent claudication. Acta Med Scand 218; 27-33, 1985. 224 non-diabetic patients studied over 6 years. Both smoking and multiple arterial stenoses in the leg were significantly correlated with an increased risk of developing rest pain. In non-smokers and in those who stopped smoking within one year after the initial examination, the cumulative % of patients without rest pain was 92, and in smokers and those who stopped smoking after more than one year it was 79 (P less than 0.03) after adjustment for the # of stenoses. In patients with a single stenosis the cumulative % without rest pain was 86 vs 70 for those with multiple stenoses (P less than 0.05) after adjustment for smoking.

Jonason T and Ringqvist I: Diabetes mellitus and intermittent claudication. Relation between peripheral vascular complications and location of the occlusive atherosclerosis in the legs. Acta Med Scand 218:217-221, 1985. 47 diabetic patients with intermittent claudication without rest pain or gangrene were followed over 6 years and compared with the 224 nondiabetic patients above (Acta Med Scand 218:27-33, 1985.). The cumulative proportion of patients with gangrene were 31% in the diabetics and 5% in the controls (P less than 0.001). The corresponding figures for rest pain and/or gangrene were 40 and 18%, respectively (P less than 0.001). The frequency of aorto-iliac and multiple stenoses was higher among the diabetics with complications than among either the controls or the diabetics without controls. Complications in the diabetics were not affected by smoking or hypertension. Six (13%) of the diabetics underwent reconstructive arterial surgery and 6 (13%) underwent amputation (2 of those bypassed). The six year survival was 50% in the diabetic group and 74% in the nondiabetics.

Juergens JL, Spittell JA and Fairbairn JF: Peripheral Vascular Diseases, 1980. W.B. Saunders Co., P269-270. Clinical course of claudication: 52% patients (20% unaware) had worsening of segmental BP's over 3 years. If gangrene developed, likelihood of limb survival poor. At the Mayo Clinic, 3% of those nondiabetics presenting with claudication but 20% of those presenting with ischemic ulcer or gangrene had leg amputation within 5 years. Diabetics faired 4 times worse than nondiabetics.

Koch1 M, Trapp1 R, Kulas1 W and Grabensee B: Critical limb ischaemia as a main cause of death in patients with end-stage renal disease: a single-centre study. Nephrol Dial Transplant 19:2547-2552,2004. Background. Patients with end-stage renal disease (ESRD) have a high overall mortality rate, particularly due to cardiovascular morbidity. In an era of decline in cardiovascular diseases and early cardiovascular intervention, non-cardiac diseases seem to have a larger impact on overall mortality. Methods. From 1997 to 2003, all incident haemodialysis patients in a single centre were enrolled in this prospective study. Those with clinical signs of vascular disease were examined by coronary or peripheral angiographies. Physicians took the patients' medical histories, examined them and followed them up until the end of the study or death. Causes of death were defined by the physicians. Results. In all, 322 patients were enrolled in the study, 38% of whom were diabetic. At the start of dialysis treatment, 38% had coronary artery disease (CAD), defined as >50% stenosis of at least one coronary artery or as definite myocardial infarction, and 14% had critical ischaemia of at least one limb (CLI). In all patients with foot lesions, CLI was defined angiographically, as evidenced by stenosis or rarefication of distal vessels in the legs. Patients who died (n = 121) [due to cardiac causes (n = 25), complications of CLI (n = 22), stroke (n = 10), cachexia following a long-standing, non-malignant disease (n = 6), malignancy (n = 24), infection not related to CLI (n = 18) and other causes (n = 16)] were older (71±10 vs 65±13 years), more often male [74/121 (61%)] and often diabetic [56/121 (46%)]. CAD was documented in 82/121 (68%). Five-year survivals in patients with no risk and diabetes without CAD or CLI, CAD and CLI were 74%, 73%, 50% and 10%, respectively. Age, CLI and smoking habits independently increased the risk of death (hazard ratios: 1.052, 4.921 and 2.292, respectively). Conclusions. These results indicate that CLI with associated complications is not only an indicator of high mortality in patients with ESRD, but is also one of the main causes of death.

Leng GC, Lee AJ, Fowkes FGR, Horrobin D et al: Randomized controlled trial of antioxidants in intermittent claudication. Vascular Medicine 2:279-285, 1997. Antioxidant capsules containing beta-carotene 5 mg, ascorbic acid 100 mg, pyridoxine hydrochloride 25 mg, zinc sulfate 100 mg, nicotinamide 10 mg and sodium selenite 1 mg was associated with a significant lowering of LDL-cholesterol but had no effect on the claudication after two years.

Lundgren F, Dahllof AG, Ludhjolm K, Schersten T and Volkmann R: Intermittent Claudication- Surgical reconstruction or physical training. Annals of Surgery 209:346-355, 1989. (Sweden) Admission criteria to study: symptoms for more than 6 months, age 40-80, BP in 1st toe over 30, maximal walking distance under 600M and absence of rest pain or ischemic ulcers. 75 patients with intermittent claudication randomized into 3 groups: 1) reconstructive surgery, 2) reconstructive surgery and physical training or 3) physical training alone. Surgery most effectively increased walking distance but training improved results even further. Age, symptom duration and history of myocardial disease correlated negatively with walking distance after treatment. 58 operations in 48 patients: 26 on aorta and iliacs, 25 femoropopliteal level, 3 on both levels and 23 bilaterally. Complications: Within 1st month of surgery, wound hematomas evacuated in 3 patients, thrombectomies and re-reconstructions in 3 patients, myocardial infarctions in 2 patients, and pulmonary embolus in one patient. Late reoperations were performed in 2 patients and 2 patients died before follow-up. In training group no complications due to training but life-threatening ischemia developed in 2 patients who underwent operation and another two developed cardiac insufficiency of a degree preventing training.

McFarland KF, Green PA and Gonzalez AF : Muscle infarction in diabetes: Clinical manifestations and course. Endocr Pract. 2: 179-182, 1996. The authors report their two cases and discuss previously reported cases of this uncommonly reported entity. Abstract results: Usually, the initial complaint in patients with muscle infarction in diabetes is swelling of the thigh or calf that has evolved over days to months. Biopsy of the muscle is often necessary for diagnosis and reveals extensive muscle necrosis. Although the pathogenesis is unknown, hypercoagulability may have a role. Bilateral involvement and recurrent disease are common. Treatment is supportive; our patients required narcotics for alleviation of pain. Conclusion: Muscle infarction in diabetes may mimic thrombophlebitis, soft tissue infection, or a neoplasm. Medical evaluation may be directed towards these entities, and the diagnosis of a diabetes-associated disorder may be completely overlooked. The presence of atraumatic swelling of an extremity in a patient with diabetes should suggest diabetes-related muscle infarction. Comments: Many of our patients who have been referred with claudication that has progressed to rest pain or a potential compartment syndrome may have had this disorder. Transaminases and CpK's are commonly elevated suggesting muscle necrosis. We have not biopsied the muscles, however. We have just treated them in the Long-Circulator Boot.

Money SR, Herd JA, Isaacsohn JL, Davidson M, Cutler B, Heckman J, and Forbes WP: Effect of cilostazol on walking distances in patients with intermittent claudication. J Vasc Surg 27:267-75, 1998. Authors conclusions: Cilostazol significantly increased ACD (absolute claudication distance) at all measured time points and initial claudication at most time points. This agent may represent a new treatment for patients with intermittent claudication. Comments: Dawson DL, Cutler BS, Meissner MH, and Strandness E (Circulation 98:678-686, 1998) likewise in a multicenter, randomized, prospective, double-blind trial report the drug is safe and effective. The mechanism of action of the drug is not fully understood. The drug (Pletal) insert points out that it and several of its metabolites are cyclic AMP (cAMP) phosphodiesterase III inhibitors (PDE III) inhibitors inhibiting phosphodiesterase activity and suppressing cAMP degradation with a resultant increase in cAMP in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation, respectively. The drug also has lipid effects, lowering triglycerides 15% and raising HDL-cholesterol about 10%. However, the effects on various vascular beds does differ; greater dilation is seen in the femoral beds than in the carotid, vertebral and mesenteric arteries. Cardiovascular effects include an increase in pulse rate and premature ventricular beats and non-sustained ventricular tachycardia. The drug insert includes a warning that the drug is contraindicated in patients with congestive heart failure of any degree. PDE III inhibitors have caused decreased survival in patients with class III-IV congestive heart failure.

Muluk SC, Muluk VS, Kelley ME, Whittle JC, Tierney JA, Webster MW, Makaroun MS: Outcome events in patients with claudication: a 15-year study in 2777 patients. J Vasc Surg 33:251-7, 2001. OBJECTIVE: The purpose of this study was to delineate the natural history of claudication and determine risk factors for death. METHODS: We reviewed the key outcomes (death, revascularization, amputation) in 2777 male patients with claudication identified over 15 years at a Veterans Administration hospital with both clinical and noninvasive criteria. Patients with rest pain or ulcers were excluded. Data were analyzed with life-table and Cox hazard models. RESULTS: The mean follow-up was 47 months. The cohort exhibited a mortality rate of 12% per year, which was significantly (P <.05) more than the age-adjusted US male population. Among the deaths in which the cause was known, 66% were due to heart disease. We examined several baseline risk factors in a multivariate Cox model. Four were significant (P <.01) independent predictors of death: older age (relative risk [RR] = 1.3 per decade), lower ankle-brachial index (RR = 1.2 for 0.2 change), diabetes requiring medication (RR = 1.4), and stroke (RR = 1.4). The model can be used to estimate the mortality rate for specific patients. Surprisingly, a history of angina and myocardial infarction was not a significant predictor. Major and minor amputations had a 10-year cumulative rate less than 10%. Revascularization procedures occurred with a 10-year cumulative rate of 18%. CONCLUSIONS: We found a high mortality rate in this large cohort and four independent risk factors that have a large impact on survival. Risk stratification with our model may be useful in determining an overall therapeutic plan for claudicants. A history of angina and myocardial infarction was not a useful predictor of death, suggesting that many patients in our cohort presented with claudication before having coronary artery symptoms. Our data also indicate that claudicants have a low risk of major amputation at 10-year follow-up.

Murabito1 JM, Evans1 JC, D'Agostino, Sr RB, Wilson PWF and Kannel1 WB: Temporal Trends in the Incidence of Intermittent Claudication from 1950 to 1999. Am J Epidemiology 162:430-437, 2005. Declines in coronary disease and stroke mortality have occurred, but it remains unclear whether intermittent claudication (IC) incidence and mortality rates have changed. The authors sought to examine long-term trends for IC in the community. Cases of IC among Framingham Study participants aged =40 years were classified according to date of onset from the 1950s to the 1990s. IC was defined as the presence of exertional calf discomfort that was relieved with rest. Age- and sex-adjusted incidence rate ratios were estimated using log-linear Poisson regression, and 10-year survival was calculated using the Kaplan-Meier method. IC occurred in 668 participants (286 women). The age- and sex-adjusted incidence rate of IC fell from 282 per 100,000 person-years during the period 1950-1969 to 225 per 100,000 person-years in the 1990s. The decline in IC incidence across time periods was significant (p for trend = 0.01), with an initial increase in the 1970s being followed by declines of 16% in the 1980s and 18% in the 1990s. Approximately 40% of persons with IC died within 10 years of diagnosis, with no significant change occurring during the study period. IC incidence has declined since 1950, but mortality has remained high and unchanged. Factors contributing to the declining incidence of IC need clarification.

Nackman GB, Horahan K, Banavage A, Ciocca RG, Graham AM: Predictors of health after revascularization for extremity ischemia. Surgery 128(2):293-300, 2000. Division of Vascular Surgery, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School and The Robert Wood Johnson University Hospital, New Brunswick, NJ 08903, USA. BACKGROUND: To assess the impact of surgical revascularization for lower extremity ischemia, we determined (with the use of the SF-36 health survey) the functional health status of patients who underwent either inflow or outflow procedures. METHODS: The SF-36 survey was given prospectively to 104 patients before operation and at intervals ranging from 10 days to 1 year after operation from January 1998 to July 1999. To determine whether revascularization was associated with improved patient health status, mean scores were compared before and after operation by univariate and multivariate analysis. To identify the factors that influenced patient health status, we performed multiple regression analysis to test the hypothesis that outcome is affected by age, gender, time since procedure, diabetes, indication, and inflow versus outflow procedure. RESULTS: There was a significant decrease in the general health score of patients before outflow bypass as compared with inflow procedure (45.3 +/- 5.3 versus 32.1 +/- 3.3 [mean +/- SEM]; P <.05). After the procedure, only those patients who had undergone inflow procedures had improved outcome scores. Diabetes, outflow procedures, limb salvage as indication, and time since operation were determined by multiple regression affecting outcome scores to be significant factors. CONCLUSIONS: The SF-36 health survey demonstrated that diabetes, procedure type, indication, and time after procedure significantly affected the functional outcome for patients who were treated surgically for lower extremity ischemia. Despite successful revascularization, significant deficits in functional health remain in patients with lower extremity ischemia.

Perkins JM, Collin J, Creasy TS, Fletcher EW and Morris PJ: Exercise training versus angioplasty for stable claudication. Long and medium term results of a prospective, randomised trial. Eur J Vasc Endovasc Surg 11:409-13, 1996. Fifty-six patients with unilateral, stable, lower limb claudication were assessed prior to randomisation, at 3 monthly intervals for 15 months, and at approximately 6 years follow-up. Thirty-seven patients were available for long term review. Ankle/brachial pressure index (ABPI), treadmill claudication and maximum walking distances and percentage fall in ankle systolic blood pressure after exercise were followed. In the angioplasty patients, significant increases in the ABPI were seen at each time period. However, in terms of improved walking performance, the most significant changes in claudication and maximum walking distances were seen in the exercise training group. At long term follow-up, there was no significant difference between the groups. Subgroup analysis showed greater functional improvement in those patients with disease confined to the superficial femoral artery treated by exercise training. Comments: What does one do if the patient has severe claudication and/or rest pain making exercise impossible? We boot them.

Purdy RT et al: Salvage of ischemic lower extremity in patients with poor runoff. Arch Surg 109:784, 1974. Femoropopliteal bypass may still benefit patient in spite of poor runoff.

Radack K and Wyderski RJ: Conservative management of intermittent claudication. Annals Int Med 113:135-146, 1990. Review article. Concluded that the limited amount and quality of reported data precluded an overall, reliable estimate of pentoxifylline's efficacy. Structured exercise and stopping smoking help.

Regensteiner JG, Steiner JF, Panzer RJ and Hiatt WR: Evaluation of walking impairment by questionnaire in patients with peripheral arterial disease. J Vas Med and Biol 2:142-152, 1990. Self-reported difficulty in walking 1/2 to 3 blocks and in walking one block with speed both correlated with peak treadmill walking time. Questions on difficulty in walking 1-2 blocks and on the speed in walking one block both correlated with claudication onset time. Perceived difficulty during walking due to calf pain correlated with both time intervals. Finally, reported changes in walking after exercise training or surgery correlated with the changes in treadmill walking time. Questionnaire approach more desirable than treadmill as (1) practical in epidemiologic studies and primary care settings, (2) evaluates patient's perceived ability to walk in nonlaboratory setting, and (3) more economical and capable of frequent repetition. Patients excluded from their study had severe PAD (rest pain, ulcers, gangrene, ankle BP under 40, or history of angioplasty or vascular surgery in last year) or angina, CHF, COPD or arthritis.

Roberts DH, Tsao Y, McLoughlin GA and Brechenridge A: Placebo-controlled comparison of captopril, atenolol, labetalol and pindolol in hypertension complicated by intermittent claudication. Lancet 2:650-653, 1987. Maximum walking distances on a treadmill and post-exercise calf blood flow availability were decreased by all except for captopril. Study patients all had occlusive disease above the knee. Captopril thought possibly to preserve collateral blood supply.

Schepsis AA and Lynch G: Exertional compartment syndromes of the lower extermity. Current Opinion in Rheumatology 8: 143-147, 1996. Summary: Compartment syndromes may be acute or chronic secondary to exertion of exercise. The chronic or exertional type most commonly involves the lower extremity, particularly the anterior compartment of the lower leg, and is the subject of this review. Rarely, an exertional compartment syndrome may become acute. The diagnosis is based on history, physical examination, and compartment pressure measurements. The differential diagnosis of exertional leg pain includes stress fractures, stress reaction, periostitis, claudication, popliteal artery entrapment, and peripheral nerve entrapment. Unusual causes, such as a ganglion of the proximal tibiofibular joint causing an anterior compartment syndrome, have recently been reported. Comments: Like many of us, I was told I had "shin splints" as a child. These authors list "shin splints" as an anterior tibial syndrome. What would I have done had I only known? Again, the authors appear handy with catheters or side-ported needles which they stick in the suspicious areas to measure pressure. An accurate diagnosis is mandatory. Therapy for the athlete who wants to continue the activity that precipitates his symptoms is surgical decompression by fasciotomy. One wonders how many patients with claudication who have long-lasting pain after unusual exertion as part of their exercise program have compartment syndromes. The therapy of an acute severe compartment syndrome is again fasciotomy. The latter is performed to preserve muscle and to prevent kidney damage from the release of large amounts of muscle protein. Unfortunately, we have had patients on whom our surgical consultants advised no boot therapy who went on to have renal failure following fasciotomy. In spite of pumping on disastrous legs with large areas of necrosis over the years, we have not had renal failure follow boot therapy.

Sladen JC and Gilmour JL: Fate of claudicants after femoropopliteal vein bypass: prospective, long-term follow-up of 100 patients. Canadian J of Surg 28:401-404, 1985. No placebo patients. Each could walk 200M and 22 50M. Cumulative patency rate, after revisions when necessary, was 89%, 86%, and 78% at 2, 5 and 10 years respectively. The "cumulative palliation rate (patient alive and graft patent) was 82% , 67% and 28% at the same time intervals. Did not operate on patients with poor outflow. 21 patients subsequently had fem-pops other leg. 10 had inflow procedures. 25 of 121 grafts thrombosed and 1 had a successful thrombectomy. 5 limbs were amputated with the procedure closely followed by patients' deaths.

van Rij AM, Solomon C, Packer SG, Hopkins WG: Chelation therapy for intermittent claudication. A double-blind, randomized, controlled trial. Circulation 90 (3):1194-9, 1994. Authors abstract: Background: The use of repeated intravenous infusions of EDTA, which has become known as "chelation therapy," has been promoted for treating intermittent claudication as well as a wide range of other disorders. Multiple reports of excellent results in large numbers of patients have encouraged use of this regimen. The lack of well-controlled studies substantiating the benefits of this treatment has limited its use mainly to private clinics. The aim of the study was to assess the benefits of chelation therapy in patients with intermittent claudication. Methods and Results: A double-blind, randomized, controlled trial included 32 patients with intermittent claudication who were randomized to a treatment group (15) and a control group (17). Main outcome measures were subjective and measured walking distances and ankle/brachial pulse indices. Other outcome measures included lifestyle and subjective parameters of improvement, cardiac function, ECG, renal function, hematology, blood glucose, and lipid biochemistry. No clinically significant differences in main outcome measures between chelation therapy and placebo groups were detected up to 3 months after treatment. Measures of mood state, activities of daily living, and quality of life factors were not consistently affected by chelation therapy. An equal portion of each group (13%) thought that they had received the active agent. The proportion of patients showing an improvement in walking distance was not significantly different between the chelation group (60%) and the control group (59%). Conclusions: Chelation therapy has no significant beneficial effects over placebo in patients with intermittent claudication. Comments: See Guldager above. The significance of success with chelation therapy in claudicants in uncontrolled studies is clouded by the high rate of spontaneous improvement with placebo... 59% in this study. We would be glad to post any chelation study with appropriate controls that showed a benefit to chelation. So far we know of none.

Wilkinson D, Vowden P, Parkin A, Wiggins PA, Robinson PJ and Kester RC: A reliable and readily available method of measuring limb blood flow in intermittent claudication. Br J Surg 74: 516-519, 1987. Of 58 nondiabetic patients, 25 could not walk on the treadmill and 12 could not walk on it for a minute. In those able to do the treadmill, limb blood flow significantly correlated with maximum walking distance. In contrast, resting, post-exercise and post-hyperemic ankle-brachial indices bore no relationship to maximum walking distance. Technique: Tc99 labeled serum albumen injected while a tourniquet above the knee for 3 minutes. Post release of tourniquet, gamma camera follows increasing activity within the calf and flow/volume tissue calculated. A value of 10ml/100ml tissue lower end of normal range. Here the mean flow to the symptomatic leg was 4.2+/-1.9 and the flow to the asymptomatic leg was 7.8+/-3/3ml/100ml of tissue/min.

Wilson SE, Schwartz I, Williams RA and Owens ML: Occlusion of the superficial femoral artery. What happens without operation. Am J Surg 140:112-116, 1980. Summary: 53 nondiabetic male patients, aged 60-81 (mean 69), with SFA occlusion were studied prospectively... All had intermittent claudication on admission to the study. Patients with rest pain, tissue necrosis or aortoiliac disease were excluded. Patients were coached to walk 4 times daily to tolerance. Abstinence form tobacco was stressed but only 15 of the 44 smokers stopped. After 5 years, 5 patients died from cerebral and coronary disease. 10 patients required vascular reconstruction for progressive disease. One patient had a BK amputation for gangrene. 26 patients had improvement or stabilization in symptoms and walking distance. 12 patients had improved ankle-to-wrist BP ratios. Conclusion: patients over 60 with an occluded SFA have a low risk of limb loss (1 of 53), most can (16 of 23) expect an improvement in symptoms if initial AWR > 0.6 and those with a AWR of less than 0.5 should undergo evaluation for reconstructive surgery.

Whyman MR, Fowkes FGR, Kerracher EMG, Gillespie IN, Lee AJ, Housley E and Ruckley CVR: Is intermittent claudication improved by percutaneous transluminal angioplasty? A randomized controlled trial. Edinburgh, United Kingdom. J Vasc Surg 26:551-7, 1997. Abstract results: At 2 years of follow-up, the PTA group and the control subjects did not differ significantly in patient-reported maximum walking, treadmill onset to claudication, treadmill maximum walking distances, or ABPI (p>0.05). However, the PTA group had significantly fewer occluded arteries (p=0.003) and a lesser degree of stenosis (expressed in terms of velocity ratio; p=0.004) in patent arteries. Quality of life was not demonstrably different between the two groups (p>0.05). Conclusions: Two years after PTA, patients had less extensive disease than medically treated patients, but this did not translate into a significant advantage in terms of improved walking or quality of life. There are important implications for patient management and future clinical research.Comments: In an earlier report (European J of Vasc & Endovasc Surg 12(2): 167-72, 1996) these same authors reported superior results for PTA vs medical treatment after 6 months of follow-up. By two years the groups are similar. Of note in their earlier report also was the fact that the authors found of the 600 claudicants they screened, only 10% had discrete lesions suitable for PTA. In general, it would appear that PTA has little to offer the claudicant.

Zannetti S, L'Italien GL and Cambria RP:Functional outcome after surgical treatment for intermittent claudication. J Vasc Surg 24:65-73, 1966. From February 1987 to April 1994, 114 consecutive patients undergoing surgical bypass on the service of Dr. Cambria are reported. Sixty-two percent were inflow reconstructions (68% of the 61% aortobifemoral bypass grafts) and the remainder were infrainguinal bypasses (93% femoropopliteal bypass grafts). Seventy-five percent underwent specific preoperative cardiac testing in spite of an absence of clinical markers of cardiac disease or a history of previous coronary bypass surgery or angioplasty. Early graft failure with successful immediate revision occurred in 5%. At a mean follow-up of 4.5 years, 96% of surviving patients had a patent graft. The primary unassisted patency rate at 4 years was superior for inflow (92%(4%) than outflow (81%(6%) procedures. Late readmission for cardiac-related events occurred in 12% and late cardiac-related death occurred in 5%. Satisfactory late results were reported in 82%. The authors concluded, that after considering the cardiac-related short- and long-term prognosis, lower extremity bypass grafting for intermittent claudication will produced optimal results when restricted to nondiabetic patients under age 70 in whom near normalization of the postoperative arm/ankle index may be anticipated.Comments: Eighty-nine percent of these patients were past or current smokers explaining the need for inlet procedures. Only 17% had diabetes. Schneider et al (see our Epidemiology library) suggest these people are unhappy even if their bypasses are successful.

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