Benjamin L. Bowers, MD, R. James Valentine, MD, Stuart I. Myers, MD, Artm Chervu, MD, and G. Patrick Clagett, MD, Dallas, Texas

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1 The natural history of patients claudication with toe pressures mm Hg or less with of 40 Benjamin L. Bowers, MD, R. James Valentine, MD, Stuart I. Myers, MD, Artm Chervu, MD, and G. Patrick Clagett, MD, Dallas, Texas Purpose: This study was performed to determine the natural history of patients with symptoms of clandication and systolic toe pressures (TP) of 40 mm Hg or less. Methods: We followed the clinical course of 56 men with stable claudication and TP of 40 mm Hg or less. All TP measurements were performed on at least two occasions 6 months apart. Primary end points included development of rest pain, tissue loss, or gangrene. The clinical course of 56 case controls with TP greater than 40 mm Hg matched for age, sex, and race was used for comparison. Results: During a mean (-+ SD) follow-up time of months, 37 (66%) patients with TP of 40 mm Hg or less remained stable, and 19 (34%) had ulceration (n = 10), rest pain (n = 6), or gangrene (n = 3). Nine (24%) of the 37 stable patients had gradual improvement of TP values greater than 40 mm Hg. Among the 19 patients whose conditions deteriorated, eight (42%) patients underwent successful bypasses, and five (26%) patients required amputations. Two patients who had rest pain had spontaneous resolution, and three patients who had ulcerations healed without intervention. In contrast, five (9%) of the case controls with TP greater than 40 mm Hg had rest pain (n = 2) or gangrene (n = 3) (p = 0.003). Among patients with TP of 40 mm Hg or less, there were no statistically significant differences between the stable patients and patients with deteriorating conditions in age, ankle-brachial indexes, or risk factors (including diabetes mellitus). However, diabetes conferred a higher probability of clinical deterioration (p = 0.005, Kaplan-Meier). Conclusions: In patients with symptoms of intermittent claudication, TP of 40 mm Hg or less portends clinical deterioration. Patients with diabetes in this group have a significantly higher risk of development of critical ischemia. Close scrutiny is warranted. (J Vasc SURG 1993;18: ) Systolic toe blood pressures (TP) of 40 mm Hg or less are characteristic of critical limb ischemia. Previous reports associate TP of 40 mm Hg or less with rest pain 1 and inadequate perfusion to support healing of digital and forefoot ulcerations 1 or amputations. 2 However, in the absence of rest pain or tissue loss, the natural history of patients with a reduced TP and its relationship to limb prognosis is unknown. Patients with lower extremity atherosclerosis and TP less than 40 mm Hg usually have From the Section of Vascular Surgery, Department of Surgery, Dallas Veterans Administration Medical Center, and The University of Texas Southwestern Medical Center, Dallas. Presented at the Seventeenth Annual Meeting of the Southern Association for Vascular Surgery, Fort Landerdale, Fla., Jan , Reprint requests: R. James Valentine, MD, Department of Surgery~ U. T. Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX /6/48351 symptoms of intermittent claudication, 1 but it is unknown whether these patients share the same natural history as patients with claudication with higher TP. The purpose of this prospective study was to determine the natural history of patients with symptoms of claudication and TP of 40 mm Hg or less but without evidence of rest pain or tissue loss. PATIENTS AND METHODS Study patients. We reviewed the medical records of all patients with lower extremity occlusive disease referred to the Vascular Laboratory at the Dallas Veterans Administration Medical Center from 1988 to Patients with stable claudication symptoms and TP of 40 mm Hg or less qualified for entry into the study. Stable claudication was defined as absence of rest pain, tissue loss, or gangrene and no change in quality of symptoms, walking distance, or ankle- 506

2 Volume 18, Number 3 Bowel's et al. 507 brachial index (ABI) during the two most recent examination intervals. 3 Approximately 50 patients meeting these criteria are seen in our vascular laboratory yearly, representing a small proportion of the almost 1300 patients with lower extremity ischemia monitored in our vascular laboratory each year. All study patients underwent initial determinations of ABI and TP on both lower extremities, and these measurements were repeated every 6 months. ABI were determined with a 5.3 MHz Ultrasonic Stethoscope Doppler blood flow detector (Meda- Sonlcs, Mountain View, Calif.). TP were determined with plethysmography on the first or second toe of both feet with a MedaSonics Enhanced Medacord PVL (MedaSonics). TP were determined with a 25 mm cuff for the first toe and a 16 mm cuff for the second toe, as previously described. 2,4 Environmental conditions in the examination room were maintained at 72 F and 40% humidity, but patient exposure time to these conditions could not be held constant. To reduce the risk of spuriously low TP measurements, we excluded patients who did not have TP of 40 mmhg or less on at least two separate occasions. Each patient's clinical condition was assessed every 6 months with history and physical examinations at the time of noninvasive evaluations. Patients were monitored until one of the following primary end points was reached: rest pain, tissue loss, or gangrene. We defined these end points as clinical deterioration. Secondary end points included death and termination of the study. Case control subjects. A comparison group of patients with claudication with TP greater than 40 mm Hg was selected from patients evaluated in our vascular laboratory during the study period. This cohort group comprised age-, sex-, and race-matched case controls whose medical records were retrospectively reviewed to determine demographic and outcome data. We included only patients with TP measurements greater than 40 mm Hg on at least two separate determinations. We did not include patients whose initial TP was 40 mm Hg or less who might have been considered eligible for inclusion in the study group. Statistical analysis. Descriptive results are expressed as mean _+ SD. Statistical comparisons between categoric parameters were performed with Fisher's exact test and chi-squared analysis. Comparisons between groups of tmpaired data were made with the Student t test. Multivariate analysis with the Cox proportional hazard model s was performed to determine which variables were related to survival and deterioration and to determine whether combi- nation of variables might serve as a significant set of predictors. Results were considered significant at the p < 0.05 level. Life-table analysis was estimated for death or deterioration by the Kaplan-Meier method. 6 RESULTS Eighty-five patients met the original entry criteria. Twenty-nine patients (34%) had only a single TP value of 40 mm Hg or less and were therefore excluded from the analysis; 20 of these excluded patients underwent less than 3 months' follow-up. The remaining 56 patients comprised the study group. All patients were male; the mean age was years (range 38 to 80). There were 19 black patients, 35 white patients, and one Hispanic patient in the study group. Forty-seven (84%) patients had a history of smoking, 26 (46%) patients had hypertension, 20 (36%) patients had diabetes, and one (2%) patient had dyslipidemia. The lowest recorded TP was noted for each patient, as was the ipsilateral ABI recorded at the same examination (concurrent ABI). The mean number of TP determinations was (range 2 to 7). The mean of the 56 lowest recorded TP was 16 _ 14 mm Hg, and the mean concurrent ABI was The mean follow-up time was months (range 5 to 92 months). Nineteen (34%) of the 56 study patients had a primary end point; that is, experienced clinical deterioration. Ten (53%) patients had ulceration, six (32%) had rest pain, and three (16%) had gangrene. The average time to development of these end points was (range 3 to 47) months, and the annual rate of clinical deterioration was 15%. The average lowest TP before the development of a primary end point was 16 _+ 16 mm Hg (range 0 to 40), and the average concurrent ABI was (range 0 to 0.7). Of these 19 patients six underwent inflow procedures (three aortofemoral, two axillobifemoral, and one femorofemoral bypass graft), and three underwent infrainguinal bypass procedures (one femoropopliteal and two distal bypass grafts). Five patients underwent amputations: three required concurrent digital amputations with revascularization, one required a primary below-knee amputation, and one patient required a below-knee amputation after a failed distal bypass. This represents an annual amputation rate of 4%. Eight patients refused intervention; two had spontaneous resolution of symptoms of rest pain, three had healed ulcerations, and three patients continued to have rest pain at the end of the study period. Four (21%) of the 19 patients died, with a mean time to death of 9 months (range 1 to 21 months).

3 508 Bowers et al. September 1993 Table I. Study variables among patients with TP of 40 mm Hg or less who reached an end point compared with patients whose conditions remained stable Patients with stable conditions Patients with development of end point n 37 (66%) 19 (34%) Mean age 64 ± 10 yrs yrs Race Black 9 (60%) 6 (40%) White 22 (55%) 18 (45%) Hispanic 0 1 (5%) Risk factors History of smoking 30 (81%) 17 (89%) Hypertension 16 (43%) 10 (53%) Diabetes meuitus 10 (27%) 10 (53%) Mean lowest TP 16 ± 13 mm Hg 16 ± 16 mm Hg Mean concurrent ABI 0.44 ± ± 0.2 No. of deaths 6 (16%) 4 (21%) Table II. Variables significantly associated with the combined outcomes of death and deterioration among patients with TP of 40 mm Hg or less Variable p Value Risk ratio Confidence interval Diabetes (1.34, 7.51) Concurrent ABI ~ (0.00, 0.64) ~Ipsilateral ABI obtained at the same time as the lowest TP. Risk ratio calculated per 0.1 unit change in ABI. Thirty-seven (66%) of the 56 study patients did not have a primary end point. The mean lowest TP was mm Hg (range 0 to 36), and the mean concurrent ABI was Six (16%) of the 37 patients died during the study period; the mean time to death was months (range 6 to 60 months). Twenty-two patients (59%) continued to have TP of 40 mm Hg or less and had not had an end point at the termination of the study. Nine (24%) patients subsequently improved TP values to a level greater than 40 mm Hg. The 19 patients who had a primary end point were compared with the 37 patients who remained stable. There were no statistically significant differences between the two groups in age, race, risk factors, lowest TP, concurrent ABI, or number of deaths (Table I). On multivariate analysis none of the variables was independently associated with either development of an end point or death, nor did combinations of variables predict either outcome. However, when the outcomes of death and deterioration were combined, the following variables were statistically significant: diabetes (p = 0.01) and low concurrent ABI (p = 0.03) (Table II). There was no ABI or TP threshold below which death or deterioration was more likely to occur. Life-table analysis was used to determine the probability of event-free survival. In Fig. 1, the probability of development of rest pain, tissue loss, or gangrene is examined. The 1- and 3-year probability of remaining event free was 0.91 (95% confidence intervals, 0.83 to 0.98) and 0.69 (95% confidence intervals, 0.55 to 0.83), respectively. This represents a rate of clinical deterioration of approximately 10% per year. The probability of surviving without clinical deterioration (event-free survival) among the 56 study patients is demonstrated in Fig. 2. The cumulative event-free survival rate was 0.85 (95% confidence intervals, 0.75 to 0.94) at I year and 0.59 at 3 years (95% confidence intervals, 0.44 to 0.75). This represents a rate of death and deterioration of approximately 15% per year. The difference in event-free survival between patients with and patients without diabetes is shown in Fig. 3. The curves of these two groups differed significantly (p ). Case control comparisons. The records of 56 age-, sex-, and, race-matched controls with TP greater than 40 mm Hg were reviewed. The mean age of these case controls was years (range 38 to 80 years). There were no significant differences in the prevalence of risk factors between the case control group and the study group: 47 (84%) case controls had a history of smoking, 29 (52%) had hypertension, 23 (41%) had diabetes, and none had a history of dyslipidemia. The mean number of TP determinations was and the mean follow-up time was months; these values were not significantly different from those of the study group. The mean lowest TP among the 56 case control patients (including those who experienced clinical deteriora-

4 Volmne 18, Number 3 Bowers et al. S ~ ~ 0.) E > LU t-._ 13_ / o9 (9 III l_ L T (56) (48) (31) (18) (11 ) I I I I I (56) (48) 0 I 0 I 10 (31) (18) (11) I I I Fig. 1. Kaplan-Meier curve demonstrates event-free probability for patients with claudication with TP of 40 mm Hg or less. Fig. 2. Kaplan-Meier curve demonstrates cumulative event-free survival among patients with claudication with TP of 40 mm Hg or less. fion) was 62 _+ 21 mm Hg (range 32 to 130 mm Hg), which was significantly higher than the mean lowest TP among the study patients (p < 0.001). The mean ipsilateral ABI determined at the same examination as the lowest TP (concurrent ABI) was , which was also significantly higher than that among the study patients (p < 0.001). Five (9%) of the 56 case control patients had a primary end point, compared with 19 of the study patients (p = 0.003). Two (4%) case control patients had rest pain, and three (5%) had gangrene. In addition one case control patient had a decrease in TP to less than 40 mm Hg without the development of rest pain or a change in claudication symptoms. One other case control patient died during the study period. Of the two case controls who had rest pain, one had spontaneous resolution of symptoms, and the other continues to have mild rest pain symptoms and a TP less than 40 mm Hg. Among the three patients with gangrene, one underwent a primary below-knee amputation, one underwent a digital amputation, and one underwent a femoropopliteal bypass. Life-table analysis was used to determine the probability of event-free survival among the patients with TP greater than 40 mm Hg. In Fig. 4, the cumulative event-free survival rate is examined and compared with that of patients with TP of 40 mm Hg or less. The cumulative event-free survival rate among patients with TP greater than 40 mm Hg was 0.98 (95% confidence intervals, 0.93 to 1.0) at i year and 0.89 (95% confidence intervals, 0.76 to 1.0) at 3 years. The curves of the two groups differed significantly (p = ). DISCUSSION The optimal TP threshold signifying critical ischemia is controversial. Bone and Pomajzl 2 demonstrated that forefoot amputations of all patients with TP less than 45 mm Hg did not heal. However, others have found a threshold of 30 mm Hg to be more reliable, because nearly all patients with TP above this level had healed forefoot amputations.~,7 Schwartz et al. 4 have suggested a value of 20 mm Hg, because their series showed a 100% healing rate above and 100% failure rate below this value. We chose to evaluate the importance of a low TP as a predictor of clinical deterioration among patients with claudication, not the significance of low TP among patients with critical ischemia. Our choice of a TP threshold of 40 mm Hg was, admittedly, somewhat arbitrary. This value was chosen to include all patients expected to have rest pain or tissue loss, whereas exclusion of those in whom the development of critical ischemia was unlikely. We also chose this threshold value because the variability of TP measurements increases at lower levels in our experience. Lowering the TP threshold to 30 mm Hg did not increase the sensitivity of this test, and we could not determine a TP threshold below which development of critical ischemia was more likely. Our data demonstrate that a TP of 40 mm Hg or less is a risk factor for clinical deterioration among patients with stable claudication. The natural history

5 510 Bowers et al. September 1993 co > LU 100 I (34) (22) 0 I 0,, ~[ '-"I----' (31) (17) f ] I--- I N= m D=... p = L 1... i... t... (22) (9) (16) (2) (9) (2) N D I I I Fig. 3. Kaplan-Meier curves demonstrate event-free survival among patients with and without diabetes with TP of 40 mm Hg or less..> CO "E uj (56) 0 r _ 1 "3_, '---~, \. L.... ;... i l i_ i Control = - - Study Group... p = (49) (33) (25) (13) I I I I Fig. 4. Kaplan-Meier curves demonstrate event-free survival among patients with TP of 40 mm Hg or less compared with case controls with TP greater than 40 mm Hg. of intermittent daudication is one of diminished long-term survival, with relatively good prognosis for limb salvage. McDaniel and Cronenwett 8 have summarized recent data related to the natural history of intermittent claudication from multiple series of patients with claudication without rest pain or tissue loss. From their extensive review the authors reported an annual amputation rate of 0.8%, an annual intervention rate of 5%, and an annual death rate of 5.8%. Our results demonstrated an annual mortality rate of 8% among patients with stable claudication with TP of 40 mm Hg or less, which is similar to the annual death rate among unselected patients with claudication in the series by McDaniel and Cronenwett. The annual deterioration rate in this series was 10%, which represents a twofold increase over nonselected patients with clandication. The annual amputation rate among our study population was 4%, which is a fivefold increase in the amputation rate over tmselected patients with claudication. These data suggest that patients with stable claudication with TP of 40 mm Hg or less have an increased risk of deterioration. Should a patient with a TP of 40 mm Hg or less without evidence of critical ischemia undergo intervention sooner than when symptoms mandate? It should be emphasized that two thirds of our study population did not have critical ischemia during a mean follow-up of 31 months. Furthermore, five (26%) of the 19 patients who had clinical deterioration had spontaneous resolution of their limbthreatening condition. In light of these results, intervention solely on the basis ofa TP of 40 mm Hg or less is not warranted; however, close observation is clearly indicated. This is especially important for patients with diabetes with TP of 40 mm Hg or less, who are at significantly higher risk for development of critical ischemia. We now monitor all patients with TP of 40 mm Hg or less every 3 months with repeat noninvasive evaluation, coupled with a thorough history and physical examination to detect progression of ischemic symptoms. Although this study did not examine the cost-effectiveness of this approach, we have identified a subgroup of patients with claudication who are more likely to require intervention. Until a thorough, prospective cost analysis suggests otherwise, we submit that close follow-up is justified to improve patient education, ensure patient compliance, and detect subtle signs of impending or actual tissue loss. The importance of TP measurements transcends simple subcategorization of patients with stable claudication. The test should be considered state-ofthe-art in the evaluation of the distal lower extremity arterial bed. In addition to increasing the sensitivity and accuracy of Doppler-derived ankle pressures, a TP determinations have been found to be important in the evaluation of thromboangiitis obliter-

6 Volume 18, Number 3 Bowers et al. 511 ans,9 embolic disease,i and vasospastic syndromes.ll It is important to note that TP may be spurious in some patients. Twenty-nine (34%) patients in our original study population were excluded on the basis of a single TP value of 40 mm Hg or less and subsequent values greater than 40 mm Hg. Most had values greater than 60 mm Hg on follow-up examinations, and there have been no deteriorations noted in this subgroup. This questions the reliability of an isolated low TP measurement. Numerous external factors have been noted to lower TP values, including ambient temperature, body temperature, and leg position, s,~214 We controlled for these external influences and still found spurious results in one third of our patients. As with all other noninvasive test results, TP values should be viewed within a patient's clinical context. We express our sincere appreciation for the research and technical support provided by Mrs. Christy Albiston. REFERENCES 1. Ramsey DE, Manke DA, Sumner DS. Toe blood pressure: a valuable adjunct to ankle pressure measurement for assessing peripheral arterial disease. J Cardiovasc Surg 1983;24: Bone GE, Pomajzl MJ. Toe blood pressure by photoplethysmography: an index of healing in forefoot amputation. Surgery 1981;89: Rutherford RB, Flanigan DP, Gupta SK, Johnston KW, et al. Suggested standards for reports dealing with lower extremity ischemia. J VASC SUV, G 1986;4:80-9a,. 4. Schwartz JA, Schuler JJ, O'Conner RJ, Flanigan DP. Predictive value of distal perfusion pressure on the healing of amputation of the digits and forefoot. Surg Gynecol Obstet 1982;154: Cox DR. Regression models and life tables. J R Stat Soc 1972;34: Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53: Holstein P, Sager P. Toe blood pressure in peripheral arterial disease. Acta Orthop Scand 1973;44: McDaniel MD, Cronenwett JL. Basic data related to the natural history of intermittent claudication. Ann Vasc Surg 1989;3: Hiral M, Kawai S, Ohta T, Seko T, Shionoya S. The value of toe blood pressure measurement in arterial reconstructive surgery. Vasc Surg 1981;15: Strandness DE Jr. Noninvasive tests in vascular emergencies. In: Bergan JJ, Yao JST, eds. Vascular surgical emergencies. Orlando: Grune & Stratton, 1987:103-1!. 11. Holmgren K, Baur GM, Porter JM. The role of digital photoplethysmography in the evaluation of Raynaud's syndrome. Bruit 1981;5: Carter SA, Tate RB. The effect of body heating and cooling on the ankle and toe systolic pressures in arterial disease. J VASC SURG 1992;16: Sawka AM, Carter SA. Effect of temperature on digital systolic pressures in lower limb arterial disease. Circulation 1992;85: Wallin L, Lund F, Westling H. Fluorescein angiography and distal medal pressures in patients with arterial disease of the leg. Clin Physiol 1989;9: Submitted Feb. 9, 1993; accepted May 3, DISCUSSION Dr. Steven J. Burnham (Chapel Hill, N.C.). We are completing a study with some similarities to this one. Our group of 184 consecutive patients referred to the peripheral vascular laboratory is retrospectively studied and does not have the purity of being limited to patients with claudication. The patients were monitored for 12 months. End points included radiologic and surgical intervention or death. We found a similar lack of predictive power for risk factors and markers of peripheral vascular disease. We did not find a difference in patients with diabetes. Instead of TP, we used ABI and found that this allowed for separation into groups that are significantly different in their risk of intervention or death. The life-table curve for the entire combined group begins a plateau at the 3-month interval, so we used intervention within 3 months for the remainder of the statistical work. Would you speculate on the virulence of the natural history for these patients compared with those having only distal occlusive disease? I was a little surprised that our own study showed that the level of occlusive disease was not associated with a difference in likelihood of intervention. The ABI was studied in several ways: the anterior tibial, posterior tibial, average of the two ratios, higher of the two, and lower of the two ratios. The higher of the two ratios had the best correlation with likelihood of intervention within 3 months. When patients are grouped in deciles according to the higher of the ABI, it seems that patients in the 0.4 to 0.5 range have about a 50% likelihood of intervention within 3 months. Dr. Benjamin L. Bowers. We reviewed those charts, and there was no isolated aortoiliac disease. Most of the patient population had multilevel disease, and a handful had infrainguinal disease only. However, the level of their disease, whether it was multilevel or infrainguinal, did not correlate with their clinical outcomes. The highest, the lowest, and the mean lowest ABIs were analyzed. The best correlation was found with the lowest Am on the ipsilateral extremity as the measured lowest TP. We found significance with the ABI in its ability to predict outcomes; however, an absolute value for an ABI did not achieve statistical significance.