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(Circulation. 1997;96:44-49.)
© 1997 American Heart Association, Inc.

Articles

Intermittent Claudication

A Risk Profile From The Framingham Heart Study

Joanne M. Murabito, MD, MSc; Ralph B. D'Agostino, PhD; Halit Silbershatz, PhD; ; Peter W. F. Wilson, MD

From the Framingham Heart Study (J.M.M., R.B.D., H.S., P.W.F.W.) Framingham, Mass; Section of Preventive Medicine and Epidemiology (J.M.M.) and Section of General Internal Medicine (J.M.M.) of Boston University School of Medicine, Boston, Mass; Division of Epidemiology and Clinical Applications of the National Heart, Lung, and Blood Institute (P.W.F.W.), Bethesda, Md; and the Department of Mathematics of Boston University (R.B.D., H.S.), Boston, Mass.

Correspondence to Dr Joanne Murabito, Framingham Heart Study, 5 Thurber St, Framingham, MA 01701. E-mail joanne{at}fram.nhlbi.nih.gov

	Abstract

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
Background Intermittent claudication identifies persons at increased risk for death and disability.

Methods and Results Using 38-year follow-up data for the original cohort in the Framingham Heart Study, we developed an intermittent claudication risk profile. Intermittent claudication occurred in a total of 381 men and women. Age, sex, serum cholesterol, hypertension, cigarette smoking, diabetes, and coronary heart disease were associated with an increased risk for claudication and were included in the profile. A pooled logistic regression model was used to compute the probability of intermittent claudication for specified levels of risk factors.

Conclusions The intermittent claudication risk profile allows physicians to identify high-risk individuals during a routine office visit and can be used to educate patients about modifiable risk factors, particularly smoking and blood pressure. Improved compliance with risk factor modification strategies may result in a beneficial impact on survival.

Key Words: claudication • hypertension • risk factors • smoking

	Introduction

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
Atherosclerotic cardiovascular disease is one of the most significant health problems faced by the elderly in this country. Intermittent claudication (IC), the symptomatic expression of lower-extremity atherosclerotic disease, is associated with a twofold to fourfold excess risk of mortality, predominantly from cardiovascular disease.¹ Functional independence is threatened in those with claudication due to limitations on mobility. Chronic peripheral arterial disease can lead to gangrene and limb loss, hospitalization, and surgical revascularization, each of which can elevate healthcare expenditures.² Decrements in functional health and sense of well-being in severe peripheral arterial disease are comparable to or greater than those in other severe chronic illnesses, even in the presence of successful revascularization.³ As the number of elderly in our population increases, IC will likely play an ever-greater role in identifying those at risk for death and disability.

The major cardiovascular risk factors predict the occurrence of IC better than they predict coronary heart disease.¹ Modification of potent risk factors may reduce the probability of IC and in turn improve cardiovascular morbidity and overall mortality. For example, smoking is not only a particularly powerful predictor of IC but is also associated with progression to rest pain⁴ and increased risk of amputation and death among claudicants.^{5 6} In one investigation, smoking cessation was associated with improved survival.⁶

In the present study, we developed an IC risk profile using 38-year follow-up data for original participants in the Framingham Heart Study. An individual's probability of developing IC can easily be assessed by the presence of risk factors identified on routine physical examination and laboratory analysis performed at a physician's office.

	Methods

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
The Framingham Heart Study was initiated in 1948 with a cohort of 2336 men and 2873 women between the ages of 28 and 62 years. Subjects have undergone routine follow-up examination every 2 years since the inception of the study. Physicians administered a standardized questionnaire at each examination to ascertain the presence of IC (Table 1). The diagnosis of IC was subjective and required the presence of exertional cramping or discomfort in the calf that appeared sooner with rapid walking or uphill walking and was relieved within a few minutes after resting. A second physician independently verified all suspected cases of claudication. An end-point committee of three physicians made the final diagnostic determination on the basis of the characteristics of the leg-discomfort history and, when available, review of personal physician notes and hospital records. Subjects with IC at the first examination were excluded from the present study.

View this table: [in this window] [in a new window]   Table 1. Physician-Administered Intermittent Claudication Questionnaire

Risk factors were measured at each clinic examination and included age, resting blood pressure, smoking status, presence of diabetes, and measurement of serum cholesterol. The classification of blood pressure was based on the average of two readings taken by the examining physician using the recommendations of the Fifth Joint National Committee on High Blood Pressure.⁷ Blood pressure was considered normal when the systolic blood pressure was <130 mm Hg and the diastolic blood pressure was <85 mm Hg. High-normal blood pressure was defined as a systolic blood pressure of 130 to 139 mm Hg or a diastolic blood pressure of 85 to 89 mm Hg. Stage 1 hypertension occurred when the systolic blood pressure was 140 to 159 mm Hg or the diastolic blood pressure was 90 to 99 mm Hg. Stage 2 or greater hypertension occurred when the systolic blood pressure was 160 mm Hg or the diastolic blood pressure was 100 mm Hg. If the systolic and diastolic pressures fell into different blood pressure stages, the higher stage was used to classify the blood pressure status. Diabetes was considered present if the subject was receiving therapy (insulin or oral hypoglycemic agents), if the subject had an abnormal glucose tolerance test, or if the blood glucose concentration was 150 mg/100 mL on at least two clinic visits. The presence of overt coronary heart disease was updated at each examination and included the diagnoses of myocardial infarction (recognized or unrecognized), coronary insufficiency, and angina pectoris.

Repeated observations of subjects attending biennial examinations 1 to 19 and free of IC at the present and all past examinations were pooled; each person-examination and its 4-year follow-up were considered as one observation in the data analysis.⁸ Pooled logistic regression was used to model the relationship of the risk factor (age, sex, cholesterol, blood pressure, cigarettes smoked per day, diabetes, and the presence of existing coronary heart disease) to the development of IC within the 4-year follow-up period. Because sex-specific models yielded similar risk factor coefficients and odds ratios for IC, a combined model for men and women was used. Sex-by–risk factor interactions were not significant. The logistic regression model allows computation of the probability of IC within 4 years for specified levels of risk factors (see Table 6 and Appendix).

	Results

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
During 38 years of follow-up, 381 persons (215 men and 166 women) developed IC. For both sexes, the 4-year rates of IC increased until age 75 years, after which the rate declined (Table 2). At all ages, men experienced nearly double the rate of claudication experienced by women. In contrast to subjects free of IC, those with IC were more likely to be male; on average were 4 years older; had a higher mean cholesterol level; had higher prevalences of stage 2 or greater hypertension, diabetes, and coronary heart disease; and smoked a greater number of cigarettes per day (Table 3). In the logistic regression model, male sex, age, and smoking were associated with an 1.5-fold increased risk for IC; diabetes and stage 2 or greater hypertension conferred a >2-fold increased risk; and coronary heart disease nearly tripled the risk for IC (Table 4).

View this table: [in this window] [in a new window]   Table 2. 4-Year Rates of Intermittent Claudication by Age and Sex: Framingham Heart Study, 38-Year Follow-up

View this table: [in this window] [in a new window]   Table 3. Summary Statistics for Risk Factors by Intermittent Claudication Status

View this table: [in this window] [in a new window]   Table 4. Logistic Regression Estimates and Odds Ratios for Significant Risk Factors in the Intermittent Claudication Profile in Subjects Aged 45 to 84: Framingham Heart Study

The probability of IC is determined by the presence and level of each risk factor. A 70-year-old man who smokes 1.5 packs of cigarettes per day is contrasted to one who is a nonsmoker (Figure). The 4-year probability of IC increases in the presence of other risk factors, and cigarette smoking dramatically escalates the probability of IC at any given risk factor level. Although the absolute probabilities are slightly lower in women than in men, the same steep rise at any given risk factor level is accentuated in smokers.

View larger version (22K): [in this window] [in a new window]   Figure 1. Estimated 4-year probability of intermittent claudication in 70-year-old men in the Framingham Heart Study. BP indicates blood pressure; Nl, normal; Stg1, stage 1 hypertension; Stg 2+, stage 2 or greater hypertension; CHD, coronary heart disease; and cigs, cigarettes.

A physician can easily determine the probability of IC for an individual patient using a point score based on risk factor data collected as part of a routine evaluation (Table 5). For example, a 70-year-old man with a cholesterol level of 240 mg/dL, stage 1 hypertension, and diabetes and who smokes 1.5 packs of cigarettes per day receives a score of 21: 5 points for age, 3 points for sex, 2 points for cholesterol level of 240 mg/dL, 2 points for stage 1 hypertension, 5 points for diabetes, and 4 points for smoking 30 cigarettes per day. A point score of 21 yields a 4-year probability of IC of 7%. Thus, this hypothetical man has an IC risk that is nearly three times greater than the average risk (the average risk for a 70-year-old man is 2.5%; see Table 2). It should be noted that for someone this age who is without risk factors, the 4-year probability of IC is virtually zero. If this man were to quit smoking, his 4-year probability of IC would fall over time to nearly the average risk (then his point score would be 17, corresponding to a 4-year probability of 3%). Although Table 5 has a point score maximum of 30, such scores were rare. Data were pooled for persons with a score >28 points to provide a more stable estimate for individuals at the highest risk for IC.

View this table: [in this window] [in a new window]   Table 5. 4-Year Probability of Intermittent Claudication for Persons Aged 45-84 Years, Framingham Heart Study

	Discussion

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
IC can be easily diagnosed with the use of a standardized questionnaire that asks about exertional calf discomfort. Claudication is associated with a substantially increased risk for death that is only partly explained by its association with coronary heart disease.^{1 5 9 10 11 12} In community-based studies, claudication predicts higher rates of myocardial infarction, stroke, and disability in older adults.¹³ The IC risk profile provided in the present report can be used to identify high-risk individuals on the basis of risk factors noted during a routine visit to a physician. This profile may help to ensure compliance with risk factor modification strategies and potentially affect survival.

The Rose questionnaire¹⁴ has been used extensively to assess the presence of IC. The questionnaire is known to be specific but highly insensitive for the diagnosis of lower-extremity arterial disease.^{15 16} People who do not exercise or walk vigorously may never experience symptoms, whereas those with advanced symptoms may stop walking or limit walking distance to ameliorate symptoms. Advanced disease may also present with atypical symptoms. Diagnosis of IC is especially troublesome in the elderly because they often experience trouble walking or require an aid as a result of underlying medical conditions. Even in a group of healthy elderly women, those older than 80 years were less likely to walk for exercise.¹⁶ In an effort to identify persons unable to walk or persons with limited ambulation, the physician examiners in Framingham now routinely query the elderly original cohort about their ability to walk 50 feet without help (no cane, walker, or wheelchair). This added question is likely to reduce the number of false-negative results from a standard claudication questionnaire.

The prevalence of subclinical cardiovascular disease (defined by ankle-arm index, carotid ultrasound, ECG abnormalities, echocardiography, and response to Rose questionnaires) in older men and women is substantial (61% and 49%, respectively) and predictive of an increased risk for coronary heart disease and overall mortality, even after adjustment for age and cardiovascular risk factors.¹⁷ The ankle-arm blood pressure index is a simple, noninvasive measure of lower-extremity arterial disease that identifies largely asymptomatic individuals. In older adults (65 years old), reductions in the ankle-arm index were associated with both clinical and subclinical cardiovascular disease in a graded, inverse dose-response relationship.¹⁸ Community-based studies have repeatedly demonstrated that an abnormal ankle-arm index identifies those at high risk for death and cardiovascular morbidity.^{19 20 21 22} Among claudicants, a severe reduction in the ankle-arm index identified a subgroup at an exceedingly high risk for coronary and cerebrovascular mortality.²³ Incorporating this procedure into a routine office visit should provide a useful means of further stratifying cardiovascular risk.

Smoking is a key risk factor for the development and progression of claudication and peripheral arterial disease, and data support a dose-dependent effect.^{1 6 10 11 12 16 24} The impact of cigarette smoking persists even into advanced age.²⁵ The population attributable risk for smoking and IC calculated for cross-sectional studies ranges from 14% to 53%.²⁶ For lower-extremity arterial disease determined noninvasively by use of the ankle-arm index, the population attributable risk for current smoking in women is 26%.¹⁶ Smoking adversely affects postoperative graft patency and increases the risk of limb loss after surgical reconstruction.^{27 28 29} The effectiveness of antiplatelet medications is diminished in smokers.³⁰

A few studies have reported that smoking cessation is associated with a rapid decline in the incidence of IC,¹¹ and the IC risk for ex-smokers 1 year after quitting approximates that for nonsmokers.^{11 12} In a referral population of claudicants without diabetes, smoking cessation was associated with a lack of progression to rest pain, a decreased surgical intervention rate, a decreased risk of cardiac events, and improved survival.⁶ In addition to retarding the incidence and progression of lower-extremity arterial disease and its associated risk of death, smoking cessation has been shown to decrease mortality risk after myocardial infarction^{31 32} and to improve clinical outcome after coronary artery bypass surgery, including recurrence of angina and myocardial infarction and the need for reoperation.³³

In accordance with our study, most previous investigators have demonstrated that blood pressure is a strong predictor of peripheral arterial disease.^{1 10 16 18 34} The population attributable risk for stage 2 or greater hypertension and IC in the present study is 30%. Among elderly women with lower-extremity arterial disease, the population attributable risk for a systolic blood pressure >140 mm Hg is 28%.¹⁶ Blood pressure is a major risk factor for both symptomatic^{1 10 16 34} and noninvasively determined¹⁸ peripheral arterial disease. Effective blood pressure treatment will not only provide a reduction in peripheral arterial disease but will also have an important impact on stroke.³⁵

The present study relied on a clinical diagnosis of IC based on subjective symptoms of leg discomfort obtained by two physicians using a standardized questionnaire. During the study period, noninvasive testing to confirm hemodynamically significant compromise of the lower-extremity arterial circulation in symptomatic participants was not available as part of the routine biennial examination. In addition, no uniform methods were used to grade the severity of the claudication symptoms. To minimize misclassification, two physicians independently interviewed symptomatic participants, and an end-point committee of three physicians reviewed all available data to make the final diagnostic determination.

The IC risk profile developed in the present study can provide quantitative guidelines for physicians and can be used to educate and motivate patients to modify risk factors, particularly to stop smoking and lower their blood pressure. The health benefits of risk factor reduction extend beyond peripheral arterial disease to coronary and cerebrovascular disease, and for smoking cessation, the benefits include a reduction in mortality from chronic obstructive pulmonary disease and a decreased risk for cancer of multiple organ sites.

View this table: [in this window] [in a new window]   Table 6. ß-Coefficients and Standard Errors Used in the Intermittent Claudication Prediction Chart

	Acknowledgments

 
This study was supported in part by NIH grant N01-HC-38038.

	Appendix 1

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
Application of Table 6
The ß-coefficients given in Table 6 are used to compute a linear function. The latter is exponentiated and used to calculate a 4-year probability of intermittent claudication after insertion into a probability function. The following explanation and an example demonstrate each of these steps in a serial fashion:

(1)

Take the negative of the value L (Equation 2). Exponentiate the latter to produce value B (Equation 3). The value B is then put into Equation 4 to produce a 4-year probability:

(2)

(3)

(4)

Consider a 55-year-old man with a cholesterol level of 250 mg/dL, high-normal blood pressure (146/88 mm Hg), and no diabetes who smokes six cigarettes per day. In this instance, after Equation 1, L=-8.9152+0.5033+(55x0.0372)+(250x0.0048)+0.2621+(0.0314x6)=-4.7154. After Equation 2, A=-(-4.7154)=4.7154, and after Equation 3, B=e^4.7154=111.65. Finally, after Equation 4, P=(1/[1+111.65])=0.00887, for an 1% chance of developing intermittent claudication during a 4-year period. Using the point-score chart, 55-year-old (2 points)+male (3 points)+cholesterol level of 250 mg/dL (3 points)+high-normal blood pressure (1 point)+smokes six cigarettes per day (2 points)=11 points, corresponding to an 1% chance of developing intermittent claudication during a 4-year period. An average 55-year-old man has a 2.1% risk. As demonstrated, the point-score chart and the probability function of the coefficients give rather similar results.

Received November 18, 1996; revision received January 15, 1997; accepted January 22, 1997.

	References

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 

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				U. Laaser and J. Breckenkamp Trends in risk factor control in Germany 1984-1998: high blood pressure and total cholesterol Eur J Public Health, April 1, 2006; 16(2): 217 - 222. [Abstract] [Full Text] [PDF]

				A. T. Hirsch, Z. J. Haskal, N. R. Hertzer, C. W. Bakal, M. A. Creager, J. L. Halperin, L. F. Hiratzka, W. R.C. Murphy, J. W. Olin, J. B. Puschett, et al. ACC/AHA 2005 Guidelines for the Management of Patients With Peripheral Arterial Disease (Lower Extremity, Renal, Mesenteric, and Abdominal Aortic): Executive Summary A Collaborative Report From the American Association for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA Task Force on Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease): Endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation; National Heart, Lung, and Blood Institute; Society for Vascular Nursing; TransAtlantic Inter-Society Consensus; and Vascular Disease Foundation J. Am. Coll. Cardiol., March 21, 2006; 47(6): 1239 - 1312. [Full Text] [PDF]

				N. A. Khan, S. A. Rahim, S. S. Anand, D. L. Simel, and A. Panju Does the Clinical Examination Predict Lower Extremity Peripheral Arterial Disease? JAMA, February 1, 2006; 295(5): 536 - 546. [Abstract] [Full Text] [PDF]

				B. Fletcher, K. Berra, P. Ades, L. T. Braun, L. E. Burke, J. L. Durstine, J. M. Fair, G. F. Fletcher, D. Goff, L. L. Hayman, et al. Managing Abnormal Blood Lipids: A Collaborative Approach Circulation, November 15, 2005; 112(20): 3184 - 3209. [Abstract] [Full Text] [PDF]

				J. M. Murabito, J. C. Evans, R. B. D'Agostino Sr., P. W. F. Wilson, and W. B. Kannel Temporal Trends in the Incidence of Intermittent Claudication from 1950 to 1999 Am. J. Epidemiol., September 1, 2005; 162(5): 430 - 437. [Abstract] [Full Text] [PDF]

				F. Youssef, P. Gupta, D. P. Mikhailidis, and G. Hamilton Risk Modification in Patients with Peripheral Arterial Disease: A Retrospective Survey Angiology, May 1, 2005; 56(3): 279 - 287. [Abstract] [PDF]

				American Diabetes Association Peripheral Arterial Disease in People with Diabetes J Am Podiatr Med Assoc, May 1, 2005; 95(3): 309 - 319. [Full Text] [PDF]

				L. Campeau, J. Lesperance, L. Bilodeau, A. Fortier, M.-C. Guertin, and G. L. Knatterud Effect of Cholesterol Lowering and Cardiovascular Risk Factors on the Progression of Aortoiliac Arteriosclerosis: A Quantitative Cineangiography Study Angiology, March 1, 2005; 56(2): 191 - 199. [Abstract] [PDF]

				C. L. Leibson, J. E. Ransom, W. Olson, B. R. Zimmerman, W. M. O'Fallon, and P. J. Palumbo Peripheral Arterial Disease, Diabetes, and Mortality Diabetes Care, December 1, 2004; 27(12): 2843 - 2849. [Abstract] [Full Text] [PDF]

				American Diabetes Association Peripheral Arterial Disease in People With Diabetes Clin. Diabetes, October 1, 2004; 22(4): 181 - 189. [Full Text] [PDF]