0895-4356/91 $3.00+ 0.00 Copyright0 1991PergamonPressplc
JClhEpidemiolVol.44,No.I,pp.15-20,1991 Printedin Great Britain.All rightsreserved
LOWER EXTREMITY ARTERIAL DISEASE IN ELDERLY SUBJECTS WITH SYSTOLIC HYPERTENSION* ANNE B. NEWMAN,’ KIM SUTTON-TYRRELL,~ GALE H. RIJTAN,~ JULIE LWHJZR’ and Lewis H. KULLER~ ‘Section of Geriatrics, Department of Medicine, School of Medicine, University of Pittsburgh, 2Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh and ‘Division of Clinical Pharmacology, Department of Medicine, School of Medicine, University of Pittsburgh, PA 15261, U.S.A. (Received in revised form 20 July 1990)
Abstraet-The ratio of ankle-to-arm systolic blood pressure (ankle/arm index or AAI) appears to be a non-invasive indicator of flow-significant atherosclerosis and may be a useful measure of burden of disease in a high risk population. The prevalence of lower extremity arterial disease (LEAD) was assessed by this method in the Systolic Hypertension in the Elderly Program (SHEP). Subjects were aged 60 and older with systolic blood pressure greater than 160mmHg upon entry to the study. An AA1 of 0.90
or less was considered indicative of flow-significant LEAD. The prevalence of LEAD by this method was 26.7% @O/187),‘whilethe prevalence of intermittent claudication (IC) was only 6.4% (12/187). Of those with IC, 66.7% (8/12) had confirmed LEAD. The prevalence of LEAD as measured by AA1 increased with age in women and was associated with a history of current smoking and lower levels of high density lipoproteins. In this study population with systolic hypertension, LEAD, as measured by the AAI, is more prevalent than previously described in elderly populations and is associated with other risk factors for atherosclerosis. Peripheral arterial disease
Systolic hypertension
Elderly
sensitive to disease than symptoms of IC; and has been shown to be both reliable and The prevalence of peripheral arterial disease valid when compared to angiography [4-6]. One increases with age whether assessed by symp- component of non-invasive testing, the ratio of toms of claudication or non-invasive testing ankle-to-arm systolic blood pressure, has been [l-3]. Elderly subjects with isolated systolic used to screen for peripheral arterial disease in hypertension are at particularly high risk of study populations [fl. Prevalence rates by this atherosclerotic events and might be expected sample method are similar to those using more to have a high prevalence of atheqsclerotic complete testing [3]. A positive test appears to obstruction of the lower extremities. be correlated with other risk factors for The prevalence of peripheral arterial disease atherosclerosis, such as smoking, diabetes, male has been shown to be dramatically underestigender and older age [7-151. mated by symptoms of intermittent claudication In this study, an assessment was made of (IC). Non-invasive testing is clearly more the prevalence of peripheral arterial disease in elderly subjects with isolated systolic hyperFollowing this peripheral arterial *Presented at the American Heart Asmciation, 60th !%ien- tension. disease was examined more closely in tlik St&on, 16 November 1987, Anaheim, Calif. MTRODU(YION
15
ANNEB. NEWMANet al.
16
comparison with other risk factors associated with atherosclerosis. MATERIALS AND METHODS
Study population
Subjects for this ancillary study were currently enrolled in the Pittsburgh Center of the Systolic Hypertension in the Elderly Program (SHEP). SHEP is a double-blind, randomized, placebo controlled trial of the treatment of isolated systolic hypertension, defined as systolic blood pressure (SBP) > 160 and diastolic blood pressure (DBP) < 90, in subjects over age 60. Subjects were recruited from shopping malls, retirement centers, churches, senior citizens’ clubs and other locations where predominantly healthy elderly adults tend to congregate. Exclusion criteria for entry into the study included recent transient ischemic attack, stroke with residua, myocardial infarction within the previous six months, advanced congestive heart failure, renal disease and malignancy. Of 200 subjects randomized as of 1 April 1987, 190 agreed to undergo peripheral arterial disease screening. Three subjects could not be studied because of inability to occlude the posterior tibia1 artery. The remaining 187 formed the study population. All participants were given a standard interview which included the modified Rose questionnaires [16] for angina and intermittent claudication. Physical exam and ankle and arm systolic blood pressure were performed by study physicians. Blood samples were analyzed using standard techniques for glucose, cholesterol, HDL-cholesterol and triglycerides. Lower extremity arterial disease (LEAD) was evaluated using the ratio of ankle-to-arm systolic blood pressure, commonly referred to as the ankle/arm index (AAI). Standard 12 cm blood pressure cuffs were applied to both ankles and the appropriate size cuff to the right arm. Measurements were taken after 5 min of the rest in the supine position. The systolic pressure was determined at the right brachial and both right and left posterior tibia1 arteries by Doppler stethoscope using a zero muddler manometer to avoid observer bias. Measurements were done twice in rapid sequence. The AA1 for each extremity was the average of the two ratios obtained. A normal AA1 should be > 1.O. Based on previous studies, a subject was defined as having LEAD if either the right or left AA1 was co.90 [7, 171.
Reliability of AAI measurement
Inter-observer reliability was studied in both normal and study subjects. Three observers repeated eight measurements on six normal subjects. Inter- and intra-observer variability was not significant by use of a paired t-test and by repeated measures analysis of variance. The p-value for within observer variability was 0.927, and for between observers was 0.568. The coefficient of variation for each subject and observer ranged for the AA1 from 3 to 6%. Reliability was also studied in the study subjects. Two observers repeated the test twice on 50 elderly subjects with systolic hypertension. Again, the variability within and between observers was not significant by analysis of variance. Most of the variance was due to blood pressure fluctuations in individual subjects. Statistical analyses
Independent t-tests were used to compare means of continuous variables. The chi-square statistic and the Fisher’s exact test, where appropriate, were used for analyses of categorical variables. Significance levels were set at the 0.05 level. All tests are two-directional. Stepwise multiple logistic regression analysis was used to evaluate different models to describe the data and to examine the relative importance of the independent variables. RESULTS
The mean age of the study population was 72 years with a range of between 61 amd 89 years. Women made up 56% of the study population. The sample was overwhelmingly comprised of white subjects with only two black males and one black female. The mean baseline systolic blood pressure was 171 mmHg with a range of 160-203 mmHg. An abnormal AA1 (< 0.90) was found in 50 out of 187 (26.7%) of the subjects (see Fig. 1). The prevalence of intermittent claudication by Rose questionnaire was only 6.4%, representing a 4-fold difference in prevalence rates. Of 12 subjects reporting intermittent claudication, 8 had an AA1 of co.90 (Fisher’s exact test p < 0.005). Of those subjects with disease, 42% were men and 58% were women, similar to the sex composition of the group as a whole. The sensitivity, specificity and predictive value of a positive Rose questionnaire were calculated compared to a positive test for lower extremity arterial disease. The sensitivity of a
Peripheral Arterial Disease in the Elderly
QUESTIONNAIRE
17
-I
ANKLE/ARM INDEX Fig. 1. Frequency distribution of ankle/arm index and intermittent claudication. An ankle/arm index less than or equal to 0.90 was indicative of lower extremity arterial disease.
positive Rose questionnaire was only 16% while the specificity was 97%. The positive predictive value for this finding was 67% in our population. Because the prevalence of IC is only a fourth of LEAD, there is insufficient power to analyze risk factors for IC in this study. Further analysis showed that subjects with LEAD were older (t = - 1.75, p < 0.08) and had a higher baseline mean systolic blood pressure (t = - 1.67, P < 0.10) prior to treatment of their hypertension. Analysis for age and SBP by
sex revealed that women with LEAD were older with higher baseline SBP (age: t = - 2.17, p < 0.03; SBP: t = - 1.72, p < 0.09); yet there were no differences in these means for men. There was also a significant trend for increasing prevalence of LEAD with increasing age in women by chi-squared ‘test of trend where p = 0.05. Univariate analyses revealed lower HDL cholesterol levels for those subjects with and without disease. For these subjects with LEAD,
Table 1. Risk factors for LEAD mean differences Variable
Present
LEAD Absent
LEAD o-Value
All Subjects
Age (yr) Systolic blood pressure (mmHg) Fasting glucose (mg/dl) Total serum cholesterol (mg/dl) HDL-cholesterol (mg/dl) Fasting serum triglycerides (mg/dl)
50 (27%) 74 173 107 245 47 179
137 (73%) 72 170 103 237 51 161
Age Systolic blood pressure Fasting glucose Total serum cholesterol HDL-cholesterol Fasting serum triglycerides
21 (26%) 72 172 119 236 42 228
61(74%) 72 170 107 227 47 168
0.87 0.55 0.31 0.44 0.11 0.04*
Age
Female Subjects 29 (28%) 76 (72%) 75 72
0.03’
0.08 0.10 0.59 0.28 0.07 0.26
Male Subjects
Systolic blood pressure Fasting glucose Total serum cholesterol HDL-cholesterol Fasting serum triglycerides
?? p < 0.05, two-tailed t-test.
173 98 251 51 144
170 101 245 55 156
0.09 0.70 0.48 0.19 0.49
ANNEB. NEWMAN et al.
18
Table 2. Risk factors for LEAD Variable
Total n
n with LEAD (%)
82 105
21 (26) 29 (28)
17 170
8 (47) 42 (25)
o-Value
Gender
0.89
Male Female Smoking status
0.05*
Current Past or never
*p < 0.05 two-tailed test of significance; chi-square with 1 df
the mean HDL level was 47.0; for. those subjects without, the mean HDL level] was 51 .l. (t = 1.85, p = 0.07). This difference was not apparent when subjects with and without disease were stratified by sex. Serum triglyceride levels were significantly higher in men with LEAD than without (t = -2.13, p < 0.05). This was not seen in women. Total cholesterol and fasting blood sugar did not differ between the two groups. Current, but not past history of cigarette smoking was also related to LEAD (Fisher’s exact test p < 0.05). Indicators of advanced atherosclerosis, including history of myocardial infarction, stroke or carotid bruit were infrequent in this group of fairly healthy elderly subjects and individually were not associated with LEAD. The presence of at least one of these findings in an individual, however, was significantly associated with the presence of LEAD (p = 0.03). Stepwise multiple logistic regression analysis was performed to examine the independent contributions of variables that were significant in
the univariate analyses, including age, systolic blood pressure, smoking, and HDL-cholesterol. The dependent variable was LEAD. Age and current smoking status entered the model as the strongest predictors of LEAD. The calculated odds ratios from the model were not significantly greater than one. DISCUSSION
In the elderly, the relationship between established atherosclerosis, risk factors including hypertension, cholesterol, smoking and further progression of disease is not clear. Because atherosclerosis is exceedingly prevalent in the elderly population, some measure of the extent of disease must be considered in evaluating the impact of other factors. Systolic hypertension was long thought to reflect loss of arterial elasticity with aging and the degree of atherosclerosis, thus an adaptive way of ensuring perfusion of vital organs. However, most data show that systolic blood pressure is an independent risk factor for subsequent cardio-
Table 3. Baseline disease status bv LEAD Total n
n with LEAD (%)
p-Value
History of intermittent claudication Yes No
12 174
8 (67) 42 (24)
o.o03*t
Carotid bruit (CB) Yes No
12 175
5 (42) 45 (26)
0.31
History of myocardial infarction (MI) Yes No
7 180
4 (57) 46 (26)
0.08
History of stroke (ST) Yes No
1
l(100) 49 (26)
0.27
186
Combined history of CB, MI, ST Yes No
19 168
41 (24)
Variable
*p < 0.05 two-tailed test of significance. TFisher’s exact test. $Chi-square with 1 dJ
9 (47)
0.03*1
Peripheral Arterial Disease in the Elderly Table 4. Relative risk of risk factors for LEAD derived from logistic mgrassion~modal
Age Current smoker
RR
95% cl
1.06 3.67
(0,3.08) (0.3,7.04)
vascular events. Kannel et al. [9] showed that this relationship persists even when arterial rigidity, as measured by pulse volume recordings, is taken into account. A simple method of identifying individuals with atherosclerosis who are at high risk for clinical events such as myocardial infarction, stroke and claudication may be of considerable value in the development of treatment strategies for risk factor identification and modification, especially in older individuals. Clinical studies of the use of the AA1 in peripheral vascular laboratories can discriminate between those with and without obstruction with a high degree of specificity [4-6]. Sensitivity is diminished in those with borderline disease or rigid arteries that preclude pneumatic cti compression. Fronek et al. [6] have emphasized the need to include quantitative Doppler velocimetry to detect disease in those with rigid arteries. Exercise testing is also important to increase sensitivity. Disease can be localized by the use of multiple levels of measurement along the leg. All of these procedures greatly increase the time and cost of testing, and are very important in the clinical setting. However, as a simple, inexpensive, non-invasive screening test, the AA1 alone is ideal for screening large populations [ 111.Because of the high correlation with symptoms of claudication, and other clinical manifestations of atherosclerosis, and the greatly increased sensitivity over symptoms alone, the AA1 is a useful way of quantitating the burden of atherosclerosis in a population in an objective way. Risk factors for peripheral arterial disease have been evaluated in case series, by interview for symptoms, and by non-invasive testing. Older age, male sex, hypertension, smoking and diabetes emerge as important risk factors across studies regardless of the method of measuring disease [I, 2,615, l&22]. Since most studies used the Rose questionnaire [16], prevalence was underestimated and risk factor analyses could only be done on those with the worst disease. The prevalence of symptoms of claudication increases with age and has been found to be 2-10% in studies of those 60 and over. Prevalence by non-invasive testing is much
19
higher, up to 20% in a study by Criqui et al. [3] in those over age 75. Considering that systolic hypertension is a risk factor for other atherosclerotic endpoints, it is not unexpected that the prevalence of peripheral arterial disease by noninvasive testing is higher in our study than has been reported in other studies [3,7l. The disparity between the prevalence of symptoms and abnormal AA1 in our population is similar to other studies [7,23,24]. These studies have found the prevalence of peripheral arterial disease to ‘be about 2-10 times higher when assessed by non-invasive means compared to standardized questionnarie. Though the sensitivity of the Rose questionnaire is low (lO-19%) [23,24], is 97-99% specific for an abnormal AAI. The variability of activity level needed to produce symptoms probably explains the low sensitivity of the Rose questionnaire. Though this elderly cohort was generally healthy and ambulatory, their level of physical activity is probably less than in a younger group. Our findings are similar to other studies in showing that while specific, Rose questionnaire is very insensitive to detecting flow-significant LEAD [23]. Other clinical measures, including pulse palpitation, can improve sensitivity and specificity when compared to non-invasive measures. Currently, however, the AA1 appears to be the best single objective non-invasive measurement for population studies [7, 10,23,24]. Within this group of elderly subjects with isolated systolic hypertension, disease prevalence increased with age and SBP. Differences were more pronounced for women than men. As in most other studies, current smoking was a risk factor for disease. The presence of any other measure of clinical atherosclerosis such as myocardial infarction, carotid bruit and stroke was also associated with LEAD, indicating the systemic nature of atherosclerotic cardiovascular disease. Since the number of cases of LEAD is relatively small, the lack of strong associations with individual risk factors and measures of clinical atherosclerosis may be related to a lack of statistical power. Though total cholesterol was not associated with LEAD in this population, a low HDLcholesterol was. While this relationship was not statistically significant, it was suggestive. Previous reports of the association of lipid abnormalities in peripheral vascular disease have not been conclusive, but the same inverse association with HDL-cholesterol is apparent [13,25,26].
ANNEB. NEWMANet al.
20
Systolic hypertension has been shown to be a risk factor for atherosclerotic events, yet to some extent may indicate presence of already established disease. Even in subjects with established systolic hypertension, there is a wide variation in extent of lower extremity arterial disease. The cause and effect relationship between systolic hypertension and atherosclerosis cannot be established by this cross-sectional study. Acknowledgement-This research was supported by National Research Service Award HL07011, Cardiovascular Epidemiology Training Program.
REFERENCES 1. Hughson WG, Mann JI, Tibbs DJ, Woods HF, Walton I. Intermittent claudication: Factors determining outcome. Br Med J 1978; 1: 1377-1379. 2. Reunanen A, Takkunen H, Aromaa A. Prevalence of intermittent claudication and its effects on mortality. Actn Med Stand 1982; 211: 249-256. 3. Criqui MH, Fronek A, Barrett-Connor E, Klauber MR, Gabriel S, Goodman D. The prevalence of peripheral arterial disease in a defined population. Circulation 1985; 71(3): 510-515. 4. Yao ST, Hobbs JT, Irvine WT. Ankle systolic pressure measurements in arterial disease affecting the lower extremities. Br J Surg 1969; 56: 676-679. 5. Carter SA. Clinical measurement of systolic pressure in limbs with arterial occlusive disease. JAMA 1969; 207: 1969. 6. Fronek A, Coel M, Bernstein EF. The importance of combined multisegmental pressure and Doppler flow velocity studies in the diagnosis of peripheral arterial occlusive disease. Surgery 1978; 84: 84&847. 7. Schroll M, Munck 0. Estimation of peripheral arteriosclerotic disease by ankle blood pressure measurements in a population study of 60-year-old men and women. J Chron Dis 1981; 34: 261-269. 8. Criqui MH, Coughlin SS, Fronek A. Noninvasively diagnosed peripheral arterial disease as a predictor of mortality: Results from a prospective study. Circulation 1985; 72: 768-773. 9. Kallero KS. Mortality and morbidity in patients with intermittent claudication as defined by venous occlusion plethysmography: A ten-year follow-up study. J Chron Dis 1981; 34: 455462. 10. Fowkes FGR. The measurement of atherosclerotic peripheral arterial disease in epidemiologic surveys. Int J Epidemiol 1988; 17: 248-254. 11. Zimmerman BR, Palumbo PJ, O’Fallon WM, Osmundson PJ, Kazmier FV. A live study of peripheral occlusive arterial disease in diabetes. Mayo Clln Proc 1981; 56: 217-253.
12. Janzon L, Bergentz SE, Erison BF, Lindell SE. The
arm-ankle pressure gradient in relation to cardiovascular risk factors in intermittent claudication. Circulation 1981; 63: 1339-1341. 13. Pomrehn P, Duncan B, Weissfeld L, Wallace RB, Barnes R, Heiss G, Ekelund L-G, Criqui MH, Johnson N, Chambliss LE. The association of dyslipoproteinemia with symptoms and signs of peripheral arterial disease. The Lipid Research Clinic Program Prevalence Study. Circulation 1986; 73(I): l-100. 14 Aronow WS, Sales FF, Etienne F, Lee NH. Prevalence ’ of peripheral arterial disease and its correlation with risk factors for peripheral arterial disease in elderly patients in a long-term care facility. Am J Cardlol 1988; 62: 644-645. 15 Laakso M, Ronnemaa T, Pyorala K, Kallio V, ’ Puukka P, Penttila I. Atherosclerotic vascular disease and its risk factors in non-diabetic subjects in Finland. Diabetes Care 1988; 11: 449-463. 16. Rose GA. The diagnosis of ischematic heart pain and intermittent claudication in field surveys. Bull Wld Hlth Org 1962; 27: 645-658. 17. Yao JST. Surgical use of pressure studies in peripheral arterial disease, In: Bernstein EF, Ed. Non-invasive Diagnostic Techniques in Vascular Msease. St Louis, MO: C. V. Mosby; 1985. 18. Kannel WB, McGee DL. Update on some epidemiologic features of intermittent claudication: The Framingham Study. J Am Gerlatr See 1985; 33: 13. 19. Strandness DE, Sumber DS. The relationship between calf blood flow and ankle pressure in patients with intermittent claudication. Surgery 1986; 65: 763. 20. Prineas RV, Harland WR, Janzon L, Kannel W. Recommendations for use of non-invasive methods to detect atherosclerotic peripheral arterial disease in population studies. Circulation 1982; 65: 1561A-1566A. 21. Friedman SA, Pandya M, Grief E. Peripheral arterial occlusion in patients with acute coronary heart disease. Am Heart J 1973; 86: 415419. 22. Harris T, Cook EF, Kannel WB, Goldman L. Proportional hazards analysis of risk factors for coronary heart disease in individuals aged 65 or older: The Framingham Heart Study. J Am Gerlatr Sot 1988; 36: 1023-1028. 23. Criqui MH, Fronek A, Klauber M, Barrett-Connor E, Gabriel S. The sensitivity, specificity, and predictive value of traditional clinical evaluation of peripheral arterial disease: results from noninvasive testing in a defined population. Circulation 1985; 71: 516-522. 24. DeBacker G, Komitzer M, Sobolski J, Denolin H. Intermittent claudication-epidemiology and natural historv. Acta Cardioloeica T. 1979: 34: 115-124. 25. Bradb; GVH, Valente AJ, Walton ‘KW. Serum highdensity lipoprotein in peripheral vascular disease. Lancet 1978; 1271-1274. 26. Criqui MH, Browner D, Fronek A, Klauber MR, Coughlin SS, Barrett-Connor E, Gabriel S. Peripheral arterial disease in large vessels is epidemiologically distinct from small vessel disease: an analysis of risk factors. Am J Epidemiol 1989; 129: 111&1120.
JClhEpidemiolVol.44,No.I,pp.15-20,1991 Printedin Great Britain.All rightsreserved
LOWER EXTREMITY ARTERIAL DISEASE IN ELDERLY SUBJECTS WITH SYSTOLIC HYPERTENSION* ANNE B. NEWMAN,’ KIM SUTTON-TYRRELL,~ GALE H. RIJTAN,~ JULIE LWHJZR’ and Lewis H. KULLER~ ‘Section of Geriatrics, Department of Medicine, School of Medicine, University of Pittsburgh, 2Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh and ‘Division of Clinical Pharmacology, Department of Medicine, School of Medicine, University of Pittsburgh, PA 15261, U.S.A. (Received in revised form 20 July 1990)
Abstraet-The ratio of ankle-to-arm systolic blood pressure (ankle/arm index or AAI) appears to be a non-invasive indicator of flow-significant atherosclerosis and may be a useful measure of burden of disease in a high risk population. The prevalence of lower extremity arterial disease (LEAD) was assessed by this method in the Systolic Hypertension in the Elderly Program (SHEP). Subjects were aged 60 and older with systolic blood pressure greater than 160mmHg upon entry to the study. An AA1 of 0.90
or less was considered indicative of flow-significant LEAD. The prevalence of LEAD by this method was 26.7% @O/187),‘whilethe prevalence of intermittent claudication (IC) was only 6.4% (12/187). Of those with IC, 66.7% (8/12) had confirmed LEAD. The prevalence of LEAD as measured by AA1 increased with age in women and was associated with a history of current smoking and lower levels of high density lipoproteins. In this study population with systolic hypertension, LEAD, as measured by the AAI, is more prevalent than previously described in elderly populations and is associated with other risk factors for atherosclerosis. Peripheral arterial disease
Systolic hypertension
Elderly
sensitive to disease than symptoms of IC; and has been shown to be both reliable and The prevalence of peripheral arterial disease valid when compared to angiography [4-6]. One increases with age whether assessed by symp- component of non-invasive testing, the ratio of toms of claudication or non-invasive testing ankle-to-arm systolic blood pressure, has been [l-3]. Elderly subjects with isolated systolic used to screen for peripheral arterial disease in hypertension are at particularly high risk of study populations [fl. Prevalence rates by this atherosclerotic events and might be expected sample method are similar to those using more to have a high prevalence of atheqsclerotic complete testing [3]. A positive test appears to obstruction of the lower extremities. be correlated with other risk factors for The prevalence of peripheral arterial disease atherosclerosis, such as smoking, diabetes, male has been shown to be dramatically underestigender and older age [7-151. mated by symptoms of intermittent claudication In this study, an assessment was made of (IC). Non-invasive testing is clearly more the prevalence of peripheral arterial disease in elderly subjects with isolated systolic hyperFollowing this peripheral arterial *Presented at the American Heart Asmciation, 60th !%ien- tension. disease was examined more closely in tlik St&on, 16 November 1987, Anaheim, Calif. MTRODU(YION
15
ANNEB. NEWMANet al.
16
comparison with other risk factors associated with atherosclerosis. MATERIALS AND METHODS
Study population
Subjects for this ancillary study were currently enrolled in the Pittsburgh Center of the Systolic Hypertension in the Elderly Program (SHEP). SHEP is a double-blind, randomized, placebo controlled trial of the treatment of isolated systolic hypertension, defined as systolic blood pressure (SBP) > 160 and diastolic blood pressure (DBP) < 90, in subjects over age 60. Subjects were recruited from shopping malls, retirement centers, churches, senior citizens’ clubs and other locations where predominantly healthy elderly adults tend to congregate. Exclusion criteria for entry into the study included recent transient ischemic attack, stroke with residua, myocardial infarction within the previous six months, advanced congestive heart failure, renal disease and malignancy. Of 200 subjects randomized as of 1 April 1987, 190 agreed to undergo peripheral arterial disease screening. Three subjects could not be studied because of inability to occlude the posterior tibia1 artery. The remaining 187 formed the study population. All participants were given a standard interview which included the modified Rose questionnaires [16] for angina and intermittent claudication. Physical exam and ankle and arm systolic blood pressure were performed by study physicians. Blood samples were analyzed using standard techniques for glucose, cholesterol, HDL-cholesterol and triglycerides. Lower extremity arterial disease (LEAD) was evaluated using the ratio of ankle-to-arm systolic blood pressure, commonly referred to as the ankle/arm index (AAI). Standard 12 cm blood pressure cuffs were applied to both ankles and the appropriate size cuff to the right arm. Measurements were taken after 5 min of the rest in the supine position. The systolic pressure was determined at the right brachial and both right and left posterior tibia1 arteries by Doppler stethoscope using a zero muddler manometer to avoid observer bias. Measurements were done twice in rapid sequence. The AA1 for each extremity was the average of the two ratios obtained. A normal AA1 should be > 1.O. Based on previous studies, a subject was defined as having LEAD if either the right or left AA1 was co.90 [7, 171.
Reliability of AAI measurement
Inter-observer reliability was studied in both normal and study subjects. Three observers repeated eight measurements on six normal subjects. Inter- and intra-observer variability was not significant by use of a paired t-test and by repeated measures analysis of variance. The p-value for within observer variability was 0.927, and for between observers was 0.568. The coefficient of variation for each subject and observer ranged for the AA1 from 3 to 6%. Reliability was also studied in the study subjects. Two observers repeated the test twice on 50 elderly subjects with systolic hypertension. Again, the variability within and between observers was not significant by analysis of variance. Most of the variance was due to blood pressure fluctuations in individual subjects. Statistical analyses
Independent t-tests were used to compare means of continuous variables. The chi-square statistic and the Fisher’s exact test, where appropriate, were used for analyses of categorical variables. Significance levels were set at the 0.05 level. All tests are two-directional. Stepwise multiple logistic regression analysis was used to evaluate different models to describe the data and to examine the relative importance of the independent variables. RESULTS
The mean age of the study population was 72 years with a range of between 61 amd 89 years. Women made up 56% of the study population. The sample was overwhelmingly comprised of white subjects with only two black males and one black female. The mean baseline systolic blood pressure was 171 mmHg with a range of 160-203 mmHg. An abnormal AA1 (< 0.90) was found in 50 out of 187 (26.7%) of the subjects (see Fig. 1). The prevalence of intermittent claudication by Rose questionnaire was only 6.4%, representing a 4-fold difference in prevalence rates. Of 12 subjects reporting intermittent claudication, 8 had an AA1 of co.90 (Fisher’s exact test p < 0.005). Of those subjects with disease, 42% were men and 58% were women, similar to the sex composition of the group as a whole. The sensitivity, specificity and predictive value of a positive Rose questionnaire were calculated compared to a positive test for lower extremity arterial disease. The sensitivity of a
Peripheral Arterial Disease in the Elderly
QUESTIONNAIRE
17
-I
ANKLE/ARM INDEX Fig. 1. Frequency distribution of ankle/arm index and intermittent claudication. An ankle/arm index less than or equal to 0.90 was indicative of lower extremity arterial disease.
positive Rose questionnaire was only 16% while the specificity was 97%. The positive predictive value for this finding was 67% in our population. Because the prevalence of IC is only a fourth of LEAD, there is insufficient power to analyze risk factors for IC in this study. Further analysis showed that subjects with LEAD were older (t = - 1.75, p < 0.08) and had a higher baseline mean systolic blood pressure (t = - 1.67, P < 0.10) prior to treatment of their hypertension. Analysis for age and SBP by
sex revealed that women with LEAD were older with higher baseline SBP (age: t = - 2.17, p < 0.03; SBP: t = - 1.72, p < 0.09); yet there were no differences in these means for men. There was also a significant trend for increasing prevalence of LEAD with increasing age in women by chi-squared ‘test of trend where p = 0.05. Univariate analyses revealed lower HDL cholesterol levels for those subjects with and without disease. For these subjects with LEAD,
Table 1. Risk factors for LEAD mean differences Variable
Present
LEAD Absent
LEAD o-Value
All Subjects
Age (yr) Systolic blood pressure (mmHg) Fasting glucose (mg/dl) Total serum cholesterol (mg/dl) HDL-cholesterol (mg/dl) Fasting serum triglycerides (mg/dl)
50 (27%) 74 173 107 245 47 179
137 (73%) 72 170 103 237 51 161
Age Systolic blood pressure Fasting glucose Total serum cholesterol HDL-cholesterol Fasting serum triglycerides
21 (26%) 72 172 119 236 42 228
61(74%) 72 170 107 227 47 168
0.87 0.55 0.31 0.44 0.11 0.04*
Age
Female Subjects 29 (28%) 76 (72%) 75 72
0.03’
0.08 0.10 0.59 0.28 0.07 0.26
Male Subjects
Systolic blood pressure Fasting glucose Total serum cholesterol HDL-cholesterol Fasting serum triglycerides
?? p < 0.05, two-tailed t-test.
173 98 251 51 144
170 101 245 55 156
0.09 0.70 0.48 0.19 0.49
ANNEB. NEWMAN et al.
18
Table 2. Risk factors for LEAD Variable
Total n
n with LEAD (%)
82 105
21 (26) 29 (28)
17 170
8 (47) 42 (25)
o-Value
Gender
0.89
Male Female Smoking status
0.05*
Current Past or never
*p < 0.05 two-tailed test of significance; chi-square with 1 df
the mean HDL level was 47.0; for. those subjects without, the mean HDL level] was 51 .l. (t = 1.85, p = 0.07). This difference was not apparent when subjects with and without disease were stratified by sex. Serum triglyceride levels were significantly higher in men with LEAD than without (t = -2.13, p < 0.05). This was not seen in women. Total cholesterol and fasting blood sugar did not differ between the two groups. Current, but not past history of cigarette smoking was also related to LEAD (Fisher’s exact test p < 0.05). Indicators of advanced atherosclerosis, including history of myocardial infarction, stroke or carotid bruit were infrequent in this group of fairly healthy elderly subjects and individually were not associated with LEAD. The presence of at least one of these findings in an individual, however, was significantly associated with the presence of LEAD (p = 0.03). Stepwise multiple logistic regression analysis was performed to examine the independent contributions of variables that were significant in
the univariate analyses, including age, systolic blood pressure, smoking, and HDL-cholesterol. The dependent variable was LEAD. Age and current smoking status entered the model as the strongest predictors of LEAD. The calculated odds ratios from the model were not significantly greater than one. DISCUSSION
In the elderly, the relationship between established atherosclerosis, risk factors including hypertension, cholesterol, smoking and further progression of disease is not clear. Because atherosclerosis is exceedingly prevalent in the elderly population, some measure of the extent of disease must be considered in evaluating the impact of other factors. Systolic hypertension was long thought to reflect loss of arterial elasticity with aging and the degree of atherosclerosis, thus an adaptive way of ensuring perfusion of vital organs. However, most data show that systolic blood pressure is an independent risk factor for subsequent cardio-
Table 3. Baseline disease status bv LEAD Total n
n with LEAD (%)
p-Value
History of intermittent claudication Yes No
12 174
8 (67) 42 (24)
o.o03*t
Carotid bruit (CB) Yes No
12 175
5 (42) 45 (26)
0.31
History of myocardial infarction (MI) Yes No
7 180
4 (57) 46 (26)
0.08
History of stroke (ST) Yes No
1
l(100) 49 (26)
0.27
186
Combined history of CB, MI, ST Yes No
19 168
41 (24)
Variable
*p < 0.05 two-tailed test of significance. TFisher’s exact test. $Chi-square with 1 dJ
9 (47)
0.03*1
Peripheral Arterial Disease in the Elderly Table 4. Relative risk of risk factors for LEAD derived from logistic mgrassion~modal
Age Current smoker
RR
95% cl
1.06 3.67
(0,3.08) (0.3,7.04)
vascular events. Kannel et al. [9] showed that this relationship persists even when arterial rigidity, as measured by pulse volume recordings, is taken into account. A simple method of identifying individuals with atherosclerosis who are at high risk for clinical events such as myocardial infarction, stroke and claudication may be of considerable value in the development of treatment strategies for risk factor identification and modification, especially in older individuals. Clinical studies of the use of the AA1 in peripheral vascular laboratories can discriminate between those with and without obstruction with a high degree of specificity [4-6]. Sensitivity is diminished in those with borderline disease or rigid arteries that preclude pneumatic cti compression. Fronek et al. [6] have emphasized the need to include quantitative Doppler velocimetry to detect disease in those with rigid arteries. Exercise testing is also important to increase sensitivity. Disease can be localized by the use of multiple levels of measurement along the leg. All of these procedures greatly increase the time and cost of testing, and are very important in the clinical setting. However, as a simple, inexpensive, non-invasive screening test, the AA1 alone is ideal for screening large populations [ 111.Because of the high correlation with symptoms of claudication, and other clinical manifestations of atherosclerosis, and the greatly increased sensitivity over symptoms alone, the AA1 is a useful way of quantitating the burden of atherosclerosis in a population in an objective way. Risk factors for peripheral arterial disease have been evaluated in case series, by interview for symptoms, and by non-invasive testing. Older age, male sex, hypertension, smoking and diabetes emerge as important risk factors across studies regardless of the method of measuring disease [I, 2,615, l&22]. Since most studies used the Rose questionnaire [16], prevalence was underestimated and risk factor analyses could only be done on those with the worst disease. The prevalence of symptoms of claudication increases with age and has been found to be 2-10% in studies of those 60 and over. Prevalence by non-invasive testing is much
19
higher, up to 20% in a study by Criqui et al. [3] in those over age 75. Considering that systolic hypertension is a risk factor for other atherosclerotic endpoints, it is not unexpected that the prevalence of peripheral arterial disease by noninvasive testing is higher in our study than has been reported in other studies [3,7l. The disparity between the prevalence of symptoms and abnormal AA1 in our population is similar to other studies [7,23,24]. These studies have found the prevalence of peripheral arterial disease to ‘be about 2-10 times higher when assessed by non-invasive means compared to standardized questionnarie. Though the sensitivity of the Rose questionnaire is low (lO-19%) [23,24], is 97-99% specific for an abnormal AAI. The variability of activity level needed to produce symptoms probably explains the low sensitivity of the Rose questionnaire. Though this elderly cohort was generally healthy and ambulatory, their level of physical activity is probably less than in a younger group. Our findings are similar to other studies in showing that while specific, Rose questionnaire is very insensitive to detecting flow-significant LEAD [23]. Other clinical measures, including pulse palpitation, can improve sensitivity and specificity when compared to non-invasive measures. Currently, however, the AA1 appears to be the best single objective non-invasive measurement for population studies [7, 10,23,24]. Within this group of elderly subjects with isolated systolic hypertension, disease prevalence increased with age and SBP. Differences were more pronounced for women than men. As in most other studies, current smoking was a risk factor for disease. The presence of any other measure of clinical atherosclerosis such as myocardial infarction, carotid bruit and stroke was also associated with LEAD, indicating the systemic nature of atherosclerotic cardiovascular disease. Since the number of cases of LEAD is relatively small, the lack of strong associations with individual risk factors and measures of clinical atherosclerosis may be related to a lack of statistical power. Though total cholesterol was not associated with LEAD in this population, a low HDLcholesterol was. While this relationship was not statistically significant, it was suggestive. Previous reports of the association of lipid abnormalities in peripheral vascular disease have not been conclusive, but the same inverse association with HDL-cholesterol is apparent [13,25,26].
ANNEB. NEWMANet al.
20
Systolic hypertension has been shown to be a risk factor for atherosclerotic events, yet to some extent may indicate presence of already established disease. Even in subjects with established systolic hypertension, there is a wide variation in extent of lower extremity arterial disease. The cause and effect relationship between systolic hypertension and atherosclerosis cannot be established by this cross-sectional study. Acknowledgement-This research was supported by National Research Service Award HL07011, Cardiovascular Epidemiology Training Program.
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