1 Department of General Practice, Research Institute for Extramural and Transmural Health Care, Maastricht University, Maastricht, The Netherlands.
2 Department of Methodology and Statistics, Research Institute for Extramural and Transmural Health Care, Maastricht University, Maastricht, The Netherlands.
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ABSTRACT |
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arterial occlusive diseases; incidence; intermittent claudication; longitudinal studies; risk factors
Abbreviations: OR, odds ratio; PAOD, peripheral arterial occlusive disease.
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INTRODUCTION |
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Population-based studies indicate that PAOD has a relatively benign course in the legs (6, 7
). However, claudicants show more cardiovascular comorbidity and have at least a twofold risk of fatal ischemic heart disease and cerebrovascular accidents compared with the general population (8
10
), which results in high health care costs (11
13
). Concomitant cardiovascular disease and cardiovascular mortality is even more frequent in studies where the ankle-brachial index, the ratio of ankle systolic blood pressure to arm systolic blood pressure, has been used to indicate PAOD. The ankle-brachial index is currently the most common and useful diagnostic instrument for detecting PAOD, including asymptomatic cases (4
, 5
, 14
, 15
). Ankle-brachial index is inversely associated with the manifestation of severe disease and cardiovascular mortality (10
, 16
). Both intermittent claudication and asymptomatic PAOD seem to be associated with higher cardiovascular morbidity and mortality. However, data on the prognosis of persons with asymptomatic PAOD are scarce (6
, 17
).
Despite the relatively decreased life expectancy of asymptomatic and symptomatic PAOD patients due to cardiovascular morbidity, there have been only a few incidence studies of PAOD. Furthermore, there are almost no prospective studies on risk factors for asymptomatic PAOD or on the development of intermittent claudication symptoms when asymptomatic disease is already present (10).
In this paper, we report the age- and sex-specific incidence of asymptomatic and symptomatic PAOD in a population-based prospective study. In addition, we present the incidence of intermittent claudication in the subgroup of asymptomatic PAOD subjects at baseline. We also investigate possible risk factors for the development of asymptomatic and symptomatic PAOD.
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MATERIALS AND METHODS |
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The population's characteristics have been extensively described elsewhere (1). All participants gave their informed consent. The Medical Ethics Committee of the University Hospital Maastricht approved the study. For the current study, baseline data were related to measurements made after follow-up; therefore, those who died before follow-up measurement (n = 481) were not included in these analyses, but their baseline data were compared with the data of the included subjects.
Baseline measurements
Each participant completed a questionnaire that included questions about age, gender, symptoms of intermittent claudication, current and former smoking habits, physical activities, and the occurrence of atherosclerosis in the family. Subsequently, a physical examination was performed by a general practitioner/physician in one of the general practice centers. A practice assistant measured height, weight, and ankle-brachial index with a pocket Doppler device (Huntleigh Mini Dopplex D500 8Mhz; Huntleigh Healthcare Ltd., Luton, Bedfordshire, United Kingdom) and a sphygmomanometer. Systolic blood pressures were recorded on both arms and both ankles (posterior tibial artery or dorsalis pedis artery) with the subject lying in a supine position. The ankle-brachial indexes were calculated as the ratio of the systolic blood pressure of each ankle to the highest arm systolic blood pressure. To achieve uniformity of Doppler assessments, the practice assistants were specially trained (18). An ankle-brachial index less than 0.95 for at least one leg, measured twice at weekly intervals, was considered indicative of PAOD. In addition, relevant data on the presence of hypertension (guideline: five instances of diastolic blood pressure of 95104 mmHg or three instances of diastolic blood pressure
105 mmHg), hypercholesterolemia (guideline: mean of three measurements
6.5 mmol/liter), and diabetes mellitus (guideline: typical complaints and one instance of abnormal serum glucose (fasting level
6.7 mmol/liter, 2 hours postprandial level
11.1 mmol/liter) or two instances of abnormal serum glucose) were collected from the patient's medical record.
Intermittent claudication was defined as pain in the calf while walking which disappeared when the patient was standing still and which was not present when the patient was resting (typical intermittent claudication) (19). Other complaints involving the calf and complaints involving the foot, thigh, or buttocks showing this ischemic pattern were included in the definition of atypical intermittent claudication (1
, 6
). Asymptomatic PAOD was defined as an ankle-brachial index less than 0.95 without symptoms of intermittent claudication. Symptomatic PAOD was defined as an ankle-brachial index less than 0.95 with intermittent claudication symptoms (1
). Overweight was defined as a body mass index (weight (kg)/height (m)2) greater than 30. Familial atherosclerosis was coded positive when the participant had a first- or second-degree relative under the age of 65 years who suffered from atherosclerotic disease. Daily work and leisure time activities were classified as heavy, moderate, or light. Participants who scored light for both daily work and leisure time activities were categorized as having a sedentary lifestyle.
Follow-up evaluation
All participants were traced by means of the general practice registers. The subjects who were still alive were invited to undergo reexamination between January 1995 and April 1997, according to the same procedures as those used for the baseline measurements. Participants who had switched from their original general practice during the follow-up period but still resided in the province of Limburg were located, contacted, and invited. Participants who could not attend the examination at a general practice center were visited at home.
Statistical analyses
Total and sex- and age-specific (three categories: 4054, 5564, and 65 years) incidence rates for asymptomatic and symptomatic PAOD were estimated by means of the person-years method (number of new cases divided by the person-years at risk of the initial population, excluding all PAOD subjects at baseline). Incidence rates were recalculated to the source population as appropriately weighted means per prior risk category, as follows. The sampling fractions from the source population were known at the beginning of the study. The study population was divided into four strata, and each stratum was attributed a corresponding weight. The incidence rates were calculated as weighted means of stratum-specific incidences. Weights were taken as the inverse of the sampling fractions. We programmed the calculations using the statistical programming language S-PLUS (20
).
Because of small numbers of observed events, the normal approximation method for confidence intervals was not valid. Therefore, the method proposed by Waller et al. (21) was used, with an adaptation for the assumed Poisson distribution for the numbers of events.
At the end of the follow-up period, subjects could be classified into the following groups: subjects who were normal (without PAOD) both at baseline and at follow-up; subjects normal at baseline but asymptomatic at follow-up; subjects normal at baseline but symptomatic at follow-up; subjects asymptomatic at baseline and not symptomatic at follow-up; and subjects asymptomatic at baseline but symptomatic at follow-up. Person-years at risk were calculated with the approximation that subjects who developed the disease during the follow-up period were assumed to contribute half of the follow-up time to the person-years at risk.
Backwards multiple logistic regression analyses were carried out to investigate the associations of possible risk factorsaging, gender, smoking, hypertension, overweight, diabetes, hypercholesterolemia, and sedentary lifestyleand the occurrence of atherosclerosis in the family (independent variables) with the incidence of asymptomatic and symptomatic PAOD (dependent variables). Multivariable analysis was also performed in the subgroup of PAOD subjects who were asymptomatic at baseline to investigate the prognostic importance of these variables in the transition from asymptomatic disease to symptomatic disease. In this subgroup, the dependent variable was the presence of symptoms of intermittent claudication at the end of the follow-up period.
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RESULTS |
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During the follow-up period, 481 participants (13.2 percent of the included cohort) died, of whom 61.4 percent were males. From the included cohort, death occurred in 11 percent of the normal subjects at baseline, 25.2 percent in the asymptomatic PAOD subjects, and 31.2 percent in the claudicants at baseline. Comparison of the baseline variables (age, sex, ankle-brachial index, possible risk factors, and cardiovascular comorbidity) among those who died and those who completed follow-up showed that those who died were mainly older men with lower ankle-brachial index, more prevalent cardiovascular disease, and a more unfavorable risk factor profile. The main causes of death were cardiovascular disease and cancer. A detailed mortality follow-up is currently in progress.
Thus, 84.2 percent of the included cohort at baseline was followed (71 percent who attended the second examination and 13.2 percent who died during the follow-up period). The remaining group (15.8 percent) was not followed for two reasons: refusal to take part or being incapable of taking part because of severe illness or hospitalization. Nonresponders and responders did not differ significantly by age or gender. Furthermore, nonresponders did not have a worse risk factor profile at baseline than responders, except for persons with diabetes.
A total of 262 subjects were excluded because of the presence of PAOD at baseline or because PAOD could not be assessed. Overall, 2,327 subjects were included in the incidence analyses.
Normal group at baseline: incidence of asymptomatic and symptomatic PAOD
At the end of the follow-up period, 200 participants had asymptomatic PAOD and 46 had symptomatic PAOD. Table 1 shows the age- and sex-specific incidence rates of asymptomatic and symptomatic PAOD among the survivors. The highest rates were observed for asymptomatic PAOD. The overall incidence rate for asymptomatic PAOD was 9.9 per 1,000 person-years at risk (7.8 for male subjects and 12.4 for female subjects). For symptomatic PAOD, the overall incidence rate was 1.0 per 1,000 person-years at risk (0.4 for men and 1.8 for women).
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Normal group at baseline: risk factor pattern
Table 2 presents the results of the multiple logistic regression analyses. Older age, smoking, hypertension, diabetes, hypercholesterolemia, and a sedentary lifestyle were the most important risk factors for asymptomatic PAOD. Older age, smoking, hypertension, and diabetes were the most important predisposing factors for symptomatic PAOD.
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Multiple logistic regression results showed the possibility that male sex (odds ratio (OR) = 1.6), hypertension (OR = 1.5), diabetes (OR = 1.7), and older age (OR = 2.7 and 3.2 for the two older age categories (5564 and 65 years), respectively) were associated with the development of symptoms of intermittent claudication. No statistical significance was reached, possibly because of small numbers.
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DISCUSSION |
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Misclassification of especially symptomatic PAOD could have occurred in the study population. Symptomatic subjects who adapted their lifestyle to avoid symptoms or subjects who had a sedentary lifestyle preventing symptom onset may have been classified as asymptomatic. In our data, it appeared that only 3.8 percent of the asymptomatic subjects reported very low mobility or no mobility. Thus, the occurrence of misclassification bias in our study was not likely to be substantial. Spuriously elevated ankle-brachial indexes due to calcified vessels, which are sometimes found, especially in diabetic patients, may also form a source of misclassification bias. In our data, only two persons with diabetes had an ankle-brachial index 1.50. Thus, possible misclassification of diabetics in our study population was, at most, fractional.
Medical care given to the PAOD respondents at baseline may also be a potential source of confounding. All of the medical data from the respondents were available for this study. Nevertheless, this potential form of confounding is inevitable.
The generalizability of our results to other populations may be limited. However, nearly all citizens of the Netherlands are registered at a general practice. Thus, by sampling study subjects from general practices, a study population can be compounded that is relatively equivalent to the general population.
The estimation of incidence rates relies on the time of disease occurrence and loss to follow-up. The exact time of disease occurrence was not known in our study, the average time lapse between visits 1 and 2 being 7.2 years. Even with the applied correction in the calculations, this probably could have led to an underestimation of the reported incidence rates.
A source of bias could be subjects who refused to participate in the follow-up measurements. To minimize this potential bias and to keep the nonresponse group as small as possible, we offered home visits to subjects who were not willing to visit their general practice. Subjects who missed their appointment were telephoned and invited to attend at a later time. The nonresponders might have had a different disease incidence than the responders because of a higher prevalence of diabetes at baseline. Quantitatively, however, this did not have any significant impact on the incidence rates.
The attrition of the cohort could also have influenced the incidence rate calculations. Mortality may censor the diagnosis of PAOD and consequently lead to conservative incidence estimations. Even though PAOD is not a short term fatal disease, subjects have a lower survival rate because of ischemic heart disease and cerebrovascular disease mortality in comparison with the general population (7, 9
11
, 13
). We gathered data on the causes of mortality and possible nonfatal cardiovascular events before death, using hospital correspondence and the patients' medical records. Among the 349 subjects who were normal at baseline and who died during follow-up, cardiovascular disease was the cause of death in approximately 50 percent. New cases of PAOD are especially probable in this group.
Finally, small numbers of events probably led to low statistical power and imprecise estimates in some of the incidence rate analyses.
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Normal group at baseline: incidence of asymptomatic and symptomatic PAOD |
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In several studies, both asymptomatic and symptomatic PAOD increased with age, which is consistent with our findings (8, 22
, 23
). Our incidence rates for asymptomatic PAOD are difficult to compare with those of other studies because of a lack of data and differences in diagnostic methods used. In the Basel Study, a cohort of 2,630 men followed for 5 years, asymptomatic PAOD, defined as pathologic findings at pulse palpation, auscultation, or electronic oscillography, was three times more frequent than symptomatic PAOD (22
). This is in accordance with our results. In the Framingham Study, an annual symptomatic PAOD incidence rate of 1.8 was reported for women, which is comparable with our findings (23
). However, the Framingham Study found a twofold male predominance, with an incidence rate similar to that of the Quebec Cardiovascular Study (3.6 and 4.1, respectively) (8
, 23
). The Edinburgh Artery Study presented the highest overall symptomatic PAOD incidence rates (15.5 per 1,000 person-years) (6
), men being at a slightly higher risk than women.
Various explanations can be postulated for the differences between the results of these other studies and our study. Firstly, the Limburg PAOD study population was younger than the populations of the Framingham (23) and Edinburgh (6
) studies. Secondly, the Edinburgh Artery Study (6
) did not exclude asymptomatic PAOD subjects at baseline from the denominator in its incidence calculations for symptomatic PAOD, even though asymptomatic subjects have, as our study shows, an incidence rate of intermittent claudication that is much higher than that of subjects without PAOD. In fact, when we calculated the overall symptomatic PAOD incidence rate, including the asymptomatic subjects at baseline in our calculations, the incidence rate for symptomatic PAOD almost doubled. Thirdly, in the Quebec Study (8
), 70 percent of the men were smokers as compared with 58.6 percent in our study, smoking being one of the most powerful risk factors for PAOD.
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Normal group at baseline: risk factor pattern |
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The roles of hypercholesterolemia and sedentary lifestyle were not evident for symptomatic PAOD. In some studies, hypercholesterolemia is reported to be a possible risk factor for symptomatic PAOD (24, 25
), but this has not been confirmed in other studies (4
, 5
). At the time of our baseline data collection, measurement of hypercholesterolemia in general practices in the Netherlands was just starting to receive more attention. Thus, the weak association found in our study might reflect an underreporting of hypercholesterolemia in the general practice centers. The relation between physical activity and PAOD has not been thoroughly investigated to date. There are indications that a sedentary lifestyle is associated with PAOD (26
). However, symptoms of intermittent claudication can be disguised by a sedentary lifestyle.
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Asymptomatic group at baseline: incidence of intermittent claudication and risk pattern |
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Older age, hypertension, and diabetes probably play a role in the progression of asymptomatic PAOD to symptomatic PAOD.
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Implications |
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Thus, among persons over 50 years of age with one or more conventional atherosclerotic risk factors, assessment of ankle-brachial index by the general practitioner could provide additional information on the patient's risk of developing manifest atherosclerotic disease.
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ACKNOWLEDGMENTS |
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The authors thank the participating physicians and the practice assistants for their contributions to this study.
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NOTES |
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REFERENCES |
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