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From: Contemporary Cardiology: Diabetes and Cardiovascular Disease, Second Edition Edited by: M. T. Johnstone and A. Veves © Humana Press Inc., Totowa, NJ
20 Epidemiology of Peripheral Vascular Disease
Stephanie G. Wheeler, MD , MPH , Nicholas L. Smith, PhD , MPH , and Edward J. Boyko, MD , MPH
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EFERENCESINTRODUCTION
The epidemiology of several atherosclerotic arterial diseases and their association with diabetes will be covered in this chapter. This chapter will focus on peripheral vascular disease (PVD), arterial disease affecting the extremities, and will include more general epidemiological aspects of PVD, including associated conditions and mortality.
Additionally, the epidemiology of cerebrovascular disease (CBD) and coronary artery disease (CAD) will also be discussed, primarily as they relate to diabetes.
EPIDEMIOLOGICAL PRINCIPLES RELEVANT TO THE STUDY OF ARTERIAL DISEASES
Measurement of disease prevalence and incidence is best conducted in a population-
based sample of study subjects. Typically, such samples are obtained from defined popu-
lations, such as all residents of a certain geographic area, or using some other characteristic
to define the population, such as enrollees of a health plan. Populations obtained from clinic-based or other medical care settings are likely to overestimate prevalence and incidence of arterial diseases because associated conditions that put such persons at higher risk of arterial diseases are likely to be present in higher proportion in these subjects who seek care rather than a random population-based sample.
In addition to measurements of disease incidence and prevalence, several methods are used by epidemiologists to assess whether an exposure (e.g., smoking, diabetes) is related to a change in risk of disease. Further methods are employed to determine if such an association may be causal, or instead as a result of confounding, selection, or measure- ment bias. Cross-sectional study designs provide weak information regarding causality.
Retrospective study designs tend to be less compelling in establishing whether an expo- sure is related to a change in disease risk, because the passage of time between the onset of the exposure and disease development may result in inaccurate exposure classifica- tion, or a different mortality rate related to exposure and disease that may induce bias in the estimates of association. Prospective research is less likely to be biased by differences in probability of subject selection based on arterial disease and risk-factor presence.
Prospective research is a stronger study design regarding inferring the possibility of causation, because the presence of risk factors may be determined prior to arterial disease onset. Many prospective studies exist on the epidemiology of CAD, but fewer have covered the topics of PVD and CBD.
The problem of measurement error in the assessment of the presence or absence of vascular disease is well recognized. Even coronary angiography for the diagnosis of CAD is likely to result in some degree of misclassification, for reasons described previously (1). A similar situation holds for the diagnosis of PVD. For example, it is likely that in some instances claudication will occur even with a normal or high ankle-arm index (AAI), if noncompressible, calcified vessels result in falsely high readings of the ankle systolic blood pressure (SBP) (2). This misclassification issue is even more problematic when a test result is used to formulate a clinical plan for an individual patient, as compared to epidemiological analysis in which population statistics are the result of interest. When misclassification of PVD status occurs nondifferentially regarding exposure (randomly), the net result is bias of any observed difference toward the null value (3). The same holds true for exposures that are nondifferentially misclassified regarding PVD. Therefore observed differences found in an epidemiological analysis of risk factors for PVD validly reflect potential causative factors for this complication, but probably underestimate the magnitude of the risk increase. Epidemiological studies may therefore draw valid con- clusions regarding risk factors for PVD, CBD, and CAD even if the techniques used to measure either vascular disease or the potential risk factor are prone to nondifferential misclassification.
The American Diabetes Association produced a consensus statement in which they recommended using AAI to screen for PVD in patients with diabetes over the age of 50 (4). The issues of screening and misclassification and the limitations of the AAI were acknowledged. However, the problems were not felt to detract from the clinical useful- ness of the AAI to screen for and diagnose PVD in patients with diabetes.
PERIPHERAL VASCULAR DISEASE INCIDENCE AND PREVALENCE
PVD affects a high proportion of older persons in general populations located in
developed countries. Meijer and associates presented age- and gender-adjusted results of
the prevalence of low AAI using different definitions (<0.75 to <0.94) for nine popula- tion-based surveys that ranged from 5.5% to 26.7% (5). In very elderly (85–93 years) Japanese-American men living in Hawaii, prevalence of PVD was somewhat higher at 27.4% (6). In a population of patients chosen because they were over age 70 or over age 50 but with a history of tobacco use or diabetes, the prevalence of PVD was 27% (7).
Claudication is an insensitive measure of peripheral vascular disease, with symptom- less diminished arterial flow estimated to occur at least two to five times as frequently as claudication (8). The Rose questionnaire has been used by investigators to assess clau- dication prevalence, but it has been shown to have only moderate sensitivity (60%–68%) in capturing persons with this clinical diagnosis (9). In the Edinburgh Artery Study, the prevalence of claudication in men increased from 2.2% in the 50- to 59-year age category to 7.7% in the 70- to 74-year age category (10). Meijer and associates reviewed 13 population-based screening surveys for presence of claudication, and reported age- and gender-adjusted estimates ranging from 0.6% to 7.4%, with one additional study finding a prevalence as high as 14.4% (5,11). Although it has been written that men are affected with symptomatic PVD between two to five times as frequently as women (10), in the review of Meijer a twofold or higher prevalence of claudication was seen in only one of the 13 studies (5).
Among patients who have type 1 diabetes, PVD is more common than for the general population. In the Pittsburgh Epidemiology of Diabetes Complications Study of child- hood onset type 1 diabetes, women who had type 1 diabetes for 30 years were found to have a prevalence of PVD greater than 30% compared to only 11% for men when deter- mined by AAI less than 0.8 at rest or after exercise (12). The Epidemiology of Diabetes and Complications (EDIC) study, the long-term follow-up of the Diabetes Control and Complications Trial (DCCT), identified those patients with AAI less than 0.9. The EDIC study found that intensively treated participants, with an average duration of type 1 diabetes of about 14 years, had a prevalence of PVD of 8.8% among women and 4.6%
among men (13).
Patients with type 2 diabetes in the United Kingdom Prospective Diabetes Study (UKPDS) had a prevalence of PVD of 1.2% (95% confidence interval [CI], 0.9%–1.5%) at the time of diagnosis of their diabetes (14). PVD in the UKPDS was defined as the presence of any two of the following: (a) AAI less than 0.8, (b) absence of both dorsalis pedis and posterior tibial pulses to palpation in at least one leg, and (c) claudication. At 6 years of follow-up in the UKPDS, 2.7% of participants (95% CI, 2.2% –3.2%) had PVD according to these criteria that was not present at diagnosis and 10.6% had at least one of these three abnormal measures. The prevalence of PVD increased to 12.5% in the smaller subgroup or participants followed for 18 years (95% CI 3.8%–21.1%). The Framingham Offspring Study examined 1554 males and 1759 females for PVD. In this population- based study, the odds ratio for PVD was 2.3 (95% CI, 1.5–3.6) among diabetic vs non- diabetic participants (15). This odds ratio associated with diabetes for developing PVD, in addition to the odds ratios associated with hypertension, current smoking, and each additional 10 years of age, are shown in Fig. 1.
Vascular disease in people with diabetes is both morphologically and physiologically
distinguished from nondiabetic atherosclerosis (16). The femoropopliteal segments are
most often affected, as in nondiabetic patients, but smaller vessels below the knee, such
as the tibial and peroneal arteries are more severely affected in diabetic than in nondia-
betic patients (17,18). In practical terms, diabetes is associated with a high prevalence of
distal arterial disease, a propensity to earlier calcification, increased thrombogenicity, and generally poorer prognosis.
Racial differences in the prevalence of diabetes mellitus (DM) in the United States are well documented. The Atherosclerosis Risk in Communities (ARIC) Study included 4264 black and 11,479 white randomly selected men and women. This study found 19%
of the black women were diabetic compared with 7% of white women and that 16% of black men were diabetic compared with 8% of white men (19). The National Health and Nutrition Examination Survey Epidemiologic Follow-up Study 1971–1992 (NHEFS) followed 14,407 subjects prospectively and found 10.6% of black subjects had diabetes at baseline compared to 6.8% of white subjects (20).
Similarly, there are racial differences in the complications of diabetes, including PVD.
The NHEFS found that among subjects with incident DM during the study follow-up period, 3.4% of blacks had lower extremity amputations compared to 1.4% of whites. The authors of the study speculated that a combination of social and environmental factors may account for the apparent ethnic difference. To examine the question of whether the observed differences in complication rates were the result of disparate access to health care, a study of an ethnically diverse population with uniform health care coverage was undertaken by the Kaiser Permanente Medical Care Program in northern California. The study observed 63,432 diabetic patients, which included 12% Asians, 14% blacks, 10%
Latinos, and 64% whites, for 4 years and measured nontraumatic lower extremity ampu- tation and end-stage renal disease (ESRD) among other outcomes. Age- and sex-adjusted incidence rates of lower extremity amputation did not differ significantly between whites and blacks or Latinos, whereas Asians had a rate 64% lower than that of whites (21). On the other hand, age- and sex-adjusted incidence rates of ESRD were significantly higher for blacks, Asians, and Latinos relative to whites (112%, 44%, and 41% higher, respectively).
RISK FACTORS FOR PERIPHERAL VASCULAR DISEASE
The Framingham Heart Study found a strong relationship between the number of
cigarettes smoked and the incidence of intermittent claudication and a multivariate analy-
sis identified smoking as the strongest single risk factor for development of symptomatic
Fig. 1. Odds ratios for risk factors for peripheral vascular disease. Peripheral vascular disease (PVD) was defined as an ankle-brachial index less than 0.9. Data taken from the Framingham Offspring Study, a population-based study of PVD and its risk factors.obstructive arterial disease, regardless of gender (22). The occurrence of intermittent claudication is twice as frequent in smokers as nonsmokers. In the Edinburgh Artery Study, peripheral arterial disease prevalence was strongly and positively related to life- time cigarette smoking (23). Smoking was related to a higher relative prevalence of peripheral arterial disease (range of odds ratios [OR], 1.8–5.6) than heart disease (range of ORs, 1.1–1.6). A prospective analysis of this cohort over 5 years revealed an incidence of new claudication of 2.6% among nonsmokers, 4.5% in moderate smokers (<25 pack- years) and 9.8% in heavy smokers (>25 pack-years) (24).
Hyperglycemia was found to be associated with an increased risk of incident PVD, independent of other risk factors including age, elevated SBP, low high-density lipopro- tein (HDL), smoking, prior cardiovascular disease (CVD), peripheral sensory neuropa- thy and retinopathy. Each 1% increase in hemoglobin (Hb)A1c was associated with a 28% increased risk of PVD (95% CI, 12–46) (14).
Many conditions associated with DM may help explain the higher prevalence of PVD seen in persons with this condition, such as other PVD risk factors that comprise features of the metabolic syndrome (hypertension, dyslipidemia) (25). Increased levels of hemo- static factors such as fibrinogen, von Willebrand factor, tissue plasminogen activator, fibrin D-dimer, and plasma viscosity explained in part the higher prevalence of PVD in subjects with diabetes or impaired glucose tolerance in the Edinburgh Artery Study (26).
Hypertensive patients show a threefold increased risk of intermittent claudication at a 16-year follow-up (27). Limb arterial obstructive disease occurs twice as frequently as CAD among hypertensive individuals and hypertension has been reported in 29% to 39%
of patients with symptomatic PVD (28). The Cardiovascular Health Study reported about a 50% higher prevalence of an AAI less than 0.9 associated with hypertension in a multivariate analysis adjusted for age, smoking, diabetes, and dyslipidemia (29). Obser- vational data analysis among 3642 patients in the UKPDS showed that the aggregate endpoint of amputation or death from PVD was associated with a 16% decrease per 10 mmHg reduction in SBP, adjusted for age at diagnosis of diabetes, ethnic group, smoking status, presence of albuminuria, HbA1c, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol, and triglyceride (30).
The association of hypercholesterolemia with atherosclerosis of the lower extremities has been known for 60 years (31). The prevalence of claudication in patients with serum cholesterol levels over 260 mg/dL is on average over twice as high as in those with a concentration below this level. The prevalence of hyperlipidemia in patients with clinical manifestations of lower extremity arterial occlusive disease ranges in various studies from 31% to 57%. The Edinburgh Artery Study reported a higher prevalence of PVD in association with higher serum cholesterol and lower HDL cholesterol in multiple logistic regression analysis (23). The Cardiovascular Health Study reached similar conclusions among its sample of 5084 subjects aged 65 years or older, with PVD defined as an AAI less than 0.9 (29).
Other risk factors have been shown to be associated with a higher prevalence of PVD.
Higher circulating levels of homocysteine have been demonstrated in this condition (32),
as have parallel low levels of folate in red blood cells and circulating vitamin B
6, which
raises the possibility that supplementation with these vitamins may reduce the incidence
of peripheral arterial disease (33). One small, randomized, placebo-controlled study of
secondary prevention has shown that oral therapy with folic acid, vitamin B
12, and vita-
min B
6decreased the need for revascularization in patients receiving percutaneous coro-
nary intervention (34). Higher levels of various hemostatic factors have been demon- strated in persons with lower AAI, suggesting that a hypercoagulable state predisposes to the development of PVD (35,36). Infectious agents such as chlamydia pneumoniae have been implicated in the development of atherosclerosis in several vascular beds (37,38). The prevalence of low AAI (<1.05) was highest among persons with a birth weight less than 6.6 pounds, a demonstration of the “thrifty phenotype” hypothesis that postulates fetal growth retardation as a cause of metabolic disorders and vascular disease in adult life (39,40).
CONDITIONS ASSOCIATED WITH PERIPHERAL VASCULAR DISEASE
Atherosclerosis, the underlying cause of PVD, is a multifactorial, progressive condi- tion that begins in childhood and involves multiple biological processes and foci. There- fore, it is not surprising that patients with PVD often have extensive CAD and CBD. The prevalence of CAD among persons with claudication in the general population is between two and four times higher than in nonclaudicants (10). Around 50% of claudicants also suffer from angina, whereas patients with angina are six times more likely to have clau- dication (41). When 200 consecutive patients admitted to a vascular surgery service in an academic teaching hospital were evaluated for concomitant diseases, CAD was present in 46%, 22% had symptomatic CAD, 37% had impaired cardiac function, and 32% had carotid artery disease (12). Both claudication and asymptomatic PVD (AAI <0.9) in the Edinburgh Artery Study population were significantly associated with greater intima- media thickness (IMT) of the carotid arteries as assessed by ultrasound (42).
MORTALITY ASSOCIATED WITH PERIPHERAL VASCULAR DISEASE Although peripheral arterial disease rarely causes death, diminished long-term sur- vival in these patients is well established. The causes of death associated with this con- dition are primarily cardiovascular. In the Framingham study 14% of men and 18% of women died within 6 years of the onset of intermittent claudication (43). Mortality rates appear to be related to the severity of the obstructive process. Szilagyi and associates found the cumulative 6-year mortality rate was 62% in patients with symptoms suffi- ciently severe to require femoropopliteal bypass (44). In the study of DeWeese and Rob, 48% of patients with claudication, 80% of those with ischemic rest pain and 95% of those with gangrene were dead within 10 years of undergoing femoropopliteal bypass grafting (45).
Patients with severe or symptomatic PVD have four to seven times the risk of mortality from all causes and a 15-fold higher risk of mortality from CVD than persons who do not have PVD (46). Simonsick and associates demonstrated that intermittent claudication was an important predictor of mortality and cardiovascular morbidity in ambulatory older adults independent of associated coronary ischemia and CVD risk factors (47). Howell and associates found that independent of age or the presence or absence of diabetes, a low AAI was strongly associated with increased mortality (48). Although the presence of arterial obstructive disease of the legs is a hallmark of generalized atherosclerosis and therefore would be expected to confer an increased risk of cardiovascular or cerebrovas- cular death, extremely severe PVD appears to carry a particularly ominous prognosis.
These researchers noted that patients with an AAI less than 0.30 had a very high 6-year
cumulative mortality rate (64%) (48).
THE EPIDEMIOLOGY OF CAROTID AND VERTEBRAL ARTERIAL DISEASE
Atherosclerosis of the carotid and vertebral arteries is related to a higher risk of stroke (49). Not all strokes, however, are as a result of atherosclerosis of the carotid or vertebral circulation. Some arise from embolic events or result from intracerebral vascular disease.
The recent development of techniques to directly visualize the carotid artery has led to a recent surge in publications on risk factors for IMT of the carotid arterial wall and presence of plaques measured using B-mode ultrasonography. These methods permit detection of subclinical atherosclerosis. It has been shown that carotid wall thickness is predictive of incident clinical stroke (50). Although visualization of the vertebral system is also possible using this same imaging technology, little epidemiological information is available to indicate the prevalence of this condition or associated risk factors.
A strong association exists between greater intima-media carotid arterial thickness and diabetes in a regression model adjusted for other CAD risk factors, as demonstrated by the Insulin Resistance Atherosclerosis Study, which was conducted among 1625 persons with different categories of glucose tolerance (51). Subjects with normal and impaired glucose tolerance had similar IMT, suggesting that higher levels of hypergly- cemia are required to promote carotid atherosclerotic lesions (51). Low insulin sensitivity as measured using the minimal model technique was found to be related to greater IMT of the internal carotid artery among Caucasian and Hispanic participants in the IRAS study (52). Several other CAD risk factors have been studied in relation to carotid wall thickness. The ARIC study found that low LDL cholesterol, high SBP, and smoking predicted greater carotid wall thickness among its 12,193 participants aged 45 to 64 years (53). Carotid plaques demonstrated by ultrasound were very common in British men (57%) and women (58%) between the ages of 56 and 77 years (54). Risk factors for presence of plaque differed depending on location but in general were associated with greater age, smoking, and higher SBP (54). Greater carotid wall thickness has also been demonstrated among persons with lower birth weights and serological evidence of past infection to Chlamydia pneumoniae (37,39). In general, the risk factors for PVD and CVD appear similar.
Intensive treatment of type 1 diabetes is associated with a decrease in IMT, although this effect was not evident after 1 year of follow-up of the DCCT cohort (55). In the EDIC, the long-term follow-up of the DCCT, intensive insulin therapy, compared to conven- tional therapy, during the DCCT resulted in decreased progression of IMT 6 years after the end of the trial (56). Progression of carotid IMT was associated with the traditional risk factors mentioned above, including age, SBP, smoking, the ratio of LDL to HDL cholesterol, urinary albumin excretion rate and with the mean glycosylated hemoglobin value during the mean duration of the DCCT. The glycosylated hemoglobin value during the DCCT explained 96% of the differences between groups in IMT of the common carotid artery at year 6 of follow-up.
THE EPIDEMIOLOGY OF CORONARY ARTERY DISEASE
The coronary arteries have received a far greater amount of clinical, public health, and
research interest and resources than the arteries of other vascular beds. This focus can be
attributed to the extraordinarily negative health impact CAD has had in the past century
on most populations in Western societies. In the United States, CAD has been the leading
cause of death for the past 80 years and, although the burden of disease is lessening in all major subpopulations, (57) it was still the primary cause of death in 2000, accounting for 35% of all mortality (58). The hallmark of CAD is acute myocardial infarction (MI), but outcomes also include angina pectoris, acute coronary syndrome, sudden cardiac arrest, and heart failure. Although other coronary outcomes have decreased in prevalence in the United States, the prevalence of heart failure has increased (59,60).
Adults with disorders of glucose metabolism are at higher risk of CAD than adults without such disturbances. Data from the Third National Health and Nutrition Examina- tion Survey found that elevated blood pressure, increased body mass index, decreased HDL cholesterol, and increased triglycerides and LDL cholesterol were more prevalent in adults with glucose disorders (fasting glucose >110 mg/dL) than in those with normal fasting glucose (<110 mg/dL) (61). Among those with glucose disorders, the prevalence of each CAD risk factor was generally greater in those with diabetes (fasting glucose
>126 mg/dL) than in those with impaired fasting glucose (fasting glucose 110–125 mg/
dL). Inflammation measures such as fibrinogen and C-reactive protein were also mark- edly elevated in those with disturbances in glucose metabolism compared to those with- out. In a meta-analysis of data from 20 prospective studies that followed nearly 100,000 adults—primarily men—for an average of 12.4 years, fasting glucose and 2-hour postchallenge glucose were associated with an increased risk of incident CVD, which included MI, stroke, sudden cardiac arrest, and cardiovascular mortality. There was a 33% increase in cardiovascular risk (relative risk [RR], 1.3; 95% CI, 1.1–1.7) when a fasting glucose level of 110 mg/dL was compared to a level of 75 mg/dL and there was a 58% increase in risk (RR: 1.6; 95% CI, 1.3–2.1) when a 2-hour glucose level of 140 mg/
dL was compared to a 75 mg/dL level (62). Among adults 65 years of age and older, 2- hour postchallenge glucose was a better predictors of cardiovascular events, primarily MI and coronary death, than fasting glucose in a biracial elderly population (63). This obser- vation has been supported by data in a younger population as well (64). Other manifes- tations of impaired glucose metabolism such as insulin resistance—a component of the metabolic syndrome—has been associated with an increased risk of incident MI and cardiovascular morbidity and mortality in large, population-based studies (65,66).
Several prospective community-based studies have demonstrated that adults with
frank DM have a multifold increase in risk of incident CAD when compared to adults
without diabetes. In middle-aged northern Europeans, the relative risk of incident MI in
men was 2.9 (95% CI, 2.6–3.4) and in women it was 5.0 (95% CI, 3.9–6.3) when event
rates of those with diabetes were compared to those without diabetes (67). Risks of
similar magnitude were seen for men and women with diabetes in a population of south-
ern Europeans when compared to those without diabetes (68). In older adults, when
compared to those without diabetes, the relative risk of incident CAD (MI or angina) was
2.5 (95% CI, 1.9–3.4) for those with diabetes and subclinical CVD and was 1.3 (95% CI,
0.8–2.0) in those with diabetes and without subclinical CVD (69). Data addressing the
association of diabetes with the risk of coronary and cardiovascular mortality are similar
to the coronary morbidity setting in which adults with diabetes—primarily Caucasian
males—had a nearly fourfold increase in mortality risk compared to adults without dia-
betes (RR, 3.8; 95% CI, 3.1–4.7) (70). In a different cohort of male Caucasians, the risk
of all-cause and coronary mortality was two- to threefold higher in those with diabetes
and without established CAD and was 4- to 10-fold higher in those with diabetes and
established CAD when compared to those free of both (71). Coronary mortality risk
associated with diabetes was higher in those less than 60 years of age (RR = 6.2; 95% CI, 3.4–11.3) than in those 70 years of age or older (RR= 2.7; 95% CI, 2.0–3.6). In a cohort of middle-aged women, diabetes was associated with a sixfold (RR = 5.7; 95% CI, 4.8–
6.6) increase in fatal coronary disease risk in those without a history of coronary disease and an 11-fold (RR = 10.7; 95% CI, 9.0–12.6) increase in risk in those with a history when compared to those without diabetes and without a coronary disease history (72). The relative risk of incident CAD and all-cause mortality in adults with diabetes compared to those without appears to be similar in African-American and Euro-American women (73). For men, however, risks may be lower in African-American and Afro-Caribbean men than in Caucasians (74,75).
Risk factors for CAD in adults with diabetes are similar to those for coronary disease in populations without diabetes. Increased age, LDL cholesterol, and SBP and decreased HDL and smoking are all associated in a dose–response relationship with increase coro- nary disease risk (76). Of the various risk factors, lipids by far have received the most research attention (77-80). The difficulty in measuring the association between many of these factors and CAD risk in adults with diabetes is that risk factors often co-occur in individuals and causality is not easily inferred.
The underlying pathophysiology of impaired glucose metabolism that leads to an increased risk of CAD and atherosclerotic diseases of the other vascular beds is an expansive area of biological research that includes genetic and molecular investigations.
The roles of endothelial cell and smooth muscle dysfunction and platelet and coagulation abnormalities appear to be key in atherosclerotic disease progression (81). Many of these topics are covered in other chapters of this book.
CONCLUSIONS
Vascular disease of the peripheral, carotid, and coronary beds probably reflects a process of generalized atherosclerosis in most cases, because co-occurrence of stenoses at multiple sites is often seen, risk factors for disease at one site usually are related to higher risk at other sites, and peripheral disease confers a higher risk of death as a result of CAD. There are important differences to note. The effects of smoking and diabetes mellitus on PVD are associated with higher relative risks than the carotid and coronary arteries. It is not yet clear whether higher circulating homocysteine will be related to greater risk of CAD or CBD. Since many of these risk factors are reversible or treatable to some extent, there is hope that primary or secondary preventive interventions may yield further benefits in reducing the impacts of these diseases on mortality, morbidity, and health status/quality of life.
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