Summary

Objective: This study was designed to evaluate the prevalence and extent of atherosclerosis in patients with a history of vascular events, current symptoms of vascular disease or who were at an increased risk of developing a vascular event in the future. The study would also help to establish the value of ankle-brachial index (ABI) measurements in the routine clinical examination of patients with or at risk of atherosclerosis and evaluate the current usage of antithrombotic medication.

Design: A convenient sample of patients was recruited into the study if they had (1) a history of vascular events or current symptoms of vascular disease defined as history of ischaemic stroke or transient ischaemic attack, myocardial infarction, stable or unstable angina, established peripheral arterial disease or prior vascular intervention (symptomatic patients), or (2) if they were at increased risk of vascular disease defined as aged >55 years and had at least two cardiovascular risk factors (asymptomatic patients).

Subjects: Recruitment commenced in January 2003 and ended in October 2003 in a private clinic setting with a total recruitment of 115 patients.

Main outcome measures: At study entry a careful medical history was taken including a detailed assessment of risk factors and antithrombotic medication. Clinical assessment included ECG, measurement of ABI by ultrasound Doppler (Nicolet Vascular, USA) and carotid echo-Doppler (optional). Data were analysed to determine the characteristics of patients with atherosclerosis, the extent of the disease and the relationship between the extent of the disease and risk factors, ABI value and treatment.

Results: In symptomatic patients (n=46), 95.6% had 1 arterial bed and 4.4% had 2 arterial beds affected (coronary, cerebrovascular and peripheral arterial). Mild obstruction (0.7<ABI0.96) was found in 28.3% of patients and moderate obstruction (0.3<ABI0.7) was found in 4.4% of these patients. In at-risk asymptomatic patients (n=69), 50.7% had diabetes, 92.8% hypertension, 73.9% dyslipideamia, 18.8% obesity, 5.8% smoking history and an abnormal ABI was found in 20.3% patients.

Conclusion: Data found in a private clinic setting in Hong Kong suggest that atherosclerosis is common; even in the absence of symptoms among at-risk patients, the prevalence is 20.3%. Atherosclerosis should be considered as a generalised disease and ABI is a useful clinical tool for identifying these high risk patients. All risk factors should be aggressively treated.

Keywords: Ankle Brachial Index, peripheral vascular disease, atherosclerosis, cardiovascular risk factors, prevalence

摘要

目的：本研究目的為評估曾患血管疾病的病人、現時有血管疾病病徵的病人以及有致血管疾病因素的高危人仕，當中患有血管硬化的普及程度及影響範圍。本文並有助臨床上例行為患有血管硬化的病人或其高危人仕足踝手臂血流指數（ABI）的價值，並同時評估現時抗凝血藥物的作用。

設計：抽樣招募符合資格的病人，（1）現有或曾有血管疾病病歷的病人，包括缺血性中風、短暫性中風、心肌梗塞、穩定及不穩定的心絞痛、患有外圍血管疾病的病人與及以往曾接受血管手術的病人（有病徵的病人）或（2）高風險人仕如年齡在55歲以上並有至少兩項心血管病危險因素的病人（沒有病徵的病人）。

對象：由2003年1月至2003年10月，於一私人診所內共招募115名病人。

測量內容：在研究初期，獲取病歷包括危險因素和抗凝血藥物的詳細評估。臨床檢驗包括心電圖、都卜勒超音波量度的足踝手臂血流指數與及頸動脈超音波檢查（非必須）。數據被分析以斷定有血管硬化問題病人的特性，其受影響的血管範圍，以及受影響的血管範圍和血管疾病危險因素、足踝手臂血流指數和治療之間的關係。

結果：在有病徵的病人中（n=46），95.6%有一個血管範圍受影響，4.4%病人有兩個血管範圍受影響（心臟、腦及外圍血管）。28.3%的病人有輕微血管閉塞，4.4%的病人有中度血管閉塞。在只有危險因素而沒有病徵的病人（n=69）中，50.7%患有糖尿病，92.8%患有高血壓，73.9%患有膽固醇，18.8%過胖，5.8%有吸煙習慣，而不正常的量度足踝手臂血流指數則佔病人20.3%。

結論：於香港一所私人診所所獲得的研究資料顯示血 管硬化問題普遍，縱使只有危險因素而沒有病徵的病人，其普及程度為 20.3%。血管硬化問題應被視為一種廣泛性的疾病，而量度足踝手臂血流指數是一項有 用的臨床方法以識別高危的病人。所有危險因素都必須積極地治療。

主要詞彙：足踝手臂血流指數、周邊血管疾病、血管硬化、心血管病危險因素、流行率

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Introduction

Peripheral arterial disease (PAD) is a powerful indicator of systemic atherosclerotic disease. Patients with large vessel peripheral arterial disease have a higher risk of death from cardiovascular causes. For patients with symptomatic arterial disease, the 10-year risk of death due to coronary heart disease or cardiovascular disease is 10 to 15 times greater than that of subjects who are free of large-vessel peripheral arterial disease.¹ Atherosclerosis shortens life expectancy. According to the Framingham Heart Study, a reduction in life expectancy of 8-12 years was seen in men with atherosclerosis aged over 60 years.² Survivors of acute myocardial infarction (MI) have an increased risk of recurrent myocardial infarction or cardiac death, with a 10% death rate in the first year after discharge and a subsequent annual death rate of 5% - six times that in people of the same age who do not have coronary artery disease.³

The pathophysiology of atherosclerosis is generally similar in different vascular beds. Therefore an atherothrombotic event in one territory implies that other anatomical sites may also be affected by a similar pathological process.^4,5

Atherosclerosis in the coronary arteries is the major cause of acute coronary syndromes (defined as unstable angina and Q-wave or non Q-wave myocardial infarction). If left untreated, it can also lead to chronic conditions, such as congestive heart failure. Atherosclerosis and/or stenosis in the carotid or cerebral arteries leads to transient ischaemic attack or ischaemic stroke. Atherosclerosis in the peripheral arteries may lead to intermittent claudication as well as critical limb ischaemia.⁶

Major risk factors for cardiovascular disease include age, diabetes mellitis, hypertension, obesity, cigarette smoking and dyslipidaemia or hyperlipidaemia. These factors are independent predictors of adverse outcome and are additive in predictive power.⁷

The presence of multiple cardiovascular risk factors greatly increases the risk of atherothrombotic events. For example, diabetes with hypertension and subclinical disease (such as PAD) produces a 12-fold increase in the risk of stroke.⁸

The CAPRA (Clopidogrel Actual Practice Rates Analysis) study⁵ demonstrated the increased risk for atherothrombotic events in patients with involvement of one or multiple vascular beds. It analysed 12,931 residents of Saskatchewen, Canada who were prescribed aspirin for secondary prevention following ischaemia stroke, MI or PAD. In CAPRA, the combined risk of ischaemic stroke, MI or vascular death in patients with atherothrombotic involvement of two vascular beds was 25% higher than in patients with a single bed affected, and the risk was 51% higher in patients with involvement of all three beds compared with those with single-bed disease.

PAD can be evaluated using the ratio of ankle to brachial resting systolic blood pressures, which will be referred to as the ankle/brachial index (ABI)⁴³ (Figure 1). This is a standard method for diagnosing occlusion or stenosis of the proximal arteries of the leg.^{34,36-41,44,45}

An ABI <0.9 is indicative of PAD. Patients with an ABI greater than 1.5 are considered to have calcific arteriosclerosis which results in spuriously high ABI readings.⁹

In the Cardiovascular Health Study, ABI was used as a marker of subclinical atherosclerosis. Epidemiological studies have demonstrated that subclinical cardiovascular disease in one vascular bed is associated with the presence of clinical disease in another vascular bed as well as subsequent cardiovascular disease and total mortality. An ABI 0.9 was an independent risk factor for incident cardiovascular disease, recurrent cardiovascular disease and mortality in this group of older adults in the Cardiovascular Health Study.¹⁰

Kornitzer et al found that decreased ABI was an independent risk factor for coronary and cardiovascular mortality in asymtomatic middle aged Belgium males. He proposed aggressive treatment of risk factors once decreased ABI is detected.¹¹

In the Atherosclerosis Risk In Communities (ARIC) study, the prevalence of clinical coronary heart disease, stroke, TIA and preclinical carotid plaque increased with decreasing ABI levels, particularly at those of <0.90. Individuals with ABI <0.90 were twice as likely to have coronary heart disease (CHD) as those with ABI >0.90. Men with ABI <0.90 were more than four times as likely to have stroke/TIA as those with ABI >0.90. Individuals with ABI 0.90 had a statistically significant higher prevalence of preclinical carotid plaque compared to those with ABI >0.90.¹²

Criqui et al¹ surveyed 565 Californian men and women with an average age of sixty-six years by means of two non-invasive techniques: measurement of segmental blood pressure and determination of flow velocity by Doppler ultrasound. After excluding 90 subjects with isolated small-vessel PAD, they identified 67 subjects with the disease, whom they followed prospectively over ten years. Twenty-one of the 34 men (61.8%) and 11 of the 33 women (33.3%) with large-vessel PAD died during follow-up, as compared with 31 of the 183 men (16.9%) and 26 of the 225 women (11.5%) without evidence of PAD. After multivariate adjustment for age, sex, and other risk factors for cardiovascular disease, the relative risk of dying among subjects with large-vessel PAD as compared with those with no evidence of such disease was 3.1 (95% CI of 1.9 to 4.9) for deaths from all causes, 5.9 (95% CI of 3.0 to 11.4) for deaths from cardiovascular disease, and finally 6.6 (95% CI of 2.9 to 14.9) for deaths from CHD.

The aim of this study was to validate the belief that atherosclerosis is a generalised disease. The objectives are to evaluate the prevalence and extent of atherosclerosis in patients with a history of vascular events, current symptoms of vascular disease or who were at an increased risk of developing a vascular event in the future, and to establish the value of ankle-brachial index (ABI) measurements in the routine clinical examination of patients with or at risk of atherosclerosis and evaluate the current usage of antithrombotic medication.

Methods

Subjects included in the study were:

1.	Patients with a history of vascular events or current symptoms of vascular disease:-
	a. Cerebrovascular disease (ischaemic stroke, TIA, carotid angioplasty or endarterectomy).     b. Coronary disease (myocardial infarction, coronary artery by-pass graft, percutaneous transluminal coronary angioplasty, stable and unstable angina.)     c. Peripheral arterial disease (Intermittent claudication, previous abnormal ABI, prior vascular intervention.)

2.	Patients without a history of prior event or current symptoms but aged >55 years and with 2 of the following risk factors:-
	a. Diabetes Melliltis (Type 1 or 2)     b. Dyslipidaemia/Hyperlipidaemia     c. Hypertension     d. Obesity (Body mass index >30 kg/m2)     e. Current (or former) smoker >10 pack (20 cigarettes each) - year consumption

Recruitment commenced in January 2003 and ended in October 2003 in a private clinical setting with a total recruitment of 115 patients out of 160 eligible patients. At study entry each patient had a medical history recorded including the demographic information (age, sex, race) (Table 1), history of previous vascular events and/or current cardiovascular symptoms. The cardiovascular risk factors were assessed and the use of antithrombotic medication was noted. A detailed physical examination including weight (Kg), height (cm), BMI (Kg/m²), heart rate (beats/min), systolic and diastolic blood pressure (mm Hg) was performed on every patient. Clinical assessment included ECG, ABI and carotid echo-doppler (optional). The data were analysed to determine the characteristics of patients with atherosclerosis, the extent of the disease and the relationship between the extent of the disease and the risk factors, ABI values and treatment.

Results

In symptomatic (coronary, cerebrovascular and peripheral arterial) patients (n=46), 95.6% had 1 arterial bed and 4.4% had 2 arterial beds affected. Mild obstruction (0.7 <ABI 0.96) was found in 28.3% of patients and moderate obstruction (0.3< ABI 0.7) was found in 4.4% patients.

In at-risk patients (n=69), 50.7% had diabetes, 92.8% hypertension, 73.9% dyslipidaemia, 18.8% obesity, 5.8% smoking history and an abnormal ABI was found in 20.3% patients.

Discussion

In this study, the prevalence rate of PAD in the symptomatic patients was 32.7% and 20.3% for the at-risk patients (Table 3). Of the symptomatic patients, 62.5% had a prior history or current symptoms of CAD, while 33.3% had a history of cerebrovascular event and 4.2% had symptoms of PAD. For the at risk patients, hypertension (92.8%) and dyslipidaemia (73.9%) were the main risk factors (diabetes mellitus, dyslipidaemia/hyperlipidaemia, hypertension, age obesity or smoking history) (Table 2).

The overall breakdown for the at-risk patients was 59.4% with two risk factors; 39.1% with three risk factors and 1.5% with four risk factors. In the at-risk patients group, those with three or more risk factors had a higher percentage of abnormal ABI than those with two risk factors (Table 4).

In the Systolic Hypertension in the Elderly Programme (SHEP), Newman et al found the prevalence rate of PAD in subjects aged 60 and older with systolic blood pressure >160 mmHgm was 26.7%.³⁵ In a study of the subgroup of SHEP over four years, Newman et al found the prevalence rate of PAD was 19.7%. A low ABI predicted a two to three-fold increase in total and cardiovascular mortality in older adults with systolic hypertension of risk for incident cardiovascular disease.⁴²

According to the preliminary data released from the A Global Atherothrombosis Assessment (AGATHA) in Asia study at the 14th Asian Pacific Congress of Cardiology, the prevalence rate of PAD in patients at risk of vascular disease was 36.3% and the prevalence rate of PAD in patients with vascular disease was 32.6%. The study design and objectives of AGATHA was the same as the present study. These were interim data in 1682 Asian patients enrolled between April to October 2002 in 9 Asian countries representing approximately 19% of the worldwide enrollment, which suggested that even in the absence of symptoms, atherosclerosis should be considered a generalised disease and that ABI measurement is a simple and useful clinical tool for identifying these patients at high-risk. It should be treated aggressively including the control of risk factors and the use of antiplatelet agents. The Worldwide data is going to be released this year and will give us a better idea of the prevalence of PAD in patients at risk or with vascular disease.

In the Rotterdam Study, Meijer et al found the prevalence rate of PAD for males aged >55 years was 17% and females >55 years was 21%. Of these patients with PAD, the prevalence of clinical CHD for males was 48% and for females was 33%.¹⁴

In the Edinburgh artery study, Fowkes et al found the prevalence rate of PAD for both sexes (age 55 to 74 years) was 18% and the prevalence of clinical CHD was 54% in those with PAD. These studies reinforce the idea that atherosclerosis is a generalised disease.¹⁵

Tierney et al¹⁶ in their review on PAD emphasised the following points:-

1.	Asymptomatic patients with ABI <0.9 have a twofold increased risk of fatal or non-fatal cardiovascular events.
2.	PAD is an independent predictor of increased risk of cardiovascular death. 3. Half of patients presenting with PAD have symptoms of CHD. 4. Symptomatic PAD carries at least a 30% risk of death within five years and almost 50% within 10 years primarily due to myocardial infarction (60%) or stroke (12%).

According to Murray and Lopez, atherosclerotic diseases such as ischaemic heart disease and cerebrovascular disease were the leading causes of death and disability in developed countries in 1990. These events are projected to remain the leading cause of death and disability in developed countries until the year 2020, despite the improvement in medical and surgical therapies.¹⁷ Prevention of subsequent/potential manifestations of atherosclerosis is a major therapeutic goal in patients at high-risk of atherosclerotic events^13,20,46-51 and will decrease the atherosclerotic disease burden.

The Joint British recommendations on prevention of coronary heart disease in clinical practice¹⁸ suggest aggressive management of risk factors, which includes emphasising the importance of life style modifications, smoking cessation, management of hyperlipidaemia, hypertension and control of diabetes. Weight reduction in obese patients, institution of regular exercise and dietary modification can all prevent cardiovascular disease.

After an MI or stroke, the risk of recurrence is reduced by 50% in those who stop smoking. Stopping smoking increases walking distance by twofold to threefold in 85% of patients with intermittent claudication.¹⁶

ABI is a useful tool to detect atherosclerosis in the general population (Figure 1). It is simple, and should be used more often in the family physician's clinic on patients suspected to have atherosclerosis. The doppler ultrasound device is inexpensive and user-friendly. The finding of an abnormal ABI <0.9 suggests atherosclerosis, a generalised disease in all vascular beds. These patients should have a complete evaluation to determine the extent of their disease in all vascular beds. They should be aggressively treated for their risk factors and life-style modification should be encouraged and monitored.

Antiplatelet agents are used in reducing the occurrence of vascular events in patients with atherothromobotic disease.^20-33 Long-term ASA therapy significantly reduced overall vascular mortality as well as non-fatal stroke and MI. ASA therapy reduced the risk of non-fatal MI by one-third, non-fatal stroke by one third and death from all vascular causes by one-sixth.⁴

In the Chinese Adult Stroke Trial (CAST), immediate treatment of acute ischaemic stroke with medium-dose aspirin (160-300 mg daily) produced a modest, but definite net reduction in early death or non-fatal stroke.¹⁹

Low to medium dose (75-325 mgm) aspirin is as effective as high dose aspirin for secondary prevention of acute MI.³

In the present study, only 44.9% of at risk patients were on antiplatelet treatment and 62.5% of symptomatic patients were on antiplatelet treatment (Table 5). There is an under-usage of antiplatelet treatment for atherosclerotic diseases in at risk and symptomatic patients. Aspirin is cheap and readily available and should be prescribed more often to patients with atherosclerotic diseases. For those patients who cannot tolerate aspirin, one may use clopidogrel,²² dipyridamole,²⁴ cilostazol^25,26,29,33 etc. as an alternative. The better clinical efficacy of clopidogrel over aspirin as evidenced by the CAPRIE Study⁴ has to balanced against its higher cost.

Conclusion

This study and the Asia study (AGATHA) have shown that the prevalence of PAD is high. This may be the result of "Westernization" of the diet and lifestyle in Hong Kong and Asia. A large randomised control trial may help to clarify this matter. Family Physicians should consider this as a "red flag" and be more vigilant in searching patients for atherosclerosis.

Atherosclerosis is a generalised disease, therefore patients at high risk of atherothrombotic events should have a complete evaluation to determine the extent of their disease in all vascular beds. ABI measurement should be part of a routine clinical examination and ABI <0.90 is indicative of atherosclerosis. PAD signifies atherosclerotic involvement in other vascular beds. Once atherosclerosis or atherothrombotic events are diagnosed, aggressive medical management should be given.

Major risk factors for cardiovascular disease (CAD) include age, diabetes mellitis, hypertension, obesity, cigarette smoking and dyslipidaemia or hyperlipidaemia. Aggressive management of risk factors for CAD is essential to prevent the progression of atherosclerosis.

The Doppler-ultrasound is inexpensive and affordable. ABI is easy to perform in the family practice setting and should be routinely performed. Family physicians can lessen the disease burden of atherosclerosis by early diagnosis and aggressive management of CAD risk factors. Life style modification (diet, regular exercise, stopping smoking and achieving ideal body weight) should be an integral part of our patient management programme.

Acknowledgement

I am indebted to Miss Karen Yuen for her work on statistical analysis and Miss Pamela Yeung for her clerical help.

Key messages

1. Peripheral arterial disease (PAD) is a useful indicator of systemic atherosclerotic disease, 32.7% of the symptomatic patients and 20.3% of the at-risk patients had abnormal ABI.
2. Major risk factors for cardiovascular disease (CAD) include age, diabetes mellitis, hypertension, obesity, cigarette smoking and dyslipidaemia or hyperlipidaemia.
3. ABI is a marker of subclinical atherosclerosis. An ABI of <0.9 is indicative of PAD.
4. Prevention of subsequent/potential manifestations of atherosclerosis is a major therapeutic goal in patients at high-risk of atherosclerotic events and will decrease the atherosclerotic disease burden.
5. Aggressive management of risk factors for CAD is essential to prevent the progression of atherosclerosis.6. Life style modification (diet, regular exercise, stopping smoking and achieving ideal body weight) should be an integral part of our patient management.

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References