A study of some aspects of the epidemiology and treatment of peripheral vascular disease

Prior to starting the research described in this thesis I had completed the first year of a residency programme in internal medicine. During this time I became interested in epidemiology and wished to learn more about how this approach could be used to examine problems in clinical medicine. When the opportunity arose to study in Oxford I considered a number of possible topics for my research but decided to study some aspects of atherosclerotic vascular disease because this was an important subject and also relevant to a possible future career in cardiovascular medicine.
A preliminary review of the literature revealed that there was a vast amount of information concerning coronary artery and cerebral vascular disease. In contrast, few data were available concerning the epidemiology of peripheral vascular disease (PVD), possibly because this condition was rarely a primary cause of death, symptoms of PVD were often tolerated by patients who did not seek medical attention, or because serious complications such as amputation were infrequent. Another reason for this lack of data may have been the assumption that the factors leading to an increased risk of developing PVD were the same as those which caused coronary artery and cerebral vascular disease. It seemed that research concerning risk factors for PVD, and the natural history of this condition, might provide new information of clinical importance, and would at the same time permit me to learn some of the techniques of epidemiology.
When I began I felt that there were several basic questions which needed to be answered. The first concerned the frequency of PVD. Few studies had attempted to determine the prevalence of PVD or that of its most common symptom, intermittent claudication (IC). Most data came from selected groups of people which were not representative of a general population. The techniques used to identify cases were poorly standardized, and few studies included an examination of the peripheral circulation. I decided, therefore, that the first stage of my research would be to determine the frequency of IC in a general population using a standardized questionnaire to identify cases and a physical examination to confirm the diagnosis. One advantage of starting with a prevalence survey was that the cases identified could then be compared with controls selected at random from the same population, and a second important question could then be answered: what factors are associated with an increased risk of developing IC?
A survey to determine the prevalence of IC and a case-control study to examine risk factors for this condition are presented in Section 2 of the thesis. The prevalence of IC in men aged 45 to 70 years was 3.0 per cent, and that of women 50 to 70 years was 0.8 per cent. A total of 54 cases of IC were identified, and the over-all prevalence in the population was 2.0 per cent. Factors associated with an increased risk of developing IC were age, smoking, a history of diabetes mellitus, hypertension or hyperlipidaemia, and elevations of blood pressure, serum triglyceride, plasma fibrinogen, and serum uric acid. Of these factors, smoking was associated with the greatest relative risk of IC and was the main risk factor for this condition. Elevated blood pressure, the chief risk factor for cerebral vascular disease, did not have the same degree of importance in the aetiology of PVD. Serum cholesterol, which is one of the main risk factors for coronary artery disease, was not elevated in the patients with IC compared with their controls. Nor was the blood glucose elevated in the cases despite a higher prevalence of diabetes. There was significant synergism among the risk factors, and the relative risk of developing IC rose sharply in people with multiple risk factors. Evidence of coronary artery disease was found very frequently among the patients with IC.
In addition to defining risk factors for IC, I also wanted to examine the natural history of patients with PVD. Data was available from a number of studies which had examined series of patients referred to hospital, but few of these had investigated the effect on prognosis of removing correctable risk factors such as smoking and hypertension. I was fortunate in having the opportunity to examine a group of 60 patients with IC referred to hospital in 1971 and 1972 who had been extensively investigated to determine risk factors for PVD. I undertook a follow-up study of these patients in order to determine whether any of the risk factors identified at the initial examination had had a significant effect on prognosis. The results of this investigation are presented in Chapter 5.
A number of the patients had died since the first referral for IC, and, in agreement with other studies, the chief causes of death were coronary artery and cerebral vascular disease. The only correctable risk factor which significantly affected prognosis was smoking. Most of the patients who stopped or reduced smoking after referral completed the follow-up period without significant complications from their PVD, whereas the majority of patients who continued to smoke had a deterioration in their symptoms and a clinical course which was punctuated with frequent hospital admission, reconstructive surgery, amputation, and death. This effect was not due to other risk factors since the smoking groups were comparable with respect to age, severity of PVD at referral, and the prevalence of other medical conditions such as ischaemic heart disease. Thus the improved prognosis associated with abstinence from tobacco could reasonably be attributed to elimination of this risk factor. Elevated blood pressure did not significantly worsen the prognosis except in those who continued to smoke, suggesting a synergistic effect of smoking and blood pressure. The only other factor which had a significant effect was a history of stroke; these people had a very high mortality rate. Patients with elevated glucose, cholesterol, or triglyceride, did not have a worse prognosis than people with normal levels.
The follow-up study described in Chapter 5 examined a small number of patients for a relatively short period of time. In order to provide further information about the prognosis of patients with PVD, I decided to identify a larger patient group and follow them for as long as possible. The presence of a unique computer-based information system, the Oxford Record Linkage Study (ORLS), enabled me to identify all people admitted for the first time to hospitals in the Oxford area in 1965 and 1966 because of PVD and to determine the frequency of subsequent hospital admissions, operations and death by means of the linked records maintained by the ORLS. This study is described in Chapter 6.
The 160 patients included in this study had a five-year mortality rate which was twice that of the general population, controlling for age and sex. Factors which worsened the prognosis were increasing age at referral, ischaemic heart disease, cerebral vascular disease, and diabetes. The patients had frequent and prolonged admissions to hospital because of deterioration in their condition, and many had reconstructive surgery or amputations. The degree of morbidity associated with PVD was striking, and the disease had a great impact not only on the patients but also on the financial resources of the health services. Thus the observation made in Chapter 5 that patients who stop or reduce smoking have a better prognosis than those who continue to smoke was seen to be relevant not only to the individual with PVD but also to have practical significance for the community as a whole.
The final chapter of my thesis contains the results of a trial of Cinnarizine in the treatment of 18 patients with IC. I chose to investigate this drug because other studies have shown an improvement in the symptoms and blood flow (measured by plethysmography) of patients with PVD who were treated with Cinnarizine. Unlike most of the drug preparations being investigated at the time, Cinnarizine was not a vasodilator and did not cause changes in blood pressure, pulse, or cause the "steal" effect which is so often reported. The trial protocol included measurements of blood flow using a mercury strain gauge plethysmograph. This enabled me to compare the plethysmograph with another objective variable, the ankle systolic blood pressure measured with a Doppler ultrasound flow meter, and to determine their usefulness in the evaluation of patients with PVD.
It was planned initially to treat 20 patients with IC for four months and then to proceed with a double-blind trial if the results were promising. Unfortunately there was little evidence of subjective improvement in patient symptoms at the end of the preliminary study and no evidence of improved blood flow to the legs as measured by plethysmography. Thus it was decided that a double-blind trial was not indicated. The objective measurement which was most strongly correlated with patients' symptoms was the ankle systolic pressure measured after exercise, and since this test was far easier to perform than plethysmography I concluded that the Doppler flow meter was the better method of evaluating PVD.
In summary, I have found that intermittent claudication occurs in approximately two per cent of adults. Peripheral vascular disease is, therefore, a fairly common disorder, and since it is associated with significant morbidity and mortality its prevention and treatment are major concerns for the medical profession. Peripheral vascular disease, coronary artery disease, and cerebral vascular disease have several risk factors in common, but smoking seems to be particularly important in promoting atherosclerosis in the peripheral circulation. Every effort should be made to encourage patients with peripheral vascular disease to stop smoking, since continuation of this habit significantly worsens the prognosis and may increase the likelihood of costly medical intervention. At the present time surgical correction of arterial lesions is the only accepted form of treatment for peripheral vascular disease. Since atherosclerosis is a generalized process, it is possible that removal of correctable risk factors may be a more effective way of preventing ischaemic complications. The peripheral circulation is uniquely accessible to examination with non-invasive techniques, and I believe that further investigations in which patients with peripheral vascular disease are observed and the effect of risk factor control are evaluated may provide new information concerning the aetiology and treatment of atherosclerosis.