Atherosclerosis
Peripheral arterial disease (PAD) is a marker for multisystem vascular disease. Workers in this field recognized this over 150 years ago, noting the similarity between claudication symptoms and angina. Since then, published work has supported this view, but the com- monality of the link between PAD and coronary artery disease (CAD) has only now been fully recognized. Myocardial infarction (MI) and stroke are the biggest risks to life and health for the PAD patient rather than amputation or critical limb ischemia (CLI). The natural history of intermittent claudication (IC), the usual symptom of lower limb atherosclerosis, is often benign. Most patients improve or their disease remains stable. Less than 5% of patients require amputation. In contrast, however, the death rate in these patients is three to four times higher than in patients of similar age without IC (Fig. 6.1). This mortality occurs due to atherosclerosis at other sites within the body.
Only one quarter of the mortality of these pa- tients is from nonvascular events. One half die from CAD, 15% as a result of stroke, and 10%
from vascular pathology within the abdomen such as ruptured aortic aneurysm. The associa- tion between PAD and generalized vascular mortality is so strong that even in asymptomatic PAD [detected by a decrease in the ankle–
brachial index (ABI)] the patient’s relative risk of a cardiac or cerebrovascular event is very much higher.
Thus we now recognize that atherosclerosis is a systemic disorder affecting the entire vascular tree. Extracranial carotid disease can lead to stroke, CAD to myocardial ischemia/infarction, renovascular disease to hypertension, and aor- toiliac and infrainguinal arterial disease to IC or limb-threatening ischemia. The mainstay of the medical management of vascular disease is to understand that it is a systemic disorder and must be managed as such. Thus the medical management of PAD is a complex area that includes strategies for vascular risk reduction, lifestyle advice, and direct pharmacotherapy for the vascular disease. Its implementation requires a multidisciplinary team, which in- cludes not only vascular physicians, vascular surgeons, and interventional radiologists but also many of the professions allied to medicine and, importantly, our primary care colleagues.
Areas of focus for such a vascular team are out- lined in Table 6.1.
Vascular Risk Factor
Modification in Peripheral Arterial Disease
The medical management of vascular disease must focus on modification of the following specific risk factors that promote the progres- sion of the disease: (1) platelet aggregation, (2) smoking, (3) obesity, (4) diabetes, (5) dyslipi-
Medical Management of Peripheral Arterial Disease
Jill J.F. Belch and Andrew H. Muir
53
demia, (6) hypertension, (7) sedentary lifestyle, and (8) type A personality or stress.
The literature suggests that cigarette smok- ing, hypertension, dyslipidemia, and diabetes mellitus are important factors in the develop- ment of PAD, and these will be addressed in turn (Table 6.2). A key risk factor for PAD is platelet aggregation along with other hemorheological factors such as increased plasma fibrinogen and decreased fibrinolysis. Currently an area of interest that is being explored is that of the con- tribution of inflammation to PAD. The high white blood count (WBC) contributes vascular risk to the patient with PAD (Belch et al., 1999) as does increased oxidative stress. Of the above, however, platelet activation and release in the patient with PAD has been well documented and has led to the evidence-based use of antiplatelet agents in PAD.
Platelet Aggregation
Platelet aggregation is increased in patients with PAD, and the role of such aggregates in arterial thrombosis has been well documented. Platelet release products also contribute to the underly- ing pathology. b-Thromboglobulin is one such product that, once released from platelets, con- tributes to neutrophil activation. Platelet factor 4 neutralizes heparin, and platelet-derived growth factor stimulates proliferation of vas- cular smooth muscle cells. Some of the release
products are vasoactive, and these include thromboxane A2 and serotonin, both potent vasoconstrictors.
Antiplatelet Agents
Current interest in antiplatelet agents relates to their use as prophylactic treatments against arterial events in other beds and atherosclerosis disease progression.
Aspirin in Peripheral Arterial Disease
Aspirin is the most commonly used antiplatelet agent, reflecting the fact that it is currently the cheapest agent available and one of the best studied agents in clinical trials. Its action includes the irreversible inhibition of the cyclo-
Table 6.1. Medical strategies for the management of peripheral arterial disease
Address vascular risk Antiplatelet therapy Cigarette smoking Dyslipidemia Hypertension Diabetes Obesity Thrombophilia
Specific therapy for intermittent claudication Exercise
?Drug therapy
Vasculitides as a cause of symptoms Connective tissue disease Raynaud’s phenomenon Vasculitis
Antiphospholipid syndrome Embolism as a cause of symptoms
Detect and treat arrhythmia and/or cardiac thrombus
Exclude aortic aneurism Chronic limb symptoms
Control edema Control infection Improve cardiac output Acute critical limb ischemia (CLI)
Thrombolysis Anticoagulation Deep vein thrombosis (DVT)
Prophylaxis Treatment Figure 6.1. Mortality of peripheral arterial disease (PAD).The 5-
year mortality of PAD is relatively equivalent to numerous cancers (prostate, breast, colorectal, and lung).
oxygenase enzyme. Platelet aggregation is there- fore decreased.
Primary Prevention of Peripheral Arterial Disease
As yet there is no published evidence to suggest that aspirin prevents the primary development of PAD in a normal population. Such a study would require a huge population base. One method of decreasing the numbers required to be studied would be to increase the risk of the population enrolled in the trial. Two such
studies are currently under way. In both these studies aspirin is being evaluated in subjects with decreased ABIs but who are currently asymptomatic in terms of PAD. One of the studies is a population-based study and the other is a study of patients with diabetes melli- tus. This latter study, Prevention of Progression of Arterial Disease in Diabetes (POPADAD) has recruited 1250 patients with decreased ABI, and aspirin versus placebo is one of the arms of this study, which has a composite end point of vas- cular events and mortality. This is a Scotland- wide study and results should be available soon.
Table 6.2. Risk factors for intermittent claudication
Risk Management
Other cardiovascular events, e.g., MI, stroke • Antiplatelet agent
Aspirin, clopidogrel, dipyridamole
Smoking • Cessation program
Counseling
Nicotine replacement, e.g., patch, gum, spray
Dyslipidemia • Lipid-lowering therapy
Diet ± drug
Target: LDL cholesterol <3.0mmol/L HDL ≥20%
Triglycerides <1.8mmol/L
Hypertension • Antihypertensive therapy
Select: ACE inhibitor
Calcium channel blockade Diuretic
Avoid beta-blockade (unless vasodilatory) Target BP <140/85 (in diabetes <140/80)
(Note: 25% will have renal artery stenosis; watch renal function)
Diabetes • Check for hyperglycemia
Fasting glucose ≥ 7.8mmol/L
If borderline glucose (random or fasting), glucose tolerance test with fasting and 2-hour sample
2-hour sample: <7.8mmol/L normal
≥7.8–11.0 impaired
≥11.1 diabetic
Obesity • Check for obesity
Body mass index ≥30
Low-fat, high-fiber diet, healthy eating Calorie control
Thrombophilia • Consider referral for thrombophilia screen (inherited or acquired) Suspect if:
Young (<50 years of age) Connective tissue disease, e.g., SLE
Additional history of unexplained venous thrombosis Previous failed vascular reconstruction
Strong family history of thrombosis
SLE, systemic lupus erythematosus.
Primary Prevention of Vascular Surgery Aspirin has been evaluated in the primary pre- vention of requirement for peripheral vascular surgery in the U.S. Physicians’ Health Study. In the aspirin group the risk of undergoing surgery for PAD was decreased by 46% (p = .03). Aspirin did not, however, affect the likelihood of devel- oping claudication de novo during the trial period.
Aspirin in the Prevention of Coronary and Cerebrovascular Events in Peripheral Arterial Disease
The Antiplatelet Trialists Collaboration, now called the Antithrombotic Trialists Collabora- tion, has provided the most convincing data supporting the use of aspirin in PAD. In a meta- analysis of 174 randomized trials of various antiplatelet agents (mainly aspirin), a decrease in nonfatal MI, nonfatal stroke, and vascular death in patients treated by antiplatelet therapy was detected. Subgroup analysis of high-risk patients was carried out. This included patients with PAD, and the percentage of risk reduction versus placebo were as follows: 46% for non- fatal stroke, 32% for the risk of vascular disease, MI, or stroke, and for nonfatal MI, and 20% for death from vascular causes. The most frequently used dosages of aspirin were between 75 and 325 mg per day. Subsequent work has confirmed that there is no evidence that the higher doses are more effective than the lower ones (i.e.,
>75 mg per day), although bleeding risk is dose dependent.
Clopidogrel
Clopidogrel irreversibly blocks the binding of adenosine diphosphate (ADP) and thus its activation of platelets. The Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) study evaluated the risk of vascular death, MI, and stroke in patients with vascular disease receiving either clopidogrel or aspirin.
Clopidogrel reduced the event rate by 5.32% per annum versus 5.83% with aspirin (p = .043).
These figures reflect a relative rate reduction of 8.7% in favor of clopidogrel. No major differ- ences in safety issues between the two drugs was detected. An ad hoc subgroup analysis in
patients with PAD suggested greater benefit to these patients from clopidogrel than in other patient populations. An event rate of 3.1 per annum compared to 4.86 per annum in the aspirin group gave a relative risk reduction of 23.8% [95% confidence interval (CI) 8.9–36.2] in favor of clopidogrel (p = .0028). A reasonable strategy, therefore, in the 30% of all patients who developed gastrointestinal (GI) side effects from aspirin is to combine the aspirin initially with the gastric protectant, and if this fails, change to clopidogrel. This drug provides an improve- ment to our therapeutic resources in terms of tolerated antiplatelet drugs.
Dipyridamole
Dipyridamole is an antiplatelet agent that is thought to work through a number of mecha- nisms including increasing the effect of prosta- cyclin (PGI2), and inhibiting the cellular uptake of adenosine and platelet phosphodiesterase, thus enhancing further the effects of PGI2. The use of dipyridamole itself or in combination with aspirin has produced much controversy.
Three decades ago there was excitement about the potential benefits of combining aspirin and dipyridamole, but by the 1980s aspirin alone became the favorite choice. Evidence that the combination treatment is effective has been forthcoming in one of the large stroke studies (Diener et al., 1996), and certainly the combina- tion has been found to be more effective in the prevention of peripheral graft failure in one study. It is our current practice to use both aspirin and dipyridamole in patients with stroke or transient ischemic attack (TIA) but to use aspirin or clopidogrel alone in patients with PAD. In stable PAD we usually reserve dipyri- damole for the aspirin-intolerant patient, al- though clopidogrel is now our first choice for this indication.
Conclusion
There is convincing evidence that antiplatelet agents such as aspirin and clopidogrel are effec- tive in preventing cardiac and stroke events in patients with PAD. It is therefore recommended that an antiplatelet drug should be prescribed for these patients unless there is a clear con- traindication to such therapy.
Smoking
Both the risk of PAD and its progression is significantly increased by the smoking of tobacco. Patients who smoke have a significantly increased risk of atherosclerosis and of another tobacco-related peripheral vascular disease, thromboangiitis obliterans (Buerger’s disease).
Of all the risk factors discussed here, the use of tobacco contributes most to the development of PAD. A number of studies have linked tobacco smoking and the development of IC. In the Framingham study smokers were twice as likely to develop IC. The progression to critical limb ischemia is more likely in smokers, as is ampu- tation. The effect of cigarette smoking on vas- cular graft patency is well recognized. In one study the 5-year cumulative patency rate for grafts was between 80% and 90% for nonsmok- ers, with the corresponding patency rates being between 30% and 45% for those who smoked more than five cigarettes a day.
Smoking cessation slows the progression of peripheral arterial disease to critical limb ischemia and lowers the risk of MI and death.
The nicotine present in tobacco products is highly addictive; hence, smoking cessation is a very difficult process for patients, and the recidivism rate is high. The key feature in the approach to smoking cessation is for the physi- cian to positively encourage the patient to stop smoking. Without a clear message from the physician that smoking is an underlying cause of atherosclerosis and promotes the progression of atherosclerosis, patients will continue to smoke. Thus, the first step is to clearly tell patients that it is medically indicated that they stop smoking.
Although the majority of smokers would like to quit, 90% are physically addicted to nicotine and at least 75% have tried to stop smoking more than once. Three quarters of those who do stop restart within 3 months, and it is clear that the issue of nicotine dependence must be addressed. During the early stages of quitting, smokers experience both behavioral and physi- cal withdrawal symptoms. It is crucial to explain to the patient that the chemical withdrawal symptoms are short lived as they can exert strong pressure on the smoker’s will to stop.
This also underlines the fact that we must provide support to these patients. After re- ceiving only medical advice, only 5% of
PAD patients stop smoking. Improved cessation rates, however, can be achieved through increas- ing support through counseling or the provision of judicious nicotine replacement therapy.
There are numerous smoking cessation pro- grams and pharmacological aids available for patients. Smoking cessation aids such as nico- tine patches and nicotine gum work best in the setting of a specific smoking cessation program.
Nicotine chewing gum was the first type of nico- tine replacement therapy (NRT) to become widely available, with subsequent development of transdermal patches, intranasal sprays, and inhalers. These latter forms of therapy may attenuate some problems with the gum such as transfer of dependency. A meta-analysis of 53 trials of NRT (42 gum, nine patch, one spray, and one inhaler) (Silagy et al., 1994) showed that NRT increased the odds ratio for abstinence:
1.61 for gum, 2.07 for patch, 2.92 for nasal spray, and 3.05 for inhaled nicotine. Nicotine replace- ment therapy can be an effective aid to smok- ing cessation. However, it is contraindicated in acute MI, unstable angina, and in patients with cardiac arrhythmias. Thus, it is important to work with patients to engage them in a specific program.
Finally, because the recidivism rate is high, it is important to be encouraging at follow-up visits once a patient has stopped smoking.
Physician encouragement throughout the process of smoking cessation and remaining tobacco free is essential.
Conclusion
Smoking causes PAD. Its cessation is difficult without support. Nicotine replacement and other aids to cessation should be made available to PAD patients.
Obesity
Obesity has reached epidemic proportions in developed countries. Obesity contributes to numerous medical problems including athero- sclerosis. It is important to recognize if patients are overweight and to obtain the appropri- ate dietary consultation to assist patients with weight loss. Most weight-loss programs are not successful unless they include lifestyle modification and a specific exercise program.
Conclusion
Obesity contributes to the development of type 2 diabetes, hypertension, and dyslipidemia, all known to be associated with PAD. Appropriate weight-reduction programs should be recom- mended. It should be noted that smoking cessa- tion promotes weight gain, and that in a patient with PAD smoking cessation is the most impor- tant element in risk reduction. A level of weight gain therefore should be tolerated, at least in the short term.
Diabetes Mellitus
Peripheral arterial disease and diabetes mellitus frequently occur together. Probably half of all patients with diabetes mellitus have evidence of PAD 10 to 15 years after diabetes onset. Fur- thermore, glucose intolerance correlates with angiographic disease extent. Diabetic patients account for one third of below-knee amputa- tions and 50% of amputations when distal amputations are included. The pathology of the diabetic limb is multifactorial, including contri- butions from both micro- and macrovascular disease. Asymptomatic PAD occurs in 20% of all diabetic patients with no other evidence of vascular disease (POPADAD screening of 8000 patients). Thus the occurrence of overt diabetes and PAD is well documented. We are less expert at detecting early diabetes in our patients with PAD, however. Distal disease on angiography or increased ABI (due to vessel stiffening) can lead to the retrospective diagnosis of diabetes melli- tus, but this still underestimates the figure. Of 100 consecutive patients presenting at our vas- cular surgery clinic, 40% had abnormal glucose tolerance tests. The majority of these patients had normal random or fasting sugars and were diagnosed only on the basis of this glucose tol- erance test. Currently we do not give a glucose tolerance test to all PAD patients but do use this form of diagnosis for patients who have raised ABI in the presence of symptomatic IC, in those in whom the distal distribution of the PAD would arouse a suspicion of diabetes, and in those with a “diabetic” lipid profile where both cholesterol and fasting triglyceride levels are elevated and high-density lipoprotein (HDL) levels are low. Detection of asymptomatic dia- betes mellitus in the PAD patient is a major part of the medical management of these patients. It
is consistently underdiagnosed in PAD and this can have serious consequences.
Diabetes contributes to atherosclerosis, and studies have indicated that tight glucose control limits the progression of end-organ damage due to diabetes, including atherosclerosis. Physi- cians involved in the care of diabetic patients with atherosclerosis must work closely, as a team, with other caregivers involved in the man- agement of diabetes to ensure tight glucose control.
Conclusion
It should be remembered that all risk factors are synergistic in terms of vascular disease, not merely additive, and the failure to diagnose underlying diabetes in a PAD patient who smokes will have serious consequences for that patient.
Dyslipidemia
Abnormal lipid profiles are well recognized in patients with atherosclerosis. The relationship between cholesterol level and CAD risk is con- tinuous, with no obvious “safe” cut-off point.
Patients with PAD are likely to be identical. A number of studies investigated cholesterol in PAD and found it to be a significant, though weak, risk factor for claudication, and above the age of 55 years to correlate with ABI. Reduced HDL is associated with increased PAD severity,6 with strong inverse relationships between HDL cholesterol and PAD that persist after adjust- ment for other risk factors. Furthermore, ele- vated serum triglyceride levels have been reported in both cross section and longitudinal studies. It has been suggested that the link between increased triglyceride level in patients with PAD and the development of the disease might be explained by the increase in low- density lipoprotein (LDL) providing the enhanced vascular risk.
Despite the links between abnormal lipid profiles and PAD, there have been no clinical studies with the PAD patient as primary end point. The situation has now been overtaken by the Heart Protection Study (2002) and various guidelines with recommendations for lipid- lowering therapy if there is a >3% chance of a vascular event per annum. Such a risk clearly occurs in patients with PAD.
All of the major trials in the field of lipid lowering that have been reported over the past decade have showed variously a decrease in CAD mortality, major coronary events, and the need for coronary revascularization.
Together the data suggest that four out of nine deaths occurring in a group of subjects with cholesterol >5.5 mmol/L will be prevented by treatment.
More recently, the Heart Protection Study (HPS) demonstrated for the first time a benefit from statin therapy for prevention of vascular events in patients with PAD (HPS Collaborative Group, 2002). This largest-ever trial of choles- terol-lowering therapy enrolled more than 20,000 high-risk patients, of whom 2700 had symptomatic PAD but no prior CAD. Treatment with simvastatin 40 mg/day reduced major vas- cular events (coronary events, stroke, and revas- cularization) by 20% in patients with PAD, a similar reduction to that observed in the study overall. Moreover, the benefits observed in the HPS were not influenced by baseline levels of blood lipids. The findings of the HPS, therefore, strongly suggest that statin therapy should be considered on the basis of high risk rather than high cholesterol, a category into which patients with PAD undoubtedly fall.
Conclusion
Elevated cholesterol and triglycerides contri- bute to the development and progression of atherosclerosis. Thus, it is important to obtain a lipid profile on any patient with atherosclerosis.
Management of dyslipidemia initially involves dietary change followed by specific medical management if necessary. The goal of lipid- lowering therapy is to achieve a serum LDL cholesterol concentration less than 100 mg/dL or 3 mmol/L and a serum triglyceride less than 150 mg/dL.
The first choice for pharmacological therapy is a statin.
Hypertension
Although it has been suggested that raised sys- tolic and raised diastolic blood pressure (BP) are linked to PAD development, results from prospective studies are less convincing. Target levels of blood pressure have been clearly defined in a number of guidelines, For example
the Scottish Intercollegiate Guidelines Network (SIGN) guideline on the management of hyper- tension and the British Hypertension Society guidelines have given clear guidance in terms of acceptable BP levels. Therapy should be started in all PAD patients with sustained systolic BP elevations recorded above 140 mm Hg or dias- tolic BP above 90 mm Hg. The optimum target blood pressure is a systolic BP of <135 mm Hg and a diastolic of <85 mm Hg. A more stringent target is required for those patients with diabetes and this is important, as many PAD patients have diabetes mellitus where a target of £130/80 mm Hg is recommended. Three long-term double-blind studies (Materson et al., 1993) have compared all the major classes of antihypertensive drug therapy and overall showed no consistent or important differences in terms of efficacy of BP control, side effects from the drugs, or quality of life. It has been suggested that hypertensive patients whose BP is controlled by thiazides or beta-blockers may continue to experience the excess risk of coro- nary death. These two drug classes change glucose intolerance and lipid profiles in a dose- dependent fashion, and it may be that the lower doses of thiazides currently employed do not show this effect. Although b-adrenergic antago- nist drugs have been previously reported to enhance PAD symptoms through their vasocon- strictor effects, more recently it has been sug- gested that this is not so. It is of interest that the new vasodilating beta-blockers do not even have this theoretical contraindication and might be used safely in patients with PAD. The use of angiotensin-converting enzyme inhibitors in patients with PAD may confer protection against future atherosclerotic events. However care must be taken in the presence of renal artery stenosis, another common finding in patients with PAD.
Care must be taken when treating hyperten- sion in the patient with CLI, as limb perfusion might only be maintained through the elevated BP. Too profound or rapid a decrease in BP may worsen the symptoms, and care must be taken with CLI in the same way as with patients with severe carotid disease.
Conclusion
Hypertension has been implicated in the etiology of PAD and contributes to its vascular
comorbidity. Blood pressure should be con- trolled to levels consistent with local guidelines.
Polypharmacy is likely to be required. Caution is advised when high BP is diagnosed in a patient with CLI, as too rapid a decrease in pres- sure may worsen the limb ischemia.
Sedentary Lifestyle/
Exercise Therapy
Intermittent claudication is a symptom of lower limb peripheral arterial disease. It arises when the blood flow is insufficient to meet the meta- bolic demands of the leg muscles in ambulating patients. Intermittent claudication is a “lever- aged” disability, as pain increases with walking, patients walk shorter distances, muscle strength erodes, and walking distances continue to decrease. This leads to other negative conse- quences such as weight gain, hypertension, and diabetes. Overall, patients with claudication have a 60% lower functional capacity than age-matched individuals without the disease (Eldridge and Hossack, 1987).
Intermittent claudication is a symptom of systemic atherosclerosis. At least 60% of pa- tients with claudication have significant disease of the cerebral or cardiac circulation. Mortality rates for patients with claudication are very high, with 30% to 50% of patients dying from cardiovascular causes within 5 years of the initial diagnosis. A meta-analysis of 21 studies on the effects of exercise on patients with clau- dication suggested that the average improve- ment in walking distance was 122% (Gardner and Poehlman, 1995) and the benefits have been shown to be as high as 180% (Fig. 6.2).
The programs with the greatest benefit were those in which patients exercised for 30 minutes at least three times a week for 6 months. How- ever, supervised exercise programs are not currently covered by most medical insurance policies.
There are numerous salutary effects of exercise that contribute to the reduction of cardiovascular events. Exercise is associated with beneficial changes in body fat percentage, lipoprotein profile, carbohydrate tolerance and insulin sensitivity, neurohormonal release, and blood pressure. There is substantial evidence that regular aerobic exercise can even alter
vessel structure. The progression of coronary lesions can be inhibited in those patients who modify risk factors and engage in regular exer- cise. Numerous studies have demonstrated a significant correlation between exercise and an increase in vessel diameter. Exercise may also induce changes in the lumen diameter in patients after coronary angioplasty. Patients randomized to a 12-week intervention program consisting of daily exercise after balloon angioplasty of the coronary vasculature had a significantly lower rate of re-stenosis than patients in the control group. However, the major benefit of exercise is likely due to the training response.
Thrombophilia
Patients under the age of 50 with manifestations of vascular disease have an increased risk of a defined hypercoagulable disorder. Thus, some believe that these patients should be screened for hypercoagulable disorders. In contrast, most hematology societies indicate that screening for thrombophilia in arterial disease does not yet have an evidence base.
There are two general categories used to describe the hypercoagulable or prothrombotic state: hereditary and acquired. The former is often referred to as inherited thrombophilia disease. Acquired thrombophilia is a term re- served for well-defined syndromes such as the antiphospholipid syndrome (APS). This was Figure 6.2. Walking distance. The improvement in walking dis- tance is much greater for a graded exercise program compared to the best medical management (cilostazol), percutaneous transluminal angioplasty (PTA), or placebo.
previously termed the lupus anticoagulant.
However, the name was changed for two very good reasons. First, the anticoagulant referred to in this latter term reflects the behavior of the blood in the test tube, and in fact a pro- thrombotic effect is observed in vivo. Second, although it can be associated with the connec- tive tissue disease systemic lupus erythemato- sus, this is by no means necessary and we are increasingly recognizing APS occurring in isolation.
Although the inherited thrombophilic disor- ders are historically linked to venous thrombo- sis, there is some evidence suggesting that they may contribute to arterial thrombosis and in particular in patients with PAD. It has been recorded that inherited thrombophilias link to failure of vascular grafting following surgery. In a prospective study hypercoagulability occurs in between 10% and 25% of patients, increasing to about 50% in the presence of clinical markers for thrombophilia. Preoperative identification of such patients is important, as the short- and medium-term failure rates of the graft are reported to be approximately 50% in such patients. Furthermore, such patients are at increased risk of deep vein thrombosis during the operative procedure (see Chapter 5 for the evaluation of these patients).
Conclusion
As the inherited hypercoagulable states such as protein C, protein S, antithrombin II deficien- cies, and factor V Leiden occur only infrequently in this patient group, it is not possible to make a formal recommendation for screening of PAD patients. Probably a selective approach is war- ranted, reserving screening to those patients with bypass failure, a history of thrombotic events, or atherosclerosis at an early age.
Homocystinemia
The clinical features of homocystinemia include the development of premature atherosclerosis, along with manifestations of arterial and venous thrombosis. Disease severity leads to early diagnosis in homozygous patients, but patients with heterozygous disease present merely with premature atherosclerosis; 20%
to 40% of patients presenting with premature PAD have been found to have heterozygous homocystinemia. Pyridoxine supplementation reduces the thrombotic events in homozygous patients. However, it is not known whether this or other vitamins such as folate affect the course of the premature atherosclerosis in the het- erozygous sufferers.
Vascular Risk Factor
Management in Patients with Peripheral Arterial Disease
The presentation of a patient with PAD to a provider of medical care presents an ideal opportunity for the critical assessment of vas- cular risk factors. Intervention at this time both decreases the risk of coronary and cerebral events and is likely to limit progression of the arterial disease in the periphery, although the latter is theoretical rather than evidence-based as yet. Thus the modification of vascular risk is of crucial importance in the patient with PAD and is likely to become an even more important area in the future for clinicians involved with the care of these patients.
Drug Treatment of
Intermittent Claudication
It is a poor reflection on us, as clinicians involved in the care of the PAD patient, that angina of the legs is addressed far less aggres- sively than symptoms of claudication in the heart! Part of the problem reflects the concern about the effectiveness of the drug treatment for the symptoms of intermittent claudication and the consequent unease over the use of financial resources to purchase these compounds. Guide- lines have been developed for prescribing. There are four oral drug therapies that have a license for use as a treatment for IC in the United Kingdom and two in the United States:
Naftidrofuryl (Praxilene, not available in the U.S.), oxpentifylline (Trental), cilostazol (Pletal), and inositol nicotinate (Hexopal).
These drugs have been evaluated in clinical
trials in terms of their effectiveness for alleviat- ing the symptoms of leg pain associated with walking (IC).
Naftidrofuryl
Naftidrofuryl is thought to mediate its benefits through vasoactivity (vasodilatation) and via a local anesthetic action. Studies have docu- mented increased tissue oxygenation, increased ADP levels, and reduced lactic acid. The recom- mended maximum dose is 200 mg three times a day.
A number of double-blind, placebo- controlled studies in this area tend to show a significant placebo response in walking dis- tance approximately 25% improvement in walking distance with placebo. With Naftidro- furyl a further 30% improvement can be expected. These estimates are supported by two meta-analyses.
Pentoxifylline/Oxpentifylline
This is a rheological agent that has been approved for the treatment of intermittent claudication. Only two of the double-blind, placebo-controlled studies of oxpentifylline that measured walking distance using treadmills showed any statistical improvement in such walking distance by patients on oxpentify- line. Furthermore, one of these was a retrospec- tive subanalysis of short-distance claudicants, patients who could only walk short distances before claudication ocurred already included in another study. A meta-analysis of ten random- ized, double-blind, controlled studies concluded that the limited amount and quality of data for this drug precluded an overall reliable estimate of its efficacy. We recommend, in the absence of any consistent clinical trial evidence, that oxpen- tifylline should not be prescribed for use in this indication.
Cilostazol
Cilostazol has recently been approved for the treatment of intermittent claudication. It is a phosphodiesterase inhibitor that has been shown in randomized placebo-controlled trials to improve walking distance by approximately
50%. However, the improvement remains modest compared to exercise programs (180%
to 200% improvement). Cilostazol is contraindi- cated in patients with a history of congestive heart failure.
Inositol Nicotinate (Hexopal)
Inositol nicotinate is licensed for use in the United Kingdom for patients with intermittent claudication. However, the evidence base for this compound is weak. Of the four double-blind, randomized, placebo-controlled trials, three were primary care based and used subjective or questionable objective criteria for assessment of IC without treadmill use. None showed clear evidence of improvement in symptoms with drug use. We suggest, therefore, that the drug may not be of value for patients with IC.
Conclusion
Some patients with IC merit drug treatment due to the severity of their symptoms. It is rea- sonable to consider Naftidrofuryl or cilostazol for the symptomatic relief of moderate disease.
The patients, however, should be reviewed 6 to 12 months after drug commencement to assess its efficacy and the need for continuation.
Neither oxpentifylline nor inositol nicotinate can be recommended for the treatment of symptomatic IC.
Summary
Peripheral arterial disease is a marker of sys- temic atherosclerosis. Patients with PAD are at high risk for MI and stroke. Thus, an integrative approach to risk factor modification and the prevention of the sequelae of atherosclerosis is the mainstay of therapy. Patients must be advised to “stop smoking and keep walking.” In addition, however, antiplatelet therapy (e.g., aspirin) is indicated in all patients with periph- eral arterial disease in whom there is no contraindication. Hypertension must be appro- priately treated and diabetes mellitus detected and managed optimally. The medical manage- ment of the symptoms of intermittent claudica- tion should also be addressed if these are significantly impairing the patient’s lifestyle.
The key feature, however, in managing these patients is to assess their overall vascular risk and treat accordingly.
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