Key Insights On Assessing The Risk Factors For PAD

Anthony Yung, DPM, and Khurram Khan, DPM

Peripheral arterial disease (PAD) is a significant risk factor for diabetic foot amputation. It is also an important marker for atherosclerosis in other organ systems and is associated with a fourfold increase in cardiovascular death.1
Current estimates suggest a 3 to 10 percent incidence of PAD in the general population but reportedly only 25 to 33 percent of these people are symptomatic. Of the patients with asymptomatic PAD, 70 to 80 percent will remain stable at five years whereas 10 to 20 percent will experience significant deterioration of their health due to the disease.
Peripheral arterial disease is associated with traditional cardiovascular risk factors. In fact, the prevailing thinking is the biology of PAD may be similar to other manifestations of atherosclerotic disease. The two strongest risk factors for PAD are smoking and diabetes. Lesser factors include age, race, hypertension and dyslipidema.
Being able to assess the risk factors of PAD will allow the clinician to determine which patients would benefit most from screening and potential risk modifications.

Recognizing The Significant Risk Of PAD Among Smokers
Smoking has long been recognized as a significant risk factor for atherosclerotic disease. The exact mechanism of atherothrombosis is unclear and independent of its modification of other cardiovascular risk factors. Interestingly, smoking has a greater effect on PAD than coronary artery disease and is twice as likely to cause PAD. The overall risk of PAD for smokers is two to four times that of non-smokers.2 Furthermore, the effects of smoking are dose- and time-dependent with moderate smokers (< 25 pack years) twice as likely and heavier smokers (> 25 pack years) almost four times as likely to develop PAD.
Smoking is associated with continued progression of atherosclerosis and an increased risk for amputation.3 Observational studies have shown that smoking cessation decreases the risks of death and myocardial infarction, and amputation is substantially greater in those individuals with peripheral arterial disease. In one study, 82 percent of non-smokers had a 10-year survival rate in comparison to 46 percent in smokers.4 Unfortunately, there are no prospective randomized trials that have examined the effects of smoking cessation on lower extremity PAD. Nevertheless, researchers have associated smoking cessation with a decline in the incidence of PAD and it is an essential part of risk management.5

When Patients Have PAD And Diabetes
Peripheral arterial disease is four times more likely when diabetes is present. In fact, the incidence and extent of PAD is proportional to the duration and severity of diabetes.6 Diabetes changes the presentation of PAD as there tends to be more distal involvement and it is also more aggressive. Patients with PAD and diabetes are at greater risk for the development of critical limb ischemia, amputation and suffer from greater cardiovascular events.6
Metabolic abnormalities that accompany diabetes cause arterial dysfunction and promote thrombosis. Hyperglycemia, a cardinal presentation of diabetes, is correlated with an increased risk of PAD. Researchers have found this correlation in the diabetic population as well as the non-diabetic population. Researchers have linked a 1 percent increase in the percentage of HbA1c to a 28 percent increase in the incidence of PAD.7
The treatment of hyperglycemia has been a mainstay of diabetes and complications. Current guidelines from the American Diabetes Association (ADA) recommend HA1C < 7.0 percent in all patients with diabetes and PAD.8
While authors have shown that glycemic control reduces the risk of microvascular disease such as retinopathy and nephropathy, there is no significant evidence to date that demonstrates an effect on large vessel disease.9,10 This suggests that hyperglycemia alone is not responsible for the development of PAD. The metabolic syndrome accompanied with diabetes may play an important role in the development of PAD.

What Influence Do Age And Race Have?
Age and race play a role in the development of PAD. The National Health and Nutrition survey in the United States found the highest incidences of PAD in African-Americans at 7.8 percent, which was nearly twice the incidence (4.4 percent) among Caucasians. The incidence of PAD increases significantly with age but not uniformly.
The incidence rises from 0.9 percent with people in their 40s to 4.7 percent for people in their 60s. When patients are over the age of 70, the incidence of PAD rises sharply to 14.5 percent.

What You Should Know About Other PAD Risk Factors
Hypertension is a known risk factor for cardiovascular disease. Its effects on PAD are weaker than diabetes and smoking, and researchers have associated hypertension with a two- to threefold increased risk of claudication.11 The effect of hypertension control on the outcome of PAD has not been established. The United Kingdom Prospective Diabetes Study (UKPDS) did not show a reduction in amputation risk. There is a demonstrated reduction in cardiovascular risk.
Therefore, the ADA continues to recommend aggressive hypertension control to reduce the associated cardiovascular risk (140/90 mmHg in non-diabetics and 130/80 mmHg in patients with diabetes). There may be a role for ACE inhibitors for cardio-protective effects.8
Elevated levels of total cholesterol, LDL cholesterol, triglycerides and lipoprotein are independent risk factors for PAD development. One study found elevated total cholesterol levels (> 270 mg/dl) increased the risk by a factor of two.12 Lowering cholesterol decreases cardiovascular events for patients with diabetes. There is also data demonstrating a reduction in cardiovascular complications with the treatment of dyslipidemia. Although there are no direct data on treating dyslipidemia in patients with both diabetes and PAD, published guidelines recommend a target LDL cholesterol level of < 70 mg/dl based on a reduction of cardiovascular risk.13
Researchers have also reported that cardiovascular markers of risk such as C-reactive protein, homocysteine and fibrinogen are increased in PAD. Elevated levels of C-reactive protein, a marker of systemic inflammation, have been linked to up to a twofold increase in developing PAD.14
Elevated levels of homocysteine are associated with a two- to threefold increased risk for developing atherosclerotic arterial disease. The role of homocysteine remains unknown. Several studies have demonstrated that the use of folic acids and other lowering agents has not affected change in macrovascular disease and suggest that it may be a marker rather than a cause of atherosclerosis.15

In Conclusion
A review of the literature reveals that smoking and diabetes are the strongest risk factors for PAD. There have been no positive prospective studies linking risk factor controls to changes in PAD. The consensus is that the cardio-protective effects of lipid and blood pressure control, and reduction of microvascular risk with glycemic are beneficial in the context of PAD (TASCII study).16 Smoking has the greatest impact on PAD and cessation is the cornerstone of PAD treatment.8
Currently, there is an ongoing North American study that is worth watching. For this study, the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, researchers have enrolled over 10,000 patients and are studying the effects of three treatment arms and cardiovascular risk. The three treatment arms are as follows:
• intensive lowering of blood sugar levels (compared to a more standard blood sugar treatment);
• intensive lowering of blood pressure in comparison to standard blood pressure treatment; and
• treatment of blood lipids by a fibrate plus a statin in comparison to a statin alone.
Recently, researchers halted the glucose control arm due to an increased mortality associated with the intensive glucose regimen in comparison to the standard glucose control. This is significant because it goes against conventional thought that the tighter the glucose control, the better the outcome. It is important to note that the increased risk was slight and was only specific to a subset of patients who had two or more risk factors for heart disease outside of diabetes, or who had preexisting heart disease upon entering the study. The study is expected to be complete in 2009 and the results are eagerly anticipated.17

Dr. Yung practices at Kitsap Podiatry and at Harrison Memorial Hospital, both in Silverdale, Wash. Dr. Khan is the Chief Resident in the Department of Orthopaedics/Podiatry at the University of Texas Health Science Center.

Dr. Steinberg is an Assistant Professor in the Department of Plastic Surgery at the Georgetown University School of Medicine in Washington, D.C. Dr. Steinberg is a Fellow of the American College of Foot and Ankle Surgeons.




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