Optimal medical therapy for the dysvascular patient : understanding atherosclerosis and the ‘big picture’

OPTIMAL MEDICAL THERAPY FOR THE DYSVASCULAR PATIENT :
UNDERSTANDING ATHEROSCLEROSIS AND THE 'BIG PICTURE'
From the Division of Vascular & Endovascular Surgery, University of South Florida Health, Tampa, Florida Correspondence : Martin Back, MD USF Vascular 2A Columbia Dr Tampa, FL 33606 Phone 813-259-0956 Fax 813-259-0606 Ema Peripheral arterial disease (PAD) describes the manifestation of atherosclerotic occlusive disease distributed in large extremity arteries. While atherosclerosis can involve other systemic vessel distributions (ie cerebrovascular/carotid, visceral/renal) outside the coronary circulation, PAD is primarily located in the lower limbs. The prevalence of PAD increases with age (Fig.1) and can be either asymptomatic (detected by an abnormal ankle brachial systolic pressure index [ABI] value) or present symptomatically in patients with intermittent claudication (IC) or more severe critical limb ischemia (CLI). Asymptomatic patients outnumber symptomatic PAD patients by about three to one. Intermittent claudication affects 5-7% of patients over the age of 70. While PAD is less common than either cerebrovascular occlusive disease or coronary artery disease (CAD), significant fractions of 'dysvascular' patients possess atherosclerosis involving at least two of these vascular beds (Fig. 2). The prevalence of PAD in patients with ischemic heart disease / CAD has been reported between 10 and 30 %. Similarly, at least one-third of PAD patients have carotid artery disease found by duplex ultrasound evaluation. In the REACH (Reduction of Atherothrombosis for Continued Health) survey depicted in Fig. 2, 65 % of patients with PAD had clinical evidence of other vascular disease. It is also not surprising that the severity of the clinical presentation of PAD is prognostic not only for the risk of limb loss and amputation but also patient survival (Fig 3). PAD patients clearly have reduced 5 and 10 year survivals compared to age and sex-matched controls without PAD. PAD patients presenting with critical limb ischemia have much higher risk of limb loss (25%) and lower 5-year survival (50%) than patients manifesting intermittent claudication (limb loss 1-3%, 5-yr survival 70-80%). The differences are generally attributable to a larger systemic burden of atherosclerotic disease present in patients with more severe symptomatic PAD (ie CLI). While death from neoplasm/cancer is nearly as prevalent as cardiac deaths in dysvascular patients as a whole, mortality due to myocardial events, stroke or other vascular causes is most frequent in patients with critical limb ischemia. While most vascular surgeons strive to ameliorate the local manifestations of PAD (ie improved walking for IC, limb salvage for CLI), these survival trends clearly illustrate the 'bigger' relationship between PAD and the ominous natural history of systemic atherosclerosis. In patients presenting with intermittent claudication, underlying PAD tends to have a 'benign' course compared to their annual 5-7% incidence of adverse cardiac and cerebrovascular events. By comparison during 5-year follow-up, roughly two-thirds of IC patients have stable or improved symptoms with medical therapy, and only one-third experience worsening symptoms requiring surgical or endovascular intervention. CARDIOVASCULAR RISK FACTORS AND THEIR MANAGEMENT While numerous risk factors are acknowledged to contribute to atherosclerotic development, individual factors possess varying effects on the distribution of disease. Both diabetes mellitus and tobacco abuse have the strongest influence on development of PAD (Fig. 4). Smoking fuels atherosclerotic plaque development in the more proximal aorto-iliac and femoral vessels and diabetes tends to accelerate popliteal and tibial occlusive disease more distally in the lower extremity. In the coronary tree, smoking plays less of a role and hypercholesterolemia appears the dominant risk factor. Hypertension, on the other hand, accelerates carotid and cerebrovascular occlusive disease to a greater degree than other risk factors even beyond its direct relationship to stroke. Multiple risk factors present in an individual patient seem to produce a greater than additive effect on atherosclerotic incidence and severity. Smoking and diabetes, if both present in a PAD patient, can lead to a more advanced and accelerated disease process in younger patients than would occur if only one of these risk factors existed. While one can do little to change genetic pedigree or chronological aging, understanding of the influences of demographic factors allows physicians to refine how diligently we must treat other risk factors because of the negative effects of factor multiplicity. The protective effect of estrogen and progestins in women is lost after menopause. Accordingly, men have a slightly higher incidence of PAD than women at younger ages (< 65-70 yrs), but equal PAD incidences are seen between genders in older individuals. Non-Hispanic Blacks have a higher incidence of PAD than Caucasians as noted in large surveys performed in the United States and Europe. These ethnic differences were not explained by prevalence differences of other cardiovascular risk PAD occurs on average a decade earlier in smokers than non-smokers. Heavier smokers tend to have more severe PAD as well. Smoking is not only a risk factor for PAD and systemic atherosclerosis but also for aortic aneurysm formation, obstructive pulmonary disease (COPD), lung cancer and other neoplasms. Efforts aimed at smoking cessation should emphasize the benefits of abstinence. Survival is on average 13 to 15 years longer for non-smokers than smokers. In fact, risk of developing lung cancer or death from cardiovascular disease falls after 5-10 years of tobacco abstinence to levels Whether smokers attempt cessation by 'cold turkey' techniques or a slower, planned tobacco 'weaning' with daily/weekly limits of allowed cigarettes, patient counseling is an essential component of our initial clinic evaluation. Formal supervised cessation programs coupled with nicotine replacement have led to 5-yr cessation rates of 25%. Addition of bupropion imparts a further beneficial effect on cessation therapies but has significant potential side effects. Recent randomized clinical trials have shown superiority of varenicline (Chantix, Pfizer) over bupropion and have led to FDA The incidence of diabetes mellitus, especially type 2 related to morbid obesity, continues to increase at an alarming rate in this country. Diabetes increases the risk of PAD three- to four-fold. Long-standing diabetes (>7-10 yrs) contributes to a peripheral neuropathy which further increases risk of pressure-related wound formation and infections of the foot and potential need for revascularization if concomitant PAD is present. Fifty percent of lower limb amputations performed in the U.S. are attributed to diabetes. While tight glycemic control has been shown to delay or prevent the onset of diabetic microvascular complications including retinopathy and nephropathy, the effects of glucose lowering on development of PAD remain unclear. General recommendations for PAD patients are glucose control with resulting hemoglobin A1c levels between 6 - 7%. Pioglitazone, a new insulin sensitizing agent to treat type 2 diabetes, decreased myocardial infarction (MI), stroke and vascular death in a recent prospective trial in Europe but further investigation is needed. This new class of diabetic agents may have additional benefits in lipid-lowering, blood pressure control, and reduced C-reactive protein levels. Insulin resistance associated with obesity has been termed 'metabolic syndrome' and patients typically manifest hyperglycemia, dyslipidemias, and hypertension. Overweight (body mass index [BMI] 25-30) or obese (BMI > 30) patients should receive counseling for weight reduction by decreasing overall calorie intake, carbohydrate restriction and increased exercise. Stricter blood pressure control (goal < 130/80 mmHg) is recommended in patients with multiple cardiovascular risk factors compared to patients with isolated hypertension (goal < 140/90 mmHg). Thiazide diuretics (especially in Blacks) and angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (especially in diabetic patients or those with congestive heart failure) are first-line agents. Beta- adrenergic blockers are beneficial for concomitant CAD and are not contraindicated in patients with intermittent claudication. Calcium channel blockers are second-line agents used to optimize pressure control in difficult patients requiring multiple agents. Renal insufficiency, independent of the presence of contributing hypertension or diabetes, also Numerous individual lipid components are independent risk factors for PAD including elevated levels of total cholesterol, low-density lipoprotein (LDL), triglycerides and lipoprotein (a). Potential PAD-protective factors are elevated high-density lipoprotein (HDL) and apolipoprotein (a-1) levels. Initial dietary modifications and use of statins are recommended to reduce LDL cholesterol levels to < 100 mg/dL in PAD patients and < 70 mg/dL in high-risk individuals with vascular disease in multiple territories. Multiple large studies have demonstrated aggressive LDL lowering with statin administration to reduce major cardiovascular events (MI, stroke, vascular interventions and cardiovascular- related mortality) by 20% on average. Benefits were observed in patients with cardiovascular risk factors even with 'normal range' lipid parameters. Fibrates and/or niacin can be added to raise HDL and lower triglyceride levels in patients with disorders Supra-normal plasma homocysteine levels are more prevalent in dysvascular patients than the 1% incidence seen in the general population. Up to 30% of young patients (< 50 yrs old) presenting with PAD possess elevated homocysteine levels. It appears that hyperhomocysteinemia is a stronger risk factor for PAD than CAD. Elevated homocysteine levels can be effectively reduced with B-vitamin and folate supplements but evidence of diminished cardiovascular event rates with such treatment is lacking The link between asymptomatic and symptomatic arterial occlusive disease in many vascular beds (eg coronary, carotid, visceral, lower limb) involves more than just the hemodynamic impact (ie reduced flow) of lumen-narrowing atherosclerotic plaque (Fig. 5). Our current understanding of 'plaque instability' involves local endothelial loss, fibrous cap rupture or erosion, and intraplaque hemorrhage and leads to platelet deposition, distal embolization of plaque or thrombotic debris, and end-organ ischemic injury (eg acute coronary syndromes, stroke, peripheral atheroembolism). Triggers of these events that result in more acute ischemic symptoms remain poorly understood but systemic 'inflammation' appears to play a significant role. C-reactive protein (CRP) is an 'acute phase reactant' produced by the liver during episodes of 'physiological stress' and is a primary marker of 'inflammatory state' in the body. Elevated CRP levels have prognosticated a higher incidence of adverse cardiovascular events or subsequent development of symptoms in PAD patients who were initially asymptomatic in recent studies. Aspirin may have some benefit in limiting inflammation. While not affecting atherosclerotic plaque development or progression, aspirin (ASA) and other anti-platelet agents are highly effective in protecting against adverse cardiovascular events (MI, stroke, acute lower limb ischemia). Up to a 25% risk reduction has been realized in PAD patients taking ASA particularly if CAD and/or carotid disease is present. Low-dose ASA (81 mg) is as effective as higher doses (>325 mg) and probably safer from gastrointestinal bleeding complications. Clopidogrel with or without concomitant ASA is a more powerful anticoagulation option with greater bleeding risk that can be used in selected patients. Clopidogrel with ASA is recommended for variable durations after many endovascular (eg coronary or carotid stenting) or open surgical interventions (eg redo lower limb bypasses). Patients with ASA allergy or history of peptic ulcer disease are best treated with clopidogrel only. Warfarin and low-dose ASA is indicated in patients with chronic atrial fibrillation, prosthetic cardiac valve replacement, severe low ejection fraction cardiomyopathy, hypercoagulable states with multiple thrombotic presentations (eg factor V leiden, lupus anticoagulant, and deficiencies of proteins C or S, or antithrombin III), and potentially prosthetic or other 'high-risk' lower limb bypasses. Warfarin and ASA was not more effective than ASA alone in the routine management of PAD patients and was associated with greater bleeding risk (WAVE trial). Optimal medical therapy for PAD patients presenting with intermittent claudication involves measurement of ankle brachial index (ABI), atherosclerotic risk factor assessment and management, anti-platelet administration, an exercise regimen, and potentially pharmacotherapy directed at claudication symptoms. Recommendations for walking exercise include using a slower pace (2-3 miles per hr) on level surfaces to prevent rapid onset of symptoms, timed sessions beginning at 15-20 minutes and gradually extended over 2-3 months to 45 minutes per day, non-exercise days between walking days, permitted rests as needed during walking for symptom relief. In some patients not tolerating walking therapy, similar aerobic benefits can be achieved by stationary bicycle riding, swimming, or walking in a pool that lessen 'loading' of affected calf muscles. Cilostazol is a phosphodiesterase inhibitor with vasodilator, antiplatelet, and metabolic activities. Walking distances are generally doubled with slower onset and severity of claudication symptoms in roughly 70% of PAD patients receiving cilostazol. Side effects (headache, diarrhea, palpitations) limit its use, can be dose related and we routinely begin patients on 50 mg twice daily for 1-2 months before attempting higher (100mg) dosing. Cilostazol is contraindicated in patients with history of congestive heart failure. Cilostazol use has proved superior in ameliorating IC symptoms in comparative studies against the older alternative, pentoxifylline. Patients presenting with weak femoral pulsation or evidence of more proximal occlusive disease distributions (buttock, hip or thigh claudication) should be considered earlier for intervention as they benefit less Fig. 1 Prevalence of intermittent claudication / symptomatic PAD relative to patient age
Fig. 2 Overlap of atherosclerotic occlusive disease in different territories from the
Fig. 3 Differing survival seen between patients with varying severity of PAD and age,
Fig. 4 Range of odds ratios for various cardiovascular risk factors on development of
Fig. 5 Influences of various factors on atherosclerotic plaque behavior.
Dyslipidemias and hypertension are more important risk factors than diabetes and smoking in the development of PAD. True or False A drug used to treat the symptoms of intermittent claudication is called

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